Alnylam Pharmaceuticals, Inc Aktie

Good morning, everyone. I'm Kelly Cronin, Senior Manager of Investor Relations at Alnylam, and I'm pleased to welcome you to the second event of Alnylam's 10th RNAi Roundtable series. Through this series, we aim to bring greater visibility to select near- and midterm pipeline programs that we believe will define the next wave of transformative medicines emerging from our RNAi platform here at Alnylam.

Today's event is focused on zilebesiran, our investigational RNAi therapeutic for patients with hypertension and high cardiovascular risk or established cardiovascular disease, which we are advancing together with our partners at Roche.

As a reminder, today's discussion will include forward-looking statements. We encourage you to review our most recent SEC filings for a more complete discussion of our risk factors. During today's event, you'll hear first from Chief Research and Development Officer, Pushkal Garg, who will set the stage with an overview of Alnylam's organic product engine and the unique potential of RNAi therapeutics to transform cardiovascular care.

Dr. Akshay Desai, of Harvard Medical School and Mass General Brigham, will then discuss the persistent burden of hypertension beyond the office setting followed by Ishir Bhan, who will review clinical evidence supporting the potential for continuous control with zilebesiran.

Simon Fox will then close out our prepared remarks with an overview of the integrated execution underway to realize zilebesiran's full potential. Following the prepared remarks, we will open the discussion for a question-and-answer session with our speakers joined by Victoria Silva, who leads zilebesiran commercial strategy at Alnylam. The Q&A will be moderated by Pushkal and questions may be submitted at any time through the ask a question field within the webcast platform.

With that, I'll turn it over to Pushkal. Pushkal?

Thanks, Kelly, and welcome, everyone, to today's RNAi Roundtable focused on zilebesiran, which we believe has the potential to transform the treatment of hypertension by providing continuous control of blood pressure. As many of you know, Alnylam has spent more than 2 decades pioneering an entirely new class of medicines based on RNA interference. What makes RNAi so remarkable is the combination of attributes you see here.

Like a biologic scalpel, we can silence virtually any gene in the genome and intervene upstream of most traditional medicines. It's a catalytic mechanism, enabling highly potent medicines at low doses while remaining highly specific and reversible. And we can engineer long durations of effect that support very infrequent administration.

Taken together, these attributes create an extraordinarily powerful therapeutic profile and we've already demonstrated what this technology can deliver, translating the science into a growing portfolio of medicines for patients. We've harnessed this natural phenomenon into a unique and sustainable innovation engine which we believe will fuel sustained long-term growth.

We continue to invest in the power of human genetics with access to data for more than 2 million lives, helping us identify and validate compelling new targets. Advance RNAi delivery to major tissues throughout the body and optimize our siRNA designs to enable increasingly potent, specific and durable molecules across a wide range of clinical applications. We paired this innovation engine with a disciplined strategy for selecting the most compelling opportunities to advance to the clinic.

Our therapeutic area agnostic approach focused on diseases with high morbidity and mortality where we can pursue highly genetically validated targets with a strong biologic rationale. This integrated approach has enabled us to generate high-quality drug candidates and achieve historical clinical success rates well above industry benchmarks building a high-value portfolio of programs targeting areas of tremendous unmet need.

And you can see the results of that strategy here in our industry-leading pipeline of RNAi therapeutics. With more than 25 programs spanning rare, specialty and prevalent indications across multiple therapeutic areas, we believe this pipeline underscores the depth of opportunity ahead for Alnylam and most importantly, our potential to deliver even more transformative medicines to patients.

We're entering a period of significant clinical momentum with three pivotal studies underway and four important data readouts expected this year. That momentum will build meaningfully through 2028 with a growing number of pivotal studies, at least five key data readouts each year and the potential launch of vutrisiran in hereditary ATTR polyneuropathy assuming positive Phase III data and regulatory approval.

Cardiovascular disease is one area where the power of RNAi offers the potential to make a major impact on the leading cause of death around the world. With our RNAi-based platform, we built a diverse portfolio of therapies designed to address major drivers of cardiovascular morbidity and mortality, including obesity, type 2 diabetes, hypercholesterolemia and hypertension. Zilebesiran is a particularly compelling example of the unique potential of RNAi in cardiovascular disease.

Hypertension remains one of the largest and most consequential drivers of cardiovascular risk and control remains inadequate for far too many patients. Together with our partners at Roche, we're exploring whether durable suppression of angiotensinogen can deliver more consistent blood pressure control and ultimately translate into a profound impact on cardiovascular outcomes. The urgency of that work becomes clear when we look at the projected burden of cardiovascular disease.

Annual death due to cardiovascular disease around the world are projected to rise over 70% from 20.5 million in 2025 to 35.6 million by 2050. And notably, high systolic blood pressure remains the leading risk factor with the CV deaths attributable to hypertension projected to increase from 11 million to nearly 19 million during that period. Despite this enormous and growing burden, hypertension has not seen the same degree of therapeutic innovation as areas such as lipids and obesity.

Our aspiration is to bend this curve by investigating whether continuous durable blood pressure control with zilebesiran can reduce cardiovascular risk. To put the magnitude of this unmet need into clinical context and dive deeper into why we've struggled to effectively manage hypertension in the past, I'll now turn it over to Dr. Akshay Desai.

Thanks very much, Pushkal. In the next 10 minutes, my job is to underscore for you the ongoing threat of hypertension as a global health priority. The burden of hypertension globally has steadily risen since 1990 in the United States and elsewhere from an estimate of about 440 million prevalent cases in 1990 to more than 875 million cases by 2015 and nearly a billion cases prevalent in modern era. And that is defined at a threshold of a blood pressure more than 140 millimeters of mercury, and we can anticipate that the prevalence would be estimated at the newer reduced thresholds that are recommended by current guidelines.

This steady rise in the prevalence of hypertension is related to secular trends and risk factors for the development of hypertension, including normal aging, but also risk factors, including obesity, insulin resistance and diabetes that drive the hypertension epidemic. Hypertension remains the leading risk factor for cardiovascular disease and associated disability and mortality worldwide and the leading preventable approach to prevention of cardiovascular disease that we have 10% of the global health care expenditure is estimated to be accounted for by hypertension, and this, therefore, represents an important target for ongoing attention.

We know that hypertension contributes to changes in the vasculature, the heart and in the kidney, that predisposed the development of a range of cardiovascular diseases, including ischemic heart disease, stroke, chronic kidney disease and then a range of other vascular disorders, including heart failure. As this slide shows the cumulative burden of disability-adjusted life years associated with hypertension is quite substantial. At every blood pressure, the highest burden of disease is contributed by ischemic heart disease with subsequent contributions by stroke, chronic kidney disease and other disorders, including heart failure.

About 70% of the disability associated with hypertension and hypertension-related mortality is related to blood pressures that are measured more than 140 millimeters of mercury, but you can see that even -- that 1/3 of the disability-adjusted life years are associated with blood pressures between 110 and 140 millimeters of mercury, which underscores the need for even more aggressive control of blood pressure to prevent disability and death in clinical practice. It's estimated that nearly $100 billion in global savings could be secured for more aggressive control of blood pressure in clinical practice, and this is really the opportunity for more effective hypertension therapies.

It's well established that blood pressure reduction is an effective way of reducing cardiovascular risk, and this data from a meta-analysis of nearly 123 studies comprising more than 600,000 patients highlights that with each 10-millimeter reduction in systolic blood pressure, there's about a 20% reduction in major cardiovascular events, a 17% reduction in coronary heart disease, a 27% reduction in stroke and another 30% reduction in heart failure.

These data underscore that with incremental blood pressure reductions, we can expect an incremental reduction in return on cardiovascular risk reduction. That said, we have a lot of effective medical therapies for hypertension, but these are heavily underutilized in clinical practice.

When we look at the total burden of hypertension, only 40% of patients are identified as hypertensive and treated in clinical practice. And among those who are treated, only 1 in 5 is actually treated to guideline recommended targets. And this implies that nearly 80% of treated hypertensive patients are still at risk for cardiovascular disease and disability. And there's substantial residual risk that is unattended in the current paradigm we need a different approach to more aggressive recognition of blood pressure management, and we need more effective therapies for blood pressure control and practice.

This problem over time has become even more important because it's recognized now based on data from the SPRINT trial that even more aggressive blood pressure targets are important to prevent cardiovascular disease and disability in clinical practice. The SPRINT trial randomized nearly 9,000 patients with uncontrolled hypertension to treatment with an intensive blood pressure target of less than 120 millimeters of mercury versus a standard blood pressure target of less than 140 millimeters of mercury, the prevailing recommendation at the time.

And you can see that the trial was terminated early for evidence of overwhelming benefit in the intensive therapy arm at median follow-up of 3.3 years based on a 25% reduction in the composite outcome of myocardial infarction, acute coronary syndrome, stroke, heart failure or cardiovascular death.

This effect was also seen in key components of the primary outcome, including overall mortality, which was reduced 27% with the more intensive therapy arm. And these data have now driven a change in practice guidelines. The modern ACC/AHA guidelines for blood pressure are outlined on this slide which highlights that our targets have now been revised to a treatment -- to recommend a treatment goal of less than 130 over 80 millimeters of mercury for all adults defining blood pressure more than 130-millimeter mercury as Stage 1 hypertension and more than 140 millimeters of mercury, our previous therapeutic target as Stage 2 hypertension.

So this new guideline recalibrates our estimates of global prevalence of disease and really reassign many patients we previously thought were well controlled with hypertension to an uncontrolled category. After a long lull in the drug development for hypertension, we've now seen an explosion of new therapeutic trials in hypertension and proliferation of new agents for effective management of hypertension since 2019.

Most of these therapies are oral agents, some of which are dosed multiple times daily with only zilebesiran being a parenteral agent that has the opportunity for being dosed once every 6 months. This long duration of action poses a unique opportunity for hypertension that we'll discuss a little bit later in the market but with this proliferation of therapies, the open question becomes what are the residual barriers to effective control.

If we have so many effective agents for treatment, why is it that blood pressure is not more effectively controlled to the guideline recommended targets? Well there are many possible explanations for this. The first is that there is generally poor access to care for many of our patients so that hypertension is underdiagnosed. Amongst those patients, there is also an adequate education and awareness of the importance of blood pressure control. So even when they hear the messages in our clinics about the need to treat hypertension, sometimes it falls on deaf ears.

Even when patients are in clinic, we sometimes fail to measure blood pressure at the clinical opportunities that we have it. And therefore, we failed to diagnose hypertension appropriately. And even when blood pressure is elevated, many providers fail to act to treat hypertension in clinical practice, and that is the problem of therapeutic inertia.

Once medications are prescribed, providers feel they've done their job, but then many of our patients who are given multiple daily oral medication regimens to take for their hypertension and comorbid medical illnesses struggle with adherence in the setting of polypharmacy and the need for multiple daily dosing of many of the pills and poor adherence to medications contributes to the burden of uncontrolled hypertension and practice.

And then finally, a certain proportion of patients, even with effective therapy remain resistant to anti-hypertensive treatment, although this is really the minority of patients estimated to be about 10% of patients with truly resistant hypertension in clinical practice.

Examining some of the barriers to hypertension in more detail, this slide focuses on the effects of adherence to anti-hypersensive therapy and cardiovascular risk. Amongst young adults in this survey, taking antihypertensive medications. About 63% were non-adherent based on proportion of pharmacy fills of prescribed medications. And those patients who were non-adherent not unexpectedly, had nearly 1.6 fold the risk of cardiovascular disease over subsequent follow-up and there was a direct correlation between the extent of adherence to prescribed medical therapy and the reduction in cardiovascular risk with more adherent patients being more protected from the downstream consequences of uncontrolled hypertension.

It's estimated that nearly half of patients prescribed anti-hypertensive therapy discontinue those prescribed medications within a year of initiation and up to 10% of daily oral medication doses are often omitted in clinical practice and sometimes these are only once-daily medicine, which means that all the therapeutic effect is lost.

Beyond the control of office blood pressure, which is typically our target for clinical intervention, we've understood now that there is a lot of variability in blood pressure outside of the office that needs attention. The mean of office blood pressure readings over several visits is typically utilized to direct therapy, but we know that blood pressure fluctuates a lot over both the short and the long term.

Episodic high values or extreme values are often disregarded as aberrations, but emerging evidence suggests that diurnal variation over the full 24-hour cycle and the variability in blood pressure between clinical visits are not just noise, but actually carry prognostic importance and maybe important targets for therapy. And this is really the rationale for thinking about opportunities for continuous control of blood pressure in practice.

We have some opportunity to measure the efficacy of control of blood pressure over the full 24-hour cycle using 24-hour ambulatory blood pressure monitoring. And although this is not commonly utilized in clinical practice, examination of 24-hour ambulatory blood pressure data gives us some understanding of how variations in the blood pressure over the 24-hour cycle may contribute to risk.

We've long understood that there is a typical pattern of fall in blood pressure during the nighttime such that blood pressure dips in healthy patients and patients with cardiovascular risk factors, particularly diabetes, obesity tend to dip less during the nighttime, and that failure of the blood pressure to dip in the nighttime is associated with heightened risk.

And in fact, some patients have increase in blood pressure during the nighttime, and this nocturnal hypertension is associated with a particularly high-risk phenotype.

If we look at blood pressure in large populations, daytime hypertension certainly contributes risk, but that risk is amplified even further if it has continued through the nighttime. And it's this data that really underscores the need for continuous control of blood pressure over the full 24-hour interval to secure effective cardiovascular risk reduction.

Beyond that short-term variability in blood pressure, it is important to control long-term variability in blood pressure. And one way to estimate that long-term variability is looking at the standard deviation of blood pressure between consecutive office visit. And as that standard deviation increases, as you can see here in the slides, looking at deciles, of the standard deviation between -- in between visit blood pressure independent of the mean blood pressure.

There's a steady rise in the increase in the risk of stroke, as well as the risk of coronary events that increases -- that is associated with that increasing standard deviation. So more blood pressure variability translates into more strokes, more coronary events. And it's estimated that for every standard deviation increase, there's an 18% increase in cardiovascular death and a 15% increase in the risk of stroke.

That variability is also captured in the measure of extremes of blood pressure. And if we look at the relationship between maximum blood pressures measured over serial follow-up and risk, there's also a greater association such that those patients having the widest spikes in blood pressure carry the highest risk of stroke. And this is data from the ASCOT trial the Anglo-Scandinavian Cardiovascular Outcomes Trial, but it's been replicated in other context. And the implication of this is that more aggressive blood pressure control, not just in the office, but over the full 24-hour interval and extending between visits, such that there's less volatility over time is critically important to effective cardiovascular risk reduction.

One way of capturing the efficacy of blood pressure control is to measure the time that patients spend in the range of target. And in this case, that blood pressure target is set by the current guidelines is less than 130 millimeters of mercury. And you can see on the slide that if patients have a higher time in the target range, where they're more in the gray zone of effective control that they have lower risk of cardiovascular events and cardiorenal events, I should say. And then if you look at the patient on the second panel of the slide, who is spending more time outside of the gray zone, that patient has heightened risk of major adverse events.

And indeed, when we look in clinical practice at large epidemiologic data sets, there's a tight correlation between the time that patients spend in the therapeutic range and the risk to both renal or kidney and cardiovascular events, with a steady decline in risk associated with heightened time in the therapeutic range. And it's really this data that supports the hypothesis that agents that could provide more continuous control of short- and long-term variability in blood pressure will return higher benefits with regard to cardiovascular risk reduction.

So I think at this point, the data suggests that hypertension needs a new approach. Despite effective therapy, many patients with hypertension remain poorly controlled, physicians commonly fail to adapt therapy even when blood pressure is high, contributing to poor time in the therapeutic range. Adherence to daily oral any hypertensive regimens is poor in clinical practice and undermines blood pressure control. Even when office blood pressure appears controlled, residual visit-to-visit blood pressure variability in nocturnal hypertension contribute to ongoing CV risk, an effective reduction in cardiovascular risk really requires a strategy then to address therapeutic inertia, treatment nonadherence and blood pressure variability over the short and long term.

And although there are a range of novel oral antihypertensives that are coming available in clinical practice, these are unlikely to effectively meet this challenge, particularly given the need for patients to take multiple medications and clinical practice to manage hypertension in the comorbidity in which it commonly lives. Thanks very much for your attention.

Thank you, Dr. Desai. I'm Ishir Bhan, Executive Director of Clinical Research and Clinical Lead for zilebesiran's Phase III study at Alnylam. As Dr. Desai and Pushkal outlined, a significant unmet need exists today, and it's projected to grow through 2050. This unmet need is driven by multiple factors that leave patients at elevated cardiovascular risk. Despite numerous classes of oral antihypertensives, the underlying contributors of this challenge remain unaddressed. Against this backdrop, I'll discuss the therapeutic hypothesis behind zilebesiran and why we believe it has the potential to address key drivers of cardiovascular risk.

Zilebesiran represents a fundamentally differentiated approach to managing hypertension by targeting angiotensinogen, or AGT, the most upstream precursor to the RAS the body's primary pathway for regulating blood pressure. By suppressing AGT production, zilebesiran acts upstream of conventional medications like ACE inhibitors, ARBs and MRAs, potentially avoiding compensatory changes in the pathway that may limit effects on blood pressure and target organ stress. Unlike conventional short-acting medications. Zilebesiran has demonstrated the potential to provide continuous control of blood pressure with just twice yearly dosing. Through this continuous control, zilebesiran has the potential to address critical gaps that contribute to the ongoing unmet need outlined by Dr. Desai and ultimately improve outcomes for patients with high cardiovascular risk or established CVD.

I'll now walk us through the clinical evidence that supports this therapeutic hypothesis. Zilebesiran was evaluated across multiple treatment settings in the KARDIA Phase II program. KARDIA-1 studied zilebesiran as monotherapy in patients with mild to moderate hypertension providing an early opportunity to understand the potential of AGT suppression for blood pressure control. As shown here, patients who received zilebesiran monotherapy achieved an average placebo-adjusted blood pressure reduction of 10 millimeters of mercury, while also experiencing continued also experiencing continued control of blood pressure throughout the 24-hour period.

The lack of sustained long-term blood pressure control is a key contributor to cardiovascular risk. We have also observed in KARDIA-1 that patients who received one dose of zilebesiran every 6 months, achieved sustained 24-hour blood pressure control for an entire year. These results, which demonstrate sustained continuous control of blood pressure further reinforce our belief in zilebesiran's differentiated profile. Zilebesiran's safety profile has been consistently reassuring throughout Phase II with experience spanning 889 patients treated with zilebesiran.

Throughout the Phase II program, we observed low rates of adverse events, including hyperkalemia and hypotension. Importantly, most of these events resolved without intervention and did not lead to treatment discontinuation. In both KARDIA-2 and 3 where zilebesiran was studied in patients receiving background ACE inhibitor or ARB therapy, low rates of hyperkalemia and kidney injury were observed.

This is particularly encouraging because therapies that inhibit the RAS are known to increase the risk of hyperkalemia and acute kidney injury, especially when used in combination. Taken together, the efficacy and safety data generated to date support continued development of zilebesiran and its valuation in ZENITH, our Phase III cardiovascular outcomes trial.

The most recent Phase II study, KARDIA-3, was key to informing the Phase III study population and dose. Just like ZENITH, this study enrolled patients with uncontrolled hypertension on at least 2 antihypertensives, with either high cardiovascular risk or established cardiovascular disease. A key objective of KARDIA-3 was to evaluate zilebesiran in patients with uncontrolled hypertension receiving treatment with a diuretic at baseline.

This was an important population study because diuretics are known to activate the RAS by increasing renin levels, potentially amplifying the response to therapies that inhibit this pathway. Based on this biology, we hypothesized that zilebesiran could be particularly effective in these patients. To better understand the importance of these factors, we conducted both prespecified and post-hoc analyses.

KARDIA-3 included a diverse patient population with meaningful proportions of black and Hispanic patients as well as patients with established cardiovascular disease, diabetes, obesity, Notably, the vast majority of the patients were maintained a treatment with ACE inhibitors or ARBs. These patient characteristics were maintained in our post-hoc study population which closely reflects the patients in our pivotal Phase III trial.

In the overall KARDIA-3 cohort A population, we observed clinically meaningful reductions in blood pressure. As expected, the prespecified and post-hoc analyses confirmed an enhanced blood pressure lowering response of approximately 9 millimeters of mercury in patients receiving zilebesiran and the background diuretic, particularly in patients with a systolic blood pressure greater or equal to 140 millimeters of mercury at baseline.

These data demonstrated zilebesiran's ability to achieve clinically significant reductions in blood pressure in our Phase III target population. As Dr. Desai outlined, nighttime blood pressure is the powerful indicator of cardiovascular outcomes. Patients who do not experience a normal nighttime dip in blood pressure faced a significantly higher risk of cardiovascular events. As you can see here, we evaluated the effect of single dose of zilebesiran in both patients with normal nighttime dipping or dippers and patients without a nighttime dip, also known as non-dippers. The majority of patients in study were non-dipper. In this analysis, we observed that a single dose of zilebesiran achieved a clinically significant nighttime blood pressure control as well as the potential to restore nighttime dipping in patients who were classed as non-dippers at baseline.

These results were observed at month 6, highlighting the durability of this control with a single dose. These findings provide additional support for zilebesiran's ability to achieve continuous control and suggest an additional mechanism by which zilebesiran could further decrease cardiovascular risk. Beyond the blood pressure control, we have observed the impact of zilebesiran on other independent indicators of cardiovascular and renal risk, including NT-proBNP and proteinuria.

In patients with modest elevation in these biomarkers we saw 21% to 26% reductions in NT-proBNP and 32% to 37% reduction in the urine albumin creatinine ratio.

Notably, these clinically meaningful events were evident as early as month 1 and were sustained through the 6-month dosing interval. These findings provide additional evidence beyond blood pressure reduction that support the potential of zilebesiran to improve patient outcomes in the Phase III cardiovascular outcomes trial.

As we conclude this section, I'll return to a key theme from Dr. Desai's discussion. Patients remain at elevated cardiovascular risk because we struggle to achieve and maintain continuous control over time. Contributing factors include poor nighttime blood pressure control, visit-to-visit blood pressure variability, poor adherence and spending too little time in the target range.

Across the Phase II program, we've seen encouraging evidence that zilebesiran has the potential to address these needs by providing continuous control of blood pressure with just twice yearly dosing. We look forward to continuing to test the hypothesis in ZENITH.

I'll now pass it to Simon Fox to tell you more about ZENITH and the potential we see for zilebesiran.

Thank you, Ishir, for that comprehensive overview of zilebesiran's clinical profile. I am Simon Fox, Vice President and Program Lead for zilebesiran at Alnylam. I'll now walk you through the progress we've made to date and how we are positioned zilebesiran for the future. As Ishir highlighted, the robust data generated in Phase II, reinforced our belief that zilebesiran's ability to provide continuous control with twice-yearly dosing could meaningfully improve cardiovascular outcomes in high-risk patients for whom the urgency to treat is the greatest. To that end, we are executing ZENITH a trial designed to generate a compelling data package for regulatory review and if approved, support broad uptake at launch.

Importantly, the program has received Fast Track designation from the U.S. FDA and breakthrough therapy designation in China, reflecting the significant unmet need and potential of zilebesiran. ZENITH is an event-driven trial comparing zilebesiran to standard of care in patients with uncontrolled hypertension despite treatment with multiple oral antihypertensives who have established cardiovascular disease or at high risk of cardiovascular disease. Patients in ZENITH will have a minimum follow-up of 2 years with a prior outcome of cardiovascular death, nonfatal MI, nonfatal stroke or hospitalization for heart failure urgent heart failure visits.

ZENITH, Alnylam's largest clinical trial to date initiated last September. The study will enroll 11,000 patients across 35 countries with a global footprint that reflects Alnylam and Roche's shared ambition of bringing zilebesiran to patients across the globe. We are now actively screening and randomizing patients in all of our 35 target countries.

Encouragingly, ZENITH has generated strong enthusiasm among investigators and the broader community, which is translating into strong execution with enrollment very much on track. We recognize that successfully bringing a medicine like zilebesiran to patients requires time, preparation and strategic investment, which is why we earn our partners at Roche are laying the foundations today.

While we focus on strong execution of the Phase III trial, we are also advancing a broader strategy to maximize zilebesiran's potential that includes generating real-world evidence to further characterize the magnitude of unmet need alongside medical education and scientific exchange to support ZENITH enrollments. Given zilebesiran's potential to provide continuous control of blood pressure, we are also assessing development opportunities in high-need populations such as heart failure and chronic kidney disease.

We are also making strategic investments to support future supply and scale. This includes expanded manufacturing capacity through our siRELIS Enzymatic Ligation platform, which is designed to increase capacity and support future launches in prevalent diseases. Finally, we're building commercial readiness by drawing on Alnylam's proven launch engine and experience navigating buy-and-bill pathways, which will scale for this opportunity. Taken together, these efforts are intended to position us to effectively deliver zilebesiran to patients and health care providers if the program is successful.

We are making these investments because uncontrolled hypertension remains the leading modifiable risk factor for death and cardiovascular disease worldwide. Across seven major markets, more than 200 million adults live with hypertension and roughly 1/3 are at high cardiovascular risk. Despite treatment with multiple oral antihypertensive therapies, up to 80% of patients remain uncontrolled and this is where we see the clearest opportunity for impact. The consequences of uncontrolled hypertension extend well beyond patients placing a significant burden on the health care system.

Hypertension accounts for an estimated $292 billion in annual costs to the U.S. and a health care system with 61% attributed to uncontrolled hypertension. This underscores that the burden is concentrating exactly the population we're focused on. And looking ahead, the global economic burden is projected to exceed $500 billion annually by 2050.

Generating real-world evidence in hypertensive populations will be critical in characterizing and quantifying the burden of uncontrolled hypertension. This analysis of contemporary U.S. claims data paints a stark picture showing that even high-risk patients being treated with multiple oral antihypertensives, spent most of their time outside of target blood pressure range, leaving them at elevated cardiovascular risk.

These findings highlight the significant gap that persists today and reinforce the need to investigate a therapy designed for durable effect like zilebesiran. We believe the opportunity for zilebesiran is not to simply become another antihypertensive, but to establish an entirely new category in cardiovascular care. That opportunity rests on four pillars: the potential to improve cardiovascular outcomes, continuous control, infrequent twice-yearly dosing and a well-tolerated profile that can complement existing therapies. Together, these attributes supported by an outcomes evidence strategy have the potential to differentiate zilebesiran from the therapies that rely on daily adherence and are designed primarily to lower blood pressure alone.

Our view of the opportunity is reinforced by encouraging signals across patients, prescribers and payers. Physicians see significant unmet need with 72% of physicians surveyed agreeing zilebesiran addresses a critical gap in care and 3 and 4 indicating intent to prescribe. Fortunately, they view zilebesiran as a differentiated therapy with the potential to become a cardiovascular protective agent.

Patients are similarly enthusiastic describing zilebesiran as promising and exciting with twice yearly dosing emerging as a key benefit that could help support long-term adherence. And finally, payer feedback is clear. Cardiovascular risk reduction is the critical decision driver, an insight that aligns with our development strategy and reinforces the importance of the outcomes data we intend to generate through ZENITH.

As Dr. Desai shared, the lack of durable blood pressure control is significantly contributing to increased cardiovascular risk. The findings from SPRINT provided unequivocal proof of both the benefits and the challenges of achieving durable blood pressure control over the long term. In the controlled clinical trial phase, patients received intensive blood pressure treatment had a reduced risk of cardiovascular and all-cause mortality compared to those receiving standard treatment. However, those benefits quickly diminished once the clinical trial ended and patients entered the observational phase, highlighting how challenging it is for patients to maintain durable blood pressure control in the real-world setting.

This raise is an important question. What if a therapy could provide continuous control of blood pressure with infrequent dosing over the long term to help address these challenges. We believe zilebesiran represents an opportunity to help answer that question with the goal of delivering continuous control through twice yearly dosing.

Before we close, it is important to remember what is at stake. Patients who continue to face significant cardiovascular risk despite today's treatment options, I would like to offer you the opportunity to hear from Bob a patient living with uncontrolled hypertension and high cardiovascular risk.

Hi. My name is Bob, and I'm living with hypertension and high cardiovascular risk. For years, I felt fine and convince myself that I had a handle on my high blood pressure. Looking back, that decision nearly cost me my life. At 45, I suffered a heart attack and left permanent damage to my heart. Hypertension is often called silent killer for a reason and my experience taught me that even when you feel healthy. Uncontrolled blood pressure can have life-threatening consequences.

As for patients like Bob that we continue to pursue innovation driven by the belief that innovation is needed and that we can do more to improve long-term outcomes.

With that, I will turn it over to Pushkal to moderate Q&A. Pushkal?

Thanks, Simon. And all right. Lots of interest I'm seeing some questions. So let's move into the Q&A section. We've already gotten a number of questions coming in, but to those on the call, if you have additional questions, please enter them into the web app.

So the first set of questions that we've gotten are all around this concept of continuous control, particularly time and target range. And so a couple of questions maybe for you, Akshay, and then Simon, you should also chime in. But really how robust is this concept of time and target range? What do we understand from real-world data? Can you just summarize some of your points, Akshay, around that?

And then Simon, to you, what gives us confidence coming out of Phase II that we might see benefits in that. And then importantly, how do you measure time and target range? Is that actually something you can measure in clinical practice? Is it something we're measuring in ZENITH? Is that something that could be a competitive differentiator for this kind of a drug?

Yes. So Pushkal, I think important questions. I think one of the points I think that needs to be made is that most of our therapeutic assessment in heart and hypertension is largely based on single measurements blood pressure in the office, and we understand the limitations of office-based blood pressure, sometimes it's not terribly representative of how blood pressure varies in the ambulatory setting and practice there's variation, as we discussed over the full 24-hour cycle in between visits and blood pressure that's not captured in those spot checks in the office. And so I think the -- we know that the blood pressure is a continuous exposure for patients and that's that continuous exposure that relates to risk.

So I think as a concept, it's very appealing to think about what proportion of time in their ambient life patients present -- spend in the optimal range of blood pressure because we think that is reasonably expected to be a better correlative risk. Now the evidence for that is largely based on clinical trials, which we've looked at post-hoc or even epidemiologic data sets, where we can measure blood pressure serially over time in the office or even at home and then look at the proportion of those measures that actually fit within our target range.

And the greater proportion of measurements that are taken over longitudinal follow-up for a patient that fit within that range the better the outcomes seem to be both when we look at renal events and we look at some positive cardiovascular events like stroke and myocardial infarction.

So I think there's a fairly robust belief that the more time you spend in a target range the better you expect our outcomes to be. And the only limitation has been our ability to continuously manage blood pressure over time to really robustly assess that treatment response.

Fantastic. Simon, do you want to just add a little bit from what we've learned...

Yes, not not much more to add but really what we saw in the Phase II, the totality of the Phase II data really does speak to that therapeutic hypothesis that Akshay just spoke to. And really, that was highlighted by this ability to achieve continuous control of blood pressure throughout the 24-hour period with only 2 doses a year. So that really does speak to that.

Fantastic. And maybe the follow-on I guess, Akshay, to you is could we just accomplish the same things by just intensifying and combining more oral therapies for patients. And do you think the aldosterone synthase inhibitors might help in that regard?

Yes, it's an appealing thought. And I think, obviously, we are extremely excited about the proliferation of new drugs for hypertension, the resurgent interest in this field. But I think that the challenge has never been in hypertension that we don't have enough drugs to treat our patients. We have very effective therapies it's that the drugs aren't deployed to complete effect in clinical practice.

And that's either a problem with access to care, it's a problem with physician use of the medications or it's a problem with patient adherence. And I think when we integrate this concept of control outside of the office and that longitudinal control over the 24-hour interval in between visits, then I think we have an even larger problem because we have these very stringent blood pressure targets that we know mitigate long-term risk of cardiorenal outcomes.

And we know that on the whole, we haven't done a great job of controlling blood pressures even with the arsenal that we have. So I think the problem is really not likely to be solved by stacking additional oral antihypertensives, I think that may indeed exacerbate the problem because some of the problem for patients is this huge array of medicines that they have to take each day and the difficulty with doing it.

There's this data that I highlighted is that most patients prescribed the medicine about half of them by a year have stopped taking it or -- and that adherence problem, I think, is a real challenge for us moving forward. And I don't think it's solved by even a more effective correlation.

Very helpful. And Victoria, I mean, for you, how do you kind of see -- let me introduce Victoria Silva, who heads up our commercial team for zilebesiran. Thank you for joining us for this portion. How -- building on what Akshay said, how do you think about these new branded therapies like aldosterone synthase inhibitors that are coming forward in a very highly genericized market? And how zilebesiran might ultimately, if it does bear out in ZENITH compete in that space?

Yes. So what we really see about zilebesiran is that we're creating a new category. We're going to be -- we believe we are a cardiovascular protection agent. We are not just another blood pressure lowering agent. And we believe that exact design is what differentiates us and sets us apart the other existing therapies. And to a lot of the points made will allow us to establish continuous control will allow us to overcome the adherence hurdles that we see with the oral therapies today.

And so we think those things combine are really what sets us apart. And that, in addition, the uptake of emerging therapies really helps validate the need for this innovation. So what we're seeing in the marketplace is actually encouraging to us that there is absolutely space for zilebesiran to enter the market.

And if I could jump in, I would just say that one of the real opportunities here is to completely reinvent the paradigm for prevention, right, which is that rather than waiting for patients to show up in the office, identify the blood pressures out of range and then react to that observation, whatever the genesis of that problem is here's an opportunity to intervene early to provide continuous background control of blood pressure and secure blood pressure lowering and cardiovascular risk reduction without the need to rely on the clastic nature of how patients take their medication.

So that's a really important point. And I imagine with wearables and things like that. that's only going to their normal lives. Ishir, maybe I can turn to you. There's a number of questions that have come through in your presentation about the learnings from KARDIA-3. And I think there's a number of questions that have come through in terms of, okay, given the study didn't sort of meet its threshold benefit that we were looking for, but then there's a series of analyses that look for enriched population. What gives us confidence? Can you just speak a little bit more to like the idea about the diuretics.

Is that just a subgroup that was identified? Or there a biologic rationale for that? The cutoff of 140 that was employed to sort of look for an enrichment in KARDIA-3. Can you just explain a little bit more about that? And what gives us confidence that the choices that we made coming out of KARDIA-3 are likely to translate into a sizable or meaningful blood pressure benefit in ZENITH?

So based on our known biology and prior research with both zilebesiran and other RAS agents, even prior to KARDIA-3, we suspected we might see enhanced responses zilebesiran in patients on diuretics as well as patients with a blood pressure of at least 140, which is a standard threshold for Stage II hypertension. And both blood pressure and background diuretic use were included as prespecified stratification factors in KARDIA-3 and both were also included in prespecified post-hoc analyses.

So I would say KARDIA-3 met its objective in three key ways. First, it helped identify the population most likely to benefit from zilebesiran that is patients receiving two or more background antihypertensives, one being a diuretic, with the systolic blood pressure at least 140 millimeters. In this population, zilebesiran achieved an enhanced response of 8 to 10 millimeters in office and 24-hour systolic blood pressure out to month 6.

Second, it confirms the safety of zilebesiran in combination with two or more background anti-hypertensive in patients with high cardiovascular risk. And third, it established the dose for the Phase III, a twice yearly 300-milligram injection. So in conclusion, KARDIA-3 helps optimize the design the target patient population and the dose for the Phase III cardiovascular outcome trial ZENITH. Taken together, the KARDIA-3 results give us and our partners at Roche, the confidence to advance zilebesiran into this pivotal Phase III cardiovascular outcome trial.

Thank you Ishir, that's really great and clear. So maybe building on that, Simon, we questions coming, you've shown blood pressure benefit already with this drug, blood pressure is a registerable endpoint Akshay talked about how important that continues to go. So why not just register on blood pressure. Why why the investment in the sizable outcome study?

Yes. So it's a great question Pushkal, and look, you heard from Ishir, we saw really encouraging results in our Phase II studies. And illustrated by a zilebesiran ability to achieve continuous control of blood pressure with only twice yearly dosing. And we believe all of the salient points that Akshay mentioned, that this has the potential to improve cardiovascular outcomes.

And it's worth acknowledging that it's an entrenched generic oral antihypertensive market. And outcomes data will be required to differentiate zilebesiran beyond blood pressure alone. And Alnylam and our partners at Roche we really do believe zilebesiran potentially become a category creator.

As Victoria's said, in cardiovascular risk management and not just another antihypertensive and generating that outcomes data for initial launch is key to our strategy. And just to repeat again, it's worth mentioning that zilebesiran was awarded Fast Track designation by the FDA, a breakthrough therapy designation in China, which we believe really illustrates how we view both the unmet need and the potential of zilebesiran to improve outcomes.

Good. And then I think a follow-up from there, as you just highlighted, why there was a biologic rationale for requiring background diuretics, we saw a larger treatment effect in that population. But all concerned, Simon, and maybe that this is going to constrain the label in some way?

And two, and maybe more importantly, I guess to you, Akshay, can you just talk about this population that we've highlighted that Ishir highlighted and Simon, that we're enrolling in ZENITH, how representative of that is that of the patients that you see? Are these zebra patients as we talk about medicine? Or are these kind of what you see -- how common is this type of patients that we're targeting. So maybe, Simon, you can start and then we'll go to Akshay.

Yes. So I'll just do it the direct look. We fully believe at launch, we'll have a broad indication and label. And we don't think like indicated to reduce the risk of cardiovascular events in patients with hypertension with either established cardiovascular disease or at high risk of cardiovascular disease.

Yes. No, I think if you look at the population of patients that I see in my clinical practice, I would say that the vast majority are diuretic-treated. The epidemiology says that about half of patients with hypertension are treated with the diuretic. But when you look at the high-risk population, the uncontrolled hypertensive be more elderly patients with hypertension, the vast majority are on a diuretic and ace-diuretic or ARB diuretic or calcium channel blocker diuretic combinations are far and away the most common combinations that are used in clinical practice.

So I think the -- when I look at the ZENITH design, I think we're talking about patients with uncontrolled hypertension on to medications, including a diuretic who are at high cardiovascular risk. Those are the patients that we see in a large proportion of a cardiology practice that's focused on hypertension. But I don't think these are zebras at all. I think this is the meat of the patients who have the most urgent need for hypertension treatment.

And it's actually worth mentioning, you mentioned first-line guideline recommended diuretics are. And for the specific target patient population of the stud in ZENITH, obviously, they're on background diuretic. It's around about 80% of the patients with high cardiovascular risk are on background diuretics. So that's why we believe that ZENITH really does represent a contemporary population.

Good. Maybe we can then turn now then a little bit to ZENITH. We got a number of questions. I guess, first of all, what level of MACE benefit and maybe Ishir, you can start and Victoria it'll good to get your comments, would be clinically meaningful and commercially compelling. Are we powered? What level of effect are we powered for. And then how do you guys handle in the study patients who might be starting new therapies, et cetera, or down-titrating their background medicines.

And does that compromise our ability to see an effect of people start a new therapy in the context of the study, et cetera. So a number of questions there. But Maybe Ishir we can start from you in terms of just how you think about the clinical effect size we're looking for powering and how background medicines are handled in the context of the study?

So given the blood pressure reductions we saw in the KARDIA-3 in this enriched population, we feel it's realistic to expect a 15% to 20% reduction in MACE, and we're conservatively powered to assess the magnitude of an effect in ZENITH our Phase III cardiovascular outcome trial. And with regard to background medications, we do allow those to be titrated in the ZENITH trial. We don't expect that's going to have a sizable effect on our impact. We also believe this magnitude of effect will be compelling to regulators. And maybe I'll let Victoria speak to what that means for us commercially.

Thanks, Ishir. So from a commercial perspective, we believe a benefit in that range would be highly compelling. A 15% to 20% base reduction and exactly have a type of benefit that resonates with cardiologists and we believe would position zelbisiran as a cardiovascular protected agent, not just another blood pressure lowering therapy.

The physician response and our research is strong, and it tells us that we're targeting the right bar. A benefit at this level supports strong access and premium positioning. We feel good about where this lands us with payers for whom MACE reduction is the #1 decision driver and the value it ultimately command.

Fantastic. And maybe Ishir, building on your point, I mean, I think we've designed ZENITH really to be, in some ways, representative a real-world practice kind of study. I mean because of the infrequent administration, these are not patients who are coming in every month or every couple of weeks to get their blood pressure checked.

You guys have designed this right, as almost a Q6-month type of visiting schedule visit schedule in the study, which mirrors real world where I think Akshay has already high adherence and titration is not always as vigorous as we would sort of see and sometimes a much more intense short-term clinical trial setting. Is that fair?

That's exactly right. And that's why we don't expect that we'll see a lot of changes in these background medications that we know that from what happens in clinical practice. And that's where zilebesiran's long-acting nature were really the advantageous.

Yes, I think one of the real opportunities in ZENITH is to examine our practice, right? I think what we can see from the work that's been done so far. If the clinicians often confronted with an elevated blood pressure in clinic, choose not to engage it. And it's largely many reasons. But I think often it's the suspicion that it may not be accurate -- may not reflect what's going on in day-to-day practice at home.

And so I think as much as you might be concerned that there would be aggressive utilization in the control arm of ZENITH of other medicines that hasn't borne out in practice general people are pretty lack of days ago about blood pressure therapy.

Yes. No, it's a really important point and hopefully, something we can help address. Maybe just building on this concept of the MACE reduction that we're looking for. And I think Simon highlighted, actually, you've highlighted that there's an element of blood pressure management that is guideline driven. And so I guess it would be helpful to understand from your perspective as an academic thought leader in medical societies.

If this side delivers a 15% or 20% MACE reduction or what else would be needed to kind of put this in guidelines, again, given there are a lot of generic medicines and guidelines do drive a certain amount of clinical practice?

Well, I think it's an important question. It's probably an important question, both for -- especially for payers and other things because a lot of how we elect to select therapies and prioritized therapies is driven by how the guidelines are written. It's -- I think that the key message here is that guidelines are heavily driven by the weight of evidence and by the science. And I think if we look at blood pressure as a target is probably not enough to simply show that agents reduce blood pressure, even if they do it over the full 24-hour cycle, that's true for many agents. It's been true for agents that we've had available for a long time.

And so I think the point of differentiation here is really the randomized outcome trial that will show that effectively addressing CV risk reduction through this strategy will actually translate into long-term outcomes. And I think with that data and the projected 15% to 20% reduction, I think that would be compelling for -- to differentiate this approach from others that exist in the literature and perhaps motivate recommendations in that regard.

Super helpful. Ishir, back to you. A couple of questions just around safety. We have a long-acting medication to treat hypertension. So I think a couple of things you did touch on the safety profile. Maybe you can just recap and what were there any surprises from a safety perspective?

And then, I guess, more importantly, the question is coming through is what happens -- how do physicians -- are they expected to manage if some intercurrent event happens like low blood pressure, et cetera. Are they able to stop their other medications? What does that mean? How do you manage those? Or if someone needs to have something happened in terms of managing blood pressure because they're having an operation or something like that?

Yes. So with any therapy that targets the rest, one would expect to see some degree of elevated potassium reduced eGFR and low blood pressure. But in our Phase II program, we were really struck by what we found. We were pleased to see that the rates of these were quite low. And even though the zilebesiran has this 6-month duration of action, when these events did happen, they were transient and really addressable with just standard of care intervention. So that's what we'd expect to see in our clinical trial and in the real world.

Overall, we've been very encouraged by the safety profile generated in the Phase I and Phase II with almost now 1,000 patients exposed to zilebesiran across really multiple settings, including monotherapy and in combination with other antihypertensives. These have included patients already on ACE inhibitors and ARBs and patients with moderate to severe chronic kidney disease as well as patients who have received multiple doses of zilebesiran.

Very helpful. Very helpful. Akshay, some questions for you that are kind of -- I think you're best positioned to answer is just the ZENITH study and zilebesiran being developed, really to focus on the secondary prevention indication and in high-risk patients. But let's assume it's successful. Where do you -- where would you be interested in understanding if this kind of a modality or mechanism would actually be useful?

Is it -- are there other spaces in hypertension? Are there other diseases we know RAS inhibition is used in other cardiac conditions and clinical conditions. So what would be of interest to you as a clinician and as clinician scientist in terms of thinking about where you might take a medication like this, assuming it continues to look favorable?

Yes. So I think there are two areas that immediately come to mind. I think if you think about the role that hypertension plays and the pathogenesis of heart failure development the role and progression of heart failure in patients with established heart failure. And then you think about chronic kidney disease in the role that hypertension plays, hypertension is the leading driver of disease progression in both of those disease states. And the renin-angiotensin system is a key mediator of disease progression in both of those states. We've known for a long time that patients with CKD and those with heart failure across the ejection fraction spectrum benefit from renin-angiotensin system inhibition.

And so I think those are two very high profile and high priority areas for expansion of a drug that is effective because we would imagine that a drug that provides blood pressure reduction, better time in the therapeutic range, longitudinal control and overcome some of the adherence challenges of daily oral medications would equally benefit, if not more so, those high-risk patients with established CKD and heart value. So I think that would be a super exciting next step.

Another way to think about this is even moving more approximately in the hypertension treatment armamentarium because I think we're now looking at a second intervention in high-risk patients but one could imagine this as a backbone for hypertension management to secure initial blood pressure lowering.

And it might be the case that for some lower-risk patients with hypertension, this might be all you need to control blood pressure in the range. And if not, it would be a scaffold on which to stack more -- fewer oral medicines to achieve blood pressure targets. So I think another direction to potentially take this.

Fascinating. Lots of opportunity potentially ahead. Victoria, maybe a question for you that's come in is another siRNA sort of in a prevalent condition is inclisiran, LEQVIO that was originated here but now being marketed by Novartis. What have we learned from that experience that helps us think about how -- again, assuming ZENITH is positive and that we would potentially launch a drug like zilebesiran and what challenges it might be faced and what have we learned from that experience that we can address?

So one of the original challenges Novartis faced actually informed our Phase III and exactly why we did a cardiovascular outcomes trial with ZENITH. We believe that this outcomes trial will actually create that differentiated profile, drive physician uptake, support broad access and establish the value of the medicine.

So we learned exactly from what inclisiran didn't initially do to design our Phase III. Today, though, inclisiran is starting to be a tailwind for us. While another challenge for LEQVIO early on was that cardiologist weren't yet comfortable with buy and bill, that has really changed significantly as customers have gained experience.

In the U.S., LEQVIO sales grew 55% last quarter. So it's a blockbuster that's really matured the whole channel. Unlike a first-time entrant, we're also not entering this from scratch. Through AMVUTTRA's cardiomyopathy launch, Alnylam is already running buy and bill and cardiology with 90% of patients able to get treated close to home. So we're -- with zilebesiran stepping into an established pathway with our own cardiology track record behind us. We're clear that we will have more work to do ahead, but we like where this positions us.

Fantastic. And then I think maybe this will be our last question. We got an interesting question, which is, is there an increased risk for ZENITH and the questioner is asking about a number of recent setbacks in terms of cardiovascular outcomes trials with Lp(a), the eplontersen study, IL-6, et cetera. And whether that poses now a risk in terms of ZENITH and how we think about that. So maybe I can start, but Akshay and others, I'd invite you to add as well.

I think I think as we look at it from Alnylam, A, we've really tried with our colleagues at Roche to really look at the risk in a number of different ways, right? There's molecule risk, there's biology risk, there's study design risk. And I do think that in this particular instance, I think we're quite well positioned. I think zilebesiran has now been studied in over 1,000 patients. I think we have a pretty good understanding of its pharmacology. We're able to pick the right dose. We have very high levels of knockdown, good tolerability. So that's one piece.

I think the second piece then is around biology risk. We've now shown, I think, repeatedly that we can reduce blood pressure in a variety of settings. The monotherapy is this year highlighted in combination with single agents and then in the intended patient population. And I think hypertension itself, I think, is very, very strongly correlated with outcome. So I don't think there's a lot of uncertainty, biologic uncertainty around predictiveness of blood pressure results translating into outcomes benefits.

And then I think the last piece is study design. And I think what you've heard is that the team really has set a lot of the details in terms of basically running KARDIA-3 is almost a run-in type of study to basically optimize the patient population, some of the study procedures, et cetera, to manage challenges that have plagued other hypertension outcomes trials. And so I think all in all, we feel quite good about what we've designed and quite confident about that.

But -- so that's how I would sort of summarize it. But I don't know, Akshay, Simon, anyone have anything to add?

I think you said it very well. And I think my only add would be that in those other examples that you highlighted, I think we've had a little less certainty about the relevance of the a for the biomarker for predicting cardiovascular outcomes. There is no uncertainty in hypertension that if you can effectively lower blood pressure to a greater extent with zilebesiran than you do in the standard of care arm in ZENITH, that should translate reliably into a cardiovascular outcome benefit. There has been a linear dose response between achieved blood pressure and outcomes in these trials.

So I am quite confident that if we can deliver on that promise, which we have every confidence we can do. And I think, as you said, the study design tuned really to deliver that outcome. I think there's every expectation of benefit.

Fantastic. Well then, I think we will leave it there with that. So thank you to Ishir, Simon, Victoria and Dr. Desai, thank you for joining us today for all your insights and contributions to today's discussion. That's going to be the end of today's RNAi Roundtable.

You can access the replay of the webinar and view the slides in the Capella section of Alnylam's website later today. And we'll welcome all of you back on October 26 for our next and final session, which is focused on ALN-HTT02, our investigational therapy for Huntington's disease. So thank you all for joining, and have a great day.

The meeting has now concluded. Thank you all for joining, and you may now disconnect.

All right. Hello, everyone, and thanks for joining us at the Morgan Stanley Global Healthcare Conference. I'm Mike Ulz, one of the biotech analysts here, and it's my pleasure to introduce the team from Alnylam Pharmaceuticals. Up to my left, Yvonne Greenstreet, CEO; and to her left is John Kennedy, Senior Vice President of Global Commercialization and Lead of the TTR franchise, which I know a lot of people are interested in.

So happy to have you both here. But just a reminder, this is a fireside chat. If anyone has questions, if you raise your hand, we can try and address them in our discussion. But before we get started, I just need to read a quick disclosure. For important disclosures, please see the Morgan Stanley research disclosure website at www.morganstanley.com/researchdisclosures.

If you have any questions, please reach out to your Morgan Stanley sales representative. And with that, maybe I'll just hand it over briefly to Yvonne to make some comments, and then we can hop into the Q&A.

Well, thank you so much. It really is a pleasure to be here, to be here with John. As many of you know, Alnylam is the leading RNAi company. We have a commercial stage TTR franchise business that's growing very rapidly.

We have a rich pipeline with a number of potentially transformative medicines that will be delivering some exciting catalysts over the next year or so. And a real pleasure to be here to dig into the questions you may have for us.

Yes. Great. Thanks for that, Yvonne. And you touched on it already, but you've had a very strong TTR cardiomyopathy launch. So maybe we can start there, and you can describe what's driven the success so far.

That's a great question. We're very proud of what we've accomplished with AMVUTTRA, particularly for patients with TTR cardiomyopathy. In Q2 this year, we crossed $1 billion of revenue in just 1 quarter. And I think that's particularly impressive given that we achieved the cardiomyopathy indication in March of 2025.

So really, really strong progress. And I think that's driven by a number of key drivers. I think the first is the strength of the data that we generated from the landmark HELIOS-B study, where we delivered impressive results with respect to all-cause mortality in all the different subgroups in the study and severity types and patients receiving stabilizers or not.

And really, I think it's been this body of evidence, which we've continued to enrich with additional analyses looking at cardiac structure and function, looking at the benefits on extra cardiac manifestations that I think really provides a compelling proposition for physicians to prescribe AMVUTTRA first line.

And then you put that together with a quarterly subcutaneous administration, which if you like, provides physicians with certified adherence because you're only going to get the benefits from the drug if you actually take the drug. And I think the profile of AMVUTTRA has been very well received by physicians and supports its position as first-line monotherapy.

I think the second key driver is really around access. Again, it's great to have delivered a successful study and have a medicine that's safe and efficacious. But patients have to be able to receive the medicine. I think we've done a really good job being able to ensure that there's unencumbered access really to AMVUTTRA as first-line therapy.

And most patients are able to get access to AMVUTTRA with $0 out-of-pocket cost. And we've really focused on trying to make this convenient for patients and 90% of patients can access AMVUTTRA within 10 miles of their home. So I think really strong setup from an access perspective.

I think the third point is really around physician preference. And what's been remarkable to us actually is that physicians who experience AMVUTTRA, who prescribe AMVUTTRA prefer it. And we have a greater than 50% market share with physicians who have used AMVUTTRA. So that's really very, very encouraging.

And the final point I'd make is just around the market. This is a rapidly growing market, hugely underserved. And so whilst we've made terrific progress with AMVUTTRA, I'm really excited by how much there is ahead of us in terms of helping patients with TTR cardiomyopathy.

Makes sense. And recently on the earnings call, you reset expectations around guidance for the year. So maybe talk about some of the dynamics behind that and what you've been seeing as the launch progresses.

Yes. No, that's a really great question. If we revised our guidance on our Q2 call to $4.2 billion to $4.5 billion for our TTR franchise. That's a $200 million reduction at the midpoint. And that was really driven by a greater understanding of the evolution of the market, particularly as it relates to second-line demand.

When we launched AMVUTTRA in 2025, there were clearly a number of patients with pent-up demand. There are patients who are progressing, they are waiting for a new treatment. And so when we looked at the mix of our business in 2025, it was pretty well balanced between first line for patients that have just been diagnosed with TTR cardiomyopathy and getting a treatment for the first time and patients who were second line, who are already on a treatment.

And what happened as we went into 2026 is that really has normalized, if you like, and stabilized. So we've gone from a mix of business that's been pretty well balanced between first line and second line to now a business that's really approaching what the market -- where the market is, which is 80% first line and 20% second line. So we're trending in that direction.

So really, our focus is, therefore, on making sure that we continue to establish AMVUTTRA as a first-line opportunity for patients. Now some patients who continue to progress will benefit from an alternative therapy. And some physicians when they have to think about how to best treat these patients will think about either adding in an additional therapy.

And if they stabilize, the only opportunity is a silencer like AMVUTTRA or they will think about this in combination.

Makes sense.

Actually, you asked a question about the market fundamentals. And maybe just to touch on that a little bit because I think it is worth emphasizing how strong the market fundamentals are. And I've already talked about access.

I've already talked about the needs in the marketplace with 80% of patients yet to be diagnosed and treated in a market that has roughly 200,000 patients in the U.S. and 500,000 patients around the world.

And so a need to really help these patients get diagnosed and treated and really also the first-line momentum that we're seeing. So I think strong market fundamentals as we look out beyond 2026.

Makes sense. And also want to just touch about on some of the pricing dynamics and maybe how that's evolved through the launch and then this 340B question that's coming up now.

Yes. John, do you want to touch on pricing on 340B?

Yes, absolutely. So in terms of pricing, we have said since launch, and we've been very consistent that we anticipate a modest and gradual reduction in net price just as the volume and experience accrues over time. And that's really what you saw in '25 and '26. And so that's been what we said, and we see that as the outlook.

For 340B, there's a proposed rule change. And obviously, that has gone through the comment period. There's been quite a few voices that have spoken up about that. Particularly on the provider side, there are some very strong voices against that. And so I think it still remains to be seen what will actually come from that comment period and actually what happens with the proposed rule change. That said, even if that were to move forward, I think the other variable is how providers will change their behavior, and there are options.

So there are eligible accounts that anyone can purchase at list price. There are also these alternate sites of care, which we have really built a robust network to make sure that patients have optionality in terms of site of care. And so those are built for volume and built for buy and bill. So there is optionality on the other side of that. And I would say the most important thing is we're focused on AMVUTTRA access, and we see access and utilization across sites of care.

So that's the bottom line for me that whatever happens, we're going to make sure that patients who need AMVUTTRA are going to be able to access AMVUTTRA.

Makes sense. And when do you think this will kind of come to an end? Is it November? Does it keep dragging on? Or just like how does this all play out?

Historically, when there's a rule -- proposed rule change, we expect that in November, somewhere in November is usually when those things are kind of concluded, but it remains to be seen.

Yes. Understood. Maybe we can shift gears to another area of focus, data from the CARDIO-TTRansform study and kind of what that means or doesn't mean for silencers. Maybe share what you learned from the detailed results and maybe how it might impact AMVUTTRA or not?

The CARDIO-TTRansform study was really very interesting. And I think the outcome was driven by a number of key factors. I think one was the depth of TTR knockdown that was achieved in the study. I think the second was around the patient population that was enrolled in the study. And I think the third was around endpoint selection.

What I think was probably most surprising to people was actually the relatively poor TTR knockdown that was achieved by eplontersen in the study. I mean, less than 70% kind of mean TTR knockdown compared to what we've seen with AMVUTTRA in HELIOS-B of 81% mean TTR knockdown. And that 11% is actually a meaningful difference.

And to me, what I think is really quite interesting is that probably what we've seen is a little bit of a dose response set of studies, if you like, in this space for patients with TTR cardiomyopathy.

Clearly, better knockdown leading to better outcomes, less good knockdown leading to less good outcomes. I think the other aspect is going back to the sort of patient selection for the study that it's quite clear that when you're thinking about a stabilizer, the best opportunity for patients is to treat patients early. You're treating them with a stabilizer.

When the heart has already had a lot of deposition of amyloid, it's obviously going to take longer for that to resolve. And we saw this in HELIOS-B actually, where patients who are at an earlier stage of their disease saw better outcomes. And that's a really, really important point.

And actually, in CARDIO-TTRansform, there's a similar finding there as well. In the cohort of 900 patients who are [indiscernible] Stage 1, so earlier stage of their disease. Actually, eplontersen was able to deliver a positive result, which would have achieved statistically nominal significance. So I think there's something around patient selection that is really, really important.

And the last point is around the endpoint. I mean the HELIOS-B was an all-cause mortality endpoint. Now we know that TTR cardiomyopathy is a multisystem disease. It affects the heart, it affects other parts of their body. And people die from the broad aspects of the disease. If they have heart failure, they get pneumonia, they die, they're weak, they fall. And so if you're going to have an endpoint, I think it's helpful to have an endpoint that is able to measure all the aspects that impact mortality.

I think the other thing is having an event-driven endpoint is also helpful, so you can make sure you cue enough events and able to see a difference.

Yes. And I guess what feedback have you gotten more recently from physicians since the detailed results. Is there any impact on AMVUTTRA or not? And I guess we did our own doc call and the view was no impact. So just curious what you're hearing out there?

Yes. So I mean I'd just like to say a little bit HELIOS-B does study. I mean it was a landmark study, delivered very impactful results. And I think the other point to make is that silence is not all silencers.

You have ASOs and you have siRNAs. And what's been quite interesting actually when you've looked at a number of programs, AGT, APOC3, PCSK9 and now eplontersen is that actually siRNAs perform better than ASOs. And I think people are beginning to understand that, that different study, different drug, not surprising, you get a different result.

So I think as we speak to physicians and we've done some surveys, they're really not seeing huge implications to their daily practice based on the CARDIO-TTRansform study. But obviously, it's our job to make sure that we're able to get out there and educate physicians on the strength of what we have in the HELIOS-B study and the compelling profile for AMVUTTRA.

What about this dynamic between the stabilizers versus the silencers? Is that kind of the same view, like no real impact or change there?

Yes. I mean I think there are some that are trying to characterize the study as something that it wasn't designed to do. But in terms of just general practice, maybe the way I can answer it is we actually did a survey of cardiologists, general cardiologists that are caring for these patients in this category.

And we actually did it between the press release announcement of the failed trial and before ESC. So if you think about it, that was the moment of probably the highest uncertainty. And we did a survey and essentially ask does anything change, especially with regards to your current behavior and your perception of silencing?

And the short answer is overwhelmingly no. Now since we went to ESC, we now have so much more data. And I think the conclusions are generally what we see. It probably worked, silencing worked, but it matters how well you silence and we have a better product, and that came across, I think, very clearly at ESC.

Yes. Makes sense. Maybe you can talk about some of the OUS dynamics you're seeing and how that might play out this year?

We're thrilled that we're able to make AMVUTTRA available to patients around the world. I think the launch has gotten off to a great start in markets like Germany and Japan. We recently effected a commercialization agreement with B1 to make sure that we can work towards making AMVUTTRA available to patients in China.

Obviously, we need to get through the regulatory process first. And whilst these are all different geographies, and they have their different systems, the different pricing and reimbursement systems, different access considerations. I think one thing is clear that patients with TTR cardiomyopathy are not sufficiently diagnosed and not sufficiently treated.

And so there's a huge opportunity as we think about building this business, obviously, in the U.S., but also around the world to meet the needs of so many patients out there.

Yes. Makes sense. Maybe shifting a little bit related, but nucresiran, obviously, lots of questions around that and implications of CARDIO-TTRansform. You shared your views on the data. I guess, on this study, how are you thinking about the implications there...

Yes. That's a really good question. I think the first thing to say around nucresiran, and we're obviously evaluating nucresiran a study that's called TRITON-CM. It's a large cardiomyopathy study. Nucresiran has 95% TTR knockdown. That's the best of any program that's out there. And we think that's going to play through into improved outcomes.

So we definitely have a molecule that is incredibly potent. I think that's the first thing to say. I think the second is that, look, we've been developing medicines for patients with TTR amyloidosis for many, many years and have real insights from all the studies that we've got.

We've got patient level data from our HELIOS-B study. And that allowed us to be really thoughtful about the design of TRITON-CM. And we've actually built in a lot of the learnings that were then validated when we saw the data from CARDIO-TTRansform in terms of patient selection in terms of the endpoints.

And so we feel that we're in a really, really good place with respect to TRITON-CM. We're obviously continuing to enroll that study. Obviously, also very thoughtful about the fact that this is an incredibly important study for the company. And so we're going to spread the details as we always do, right? And we're going to think about whether there's anything that we need to do to modify the study, which really falls into 2 buckets.

One is thinking about the patients that we enroll and enriching for certain types of patients potentially, maybe increasing the size of the study, that's another option. And those are decisions that we would have to make pretty soon whilst we're still in this enrollment period. And obviously, if we make those decisions, we'd communicate that broadly.

The other approach might be to think about the analytical plan a little bit like we did with HELIOS-B. And that's a decision that we can make at any point in time over the duration of the study. It's probably something that we think about kind of later in the course of the study.

But I think it's really important to kind of just, I think, underscore that actually, the learning from CARDIO-TTRansform to a certain extent, has actually strengthened our conviction around the design of the TRITON cardiomyopathy study.

If you decide to make some fine-tuning to the study, I guess, when would that happen? And then I guess, related to that is, obviously, there's a lot of interest in probably the baseline characteristics because those are going to matter as we try and think about the probability here, I guess, when might you share those what's the thinking there?

So if we do anything different with enrollment, I mean, if you remember, I think it was earlier on this year, we announced that we were upsizing the study. We're adding another 500 patients to the study. And we announced that as soon as we made that decision.

So if we're making any changes to enrollment, that's something that we would communicate before the end of the year. But as I said, if we're refining the stat plan, we can do that at any point in time. So I wouldn't expect that we would be communicating anything on that front in the near term.

Increase in the confidence, is that about monotherapy effect? Is that combo effect? Is there some way to -- is there some limit on background path you can have to be successful? I know these...

So what -- I mean, it's important to just say what we're trying to achieve with the study was actually say effect a broad label for nucresiran, the way that we have done for AMVUTTRA. And therefore, it's going to be important that we study a range of patients and study both monotherapy and combination therapy. Really, the goal is to make sure that we deliver a successful study, which can then meet the needs of patients with TTR cardiomyopathy, whatever types of patients those are.

Yes. Another question that comes up for TTR cardiomyopathy is just the impact of generic tafamidis in 2031. And maybe you can just share the latest thinking there and the impact to your...

Yes. So we'd originally thought that generic tafamidis would become available in 2028. And now we understand it's more likely to be 2031. And actually, that's a pretty good thing for AMVUTTRA. It reduces the pricing pressure of having a generic come into the market sooner. And it allows us more time really to establish AMVUTTRA to continue to establish AMVUTTRA as the foundational therapy for patients with TTR cardiomyopathy.

So we think it's actually a good thing for us. The other thing is actually the timing juxtaposed is really nicely with nucresiran and the TRITON-CM study because we will be delivering data for the polyneuropathy TRITON-PN in 2028 and then for TRITON-CM around about 2030. So it actually all comes together rather nicely.

And maybe last question on TTR. I guess as you look sort of near term through the next couple of years, just the key drivers of growth to really push the frontline use up. Is it just helping find more patients more quickly? Is it more education around the profile? What are the key...

So I think if I think about -- I'll step back and then I'm sure John will add some color. But I think about, okay, what are the key drivers of the business over the next period. And you're absolutely right. I think the really important thing is to establish AMVUTTRA as first-line monotherapy and obviously doing that in a number of ways in terms of continued evidence generation, continued education of physicians, continued support around patient identification and diagnosis and helping patients get through the various care pathways so they can actually receive treatment. So that's really, really, really important.

I think the second area is around continuing to help grow the market. When you've got a market where 80% of patients are undiagnosed and untreated, I think it's a really important opportunity and obligation for us to continue to educate physicians and improve the diagnosis rates and improve the treatment rate. So investing in helping to grow the market is also very important.

I think the -- when we think about educating physicians, I think what we also need to do is to broaden the prescriber base. So I said, physicians who use AMVUTTRA prefer. We're currently addressing about 1/3 of the prescribers out there. And so there's a lot of runway. And so we're investing in broadening the prescriber base as well as obviously also deepening prescribing within physicians who are already prescribing AMVUTTRA.

And then you touched on markets outside the U.S. and we'd like to continue supporting patients who live outside the U.S. and so continued geographical expansion is going to be very important to us. And we spent a little bit of time also talking about nucresiran. I think AMVUTTRA is a very important medicine for Alnylam.

It actually is a medicine that's going to allow us to fund a very exciting pipeline that we're developing and build the company. So we really are aspiring to ensuring that we're leaders in the TTR space. And we like to leaders for a long time.

And so developing our third generation with nucresiran, as I said, much better, much 95% TTR knockdown is another important aspect as we think about the long-term opportunity for the TTR franchise and AMVUTTRA. JK, anything else?

I mean you covered all the levers, but just for color or commentary, what I'd say is this category is rapidly expanding. So that's patient volume, but it's also just the number of prescribers that are involved in the category. And that's why being able to expand the prescriber base is important. We're doing more. So we're actually -- we have more physician engagement with more people in the field, more investment.

And then the other investments to drive diagnosis, we're not doing this alone. We feel compelled as we aspire to be the leader to do more to drive diagnosis, but we're doing that in partnership with others. This AI is an AI provider is one example, the American Heart Association, et cetera. So those are partnerships we're building.

And Yvonne, you brought this up pipeline, which we got about 8 minutes left here. So maybe we can dig in there a little bit, and you've got a bunch of updates later this year, but maybe just high level, maybe just talk about pipeline and kind of what you think investors should focus on there.

Yes. No, I'm really excited about the progress of the pipeline. As I said, a number of important catalysts this year. So I'll start with the first, which is our Huntington's program. And I know I don't have to convince any of you here how much unmet need there is for patients with this disease. It's been described as being a combination of ALS and Parkinson's and Alzheimer's, and there's really nothing out there for these patients.

And we have at Alnylam a program, which we believe has a really important mechanism of action where we're able to address not just the full men Huntington's gene, but also the exon 1 fragment, which is increasingly being implicated in the pathophysiology of the disease.

So we think we've got something in our hands that could be really impactful. And I think this has been supported by some of the data from uniQure natural history study, which showed the importance of actually having this exon 1 fragment.

And this is program. It's administered intrathecally. It's probably going to be a couple of times a year, we'll be getting Phase I data in October. So it really is imminent, and we're hoping that they will be able to demonstrate safety and tolerability. We'll be able to demonstrate -- we'll be able to understand PK/PD.

We'll be able to measure Huntington lowering through CSF. And so if this program is successful, we think we'll be able to move it very quickly into Phase III. I think there'll be a lot of support for trying to progress this medicine towards patients. It's something that we are kind of very excited about, and we hope to be able to move rapidly forward. And there'll be more information being presented at the EHD meeting in October, so just around the corner.

So I would ask you all to stay tuned. That's a really, really exciting program. Probably the second program to touch on is called ALN-6400, what we call our plasminogen program. It's for bleeding disorders. And really, it's got, again, a really interesting approach where we can stabilize clot and the potential here is to be able to stabilize clot and therefore, reduce bleeding without any thrombotic risk and there's some good genetics and biological evidence for this.

And the other kind of exciting thing about this program is the mechanism of action could apply across a range of different bleeding disorders. So we're starting with a study in patients with Hereditary Hemorrhagic Telangiectasia, and I'll talk a little bit more about that.

But we can -- we're also then in a Phase II for patients with Von Willebrand Disease. So you can see how start off with indication and we start to kind of go after one indication after the other with bleeding disorders. So we have a Phase II ongoing in patients with HHT. And there, we're measuring numbers of bleeds in the patient, severity of bleeds.

These are patients actually that have incredibly severe nose bleeds, GI bleeds and require -- they're often anemic, they require transfusions. There's actually significant unmet medical need for these patients, which we hope to address with this particular program, and we'll be able to complete this Phase II study shortly.

And if we're able to move this program into Phase III, it's something that actually could also move very quickly. You don't need large outcome studies to measure bleeding. So we're pretty excited about this.

Can you just quickly touch on the bar for bleeding, like what's a meaningful decline in the bleeding rate or any particular bar you're looking for?

So we'll come back at that on that as we get the results. But clearly, we only want to progress a program that's going to have a significant benefit to these patients. So it's not just the numbers of bleeds, but it's also the fact that these patients are anemic.

They often require transfusion. So you also have to think about are you able to reduce the hematological support that these patients require.

Got you. Maybe we just keep going with the pipeline, just the obesity program and your strategy there and when we might see some data.

Yes. So a lot of people are excited about obesity. There's a lot going on. We're hoping to be able to demonstrate that we're able to deliver our siRNAs into adipose tissues. That will be a first for us. So that in itself will be a significant milestone. And when we think about what the opportunities are in obesity, really thinking about beyond incretins. How can you think about better quality weight loss.

And as we think about our strategy, it will be thinking about the monotherapy. It will be thinking about in combination with other siRNAs, we'll be thinking about in combination with incretins as well.

So we're fortunate as Alnylam that we're able to think about how we can progress our pipeline in creative ways to meet the emerging needs of patients with obesity. And again, we'll be getting sort of proof-of-concept data later on this year. So we're eagerly looking forward to that.

Yes. Great. And maybe we keep going with the pipeline. So zilebesiran, maybe just give us a quick background there. And I think you're going to have a webinar later this week.

Yes. No, the webinar is coming up, so I'd encourage you all to tune in and said, look, I think zilebesiran really has the potential to transform how hypertension is treated because hypertension is not just about lowering blood pressure. It's about the durability of lowering blood pressure, that continuous control.

And one of the other issues with patients who are receiving treatment for hypertension is around adherence. They just don't take their tablets. And here, we can conceive of infrequent dosing of subcutaneous [ ilebutiran ] to really maintain continuous control for these patients, restore nighttime dipping, reduce variability.

And we believe that all of this will lead to better outcomes for patients. So it's not just about blood pressure lowering. It's about improving outcomes for patients. So we have a large outcome study ongoing where we hope to be able to demonstrate this over the next few years.

Great. Maybe I can ask on another hot topic, the AI topic. John, you mentioned some ways you're using it in diagnosis, but any other ways across the company are using it to accelerate development or things like that?

Well, we're using AI broadly across the company as many organizations are to improve our efficiency, improve our productivity. Obviously, some of the approaches that John touched on, on the commercial side of our operations. We're also very excited that we signed an agreement with a company called Inceptive Nucleics who are helping us think about how we can combine their frontier models with all the data that we have with respect to sRNAs and actually see whether this could help us accelerate innovation and be able to move our incredibly already productive R&D engine even faster.

Yes. Okay. Great. It looks like we're just about out of time. So why don't we end it there. Yvonne and John, thanks so much. Appreciate your time.

A pleasure. Thank you so much.

All right. Good morning, everyone. Thanks for joining us for our next session. My name is Derek Archila. I'm one of the senior biotech analysts here at Wells. With us today is Alnylam Pharmaceuticals. And from the company, we have John Kennedy, Head of Commercial; as well as Pushkal Garg, the Chief of R&D. So gentlemen, thank you so much for joining us and I look forward to the discussion here.

Thanks for having us.

Excellent. So maybe the first place to start here would be kind of the TTR revenue outlook for 2026. So John, during the quarter, we learned there were some things that maybe were not really reflected in the guidance and you kind of gave us a little bit of a reset. So I guess the question now becomes what's the confidence level in kind of the reset guidance? And ultimately, how should we be thinking about future growth, not only for 2026, but kind of beyond?

Yes. Thank you for that. So maybe I'll just start by characterizing launch, what we see when we look back and then what that means going forward, and we'll talk about the guidance along the way. So first and foremost, we're about 18 months into this launch for cardiomyopathy. So AMVUTTRA was already approved for polyneuropathy, hereditary polyneuropathy. We added cardiomyopathy in March of '25. So we're about 18 months in, and the launch has gone exceptionally well.

Just a single headline. If you think about the last quarter, we passed $1 billion quarter for the TTR franchise. So this is very, very strong. Now when we look back, there are several things that we were really focused on to make sure that this had the fundamentals in place for sustainable growth. And they're there. Generally speaking, the first area of focus for us has been access. That's both provider access, but also payer access and the access is very, very strong, generally unencumbered access to AMVUTTRA, particularly in first line with the majority of patients paying $0 in out-of-pocket cost. That has allowed us to focus on demand.

And now if we look at physician experience and demand, since the launch of the cardiomyopathy indication through the end of last quarter, we had -- we've seen more than 1,700 physicians have a first experience with AMVUTTRA. So there's tremendous uptake, especially in a rapidly growing category where more physicians are coming in. Now what we look for is what is that experience and a great indicator of that experience is if we look at those physicians that have experience, we have north of 50% share of new starts with those physicians.

So in other words, trial results in a favorable experience and preference for AMVUTTRA. So that's all very, very strong and encouraging. And of course, this isn't a category that has grown. It's grown for the last 6, 7 years. It will continue to grow when you think that the majority of patients, unfortunately, are still untreated. So those are all the fundamentals that we're very, very confident in and give us quite a bit of runway for opportunity moving ahead.

Now as it relates to the guidance, one of the things that we talked about was just the learning in terms of the contribution of the AMVUTTRA source of business. So to back up a little bit, there is a first-line segment and the second line. So first line are these newly diagnosed patients that are looking for that very first treatment choice. First line has, from the very beginning, been our strategic area of focus.

We want to establish AMVUTTRA as a first-line choice knowing that, again, the vast majority of patients in this category are untreated, they will come in and seek that first-line treatment choice. So that's -- long term, that's a significant part of the opportunity, and that has gone very well. There's a second component, which is second line.

What we've seen from real-world evidence data sources is that patients treated with stabilizer unfortunately continue to progress. There was one analysis that looked at more than 800 patients treated on stabilizer, mostly tafamidis. And what we saw was that within about a year on average, about half of those patients experienced cardiac worsening.

So these patients continue to progress, and they will be looking for another treatment choice. Now we are the first and only alternate mechanism of action in cardiomyopathy. And so we're a natural option for those patients. So going back to the guidance, what we saw early on the launch is we had many of these high-volume prescribers start using AMVUTTRA, which is a good thing.

And with those higher volume physicians, they had more of these patients that had been treated with a stabilizer for some period of time. And as you can imagine, many of those patients were progressing. So what we saw in the first several quarters of launch is those physicians move more of those patients to AMVUTTRA in the second-line opportunity, and that was a robust part of the opportunity. So early on, it was relatively balanced where our source of business is coming from that first line and the second line.

Now take a step back, if you look at the category at large, this is more of a first-line category. Now part of that is because there hadn't been another option for a long time, but switching behavior is a relatively new behavior. That will take some time to really form and unlock. And so when we look at the category, generally, about 80% of new treatment initiations are first-line treatment initiation. It's the minority, about 20% that are second-line.

So as you can see, when we started, we have more of a balanced contribution across both lines of therapy. But with those higher volume physicians that were earlier adopters, they moved more of those patients to AMVUTTRA. And so what we saw is that second-line inflow has normalized. So there's still robust inflow of second-line starts. It's still an opportunity, but it is normalized so that it's less of a contribution in terms of the AMVUTTRA source of business.

Now the good news is our volume has continued to grow. And so it just means that a greater proportion of our volume is now in first line, which strategically was the priority for us. So the guidance is to reflect this change where there's a normalized volume of second-line inflow. It is different than what we saw in the first several quarters.

And that was a learning for us. And so we had to adjust the guidance to reflect that normalized flow of second-line volume starts. And that's on us in terms of the guidance. But again, just the context is prior to us, there really wasn't a second-line market. And so that was the newest part of this category where we had to observe and just see how that would play out.

Got it. No, that's very helpful. So as we think about, again, first line is where you're seeing the majority of the new starts, kind of how you think about the split between community and centers of excellence for AMVUTTRA usage? And how much does kind of the 340B kind of incentive play a role there?

Yes. For -- what we're looking at for the initiations of AMVUTTRA, what we're seeing is it is still very balanced across the centers of excellence and the community. So just to step back, this is a category that is growing. It's growing very, very rapidly in terms of patient volume, in terms of Rx volume, but also in terms of physicians that are active in the category, meaning they're diagnosing and they're initiating treatment. So there's an expansion of the physician growth.

About half of that growth is coming from these more community centers as opposed to the centers of excellence. So we still have a robust business in the centers of excellence. We continue to see depth of penetration. That's a good thing. But in terms of the growth, we're also seeing quite a bit come from the community. Now again, we're seeing balanced utilization of AMVUTTRA. The reason for that is because AMVUTTRA is very widely accessible.

So I talked about at the beginning, access is a function of both provider and payer. On the provider side, if a community cardiologist chooses to engage in buy-and-bill, that's fine. That is a relatively well tried and easy experience. And by the way, we're not the only ones that are engaged in that space. Think of LEQVIO in the lipid-lowering category. There are more experiences that cardiologists are having engaging in buy-and-bill.

But if there's a physician that says, I don't want to get involved for some reason, that's okay, too, because we've established a very, very broad network of buy-and-bill alternate sites of care, such that about 90% of patients anywhere in the United States, about 90% of patients can receive AMVUTTRA within about 10 miles of their home, whether that's in the physician's office, in a site of care that's part of a large integrated network that the physician is part of or one of these clinics that is often down the street from where the patient lives.

Got it. So going back to kind of the first line. So I guess where do you think you guys can peak out or what's the aspirational share in that first line? And how much of the growth is really about share gains versus stabilizers versus just overall category growth?

Yes. Moving forward, what matters is both share and category growth, both, just to be there. So what we're seeing in terms of first line is very encouraging. So again, within the first couple of quarters in terms of share of new starts, we had surpassed one competitor that launched just before us, and we are challenging the 6 at the time, 6-year incumbent in the category for share of new patient starts.

And so we saw that within the first couple of quarters of launch, and we continue to work towards that ambition today. We've got a tremendous data set. Again, physician experience tends to be favorable and drive greater utilization. And then on top of it, what we haven't talked about is just the dosing experience where we are a quarterly physician-administered dose. That is part of the value proposition of the product, which contributes again to the patient and the physician experience.

So all of that allows us to compete aggressively for first-line choice. Let's also not forget that after CARDIO-TTRansform, presumably, there's one less competitor that we have to contemplate in the future. And then moving forward in terms of category growth, I think it's informative for me to look back before looking forward. So looking back, we have about now 7 years of category experience.

You can look at tafamidis volume as a proxy of category volume for the last several years. And what you see is for years, this was stable and robust growth in excess of about, I think, 40% volume growth year-over-year for the last several years. Looking forward, the majority of these patients continue to be untreated. So I would expect that you will continue to have robust growth in the patient inflow, especially with more voices in the market, driving greater awareness, more suspicion diagnosis. And we will continue to play our part to facilitate that. We can talk about it if helpful, but we have several initiatives, partnerships with others that are focused on driving even greater diagnosis and category growth also.

Got it. So maybe one of the things that post-ESC, post-CARDIO-TTRansform, a lot of us are trying to work out, is there going to be an impact to AMVUTTRA usage? And is there kind of a ceiling in that first line in terms of share? So I guess, like how do you think about the overall value prop for AMVUTTRA relative to stabilizers and kind of points to some of the differentiating data maybe that the doctors are really pulling and being like, hey, this is why I want to prescribe it first line.

Yes. I think first and foremost, in the aftermath of CARDIO-TTRansform, which is a competitor trial, one thing is true: Nothing has changed with regards to our data. So HELIOS-B is a tremendous data set. It has been part of what has driven the initial uptake and demand for AMVUTTRA. And so that continues to be true. What we saw in that was a very robust impact on cardiovascular outcomes, about 40% reduction in all-cause mortality over 4 years.

And by the way, this is on top of aggressive standard of care background treatments. And so that's remarkable in terms of what you expect to see in categories like this or in heart failure or in cardiology categories at large.

That is a really, really remarkable finding. And then on top of it, to have had the impact on functional capacity with this, again, quarterly physician-administered dose, which is not just a convenience thing. I'll go back to what we've seen in this category. We've seen in many categories, daily oral treatments as much as we'd like to believe patients are adherent and persistent. They're not.

What we see is after about a year, about 30% of patients on a daily oral treatment stopped taking their medicine. By the end of the next year, another 30%. So that is -- it's a very real dynamic that we see with daily oral treatment. So again, that's all part of the value proposition. Now what I've talked about is what we saw from the HELIOS-B primary results. But since then, we've also had additional analyses drawing from HELIOS-B, and we have other data generation initiatives that continue in the background.

Other things that we've seen is that AMVUTTRA appears to have very remarkable impact or the potential for impact on cardiac structure and function. And there are multiple ways to look at it, but we have some MRI data that has now not just been presented but published in peer-reviewed journal that showed that there is a very serious signal with the potential of showing an improvement, improvement versus baseline on some parameters of cardiac structure and function.

We also know that this disease affects multiple systems of the body. And what we've seen is that not only are we having an impact on the cardiovascular manifestations, but there are some signals that suggest extra cardiac manifestation impact. So to give you an example, we have a post-hoc safety analysis that suggests that about half of patients or there was a halving of the incidence of GI issues or manifestations. It all suggests that this is a very, very potent drug that is having a tremendous efficacy signal for these patients. So that matters quite a bit for sure.

Understood. I guess we were talking about the second line, smaller part of the AMVUTTRA business. But I guess what are the kind of the pushes and pulls on that business in terms of stabilizer use being used earlier, so longer duration versus maybe less complacency around physicians looking for progression?

Yes. I think there are multiple dynamics at play. For sure, as there are more voices in the market, there's better awareness, better understanding of the disease, we expect that diagnosis will happen more consistently and earlier, and that's a good thing. And in fact, we intend to continue to facilitate that.

But unfortunately, it's not like these patients are at the very earliest stages of manifestation, unfortunately. So these patients are still recognized later than they should. There are many pieces of the data you can look at to get a sense of how the market is behaving, but there is one analysis that was done by the National Amyloidosis Centre in the U.K. that looked at cohorts of patients over time. And it generally showed that, yes, diagnosis is, in fact, happening earlier.

But the majority of these patients are still Stage I, II in terms of NAC staging or just, I'll say, progressed in the disease. So there's still ample opportunity for us to help these patients. What we know from the HELIOS-B data set is the earlier you're intervening with AMVUTTRA, the better. That is clear, and we continue to communicate that. For patients that have started on the stabilizer, we've seen in real-world data sets that, unfortunately, those patients do continue to progress.

They will be looking for something else. And so we are the first and only product approved in cardiomyopathy that is in a different mechanism of action. And so whether it's an add-on or a switch, we are really well positioned for that. And I do think that with increased awareness, there is greater opportunity to identify those patients that could benefit from more aggressive or more intensive treatment options, whether -- again, whether that's a switch or add.

So that's all helpful. In terms of duration of time on treatment, again, the earlier you help patients, it is likely those patients will remain on treatment for longer. I think that's particularly helpful for us because we have quarterly HCP administered dosing. So whether that benefit accrues to the stabilizers, remains to be seen, but I would go back to what we've observed in this category and others, where, again, by the end of the first year, about 30% stopped taking their medicine that repeats again. So ample opportunity.

Understood. So we've talked a lot about the U.S., but maybe you can kind of give us a sense of how AMVUTTRA ramp in ex-U.S. And we had a little bit of lumpiness earlier this year with some pricing resets in some countries, but what should we kind of expect out of that business?

Yes. So for outside the United States, we're launching in several countries. Our goal is to bring AMVUTTRA to as many patients as we can, as fast as we can around the world. One of the things that you've heard us talk about in the earnings is that in Q1, we are expecting a reduction or a decline in the revenue, but then sequentially, that would improve over time. So just to give you a sense for the why.

One of the earlier countries we had launched in was Germany. It's a relatively higher volume country. And when I say higher volume, don't forget that we had approval for AMVUTTRA in the hereditary polyneuropathy before adding cardiomyopathy. Now outside the U.S., the pricing reimbursement system is different from country to country. But generally, and in a country like Germany, we have a negotiated price for cardiomyopathy.

That negotiated price for cardiomyopathy is lower than polyneuropathy. The reason for that is prevalence. Cardiomyopathy is about tenfold greater prevalence than polyneuropathy. And so what that means is the volume -- the legacy volume of polyneuropathy business has a correction as you reset the price for cardiomyopathy.

And so that results in a transition where in the first quarter, you have a reduction in your revenue, but then sequentially, the volume grows past that, and there's ample volume to grow. And so that's kind of the dynamics that we saw in the first quarter. And so what we have said is you saw that in Q1, but we expect quarter-over-quarter improvement in that ex U.S. contribution.

And then in absolute terms, the revenue growth for 2026 outside the U.S. will be very similar to the absolute revenue growth we saw outside the U.S. for 2025. But again, that's just a function of countries launching progressively throughout the course of the year. Many of them will have that kind of transitional adjustment at the beginning of the launch. And then because the cardiomyopathy volume is so much bigger, we'll continue to grow through that.

Got you. And then just a question that we get frequently is around kind of 340B and kind of the potential impact of some future legislation here. So maybe kind of talk through what you guys are thinking about and how things could be mitigated depending on that advances.

Yes. So in terms of the proposed rule, there has been a proposed rule. It remains to be seen what happens, if it happens and in what form. We just went through a comment period. So we haven't seen the conclusion of that. What I do know is that there are many voices that likely participate in the comment period that have some strong feelings about this, particularly on the provider side with regards to reimbursement rates.

So I think it remains to be seen what will play out. What I can tell you is that we have secured broad access for AMVUTTRA across sites of care. And if you look at utilization, we're seeing broad utilization across sites of care. And so we are very focused on maintaining that access, and we expect that there will demand. Again, what actually happens with this proposed rule, I think, remains to be seen.

And if something like that goes through, what happens in terms of provider behavior remains to be seen, but there is quite a bit of optionality on the provider behavior side, whether they participate, whether they go outside of 340B or we have alternate sites of care. So we have a broad network, broad access and broad utilization, again, across sites of care.

Got you. And we were talking earlier at the breakfast in terms of like we've had a lot of new developments with kind of more clarity around tafamidis generic, obviously, partners to CARDIO-TTRansform and all that stuff. So I guess, how do you kind of envision that both on kind of price mix and volume mix for AMVUTTRA in the future?

Yes. So what we're referring to is there have been a couple of events in the marketplace that I think lend a little bit more certainty. So number one, we saw that the tafamidis loss of exclusivity according to Pfizer, we now expect later in 2031. That does 2 things, in my opinion. Number one, it removes some of this pricing risk or pricing pressure in the midterm. And number two, it just gives us more of this time to continue to compete for first-line preference. So a net good thing.

The second event is CARDIO-TTRansform from Ionis and AstraZeneca, which unfortunately was a failed study. Again, I think that has 2 implications. One is that likely also removes some potential for pricing pressure in that midterm. That's a net good thing for us. And then presumably removes a competitor from the mix. So a net good thing on share. So I think if you were to just look at where we are today in terms of what we're capturing for new patient starts, you take more certainty in the midterm in terms of the pricing dynamics in a category that continues to grow, I think there's quite a bit of reason for optimism here.

Yes. I mean, I guess in terms of generic tafamidis, how much do you think that is either a headwind neutral or tailwind for the AMVUTTRA business? And kind of in light of CARDIO-Transform, kind of the push to potentially use combo. Is that still on the table? Or do you think that's kind of -- it will be more modest than maybe the original kind of assumptions?

One of the things that we've said really since launch is that until you have loss of exclusivity for tafamidis, we expected this category to be more of a monotherapy market. And generally, that's what we see. So we do see some combination treatment. There are physicians and there are also patients who are looking for the most intensive treatment regimen that they can have, just knowing that this is functional capacity at stake, not to mention, obviously, morbidity and mortality.

And so we do see combination therapy, but the majority of this market has been monotherapy. I can put that into context for you. So at the beginning, we were talking about this first line, second line. Most combination treatment tends to be in that second line. So again, it's about 80% of new starts in the category first line, then you have about 20% that are second line, some portion of that is combo. So that gives you kind of a sense. I expect that you'll continue to see some of that.

The reason for it is HELIOS-B. It's a tremendous study. And what that showed is that you had consistency of treatment effect with AMVUTTRA with or without background tafamidis. That's in the label. It's in the data set. So there's substantiation for those physicians and/or patients that pursue that. So I think it will persist. But the real unlocking event would likely be tafamidis generic. By that point, though, we expect that we'll have nucresiran. So another data set with another tremendous asset with a different dosing frequency that I think would make it a wonderful foundational treatment option.

Incredible segue. So maybe we can talk to TRITON with Pushkal here. So coming out of ESC and kind of CARDIO-TTRansform a lot of questions around kind of TRITON and what could be done around that trial or what needs to potentially be done to that trial, if anything, to make sure and ensure it's successful. So maybe just talk about kind of the key learnings from kind of the more detailed data set at ESC. What else you might want to know prior to making any sort of modifications that would help the probability of success for vutrisiran?

Yes. Thanks, Derek. So look, I think the ESC presentations around CARDIO-TTRansform were quite informative, right? I think a number of things that we think really point, unfortunately, to why the trial didn't succeed as anticipated. I think, one, probably the biggest surprise was the knockdown levels, right, that they saw 70% knockdown at a mean level with vutrisiran -- I mean, with vutrisiran, we're at 81%, 87% depending on mean and median.

So pretty sizable difference in terms of that knockdown. And I think you saw that really play out even if you look across the data, you saw benefits of that drug in monotherapy. And even when you look at across the endpoints, you saw some benefits in combination across a variety of endpoints, not the top line one, but a variety of other endpoints, suggesting there was really an example of basically a dose response effect, less knockdown, less effect, more knockdown, greater effect compared to HELIOS-B in the AMVUTTRA data set.

I think the second thing was patient selection. I think we've seen coming out of HELIOS-B as a learning and actually even earlier studies that with the silencing mechanism, when you're turning off production, you actually really want to get in upstream, you want to get in before patients accumulate a lot of irreversible damage to their heart, right? That's harder to change if you're turning off the spigot and production. It's not to say you can't change it. It just may take longer beyond what you can do in a short-term clinical trial.

And so we saw there again that the greatest benefits of that drug really occurred in the earliest patients. And the most noteworthy example of that was if you look at the NAC Stage 1, which is largely defined by BNP under 3000, we know BNP is probably the strongest predictive factor in heart failure. In 900 patients, they actually would have seen a stat sig effect. And that's including all the patients who are on combo, right, which was 60% on the onset and another pretty much 20%, 25% who dropped in.

And so in a 140-week trial in those earlier patient population, that's where they would have seen a stat sig effect. And then the third was around endpoint selection. And there, again, I think they focused on CV mortality and CV events. We've tended to focus on all-cause mortality because this is a systemic disease, and we think that captures the totality of what happens to a patient tends to be more sensitive.

So I think those were the kind of the key learnings coming out of CARDIO-TTRansform that really tended to point to why the study didn't succeed. And really said, look, not all silencers are created equal and ASO is different from an RNAi. But importantly, that as we designed TRITON-CM, these were actually learnings that we carried forward from HELIOS-B and we had incorporated.

So a, we've got a molecule with the deepest knockdown ever studied, nucresiran, median knockdown 95% gets everybody more or less to deep levels of knockdown. Two, we focused on the earlier patient population. We have compared to the eplontersen study, real caps on BNP, not only at the higher level, but even at intermediate levels within the study. And then we focused on endpoints that we think are most sensitive. And then lastly, we have an event-driven study as opposed to a fixed time study. So we think there's a lot of tailwinds.

And frankly, what we learned corroborated a lot of the design choices we made for TRITON-CM. You'll recall that we recently upsized the study early in the year from 1,250 to 1,750, recognizing as we had intended that we were getting an earlier patient population. This just increased the probability of getting more events, accruing events earlier. So -- so we feel like we're in a good position. But look, we just got the data this last weekend. Our teams are going through it. There was a lot there, and we're doing a lot of simulation work, et cetera, to think about if there's anything more that we need to do in terms of optimizing TRITON-CM. It's obviously a very important study.

Those probably fall into 2 main categories. One could be things that relate to enrollment, whether we enrich or further accrue more patients, et cetera, in certain segments. That's something if we decide to do, we have to do this year. And then the other would be something that could be more in the analytics category, endpoints, et cetera, like we did with HELIOS-B, that would happen further down the line after we've kind of accrued the patients and seen what their trajectory is over time.

I guess what's your confidence level based on kind of what you've already talked about in terms of stratifying those patients and BNP levels that these patients would be kind of earlier stage relative to CARDIO-TTRansform?

No, I think we feel quite confident that the way we've designed the study and what we're accruing, these are going to be milder patients or earlier patients than that in CARDIO-TTRansform. We already are -- and we even did this in HELIOS-B, right? If you compare the eplontersen study to HELIOS-B based on the way that we designed it and the caps we put in place, there were twice as many NYHA Class III patients in CARDIO-TTRansform.

There were twice as many NAC Stage II patients in CARDIO-TTRansform. The median BNP level was higher. So there was a number of things that really pushed them a little bit towards a more advanced population that we had purposely avoided in HELIOS-B, and we've further exploited those learnings in the way that we've designed TRITON.

Got it. And I think you alluded to this, but we also talked about this morning, but you don't really view this as like monotherapy versus combo. It's more about kind of the advanced patient population. So I guess if you were to look at the mix and make any changes, would that mean more of like changing those caps that you talked about? Or would it be more about looking for mono? Or what would be kind of the mix that you'd want to?

Yes. What I would say is there's a number of different things we can pull. Again, we want to develop the medicine ultimately to have a label that's going to be most supportive of what John does in terms of getting this medicine out to patients, right, and to the broadest mix of patients that we possibly can and where it's going to have the greatest benefit-risk for patients. As we said, we always think this drug should be used early as first line. That's been our objective with AMVUTTRA and with nucresiran, we're seeking a broad label, both as mono and combo.

There's a number of levers you can kind of pull. But again, we want to support the label that we're trying to get that we think is going to help patients. Mono/combo has been kind of an incessant focus. I get why based on what the top line release is, but I think it misses the forest for the trees a little bit that there are multiple other important levers that really help.

And that's, again, proper patient selection, high levels of knockdown. We put out some clinical trial simulation work that we've done that really showed that with high levels of knockdown, we expect to see benefit both as mono and as combo, which is what the biology would suggest very strongly and existing clinical trial data supports. So that's where we're focused.

So is it fair to say, regardless if you make changes this year to kind of like enrollment criteria or SAP design, which we find out later that you're going to basically -- you're not going to sacrifice a broad label, like that's like first and foremost.

We think it is important as we kind of think about where the field is going and how patient care is going to evolve. And so we're committed to showing the benefit of this therapy in both settings.

Very helpful. So maybe with the last couple of minutes here, it would be great to kind of talk beyond TTR and maybe talk about some of the pipeline. So near term, you're going to talk about some Huntington's disease data from one of the programs. I think that's coming out late October. So maybe talk about that and give us a little bit of context of like what would constitute a good update there?

Yes. I mean, look, I don't think we have to do a lot of educating about Huntington's disease, really incredibly devastating disease with no approved therapies been likened to having Parkinson's, Alzheimer's and ALS all at the same time. And we're excited about the molecule we brought forward.

It's an siRNA that's now built upon the platform that we've developed that really allows us to usually dose about twice a year. It's intrathecal dosing that actually has deep knockdown and broad biodistribution in the brain. And that's really important in this disease where you're really trying to get into the deeper brain structures like the caudate nucleus. We also have a unique targeting approach.

And so we're not only targeting mutant huntingtin, which has been tried before, but we're specifically targeting a segment of the gene that includes something called exon 1 that codes for a protein called HTT1a. And we know that, that small fragment is really critical in terms of the biology of this disease in terms of nucleating the tangles and that happen in Huntington's disease. And so very exciting approach.

I'll note that uniQure actually where they've shown some benefits compared to natural history is the one other approach that actually specifically targets exon 1. So that's in a Phase I study. We'll have some data out in October at EHDN -- and what we'll be looking for there is, a, what's the safety and tolerability; b, can we get to deep levels of knockdown. This will be single-dose data. I'll remind you that previously, Roche and Ionis had brought forward tominersen, which had about a 25% knockdown and had some tolerability issues in terms of NfL increases, ventricular enlargement, et cetera.

We think that's largely ASO related, but it will be important that we can hopefully get a well-tolerated level of deeper knockdown than that. And so we'd love to see 50% or greater. And so that's -- and then I think if we can get to that, then we think we'll be off -- be able to move this program quite rapidly. It's also encouraging to see that there may be some regulatory flexibility in the Huntington space as well. So all of that will stay tuned for, but we're excited.

Got you. And then maybe just quickly on 6400. So looking at development in a couple of bleeding disorders. So what should we kind of expect from the data later this year? And I guess, maybe sketch out for us a little bit about the opportunity in von Willebrand.

Yes. So ALN-6400 targets a protein called plasminogen, which is a liver-derived protein that's involved in fibrinolysis or clot breakdown. By silencing it, we can stabilize clots. So think of it like a Band-Aid. Beauty of the Band-Aid is it can be used across a variety of bleeding disorders. And two, we believe based on very strong genetic evidence from patients with plasminogen deficiency that it will not be associated with thrombosis. A lot of times, we worry about drugs that help with bleeding that they promote thrombosis. Here, we think we can dissociate those 2 phenomenons.

So very interesting program. We'll have later this year some Phase I data which will have evidence of knockdown and safety. And then second -- and then we'll also have data later this year in our first indication, which is hereditary hemorrhagic telangiectasia, really devastating disease, affects about 70,000 patients in the United States. They are affected by telangiectasia, which is small arteriovenous malformations at the capillary level. They can affect the gut, really impact the nasal mucosa.

So these patients can have incessant bleeding hours at a time, several days out of the week. Half these patients are anemic, require blood transfusions. And so our hope is that we can actually start to reduce the bleeding in a prophylactic way for these patients, giving it several times a year to prevent bleeding. Our second -- and so we'll have data in HHT later this year. And then next year, we expect to bring forward -- we're bringing forward data in Von Willebrand's disease, which is more of a platelet type of disorder, again, sort of highlight the impact of this drug across a variety of bleeding disorders.

Got it. Well, I think we'll leave it there. Gentlemen, thank you so much for the conversation.

Thanks, Derek.

Thank you.

Thank you for standing by. My name is Sprila and I will be your conference operator today. At this time, I would like to welcome everyone to the Alnylam Pharmaceuticals Q2 Earnings Conference Call. [Operator Instructions]

I would now like to turn the conference over to the company. You may begin.

Good morning. I'm Josh Brodsky, Vice President of Investor Relations Island. With me today are Yvonne Greenstreet, Chief Executive Officer; Jeff Poulton, Chief Financial Author; Tolga Tanguler, Chief Commercial Officer; and Pushkal Garg, Chief Research and Development Officer. For those of you participating in a conference call, the accompanying slides can be accessed by going to the Events section of the Investors page of our website investors.alnylam.com/events.

During today's call, as outlined on Slide 2, Yvonne will offer introductory remarks and provide some general context, Jeff will review our financials and guidance, Tolga will provide an update on our global commercial progress, and Pushkal will discuss our TTR franchise, our confidence in TRITON-CM and upcoming pipeline milestones before we open the call for your questions.

I would like to remind you that this call will contain remarks concerning Alnylam's future expectations, plans and prospects, which constitute forward-looking statements for the purposes of the safe harbor provision. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important risks and uncertainties, including those discussed under the heading Risk Factors in our most recent periodic report available on our website and on file with the SEC. We disclaim any obligation to update such statements.

And with that, I'll now turn the call over to Yvonne. Yvonne?

Thanks, Josh, and thank you, everyone, for joining the call today. During the second quarter, we demonstrated strong performance across all aspects of the business. Notably, it marks the first time and virtual revenues exceeded $1 billion in a single quarter, representing an annual run rate of more than $4 billion, just 15 months into the ATTR cardiomyopathy launch, a testament to both the commercial opportunity and Alnylam's execution. As I reflect on the launch, several insights reinforce our confidence in the durability of AMVUTRA growth over the years ahead.

First, this has been an impressive launch by industry benchmarks when looking across market share, access and revenue generation. Second, the fundamentals of our TTR business are strong, and they include a virtuous compelling clinical profile and label the strong access that we established at launch, which continues to improve and our robust and expanding provider network. Third, Patient demand for AMVUTRA continues to grow robustly, particularly in the first-line setting, which has been our focus as we aspire to market leadership. Given AMVUTRA's clinical differentiation and desirability as a foundational therapy for newly diagnosed patients. Tolga will discuss how we are now further investing in broadening our AMVUTRA prescriber base and supporting overall category growth, the latter of which have been accelerating.

Finally, our geographic expansion strategy continues to gain momentum. And today, we are pleased to announce our collaboration with Ben through which they will have exclusive commercialization and distribution rights for AMVUTRA in Mainland China account, subject to AMVUTRA receiving marketing authorization. Together with B1, we aim to help advance awareness and support diagnosis of ATTR amyloidosis and if approved, bring the strength of TTR silencing with AMVUTRA to patients in these underserved regions.

As Jeff will describe shortly, we are lowering our 2026 revenue guidance today to reflect a better understanding with hindsight of the first few quarters of our U.S. launch. Specifically, that early second-line demand growth in 2025 benefited significantly from pent-up demand for a new therapy that has since normalized. With that learning, and our strong 2026 second quarter performance. Our confidence in AMVUTRA's growth trajectory has never been stronger. First-line new patient starts and now responsible for about 80% factory growth in this accelerating market. And we believe we're making great progress in establishing AMVUTRA as a foundational therapy.

I will now turn to recent developments in the competitive landscape, specifically the negative outcome of the CARDIO-TTRansform study of eplontersen. We recognize investor interest in understanding potential implications of that failure for our probability of success and TRITON-CM, our Phase III cardiovascular outcomes trial of nucrisiran. Let me be clear. This outcome does not alter our conviction in the TRITON-CM study. And as Pushkal will share in greater detail, our strong confidence is grounded in the established clinical evidence for RNAi therapeutics in TTR and a track record of our clinical organization. At the same time, we have a variety of options at our disposal to potentially adapt the study and position it for optimal success. We will carefully review the full eplontersen data set when it becomes available. and adapt our study plan, if appropriate.

We have successfully navigated complex TTR development before and believe we are exceptionally well positioned to do so again with nucresiran. Additionally, in the quarter, we are pleased to announce the [indiscernible] strategic AI corporations across the enterprise, including with inceptive to expand the next frontier in the discovery of RNAi therapeutics. And the collaboration, we are pleased to announce today with a large health care system in California aimed at support early identification of ATTR cardiomyopathy in routine care. This builds on our previously announced partnerships with Viz.ai and Komodo Health.

Together, this cohesive AI strategy from discovery and evidence generation to disease identification, clinical practice and commercial execution reflects our long-term conviction that AR fundamentally reshape how medicines are discovered, developed and ultimately delivered to patients. Finally, we also continue to progress our deep line of investigational medicines, initiating Phase II trial of ALN-6400 in Von Willebrand's disease and a Phase II trial of mivelsiran in down syndrome associated Alzheimer's disease, and we look forward to a series of clinical data readouts in the back half of this year, including presentation of initial Phase I results of ALN-HTT02 in patients with Huntington's disease at EHDN in October. All of this progress builds our momentum towards accelerating innovation, scaling our impact as we look to deliver our 5-year vision on line in 2030.

And our strategy is anchored around 3 pillars. The first pillar is to establish global leadership in TTR while continuing to build a doable franchise. The momentum we have built with ATTR cardiomyopathy dates along with recent developments in the competitive landscape, including the CARDIO-TTRansform Phase III top line results and in laying expected U.S. generic entry for tafamidis until mid-2031, further reinforce the strength of our position and the significant opportunity ahead to establish AMVUTRA as a foundational therapy and realize our TTR leadership ambitions.

The second pillar is growing through sustainable innovation where we aim to deliver therapy but not only slow the progression of disease, could prevent, halt or reverse it. And the third pillar is scaling with discipline and agility to enable durable, profitable growth. Alnylam 2030 represents our commitment to becoming the leading science driven fully integrated global biopharmaceutical company and to maximize the full potential of RNA therapeutics for patients.

With that, let me now turn the call over to Jeff for a review of our second quarter financial results and 2026 guidance. Jeff?

Thanks, Yvonne, and good morning, everyone. This morning, I'll be presenting the summary of Alnylam's second quarter 2026 financial results and discussing updates to our full year guidance. Let's begin with a summary of our P&L results for the second quarter. Total net product revenues were approximately $1.2 billion, representing 74% growth versus Q2 last year, driven by the continued uptake of AMVUTRA and ATTR cardiomyopathy.

Second quarter of 2026 marks the first time we achieved more than $1 billion of TTR revenue. These results reflect a substantial improvement in quarter-on-quarter growth compared with growth in Q1 this year consistent with the phasing expectations we discussed on our year-end and Q1 earnings calls earlier this year. Tolga will share more details on our TTR performance in the quarter. In Q2, collaboration revenue was $47 million or a 23% decrease compared with the same period last year due to lower revenue recognized from our Regeneron collaboration, partially offset by increased revenue from our Roche collaboration, driven by higher reimbursable development activities related to the ZENITH Phase III clinical trial of zilebesiran.

Royalty revenue for the second quarter increased 79% to $72 million, driven by higher LEQVIO sales by Novartis. Gross margin on product sales was 75% or 4% lower than Q2 last year, the decrease in margin was primarily driven by increased royalties on AMVUTRA as higher revenues in 2026 resulted in an increase in the average royalty rate payable to Sanofi. Our non-GAAP R&D expenses of $377 million increased 38% compared to last year, primarily driven by costs associated with our 3 ongoing Phase III clinical studies including the ZENITH Phase III cardiovascular outcomes trial for zilebesiran in the TRITON-CM and PN studies for nucrisiran.

Beyond the pivotal studies, we also continue to increase investment to support important programs for bleeding disorders Huntington's disease and CAA. Non-GAAP SG&A expenses of $297 million increased 14% compared to last year driven primarily by investments in support of the AMVUTRA ATTR cardiomyopathy launch in the U.S. and in key international markets. We achieved non-GAAP operating income of $318 million more than triple the amount we achieved last year, driven primarily by the strong top line results they have previously highlighted. Finally, we ended the second quarter with cash, cash equivalents and marketable securities of $3.3 billion compared with $2.9 billion as of year-end 2025. The primary driver of the increase in cash year-to-date is our strong operating performance.

Now turning to our full year 2026 guidance. As Yvonne noted, we are revising our total net product revenue guidance to $4.7 billion to $5.1 billion, driven fully by an update of our TTR revenue guidance to $4.2 billion to $4.5 billion, representing a $200 million reduction from our original TTR guidance at the midpoint and still reflects a robust 75% growth year-over-year. Guiding the market's expectations appropriately is important, and we didn't get it right with our original guidance. We own that. Revised guidance we are sharing today reflect a better understanding of the evolution of second-line demand as our launch has progressed.

Let me provide some additional color on the basis for this revision. Overall, the AMVUTRA cardiomyopathy launch continues to perform ahead of analogs. And importantly, we are pleased with uptake in the first-line portion of the market which has been and remains the primary focus of our commercial efforts given the importance of this segment to driving long-term growth. When AMVUTRA was launched April 2025, the compelling HELIOS-B data and our team's success in establishing access enabled physicians to rapidly transition existing patients who are progressing on stabilizers on AMVUTRA. As a result, second-line demand volumes remained consistently robust throughout 2025, and which informed our original 2026 guidance. However, as the launch progressed into 2026 and with the benefit of hindsight, it is now clear that a green understood proportion of early second line volume growth was driven by pent-up demand from patients who are waiting for a new treatment option.

Consistent with the trend we highlighted in our Q1 2026 earnings call, growth in second line volumes began to moderate in early 2026 to what we now recognize as a normalized level. This normalization of second-line demand is the driver of the $200 million reduction in TTR guidance that we are announcing today. Tolga will share more perspective in just a few moments on our confidence in future TTR growth, which is grounded in 3 key elements: the strength of our current market fundamentals, positive impact we expect from new investments we're making based on early launch learnings and lastly, the favorable competitive developments that Yvonne mentioned in her opening remarks.

Now back to update on our guidance. We are also updating our guidance for collaboration and royalty revenues to a revised range of $575 million to $625 million, representing a $150 million increase at the midpoint of the range driven primarily by strong performance of LEQVIO and the resulting royalties from Novartis as well as higher cost reimbursement from Roche favorably impacting collaboration revenue driven by the pace of enrollment in our ZENITH Phase III study with zilebesiran. The remainder of our non-GAAP financial guidance remains unchanged.

Let me now turn it over to Tolga to provide more color on our commercial performance in the second quarter. Tolga?

Thanks, Jeff, and good morning. I'm pleased to share our continued progress in bringing Alnylam's therapies to patients globally. AMVUTRA is delivering a category-defining ATTR-CM launch and is on track towards delivering on our Alnylam 2030 ambitions. As Yvonne and Jeff mentioned, we have gained valuable insights as the launch has progressed. These learnings have sharpened our understanding of demand dynamics, while also reinforcing our confidence in the fundamental drivers of sustainable growth. .

Overall, we remain highly confident in our path to achieving TTR leadership. The momentum of the business, coupled with an increasingly favorable competitive landscape reinforce our conviction in achieving our long-term ambitions. Q2 marked another quarter of strong commercial execution and growth. Specifically, we delivered $1.17 billion in combined net product revenues, up 74% year-over-year and 13% over Q1 2026. In just 5 quarters since our CM launch, we have generated over $4 billion in total revenue, reflecting both a strong base and a clear growth trajectory. Our rare disease portfolio also continues to deliver meaningful impact for patients and consistent performance for our business. In Q2, we generated $142 million in rare disease net revenue, up 11% year-over-year.

Turning to our TTR franchise. Global TTR net revenues reached $1.03 billion in the second quarter, increasing 13% versus Q1 at 89% year-over-year, reflecting the continued strength of the launch and the robust execution of our global teams. In the U.S., TTR revenues increased 15% versus Q1 and 114% year-over-year, reflecting robust underlying demand with reported revenue partially held back by changes in inventory days on hand during Q2. Access remained broad, pull-through was strong and adherence continue to exceed 90%.

Outside the U.S., TTR revenues increased 7% versus Q1 and 31% year-over-year. Continued ATTR-CM uptake in Japan, the U.K. and Germany, along with strong polyneuropathy performance across our international markets drove Q2 growth despite pricing headwinds related to ongoing CM matches in several countries. Double clicking on our Q2 TTR performance in the U.S. Underlying demand was exceptionally strong, increasing by $129 million in the quarter, more than doubling the demand growth achieving in Q1. A portion of that demand was offset by inventory dynamics, which reduced reported growth by $21 million and to a lesser extent by the continued and anticipated modest reduction in net price.

As a reminder, our Q1 U.S. TTR growth was more modest and was impacted by several sea phasing dynamics, and we are, therefore, pleased by the robust reacceleration demand in Q2 and the continued strength of the business. Our ultra differentiated clinical profile underpins our confidence in the long-term growth opportunity. We believe that ultra stands apart as a first-line choice on attributes that matter physicians and patients. It is the first and only product approved in the U.S. for both ATTR-CM and hereditary ATTR PN. It works upstream at the source, delivering rapid, deep and sustained knockdown of the disease-causing protein. In the pivotal HELIOS-B study, AMVUTRA met 10 out of 10 endpoints and demonstrated robust treatment effects in the primary endpoint of all-cause mortality and recurrent CV events and secondary endpoints of function capacity and health-related quality of life. Across all of these end points consistent treatment effect with or without background stabilizers were observed, combined with the convenience of once quarterly health care provided administration and real-world data that is greater than 90% adherence, we believe AMVUTRA is uniquely positioned to address the needs of growing ATTR-CM patient population.

The first 5 quarters of launch have provided valuable insights that are informing where we increase investment and how we position the business for its next phase of growth. During the initial quarters following approval, many of our high-volume early adopters transitioned a substantial number of stabilizer treated progress in patients to AMVUTRA, while those transitions continue, we are now seeing that portion of demand volume growth normalized towards the more sustainable underlying rate, and we continue to capture leadership share of second-line starts. Today, approximately 80% of new treatment initiations are first-line starts. Establishing AMVUTRA as first-line treatment choice has been our priority since launch, and we continue to strengthen our competitive position. What's more? While our strategy has never dependent on competitive outcomes, 2 favorable developments in the external landscape have cleared a path for us to be even more competitive in the first-line setting.

First, we now anticipate tafamidis U.S. loss of exclusivity in 2031. AMVUTRA is already challenging the 7-year incumbent for leadership share of new patient starts, and we see a significant opportunity to continue strengthening that position years ahead of generalization of the stabilizer class. Second, based on the CARDIO-TTRansform study top line results, we now anticipate one fewer branded ATTR-CM competitor in both the first line and stabilizer progressive segments. Finally, category growth continues to accelerate at our competitive first-line share, coupled with this clear competitive path to greater first-line penetration aligns well with where we see the largest opportunity. With an estimated 80% of patients still untreated and additional physicians and health systems initiating treatment of ATTR we expect the robust growth in first-line starts to continue. And we're helping to drive that category growth. More specifically, we're accelerating our investments in diagnosis enabling initiatives, investments to identify patients earlier to expand the treatable population and ultimately, to improve patient outcomes.

Taken together, these insights provide great confidence in our ability to expand leadership across both ATTR-CM and ATTR PN and delivered on our 2030 ambitions of TTR leadership and a 25% revenue CAGR during the period. As we shared today, our differentiated profile has translated into exceptional launch momentum and that experience has sharpened our understanding of what will drive the next phase of growth. First, after 5 quarters in the market, Auto's compelling profile and our focused efforts have driven broad coverage and efficient patient access with no meaningful reimbursement headwinds.

We believe this strong access foundation will continue to support physician confidence and patient adoption and as we expand the franchise. Second, we continue to deepen adoption among physicians who have already incorporated AMVUTRA into their practice. Among prescribers using our AMVUTRA. It now represents more than 50% of new patient starts, underscoring the strong physician preference that develops with experience. And from ATTR-CM launch through the end of Q2 we have added over 1,700 new prescribers. Third, and perhaps most importantly, we have significant opportunity to expand the breadth of prescribers who have experience with AMVUTRA, which we estimated about 1/3 of the growing pool of TTR prescribers. While we know that experience drives preference. There are many more physicians, including many who are new to the category, who have not yet prescribed AMVUTRA.

To capture that opportunity, we are intensifying our focus and increasing our investment in customer-facing activities to expand the breadth of prescribing. We are already seeing early progress around these efforts with accelerated growth in new AMVUTRA prescribers during the second quarter. We believe we are in the early stages of that expansion opportunity. While we're still in the -- while we're still early in the commercialization journey, we believe AMVUTRA is well positioned to capture the significant opportunity ahead as we bring this differentiated therapy to more patients living with ATTR-CM.

With that, I will now turn it over to Pushkal.

Thank you, Tolga, and good morning, everyone. As Tolga just highlighted, we believe AMVUTRA has a remarkable clinical profile that supports it being the first line treatment of choice for patients with ATTR cardiomyopathy. These key attributes are highlighted here with data from the landmark HELIOS-B screen. First and foremost, we've seen substantial benefits with garden proving clinical outcomes, both all-cause mortality and cardiovascular events with reductions of nearly 40% over 48 months across these 2 endpoints.

Second, the treatment effects are largest when we intervene early. You can see that in the forest plot on the bottom left where patients with lower BNP, greater walking ability and younger age have had even greater reductions in the composite endpoint 47%, 42% and 45%, respectively. And importantly, in data recently presented at ESC Heart failure and shown on the lower right quadrant, we see that the treatment effect is preserved, irrespective of background medications in TTR stabilizers. These attributes, along with the quarterly dosing that supports adherence in our view, represents an ideal profile for first-line agent for patients with ATTR cardiomyopathy.

Now the strength of these HELIOS-B results, along with our many learnings from our deep experience in TTR amyloidosis provide us with stance conviction in the value of nucresiran, our next-generation investigational RNAi TTR silencer, which we believe has the potential for even greater improved efficacy by a greater knockdown over 95% with just 2 doses per year. As you're aware, we continue to advance nucresiran in the TRITON Phase III program. TRITON-CM is a randomized double-blind, event-driven out study of nucresiran versus placebo. We announced last quarter that we utilized a prespecified option in our product while expanding enrollment by about -- by approximately 500 patients to 1,715 total, further mitigating the potential risk of low event rates while maintaining or potentially even accelerating time lines for this important study.

Now given recent competitor data and given that many patients in TRITON-CM will be on a background stabilizer, we understand that there have been many questions raised about the feasibility of delivering positive results from this clinical trial. While we still have more to learn about the eplontersen results, we believe they're likely attributable to a combination of molecule and study-specific issues. And as we compare what we know about nucresiran with what's been reported about eplontersen, I want to assure you that we remain highly confident in nucresiran and TRITON-CM.

I'll explain more in a moment, but first, let me share what we'll be looking for in the upcoming data presentations of the CARDIO-TTRansform results to better understand the reasons why the study did not meet its primary endpoint. First, we'll be interested to learn more about the population and baseline characteristics of the CARDIO-TTRansform study, particularly in the 2 key subgroups of monotherapy and in the patients on background stabilizers. As I noted, in HELIOS-B, we saw the treatment effects with AMVUTRA were greatest in early patients. And so a drug signal may be obscured if many advanced patients were enrolled. We already know from published data that the cardio transform study enrolled 17% NYHA Class III patients, nearly double that in HELIOS-B. Patients with higher NAC stage in patients with higher BNPs.

Importantly, as I'll explain further in a moment, we believe deep rapid knockdown of TTR is critical to improving outcomes in ATTR cardiomyopathy. Graphs in the primary manuscript for the eplontersen-PN study indicated it took longer to get to peak knockdown than AMVUTRA, but the depth and variability of knockdown are also important. So we'll be looking for those details. Safety will be given what we know about ASOs in the past and the frailty of the ATTR cardiomyopathy population. The patients stay on drug and were there any competing risks that impact the study outcomes. We also want to look at study execution and completeness of follow-up.

And finally, we'll want to take a much deeper look at the outcomes data. For example, how do the individual components are primary endpoint, CV mortality and CV events look. And what about all-cause mortality, which is part of our primary endpoint? How did these accrue over time and do the results vary in particular subgroups, particularly by disease severity? Bottom line is there are a lot of details, not yet known about failure of CARDIO-TTRansform. However, we are in an ideal position to learn from it, with enrollment ongoing and a projected launch for nucresiran in 2030 in for ATTR cardiomyopathy. We have plenty of time to digest this information, thoroughly consider our options and implement appropriate changes to TRITON-CM, assuming any are even warranted.

Let me turn now to why we remain confident in TRITON-CM following the CARDIO-TTRansform top line release. The reasons come down to 3 key factors: the specific attributes of our molecule and nucresiran, key design elements of the TRITON-CM study and the track record of our team here at Alnylam. Starting with the molecule. First, RNAi therapeutics are fundamentally different than antisense oligonucleotides. In our hands, our NII has been able to deliver rapid, deep and durable TTR knockdown, which we believe has implications on treating the course of disease. There are now several recent examples of SOs and RNAi silencing the same genetic target with very different profiles. We've also seen that the safety profiles of these approaches differ as well.

Second, nucresiran's depth of TTR knockdown is expected to be best in mass based on preliminary Phase I results showing over 95% TTR knockdown with much tighter interpatient variability. I'll explain why we believe that will result in strong efficacy in a moment. And finally, we have data from 2 prior studies, evaluating RNAi in ATTR cardiopathy patients, APOLLO-B and HELIOS-B both of which generated get us supporting a combination benefit. You've seen the HELIOS-B data in label, which shows a clear benefit of RNAi-mediated TTR silencing in a population that included heavy stabilizer use and consistent effects in combination in monotherapy. But as I'll show you in a moment, we saw the same effect with patisiran as well.

Moving to the study. TRITON-CM, now with 1,750 patients will be the largest study conducted in ATTR-CM, which will allow us to accrue more outcome events. And further to that point, we designed TRITON-CM as an event-driven study. Given the evolving treatment landscape, patients with somewhat milder disease on baseline on average and other dynamics we determined that a time-based primary endpoint was not ideal. Instead, we'll continue the study until we have enough endpoint events to ensure sufficient study power. Third, we've used our insights to define entry criteria that enrich for patients were most likely to benefit based on our prior learnings. And finally, we have an outstanding experienced team here at Alnylam. We've been focused on TTR drug development for well over 15 years, delivering 2 approved products, we've amassed tremendous experience across study design, execution and analysis to maximize the probability of success of a trial in this area. Part of this experience in history of conducting TTR trials is our vast database of deep patient level insights that we can leverage to optimize study design and conduct.

And to that last point, we have a track record of meticulous execution to ensure study success. This was more recently exemplified by how we optimize the endpoint structure and analytic plan for HELIOS-B to deliver remarkable results, resulting in a strong label that Tolga highlighted earlier. Before I move on, I'd like to underscore a few of the points I just made by sharing some clinical data that support the additive benefits of RNAi media silencing on top of a stabilizer. As you'll recall, the HELIOS-B study demonstrated an approximately 41% reduction in the risk of all causality up to 42 months when AMVUTRA was given to patients on a stabilized or at baseline, highlighting both the residual unmet need in these stabilizer treated patients as well as the additive benefit of vutrisiran.

But what you may not know is that we saw a nearly identical effect in APOLLO-B. As shown here, with just 24 months of follow-up in a comparable population of that study, we saw an estimated 44% reduction in all-cause mortality. Hence, we have data from 2 different molecules in 2 different studies showing comparable improvements in outcomes, which provided the strongest evidence of a combo effect. We believe these clinical data results from the knock-down profile of these 2 medicines. There are many ways to look at TTR knockdown, but what we believe matters is the speed and depth of buck down and particularly getting as many patients as possible to deep knockdown. Here, we show TTR knockdown from our polyneuropathy studies, which had the richest sampling of TTR levels. Both show median knockdown of approximately 90% of study state.

Now we don't know exactly what level of knockdown is critical for efficacy in cardiomyopathy but we have robust data in hereditary ATTR, where we have more sensitive endpoints that suggest on a population basis, achieving 80% knockdown or greater is associated with halting of polyneuropathy. And based on our depth, speed and variability of knockdown, the large majority of patients, about 82% to 84% of vutrisiran treated patients reach that threshold at steady state. So how does this compare to other molecules? Here, we plotted the same data as on the prior slide for vutrisiran, now shown as bar graphs. You see 91% median knockdown with about 82% of patients achieving that 80% threshold of deep knockdown.

So how does that compare to the data reported for eplontersen? Our team used published data from the eplontersen TN study, which showed a median knockdown of 84% at steady state as well available data on variability to model the expected proportion of patients who will reach that same 80% knockdown threshold. Our model estimates that only about 67% of eplon-treated patients would reach that same level of knockdown or said another way, 1/3 of patients may not reach the threshold to knockdown we've seen to be associated with strong efficacy, nearly double that calculated for vutrisiran. These are estimates and should be interpreted with appropriate caution that they highlight that the TTR knockdown data in CARDIO-TTRansform will be critical to review an insufficient knockdown is one plausible contributor to the fail of that study.

We ran same modeling exercise for nucresiran using the same dose and regimen that we are using in the TRITON-CM and PN studies. And the good news is that by these same metrics, nucresiran has the potential to be even better than vutrisiran's high mark. With median knockdown of 95% in low variability over 99% of patients, truth nucresiran are expected to surpass the deep knockdown threshold. So in sum, we don't believe that the top line results shared a few weeks ago negate the hypothesis and rationale of using a silencer for ATTR-CM patients who are already on a stabilizer, more likely as we -- they may demonstrate that the type and depth of silencing along with aspects of the study design are what really matter.

With that, I'd like to remind you that we're progressing a broad pipeline of medicines beyond TTR with over 25 clinical programs multiple therapeutic areas across rare specialty and prevalent indications. This robust pipeline represents a tremendous opportunity to improve patient health and create value in the years ahead. To that end, we look forward to a lot of pipeline momentum in the next few years. This year, in 2026, we continue to execute on our 3 ongoing pivotal studies, including 2 cardiovascular outcomes trial. We also anticipate 4 key data readouts in the second half, which I'll outline on the next slide. And looking ahead, we anticipate many more data readouts and pivotal trial starts in '27 and '28.

Additionally, in 2028, we anticipate the launch of nucresiran in hATTR polyneuropathy assuming positive Phase III data and regulatory approval. And of course, we'll continue to build the pipeline through the filing of 3 to 4 new INDs each year as we scale to meet our Alnylam 2030 ambitions. Coming back to '26 and our pipeline goals for the remainder of the year, we're looking forward to 4 important data readouts from 3 key programs. For ALN-6400, we plan to share healthy volunteer data from the ongoing Phase I study as well as initial results from the Phase II study in patients with hereditary hemorrhagic telangiectasia. We also expect to initiate Phase I data from both ALN-HD202, our Huntington's disease program and ALN-2232 in development for obesity and weight management.

With that, let me turn it back to Josh to coordinate our Q&A session. Josh?

Thank you, Pushkal. Operator, we'll now open the call for questions. [Operator Instructions]

[Operator Instructions] Your first question comes from the line of Paul Matteis with Stifel.

Great. I appreciate it. I wanted to just talk about like the change in guidance. By our math, under the new guide, you're growing around 50-ish percent at the midpoint in the second half of this year. And for 2030, I think you still guided to this 25% CAGR given this drop off versus your original expectations and when you gave this one-term guidance, I was wondering if you could talk a little bit more about the next sort of 12- to 24-month outlook and your confidence that you can keep the growth rate on track likely above that 25% number for a while and still meet your long-term goals?

Thanks for the question. Clearly, we're not pleased to be lowering guidance, as Jeff said, we own it. But I think it's really important to emphasize that we believe that the fundamentals driving our opportunity a really strong, particularly market growth in our first-line momentum. And it's difficult to know every single factor when you kick off a launch from the get-go. But we're very pleased with the outlook that we have in front of us. both in the near future, but also in the longer term and reaching our 2030 goals. Jeff, do you want to add some comments?

I mean I'll just kind on the second half of '26 and what the revised guidance implies and then maybe Tolga would like to make some comments on longer-term confidence in the Alnylam 23rd guidance. Paul, the revised guidance that we've given of $4.2 billion to $4.5 billion in terms of the midpoint of that, just relative to the growth that we just put up in the second quarter, the midpoint to achieve the midpoint, we would need to deliver growth in Q3 and Q4 that's consistent with what we just put up in Q2. And I think we do have confidence in that given some of the things that Tolga talked about, particularly strength in the first-line part of the market in terms of demand we saw in the quarter in the U.S. But Tolga, any more comments on the confidence in the longer term?

Yes. Maybe I'll combine both Yvonne and Jeff's point, which is, first and foremost, we are competing in a in a highly untapped market, 80% of patients remain untreated. And within that category, in a short [ 15 ] months, we've already been able to actually build a very strong base for our business. And what's exciting about that, frankly, to me is while we're obviously normalizing our second-line new business, our first-time business is really rapidly replacing that. And if you think about the fact that 80% in this category comes in as new patients as first line, we really like how we're positioned with the existing prescriber bases. And as I highlighted in my remarks, one of the areas where we still need to do some work, which I believe we'll be able to do is continue to expand our prescriber bases. And that's where we're really investing our efforts, and we've already done that. So given matching that with actually the access that we've been able to secure and good achievance rates, our ability to demonstrate 25% CAGR growth year-over-year is definitely within our reach.

And if I can add, we're actually even more confident now with the results of the CARDIO-TTRansform study. I mean there's likely to be one less branded competitor in the market. And Pushkal structured all the reasons why our confidence in nucre and TRITON-CM is on diminished. So I think if anything, actually, we're sort of more confident about our future outlook given these developments.

Next question please. It's from Salveen.

This is Tommie on for Salveen. Curious on if you're seeing a slower rate of second-line patients TAF progressors per year, given trends in earlier diagnosis and potentially patients staying on TAF for longer. And also, if you could maybe comment on how you expect the timing for your diagnosis and awareness efforts to start playing a key role in first line capture.

That's a great question, both for Tolga.

Yes. So it's a good question around the early diagnosis. Frankly, the when we started just like any launch when you have an artogonol mechanism of action product like we do, we knew that there was going to be a level of pent-up demand. And it certainly, over time, we've seen that being normalizing. So we're still seeing actually a healthy number of patients that are coming into category. That's about 20% of switch and combo. That will continue to be the same. What's even more important to me is these early diagnosis is actually going to hopefully help to increase the category growth and accelerating that category of growth. We've already seen that. It's gone up from the prior years into -- since we launched an acceleration of these new patients. So in fact, those patients that are getting treated early is going to be a nice tailwind for us.

Your next question comes from the line of Tazeen Ahmad with Bank of America.

I wanted to get a little bit more color about your comments about frontline, it's now about 80% of new starts. Can you just tell me what the split is for use in community physician practices versus centers of excellence? And I guess the question that a lot of people are asking is if for better or for worse right now, physicians are looking at stabilizers as being similar in efficacy to silencers, how do you kind of maintain that growth that you're seeing in front line with needing to balance educating physicians, presumably community-based physicians on the real differences between silencers and stabilizers?

\

Yes. So I'll say a few words, maybe I'll [indiscernible]. Look, I mean, first and foremost, we continue to compete for category leadership against the product that's been in the market for approximately 7 years. And obviously, we remain ahead of the other recent ended. But more importantly, how the business is evolving beneath the overall share, I think, is really, really important. Early in the launch, growth was more balanced between first and second line patients. Today, as second line demand, as we described, has moved toward a more sustainable rate, an increasing proportion of our growth is not coming from first-line patients, which represents the larger and the more durable opportunity.

At the same time, I think this is really important. We are deepening adoption within existing accounts and rapidly expanding that prescriber base. So we're essentially maintaining a strong overall share while improving the underlying composition of the business through a broader physician adoption. Now you brought up the point around the COEs and community experts. What's been really encouraging for us is, as we establish that early base business, that business didn't just come from the COEs. We actually had a very healthy balance of COEs academic centers as well as community experts. What we need to continue to do is to actually expand out those community expert centers, and we know how to do that. Some of the challenges we faced with them early on was, well, okay, I don't know what differences are between the silences and stabilizers. Now those physicians have actually adopted AMVUTRA and all other stabilizers, we actually have a significantly higher market share. When it comes to, oh, well, I don't know how to buy and build this product, particularly around the community expert centers. We know how to bring them along with that, whether through building there are helping their own practice or creating alternative sites of care for their injections. So it is something we've done already, and now we're essentially intensifying our efforts to make sure that actually that adoption curve continues to get deeper.

Yes. And Tazeen, may, I'll just add to what Tolga said in response to your question. Look, there's no head-to-head data, of course, we know between these different classes of medicines. But as tried to highlight in the main presentation, we think we have actually an incredibly unique profile for AMVUTRA. It starts with the outcomes data, which we think are really quite remarkable. I've shown you a substantial impact on outcomes. And importantly, the fact that we've seen now in 2 studies, additive benefits on top of stabilizers would suggest there is efficacy left that's not fully addressed by the stabilizers alone, indirect evidence, but we think it's very strong and reproducible evidence.

We've also seen it starting this class of agents early silencers and the greatest treatment effect and even approaching almost 45% reductions in mortality, which I think is quite remarkable. And we're seeing evidence of disease remodeling when we look at echocardiographic parameters, we look at cardiac MRI, et cetera. So look, our job as Tolga highlighted is to continue to educate on those attributes, continue to generate evidence you've seen it recent means more and more that we're putting out and to continue to educate. And so as Tolga has talked about expanding the prescriber base, important aspect of is educating these prescribers on the attributes of this class of medicines. And we've seen that once they gain experience with it that they find that it actually becomes a dominant part of their practice in terms of the prescribing. So that's going to be our goal.

Your next question comes from the line of Konstantinos Biliouris with Oppenheimer.

One on Europe, given that VYNDAQEL will soon be generic in Europe, to what extent do you seeing the commercial dynamics between AMVUTRA and a generic drug in Europe will reflect what may happen in the U.S. post 2031 when tafamidis goes generic?

Thank you very much. Tolga?

So thank you, Kostas, for that question. First and foremost, I think we've always highlighted that the contribution of growth for Europe is going to be relatively modest, similar to the growth that we had last year. And that had a lot to do with the fact that we were going to actually make appropriate price adjustments in order to capture a larger cardiomyopathy volume.

Now in terms of tafamidis, the 80 milligram, the 4 pills a day option is going to be going generic. I believe 61-milligram will continue to be available for a while. Now in respect to our ability to actually capture those reimbursements since these are single-payer systems, these systems have already anticipated that genericization transition. And what I'm pleased to say that we've actually, in most cases, been able to secure premium pricing versus tafamidis and quite pleased with the ongoing negotiations we have, whether it's Germany, Spain, Italy. And Japan, we highlighted the fact that we are competing very effectively, essentially exceeding all analogs and a good uptake. So while, again, because of the pricing changes, we're going to have a modest growth contribution, particularly in '26, we see '27 and beyond the launches is going to have a meaningful impact on our overall business.

Your next question comes from Eli Merle with Barclays.

Just curious if you could give us more color on what a steady-state level of second line starts look like. I think you said 80% of starts in 2Q were from the front line. So it's 20% a steady state for second-line start? Or do you expect that to decline over time? And then, I guess, what drives your confidence that the front line starts will continue at this cadence going forward? And specifically, if you could give us more color on if we strip out the second line start, have you seen growth in first-line starts or a stable number of first-time starts each quarter?

Thank you, Eli, for that question. I mean just to be clear, when we talk about 80/20 perspective, that's mainly driven by the overall category. And what we've seen essentially is not a market share loss on second line. But the overall volume shift into a lesser contribution of the new brands from switches for the entire category. What I'm really pleased about is while we're continuing to maintain and having a nice gradual progression of our market share, that market share growth is actually being contributed by the first line share. So that's actually a very healthy sign of our business. .

And in respect to the first line contributions, as I alluded to earlier, those physicians that actually use all 3 products predominantly used AMVUTRA is their first time choice. That's the analysis that we have. So now the question is how can we actually continue to expand the prescriber base. So more physicians actually test and understand and experience on AMVUTRA because they experience biggest preference. And this is where we're really putting our efforts in. And we've been able to expand that prescriber base at 1,500 new prescribers since the launch, and we believe we're going to be able to continue to do that. And again, the goal has always been actually on first line. And this is -- this normalization is just question actually, frankly, not just the dynamic, but also the strategy.

Your next question comes from Luca Issi with RBC.

Maybe a quick one for Tolga. Pretty clear at AstraZeneca, I did not show any additive effect stabilizer and silencers in their trial based on the press release, you got to appreciate that different molecule, that's pushed all nicely articulated. But are you seeing any impact commercially based on that data? Are you seeing payers forcing docs to pick one versus the other and no longer allowing patients to be on the combo? Any color there are much appreciated. And then super quickly, can you comment on the evolution of net price in the U.S. for the rest of the year?

So that's a 3-parter, right, I guess. So maybe I'll start. I mean obviously, Pushkal laid it out very clearly why we believe what we believe. Look, in terms of -- in terms of the payer pushback, obviously, it's too early to say, but what I can tell you is this, overall access to AMVUTRA remains very strong. Some Medicaid Advantage policies that are already placed that already puts limitation on combination use and in fee-for-service coverage always follow label. And frankly, physicians continue to have pathways to pursue access when they believe that particularly when the approach is medically appropriate given the severity of this disease.

What's also very important is CARDIO-TTRansform does not change ultra's evidence or its label. It was a study of a different molecule. We would not expect payers to offer alter AMVUTRA coverage based on those results. Our priority remains ensuring appropriate path patients can access AMVUTRA whether they're initiating first-line therapy or switching from another treatment. So we're not seeing any pushback again, given the fact that actually the policies are already in place and yet when a physician wants to have access, they obtain it if they provide the right appropriate materials.

Thanks. Look, I think there are many examples of drugs in similar classes where one drug fails and the other succeeds. And we really believe what we have here at 2 distinct molecules with different mechanisms as well as different profiles and a different study. And really, our job is to get out there, as Tolga was saying and educate physicians on the compelling benefits that we see for AMVUTRA the focus on first line because we believe this should be a foundational therapy as well as explaining the benefits that we've seen in 2 separate studies as Pushkal has explained with respect to combination is. So...

There was one question on net price in terms of what we expect. And I think the slide that Tolga showed that showed the first half dynamics showed the modest quarter-to-quarter decreases in net price. We expect that will continue for the second half. And if we were to show you that on a year-over-year basis, the way we had guided was mid-single-digit net price decrease year-over-year. We're still on track for that, Luca.

The next question comes from Jessica Fye with JPMorgan.

Question for Pushkal. Recognizing that this is hypothetical. Can you elaborate on some of those potential changes available to you with TRITON-CM to maximize its probability of success? And then maybe as a follow-up to that, are there potentially other paths to approval for nucresiran in ATTR-CM beyond TRITON-CM? For example, would it be feasible to run a non-inferiority trial against AMVUTRA?

Yes. Thanks, Jess, for your question. Look, again, we feel really good about what we have in our hands, both in terms of the molecule and nucresiran for all the reasons I talked about and the and the study that we have. So again, I want to reinforce, we may not need to do anything different from what we already have ongoing. That said, we do have options at our disposal. We'll look at the data and we'll consider. I think they broadly fall into a couple of buckets. One is whether we modify enrollment in certain subpopulations, for instance, and enrich in certain ways for those -- again, we've done that already in the context of the study, but we could potentially further do that based on formation that we see. .

The other thing would be to make modifications around the analytic plan in terms of how we think about various endpoints, the hierarchy, et cetera. And so they're largely in those 2 big buckets. I mean, to the second part of your question, is there a possibility that if we wanted to, we could do additional studies. Yes, certainly, those things are potential. I'm not going to speculate though further on what those might look like. But I think broadly speaking, I think there's a variety of options that are in. Again, we're playing the long game here. I think our commitment is to deliver a successful study. We've done that in the past. We think nucresiran has the opportunity to be an amazing medicine for patients, and we're committed to delivering a positive study for that. And so we will consider all the potential options in the hand. As I said, they fall into several key buckets, and we'll kind of consider all those opportunities and see if anything at all is warranted.

The next question comes from Whitney Ijem with Canaccord Genuity.

Just -- sorry if I missed it, but can you remind us on how -- any updated thinking, I guess, around the total U.S. patient population or TAM for ATTR-CM and where you are with diagnosis rate currently? And then just as a point of comparison ahead of the 6400 Phase II data later this year, what are the comparable numbers HHT U.S. TAM in terms of patient number diagnosis rate?

So for TTR, what I can tell you is in our less system, if you go back to our TTR webinar, we've highlighted, we estimate around 200,000 patients and about 80% of those remain untreated. What to me is sort of a good confirmatory data set is the fact that you're seeing around 40% year-over-year growth of the category with a single option on the table that has actually accelerated since we launched. So -- and that remains very robust. So we believe more competitors, more awareness, more education. And frankly, some of those initiatives that we've just actually laid will continue to help accelerate those patients getting diagnosed. And as you all know, we have excellent data that demonstrates those patients that are treated earlier end up actually getting our benefit from AMVUTRA. So we're very actually excited about that. And again, our position on first-line gives us the confidence that we can actually continue to be the leading option on table in this growing category.

Yes. And with regard to hereditary hemorrhagic telangiectasia. There are -- there really are no approved treatments for this disease. It's actually the second most common rare bleeding disorder that's out there. I think globally, there's about 1.5 million patients with this disease. I think when we think about the addressable population in the United States, I think, again, those estimates vary. I think there's a number of these patients who don't actually get to medical attention, but we think there's probably about 70,000 or so patients in the United States who may be addressable with this condition. But again, that epidemiology will firm up again as we've seen with rare diseases where there aren't treatments once there are effective treatments, more and more come to attention. So that's probably a ballpark though, for you.

And that concludes our question-and-answer session. I will hand it back to the company for closing remarks.

Thank you. So to close, we continue to build momentum across our business as we execute against our strategy and advance towards our 2030 goals. And I'd like to thank everyone who's joined us today. Thank you.

Thank you, presenters. And ladies and gentlemen, this concludes today's conference call. Thank you all for joining. You may now disconnect.

Good morning, everyone. I'm Chris Brickley, Director of Investor Relations at Alnylam, and I'm pleased to be kicking off our 10th RNAi Roundtable series this morning. Throughout these events, we aim to highlight a few of the exciting programs in our pipeline that represent some of the next wave of transformative medicines we expect to deliver from our RNAi platform.

Today, we'll be covering ALN-6400, which is an investigational therapy targeting plasminogen with the potential to address rare bleeding disorders. Today's event is expected to run approximately 75 minutes. Pushkal will moderate a question-and-answer session at the conclusion of the presentations. And if you'd like to submit a question, you can do so at any time during the event by typing your question in the Ask a Question field located within the webcast platform.

As a reminder, we will be making forward-looking statements during this webinar, and we encourage you to read our most recent SEC filings for a more complete discussion of our risk factors. With that, I'd like to turn it over to Pushkal Garg, our Chief Research and Development Officer. Pushkal?

Thanks, Chris, and welcome, everyone, to today's roundtable on ALN-6400, which we believe represents a potentially transformative RNAi therapeutic for patients living with rare bleeding disorders. With me today are 2 accomplished scientists, who embody our world-class R&D capabilities, John Gansner, Hematologist and Executive Director and the Program Lead for the ALN-6400 Program; and Martina Slingsby, Senior Clinical Scientist and ALN-6400 Clinical Science Lead. We're also delighted to have with us today Dr. Hanny Al-Samkari. Dr. Al-Samkari is Associate Professor of Medicine at Harvard Medical School and Co-Director of the HHT Center of Excellence at Massachusetts General Hospital. He's a globally recognized authority on HHT and other bleeding disorders.

As you all know, Alnylam is pioneering an entirely new class of medicines to treat human disease. This generational technology leverages the mechanism of RNA interference, a natural process of gene regulation that occurs in every cell of our body.

RNAi works like a biological scalpel, allowing to silence any gene in the genome. Moreover, RNAi is a catalytic mechanism that lends itself to highly potent molecules that require low doses to affect biology and the approach is highly specific and entirely reversible, which minimizes safety liabilities.

Additionally, we're able to engineer long half-lives to enable very frequent administration, which allows us to improve patient adherence and convenience. We've harnessed this natural mechanism into a unique and sustainable innovation engine, which can enable sustained long-term growth. We continue to invest in the power of human genetics, where we now have access to more than 2 million lives through various biobanks that allow us to uncover new genetically validated targets.

We also continue to advance the delivery of RNAi to major tissues throughout the body. Beyond the liver and CNS, we have our first adipose targeted program in the clinic, and we believe we're well positioned to achieve delivery to 10 tissues in the next several years. And of course, we continue to optimize the oligonucleotide backbone of our siRNAs for a wide range of clinical applications. Not only do we continue to evolve our underlying platform capabilities, but we seek to deploy our technology towards creating medicines that have a material impact on the lives of patients with significant unmet medical needs.

To do so, we employ a therapeutic area agnostic approach, pursuing diseases with high morbidity and mortality and -- which we can address with highly genetically validated targets with a strong biologic rationale.

Overall, this integrated approach has enabled us to create drug candidates with high quality and historic clinical probabilities of success far in excess of industry benchmarks. To date, this strategy has yielded what we believe to be one of the most robust pipelines in the biotech industry with over 25 programs spanning rare, specialty and prevalent indications across multiple therapeutic areas.

The investigational therapeutics underscore the depth of opportunity we have at Alnylam to deliver meaningful growth in the years ahead. Indeed, you'll be seeing this growth accelerate in the near term as these programs move forward and reach important inflection points. This year, in 2026, we have 3 pivotal studies ongoing, including 2 cardiovascular outcomes trials for Nucresiran in ATTR cardiomyopathy as well as zilebesiran in hypertensive cardiovascular disease.

We also anticipate 4 key data readouts before the end of this year. We expect Phase I data for both ALN-HTT02, our Huntington's disease program and ALN-2232 in development for obesity and weight management. As you'll hear today, we also expect results from the ALN-6400 program. We plan to share healthy volunteer data from our Phase I study, and we expect initial results from our Phase II study in hereditary hemorrhagic telangiectasia.

And as we look ahead to the next couple of years, the milestones continue to ramp up. In 2027, we anticipate 4 or more pivotal studies ongoing by the end of the year, growing to 5 by the end of 2028 and over 5 key data readouts in each of those years.

Additionally, in 2028, we anticipate the launch of Nucresiran in hATTR polyneuropathy, assuming positive Phase III data and regulatory approval. And of course, we continue to build the pipeline through the filing of 3 to 4 new CTAs each year as we scale to meet our Alnylam 2030 goals.

A key component of our Alnylam 2030 goals is the growth through sustainable innovation pillar, where we aim to deliver 2 or more new transformative medicines beyond TTR that have blockbuster potential.

As mentioned earlier, we also aspire to achieve RNAi delivery to at least 10 tissue types and have over 40 programs in the clinic by the end of 2030. Now when we think of the next wave of growth in Alnylam, there are several programs that we believe can represent the next wave of transformative medicines to be delivered from our pipeline.

We'll cover those during our RNAi Roundtable series throughout the rest of 2026, starting with today's session on ALN-6400. As you'll hear from the speakers, we have a promising and differentiated approach that has the potential to address rare bleeding disorders by targeting plasminogen. In this instance, we're not knocking down a disease-causing protein, but rather reducing expression of a downstream protein that is involved in all forms of bleeding disorders. This strategy has a very strong genetic validation and clinical rationale, and we believe it has the potential to offer durable bleed protection across a variety of bleeding disorders without increasing thrombotic risk.

In upcoming roundtables, you hear about 2 other investigational programs that we have -- we believe have the potential to change the practice of medicine. Zilebesiran, our program targeting angiotensinogen with the potential to reduce the risk of cardiovascular disease by providing continuous control of blood pressure and ALN-HTT02, which we're studying to treat Huntington's disease.

And with that, I'd like to hand it over to my colleague, John Gansner, who will discuss the compelling opportunity we see for ALN-6400. John?

Thanks, Pushkal. I'm John Gansner, a practicing hematologist and the program lead for ALN-6400 here at Alnylam. I'm delighted to be able to tell you about the opportunity in front of us, which I think has the potential to revolutionize care for patients with bleeding disorders. We believe there's a broad opportunity across a range of bleeding disorders and that the high disease burden patients with bleeding disorders experience underscores the unmet need for therapies that provide durable and safe bleeding protection.

There are approximately 5 million people living with bleeding disorders globally. These disorders have various etiologies, but they all share a common phenotype bleeding. And this bleeding has a significant impact on patients. It is associated with anemia, iron infusions, blood transfusions, various procedures, ER visits and hospitalizations.

Patients living with bleeding disorders experience disruptions to their daily lives and experience social stigma and anxiety. Furthermore, there are limited or no approved treatments for most of these bleeding disorders. We are developing ALN-6400 to address the significant unmet need in the treatment of bleeding disorders. ALN-6400 targets liver-expressed plasminogen or PLG to prophylactically reduce bleeding.

On the left side of the slide is a schematic of ALN-6400 mechanism of action. ALN-6400 is delivered by subcutaneous injection and lowers liver production of PLG. This reduces the amount of a protein in the blood called plasminogen that is converted to plasma and decreases fibrinolysis or clot breakdown. By stabilizing what I like to refer to as an inner Band-Aid or the natural clot that forms to stop bleeding, we expect ALN-6400 to reduce bleeding in a range of bleeding disorders.

We have 4 strong reasons to believe that our approach will be successful. First, we have a genetically and preclinically validated target. Second, the mechanism is clinically derisked by an existing class of medications called antifibrinolytics.

Third, early data have shown that ALN-6400 is not expected to increase thrombotic risk. That's really quite critical here, and we believe it could be a key differentiator. And fourth, our platform allows for infrequent subcutaneous administration to enable effective prophylaxis. I want to showcase some of the genetic evidence and preclinical data that lead us to believe that PLG knockdown will reduce bleeding.

Based on a U.K. biobank analysis, genetically predicted lower levels of circulating PLG protein are associated with reduced GI bleeding, reduced nose bleeding and reduced heavy menstrual bleeding. In addition, preclinically, we have shown that a PLG siRNA reduces fibrinolysis and mucosal bleeding in nonhuman primates. We observed a near 70% reduction in menstrual bleeding in this model. That's pretty impressive given this is not a model of heavy menstrual bleeding and the animals are starting with what we consider to be normal menstrual bleeding.

We've been steadily generating evidence that, to this point, show there is not expected to be an increase in thrombotic risk with low PLG and PLG knockdown. Genetic and proteomic data, some of which will showcase at the ISTH Congress next month, suggests that low PLG levels are not associated with an increased risk of arterial or venous thrombosis. Natural history data from 107 patients with plasminogen deficiency showed no history of venous thrombosis.

And preclinical models of provoked thrombosis have been reassuring. Despite near complete knockdown of PLG, thrombotic response was the same as control. This could be because our mechanism of action does not alter thrombin generation, which we've confirmed preclinically, as shown in the figure on the far right.

We think the fact that we have not observed an increase in thrombin generation with near complete knockdown of PLG could be a differentiator when it comes to safety. I'm excited to say that we prioritize not just 1 but 2 indications based on high unmet need and disease burden, specifically hereditary hemorrhagic telangiectasia or HHT and von Willebrand disease, or VWD. These are the 2 most common bleeding disorders worldwide, affecting approximately 1.5 million patients globally in the case of HHT, and 1.5 million to 3 million in the case of VWD.

It's important to note that despite the high unmet need, there are no approved treatments for HHT and that the current prophylactic treatments for VWD have high burden, which I'll touch on later. HHT is a multisystem bleeding disorder with high clinical burden and no approved treatments. This is a disease of abnormal blood vessels that are fragile and prone to rupture and bleeding. Here, I highlight some quotes from Austin, a patient with HHT, who we will hear from at the end of this presentation.

95% of patients with HHT experience nosebleeds, but you really need to hear the patient stories to understand what this means. Picture a faucet of a sink turned all the way on. That's very distressing and dangerous. More than 2/3 of patients with HHT are anemic or iron deficient due to blood loss. About 1/3 have gastrointestinal or GI bleeding and 11% are hospitalized due to HHT at least once a year. It's a terrible disease. We believe that ALN-6400 has the potential to be a first-in-class treatment for HHT.

It brings hope with the possibility of durable and safe bleeding control. We think that its long-acting mechanism could provide sustained bleeding protection with only 4 injections a year. We also expect that as treatments receive regulatory approval to treat HHT, diagnosis rates will increase as we have seen in other disease areas after the first treatments are approved.

Currently, it is estimated that only about 35% of patients with HHT are diagnosed. This could be much, much better. I'm going to turn now to VWD, where there are really limited and burdensome treatment options for prophylaxis. Patients with VWD are either deficient in something called von Willebrand factor or make a defective version of it. This disrupts platelet adhesion and affects the stability of Factor VIII, leading to increased bleeding. So a completely different mechanism from HHT.

But these patients also suffer from substantial bleeding manifestations, which we believe ALN-6400 has the potential to address. There is a disproportionate burden for women with VWD and 90% experience heavy menstrual bleeding. Hysterectomies are unfortunately all too common as is highlighted by the patient quote. And then you see the reference to getting stuck over 32 times a day. The injection burden with existing prophylactic treatments is so high that some patients even require ports, which are medical devices that can be used to simplify I.V. injections, but also have drawbacks.

The current state of prophylaxis for VWD is limited to IV factor infusion, which you have to do 2 to 3 times a week. This is very burdensome and particularly difficult for children. As you can imagine, it's hard to put an IV in your child 2 to 3 times a week. There are many patients who would benefit from prophylaxis that choose instead to manage their bleeds on demand because of the burden of multiple IV infusions per week.

We believe ALN-6400 has the potential to transform prophylaxis for patients with VWD who need effective, durable and safe bleeding control. Based on ALN-6400's mechanism of action, we believe that patients with VWD would benefit from improved protection from bleeding regardless of VWD type or bleed type. By offering patients an innovative, less burdensome option to manage their disease, we anticipate that more patients will opt for prophylactic treatment than do today. We believe ALN-6400 has the potential to transform treatment across both HHT and VWD, offering 2 unique and sizable opportunities.

In HHT, there are no approved treatments currently available. So it's no surprise that current diagnosis rates are quite low at about 35%. Based on what we have seen in many other disease areas, we expect that diagnosis rates will increase significantly once a treatment becomes available. We estimate there are approximately 1.5 million patients globally and 70,000 in the U.S. In VWD, while there are treatments currently available, they are burdensome, resulting in low treatment rates as patients often avoid prophylaxis and seek treatment only for severe cases.

The opportunity here is to increase the treatment rate as more patients adopt prophylactic treatment as efficacious and lower burden options become available. This, too, represents a sizable opportunity given we estimate there are approximately 3 million patients with VWD globally and 140,000 in the U.S. We are really excited about the potential of ALN-6400 as a hemostatic agent with its differentiated approach that has the potential to improve the lives of patients across multiple bleeding disorders by providing long-acting durable protection from bleeding.

We are highly encouraged by its early safety profile and expect that it could reduce treatment burden, enabling more patients to benefit from prophylactic treatment. And with that, I'd like to turn it over to our guest speaker this morning, Dr. Hanny Al-Samkari. Dr. Al-Samkari is an Associate Professor of Medicine at Harvard Medical School and holds the Peggy S. Blitz Endowed Chair in Hematology/Oncology. He is a classical hematologist and clinical investigator, who co-directs the HHT Center of Excellence at Massachusetts General Hospital.

Dr. Al-Samkari has published extensively about HHT and cares for several hundred patients at his center. Hanny?

Thank you so much, John. So it's my pleasure to chat a bit about HHT and von Willebrand disease and talk about the manifestations of these diseases and a bit about the patient journey and the unmet need from my perspective as a bleeding disorders expert and a provider for these patients. Next slide. Here are my disclosures. Next slide. So this is how I think about the spectrum of inherited bleeding disorders. And I encourage you to think about it in a similar way. So on one end of the spectrum, we have coagulation factor problems. And the classic disease there is hemophilia, where you have a deficiency of a coagulation factor that leads to bleeding, you have normal angiogenesis and therefore, normal blood vessel structure.

On the other end of the spectrum, you have hereditary hemorrhagic telangiectasia, which is -- there's no coagulation factor deficiency but is a disease primarily of angiogenesis and angiogenic problem. That results in abnormal blood vessels, which we call telangiectasia and arteriovenous malformations that are fragile and they don't properly mature and they bleed and they cause a huge burden of bleeding in these patients.

Now if you look at the incidences, and John already highlighted this, right, we -- when we think of inherited bleeding disorders, the first thing that comes to mind is hemophilia. And hemophilia is obviously a very important inherited bleeding disorder and one of the most common inherited bleeding disorders, but it's actually the third most common, right?

So I think of these as the 3 "common" inherited bleeding disorders. They're all rare diseases technically, right? But when we talk about bleeding disorders, there's the rare and there's the ultra-rare, and these are the rare, which makes them more common relatively speaking. So HHT is about 1 in 5,000. Von Willebrand disease is in the middle. Von Willebrand disease is a coagulation factor deficiency that actually causes angiogenic disruption. So these patients have both impaired hemostasis from bleeding as well as impaired hemostasis from abnormal blood vessels that form and often form in their intestines.

So we have over 30 FDA-approved agents for hemophilia. We have addressed really a massive amount of the need there. Thankfully, my colleagues in the hemophilia space as well as their industry partners have really transformed this disease in a really incredible way. Whereas for the other 2 of these diseases, we are really -- we have a drastic amount of unmet need.

We're really in a difficult place, okay? So for HHT, I don't express hyperbole when I say I believe it is the nonmalignant hematologic disorder that has the greatest amount of unmet need in 2026. And then von Willebrand disease is rather common, and there is a significant gap for patients that have moderate-to-severe von Willebrand disease that is not currently being addressed by the therapies that are FDA approved right now.

I have platelet problem over in the corner. And I think it's just -- I'm just happy to mention or I think it's important to mention that right now, we have no approved therapies for the vast majority of the inherited platelet disorders, but that we actually use plasminogen inhibition primarily to treat them. That's a totally separate talk from other time, but is, I think, somewhat relevant to the topic of today's conversation. Next slide.

So let's talk about HHT. Next slide. So I'll give you a few cases. So this is a 41-year-old man with severe nosebleeds. He works in the biomedical field, diagnosed HHT in his 20s, sent for regular nasal and intestinal cautery procedures that each worked for a couple of months, but ultimately, his bleeding came back worse after each procedure as we know happens in this disease when we use procedures because it's an angiogenic problem. And the more tissue injury you cause, the more you provoke the body to create more telangiectasias and AVMs in these patients. And this patient, unfortunately, ultimately went on disability and his promising career halted because he just could not work with blood gushing from his face, constantly limiting him at work.

I think we all have experienced nosebleed at some point in our life. And so it's easy to maybe make the I think, misunderstood thought that nosebleeds aren't that big of a deal, right? They're not as bad as other kinds of bleeding. When in reality, when they are severe and when they are recurrent, they are perhaps one of the worst kinds of bleeding because they're so obvious and they impact you doing almost anything in your daily life, and that includes working.

And he had chronic anemia requiring regular intravenous iron, constant ER visits for severe nosebleeds. He was diagnosed with major depressive disorder, not surprisingly from his nose bleeding. About half of patients with HHT ultimately are diagnosed with a DSM-5, diagnosed with psychiatric comorbidity because of their nose bleeding. And his well-meaning doc started him on an antidepressant an SSRI, which reduces platelet function. So that worsened his bleeding, right? He said to me, I'm barely 40, but I feel like my life is nearly over, I just want to go back to work and maybe one day be able to have a girlfriend, right?

This is a typical -- this is not an unusual case or a kind of a corner case. This is a typical patient I see in my clinic. Next slide. So HHT is not "that hereditary nose bleed disease, " right? It is a multisystem inherited bleeding disorder with numerous morbid and potentially fatal manifestations. So we've talked a lot about the nose bleeding, and John mentioned 30% of these patients have chronic GI bleeding, right? Between the nose bleeding and the GI bleeding, there is a huge burden of iron deficiency anemia, and it's very common for these patients to be dependent on intravenous iron infusions.

And there is a small subset of the most severe patients that are dependent on red cell transfusions. In addition to that, we have visceral arteriovenous malformations in lung, liver and brain, which can cause a whole host of complications that are quite morbid, high output heart failure, liver disease, pulmonary hypertension, pulmonary hemorrhage, hemorrhagic stroke, epilepsy, other really serious complications.

But you might think, well, gosh, those are the real problem with this disease. But actually, no, right? Patients rank bleeding as by far the most important clinical manifestation because it impacts them on a daily basis and so profoundly, right? So AVMs and anemia tie for second behind bleeding, far behind bleeding. And as has been mentioned, there's no FDA-approved or EMA-approved therapies to date. Next slide.

So because this is an autosomal dominant disease, when I see a patient in clinic, half of their family has HHT. Many of them have not yet been diagnosed, right? So you find one patient and you find 20 more. And this is why at the HHT Center at MGH, I care for several hundred of these patients, several hundred of these families. This is a disease unlike hemophilia, which is a disease primarily of men as an X-linked disease, this affects all sexes equally and actually is the most clinically significant and morbid inherited bleeding disorder of women.

And women actually tend to have more severe bleeding and visceral disease manifestations than men, although both certainly can have severe manifestations. These patients have reduced overall survival because of their bleeding and non-bleeding manifestations. Next slide. The pathologic lesion of HHT is the arteriovenous malformation or AVM. So this is an abnormal lesion, abnormal vascular structure, whereby there are these abnormal fragile friable connections between artery and vein that bypass the normal capillary network. These lesions appear on mucocutaneous surfaces. They appear within organs. When they're small, less than a few millimeters, we call them telangiectasias. When they're bigger than a few millimeters, we call them AVMs.

But the important thing to recognize about them is that they're high flow lesions. These are connected to arteries and arteries have the high pressure inside them. So when these lesions rupture, they often cause squirting bleeding, gushing bleeding, and that's why we can often see the very profound nosebleeds in these patients. Next slide.

These are just some examples of patients that have a lot of telangiectasias. These are very obvious. You don't need 20 or 30 telangiectasias. You only need 2 or 3 to make the diagnosis. I've never met a patient yet in my career that has mucocutaneous telangiectasias in typical locations and recurrent epistaxis who didn't ultimately have HHT.

And as has been pointed out, this is significantly underdiagnosed because, well, for one thing, there's no approved therapies. And another thing, it's something that has not been adequately, I think, given enough time in medical training and medical school, and that's all changing now. Next slide.

More examples of telangiectasias. Next slide. These are telangiectasias in the gastrointestinal tract. And when you zoom in very closely, you see the very kind of spidery appearance of them, the very tortuous abnormal vessels. And these chronically ooze in most patients with HHT. So 3/4 of patients with HHT actually have chronic gastrointestinal -- have telangiectasias in their gastrointestinal tract and about half of them have chronic bleeding that is very clinically significant and usually leads to hematologic support dependence through IV iron and/or red cell transfusions.

Next slide. These are the telangiectasias in the nose that cause the recurrent epistaxis. Next slide. So again, because of these manifestations in these telangiectasias, we have 95% of patients. This was from the comprehensive HHT Outcomes Registry of the United States, a U.S. government-funded registry of HHT Centers of Excellence that enrolled unselected patients with HHT, patients of any age, patients of any severity. And this is the initial report that we just published in blood, 95% with chronic recurrent epistaxis and almost 2/3 of these patients that have moderate to severe epistaxis as is defined by thresholds based on international consensus report in defining epistaxis severity HHT. Next slide.

So 30% with chronic GI bleeding, although only 40% of the patients had even had an upper endoscopy. And by the way, many of the lesions are buried deep in the small bowel. They're not easy to find. And so for the patients that had GI bleeding, 3/4 of them required IV iron and half of them have required red cell transfusion. Next slide.

Heavy menstrual bleeding observed in the setting of essentially chart review was seen in 35% of patients. There's another study actually that is soon to be published that shows a rate of heavy menstrual bleeding of 3/4 of patients with -- of women, menstrual-aged women with HHT. So certainly something that's been underrecognized and people haven't asked about it. If you don't ask about it, you don't diagnose it. And then other bleeding from other areas as well in 41% of patients.

Next slide. So the overall burden of mucosal bleeding in patients with HHT that is moderate-to-severe is 3/4 of these patients, which this is the level of bleeding that is very clearly indicated to treat, right? We want to treat patients with mild bleeding also. But right now, we are forced to use off-label therapies that have a lot of toxicity. And so we only treat the moderate to severe bleeders. Next slide.

Iron deficiency and iron deficiency anemia is "the norm" in this disease, which is a big problem because in addition to drastic reductions in quality of life, one of the most -- one of the clearest things you can do to increase somebody's quality of life is fix iron deficiency in a patient who's iron deficient, but these patients are chronically bleeding. And so it's constantly a game where you're chasing your tail trying to make sure they remain iron replete.

About half of these -- half of patients with HHT, more than half have anemia in this study that evaluated a snapshot in time, 1 year of patients with HHT using ICD-10 codes. And then about half of those patients received iron infusion or red cell transfusion within that year. Next slide.

So when we talk about the bleeding complications of HHT, this is sort of a summary from the CHORUS Registry that I mentioned. And I didn't mention the pulmonary hemorrhage from ruptured pulmonary AVMs that happens in 1 in 50 patients with HHT, which is certainly potentially fatal and this happens in 1% of all pregnancies in women with HHT. And then 1 in 30 patients with HHT developing intracranial hemorrhage. And just to give context, right, that is similar to hemophilia in the '90s before routine factor prophylaxis. The rate of intracranial hemorrhage in 2026 in patients in the United States treated with nonfactor prophylaxis is 0.4% for hemophilia. It's 3% for HHT.

Next slide. So the standard of care for bleeding in HHT is highlighted on this slide or described on this slide. And really, what we are forced to do is supportive therapy with iron. We do procedures when we have to because, again, we really have moved away from recurrent procedures, certainly at HHT centers, although in the community because as you can see, the drugs on this slide are cancer drugs that are FDA approved only for patients with terminal or metastatic cancer, which a lot of docs in the community, including hematologists, oncologists are not comfortable administering drugs like pomalidomide and bevacizumab, administered indefinitely to patients with HHT who have decades of life ahead of them.

The procedure piece is primarily used in HHT Centers to stabilize unstable patients. And then we treat with drugs, and we treat with oral antifibrinolytics, primarily in those patients that have mild-to-moderate disease, and these are patients with patients getting tranexamic acid or aminocaproic acid 2 horse pills every 6 to 8 hours, which is not the easiest thing for patients to take, as you can imagine. And the efficacy of this approach is really limited by/patient compliance, ability to take the pills, side effects that patients have.

And then we have, on the other end, clinical trials of novel agents because, again, we have no approved therapies or repurposed systemic anti-androgenic drugs, which work, by the way, on average for about 3 to 5 years and then they stop working. And so the unmet need here is really profound.

Next slide. All right. So let's switch gears and talk about von Willebrand disease, the most common inherited bleeding disorder. So here's another case, a 40-year-old woman with type 2b von Willebrand disease, complicated by chronic GI bleeding. She's previously managed on 3 times weekly intravenous von Willebrand factor, plasma-derived, but developed infusion fatigue.

She was switched to twice weekly recombinant von Willebrand factor, but this only treated her heavy menstrual bleeding, not the GI bleeding she had from these abnormal vascular lesions in her intestines. On endoscopy, she has these vascular malformations that intermittently bleed, put her on octreotide with minimal effect. This is a drug that reduces blood flow to the intestines.

And she's still missing infusions of recombinant von Willebrand factor, which is normally given twice weekly due to the fact that she's a single mother of 3 kids. She has a busy job, which she works almost 60 hours a week, and she has infusion fatigue. It's not the easiest thing to continue to do this forever. Next slide.

So von Willebrand factor is an important blood protein that forms clots to stop bleeding, okay? It protects clotting factor VIII. And so people who have low von Willebrand factor also have low factor VIII levels. typically in conjunction with the reduced von Willebrand factor. And it facilitates the binding of platelets to subendothelial collagen, these glycoproteins -- platelet glycoproteins that bind subendothelial collagen as well as platelet-to-platelet interactions.

So it serves in many ways as kind of the glue that helps platelets stay together and helps platelets attach to the site of vessel injury. Next slide. So von Willebrand disease is quite common in the bleeding disorder space, the most common inherited bleeding disorder. It's frequently missed. Like HHT, it's frequently missed. And in both of these cases, right, von Willebrand disease -- type 1 von Willebrand disease is the most common type is autosomal dominant, right? Like HHT is autosomal dominant.

So what happens is the bleeding gets normalized in families. Oh, yes, women in our family, they have heavy periods. People in our family, they get nosebleeds. That's just "our family curse. " We just have a lot of bleeding. It gets normalized. And so people don't even know that they have heavy menstrual bleeding. If someone -- if a doc asks, it's normal because the mother of the woman told them it's normal because their sisters have it.

It's just normal to them. So it's very frequently missed. And it can come to attention because of severe iron deficiency anemia or in the case of von Willebrand disease, profound or complicated postpartum bleeding or post-procedural bleeding. Next slide.

So these are the manifestations of von Willebrand disease. Again, not to belabor the point, but heavy menstrual bleeding being a really major one. And this heavy menstrual bleeding in patients that have more mild disease can be managed with tranexamic acid and can be managed with oral contraceptives. But in many cases, it's not adequately managed by our current therapies, and there is a gap and a need for a better therapy for these patients. And then on top of that, right, these patients not infrequently will have some epistaxis. They can have gingival bleeding, they can develop gastrointestinal hemorrhages, and there are increased risk of surgical bleeding and more bleeding after trauma and more bleeding with pregnancy and pregnancy complications with delivery.

In patients who have the most severe kind of von Willebrand disease, they can actually look like a severe hemophilia A patient. Next slide. So not to get too into the weeds, but here are the types of von Willebrand disease. Type 1 is a quantitative deficiency. Most patients have a mild to moderate bleeding propensity. Type 2 is a qualitative deficiency. And the typical type 2 patient has moderate bleeding, but these patients can have mild bleeding and they can have severe bleeding.

And then there's type 3, which is autosomal recessive, essentially an inheritance of 2 type 1 -- drastic type 1 mutations. And this is quite rare, but these patients can look for all the world like a severe hemophilia patient. Next slide. So our current treatments for von Willebrand disease really leave a conspicuous gap. Patients with mild type 1 and type 2 disease are generally managed all right with desmopressin before most procedures, von Willebrand disease factor containing concentrate before major procedures and they have -- they take antifibrinolytics, which certainly do work to help with bleeding after dental procedures, certain surgeries. Sometimes these can be used as an abortive for a particularly bad nosebleed, patients will take 2 tranexamic acid pills.

Patients that have moderate to severe type 1 and type 2 disease and the patient's type 3 disease, however, there is a clear unmet need in this group of patients. So the type 3 patients, as was given -- type 3 patients and severe type 2 patients as was given in the example case that I gave, right, they are often dependent on intravenous infusions of von Willebrand factor, plasma-derived or recombinant -- and these infusions can reduce bleeding and they do reduce bleeding, but they're a really significant burden on the patient.

And it's really challenging if you're in this kind of middle group where you have multiple nosebleeds a week, you have heavy menstrual bleeding that's not managed by typical therapies. You don't technically have type 3 disease. You don't technically have severe type 1 or type 2 disease, but it's moderate. Most of these patients don't want to go on regular infusions. It's just too much of a burden. So there is a clear gap there for those patients. And it's not enough to give these patients oral antifibrinolytics because they don't -- they're not adequate in managing bleeding.

Next slide. So what do we need in von Willebrand disease and HHT? We need safe and effective medications for moderate to severe mucoccutaneous mucosal bleeding. We ideally want a drug that's convenient. It should be -- should have a minimal or nil thromboembolic risk. In patients with HHT, they have increased thromboembolic risk over the general population. And in any bleeding disorder, you don't want to give patients a higher thromboembolic risk if you can avoid it because of, obviously, the challenges with antithrombotic therapy in these patients. The ideal drug is prophylactic as opposed to something on demand and should be ideally administered infrequently.

And it's got to reduce epistaxis in HHT, and it's got to reduce overall mucocutaneous bleeding in HHT and von Willebrand disease. And in a perfect world, would reduce the burden of anemia and the requirements for hematologic support, I.V. iron, red cell transfusion, particularly in HHT, and of course, would improve patient-related health-related quality life. So with that, I'm happy to hand it off to Dr. Martina Slingsby.

Thank you, Dr. Al-Samkari for the excellent and comprehensive overview of the clinical burden of HHT and von Willebrand disease. Your examples really bring to light the devastating impact of these diseases on patients' lives. My name is Martina Slingsby, and I'm a PhD scientist, and I've been the research lead and now the clinical science lead for the ALN-6400 program at Alnylam.

I will now take you through our clinical plans and progress. I've had the privilege of working on this exciting program right from the idea stage around 4 years ago, where the Alnylam model of genetic and preclinical validation and a streamlined approach allowed us to quickly identify a lead candidate and start a Phase I study at the end of 2024. Only about a month later, under 3 years from the idea, we were able to demonstrate clinical proof of mechanism in humans. In September last year, we initiated a Phase II study in patients with HHT.

And last month, we initiated another Phase II study in patients with von Willebrand disease. Here is an overview of our Phase I study in healthy adult volunteers. This was a double-blind, placebo-controlled study testing 4 ascending single-dose levels of ALN-6400. An innovative aspect of this Phase I study was the oral tranexamic acid or TXA benchmark run-in and washout period.

As we heard from Dr. Al-Samkari, the antifibrinolytic drug, TXA is commonly used in both HHT and von Willebrand disease, but is not an approved therapy for these conditions. Due to its short half-life, it needs to be given frequently at high doses, typically at 2 tablets, 3 times a day for a total of 3 to 4 grams a day. It is common for patients with HHT to take this dose of oral TXA continuously every day for years, whereas patients with von Willebrand disease typically take TXA more on demand. In Phase I study, we performed this TXA benchmark run-in where all participants received standard of care doses of TXA prior to their subcutaneous injection of ALN-6400 or placebo. This allowed for mechanistic comparison of the intra-individual antifibrinolytic effect and how durable this response was with TXA relative to ALN-6400 using a mechanistic assay called tPA-ROTEM, performed at various time points in the study, which I will show on the next slide.

We designed the study like this to learn what level of plasminogen lowering is needed in order to have a similar antifibrinolytic effect as oral TXA and what level of plasminogen lowering could lead to a more durable antifibrinolytic effect in the blood. This study has now been completed, and we remain on track to share data in the second half of this year. In the Phase I study, we demonstrated clinical proof of mechanism that ALN-6400 is able to inhibit fibrinolysis in humans. For this, we use tPA-ROTEM, which is an ex vivo assay, which shows whole blood clot formation, clot stabilization followed by clot breakdown or fibrinolysis.

A larger area of blue trace means that the clot is more stable and lasting for longer, signifying an antifibrinolytic effect. The top panels show representative ROTEM traces from a healthy volunteer dosed with oral TXA. And as you can see, at the TXA peak effect, the blue trace was extended, meaning clot breakdown of fibrinolysis was reduced. This effect only lasted for a few hours since the TXA trough 8 hours after TXA dosing, the antifibrinolytic effect had to a large extent, worn off.

The lower panels show the ROTEM rotent responses from the same healthy volunteer after they were dosed with ALN-6400, showing a deep antifibrinolytic effect that was sustained for 3 months. Based on the Phase I results, we have now selected 2 dose levels of ALN-6400 that demonstrated mechanistically greater and more durable antifibrinolytic effects in the blood compared to oral TXA, which we hypothesize will translate to a greater reduction in bleeding.

The bleeding protection effect of TXA last hours per dose. We now plan to investigate whether a single dose of ALN-6400 can offer bleeding protection for several months in our Phase II studies, where we hope to demonstrate clinical proof of concept of ALN-6400 for the reduction of bleeding.

Here is an overview of our multinational HHT Phase II study called InsigHHT, where patients with HHT are randomized to receive multiple doses of ALN-6400 dose level 1, 2 or placebo. In this study, we are focusing on patients with HHT who suffer from moderate-to-severe nosebleeds, like Dr. Al-Samkari referred to in his talk, make up the majority of the HHT patients that he sees. The goals of the study are to evaluate safety and tolerability to determine the Phase III dose and regimen and assess efficacy by a reduction in nosebleeds.

We expect initial results in the second half of this year. We aim to begin a Phase III study in HHT as well as to present full Phase II data at a scientific congress in 2027. We have just started a multinational von Willebrand disease Phase II study called HMBeacon, where adult and adolescent patients with all types of von Willebrand disease and heavy menstrual bleeding are randomized to receive multiple doses of ALN-6400 dose level 1 or 2. As you heard from Dr. Al-Samkari, heavy menstrual bleeding despite the current treatment options remains a huge unmet need in von Willebrand disease. Yet a paper was just published that emphasized that menstrual outcomes are frequently overlooked in von Willebrand disease trials. I am very proud to be part of this Alnylam effort to change that and to be the first company to do a study focusing on women with heavy menstrual bleeding.

The goal with this study is to evaluate safety and tolerability, determine the Phase III dose and regimen, achieve a quick path to proof of concept by focusing on reduction in menstrual bleeding since that is a reliable bleed type that happens every month. We will also be collecting information on other types of bleeds since we're planning to conduct a Phase III trial in both male and female patients with von Willebrand disease of all types, where the primary endpoint is anticipated to be annualized bleeding rate.

In summary, we believe ALN-6400 offers a differentiated approach with broad impact potential across bleeding disorders. We are encouraged by our data so far and believe that ALN-6400 has the potential to safely provide durable protection and reduced treatment burden, which could meaningfully address the unmet needs of patients living with rare bleeding disorders.

Now we will listen to a patient story from [indiscernible] and his family about what it is like to live with HHT.

[Presentation]

And giving us such a powerful window into the realities of living with HHT. Their experience is really brings to life what Dr. Al-Samkari was highlighting in his presentation about the profound unmet need, this disease places on patients, their families and why we're working with such urgency to advance ALN-6400 for patients with HHT and Von Willebrand disease.

We're going to move now into the Q&A session.

So as a reminder, please submit your questions through the dialogue box located within the webcast platform, and we'll answer as many as we can within the time remaining.

Joining me today for Q&A are our 3 presenters, John Gansner; Martina Slingsby and Dr. Hanny Al-Samkari. And in addition, Christi Kelsey, Senior Vice President of Value and Pipeline Commercialization at Alnylam will be joining us for the Q&A session.

So I'll just give a moment for the questions to come in.

All right. And so maybe here we go here. So one is maybe for you, John, Dr. Al-Samkari talked a little bit about the variety of bleeding disorders that are out there across a spectrum of factor, structural defects, platelet defects. What gives us the confidence -- for you the confidence that plasminogen lowering would work across these various etiologies?

That's a very important question, Pushkal, and I'll start by just saying that ALN-6400 targets liver-expressed plasminogen or PLG, which is really a central mediator of fibrinolysis. And that, again, is the process that breaks down blood clots. And so our goal with ALN-6400 is to stabilize the fibrin mesh that holds together naturally occurring blood clots thereby reducing and preventing recurrent bleeding. So you can really think of the therapeutic hypothesis as ALN-6400 is a drug that aims to stabilize and inner bandaid. We believe our approach could be effective across multiple bleeding disorders because plasminogen is a central mediator of fibrinolysis across bleeding disorders in blood and bleed types. And this is really substantiated by the fact that antifibrinolytics are used to reduce bleeding across multiple bleeding disorders.

That's super helpful. And maybe then a related question that came in is, I guess, this assumes if you described this as an inner -- there is a band aid approach that these patients caught sufficiently for this mechanism to work. So maybe Dr. Al-Samkari, can you just talk about across the variety of bleeding, do they have enough clotting that's happening for this kind of an approach to work? And then what would we expect? Would we expect this to reduce the intensity of bleeds that have already started or to prevent bleeds or both?

Yes. Great question. So yes, these patients do have adequate clotting, adequate thrombin generation for this approach to work. They do produce clots. The issue here, and with HHT the amount of thrombin generation is totally normal, and other bleeding disorders, the amount of thrombin generation is reduced, but still adequate to produce clot. Just one thing I think it's really important to recognize is that when we talk about the hemostatic system, we have the coagulation system and the fibrinolytic system. They are 2 separate systems under the hemostatic system. And they both are important.

And the fibrinolytic system, it functions -- it was a kind of constitutively and normally independent of what's going on with the coagulation part of the system. And so this helps us to address sort of rebalance the amount of fibrinolysis with the amount of coagulation that's going on in patients that have coagulation defects and reduces fibrinolysis in patients that have -- sort of rebalances the amount of fibrinolysis that's occurring in patients that have vascular structural defects.

It's also worth noting that in HHT patients do have increased fibrinolysis within lesions. That's something that we didn't actually mention. And so it is also relevant to reduce that as well. But should -- would I expect it to reduce bleeding incidents, bleeding intensity, bleeding duration, all of those things.

And we know that currently, right, are sort of not very adequate from a PK/PD standpoint, antifibrinolytics that we use. They certainly work. But when you give somebody 2 horse pills every 6 to 8 hours and the effect is only really therapeutic for about 2 to 3 hours after the patient takes the medication takes the pill, we know that these drugs work when we give intravenous infusions, right, in the hospital, they work quite a bit better because the person is getting a high dose and good inhibition of plasminogen. It reduces frequency of bleeds. It reduces intensity of bleeds and it reduces duration of bleeds. So all of those things, I expect this approach to work for.

Super helpful. Martina, maybe a question for you. There are a variety of indications. These are 2 diverse indications that we're pursuing. Why did -- why do we pick these 2 sort of deliver proof of concept and to pursue first?

As you mentioned in your presentation, Pushkal, it's really the philosophy at Alnylam when we select indications is really based on around 3 main criteria, and that is the first being the overall scientific rationale, it's got to make sense. Second, the degree of unmet need; and thirdly, and probably most importantly, where do we have the potential to show the greatest impact on patients' lives. And looking at these three criteria, HHT and Von Willebrand disease really fulfill them and really rose to the top here as a good starting point, where, as we've heard, the mechanism of lowering fibrinolysis to reduce bleeding, it's likely to have a transformative impact on the management of these bleeding disorders.

And then based on their high unmet need, but they have high unmet need for different reasons, as we had mentioned in Dr. Al-Samkari's talk in HHT, there are no approved treatment options. So there is really a medical need for a therapy that can offer prophylactic bleeding control, reduce nose bleeding and overall blood loss from other sources of bleeds alleviate the profound anemia burden and the need for frequent hematologic support such as iron infusions.

Whereas in Von Willebrand disease, there are prophylactic treatments, but they are burdensome, requiring IV infusions 2 to 3 times a week, leading many patients to opt out of prophylaxis, which results in under treatment. We believe that ALN-6400 can potentially offer a durable bleed protection across all Von Willebrand types with a lower treatment burden of infrequent quarterly subcutaneous dosing. So this is why we selected HHT and Von Willebrand disease.

That's great. And maybe Dr. Al-Samkari, I think questions for you around -- given in your kind of perch across all that's happening in this space, can you just kind of calibrate your level of, I guess, enthusiasm based on all the biology that was covered here today and what you know in terms of potential of this therapy. What's your sort of general level of enthusiasm about this approach to treat these bleeding disorders?

Yes. I mean I'm very enthusiastic. So I -- right now, when I write about antifibrinolytics, and when we talk about them and use them in clinical practice, we refer them as nonspecific universal hemostatic agents. The challenge is they just are not good at an outpatient perspective, use an outpatient perspective and use chronically because of their pharmacokinetic and pharmacodynamic limitations. And we know we have lots of evidence that they're safe in patients with bleeding disorders. We have lots of evidence even in HHT as an inherited bleeding disorder with an elevated thromboembolic risk that they're safe.

We have longitudinal data. We have multiple randomized controlled trials that they're safe. It's just that we need a better mousetrap. We need a way to affect plasminogen at a greater -- to a greater degree and much more consistently, which is why I'm very enthusiastic about the prospect for plasminogen knockdown in HHT and other -- across other bleeding disorders. Right now, when we have any inherited bleeding disorder that has no FDA-approved therapies and even for those with FDA-approved therapies, one of the most common drugs, if not the most common drug we use is tranexamic acid, right? So if you could have a much, much better version of this, right, that is easier to use, that has longer effect that is much better at actually reducing fibrinolysis. We anticipate the safety profile will be similar and tranexamic acid is very, very good. And so that's one of the main reasons why I am as enthusiastic as I am.

It's good to have something that works across different pathophysiologies. These diseases are genetically heterogeneous. Von Willebrand disease and HHT both are very genetically heterogeneous and bleeding is the major problem to both of them. And so having something that works independently of what's going on from a genetic standpoint, is also very reassuring that I can have a therapy that will work -- that most likely will work for any of my patients with the disease.

Fantastic. And then you started to touch on this, but can you just elaborate in terms of what safety concerns? I mean, thrombosis is one, what -- Martina reviewed some of the data, what's your take on data supports or around the thrombosis risk. These patients have a baseline thrombosis risk? What is that? And how do you monitor for thrombosis in the clinic?

Yes. Excellent question. So the baseline increased thromboembolic risk in patients with HHT is about two- to fourfold that of the general population. It is driven by multiple different mechanisms, but one of the major ones is chronic iron deficiency, which is -- which causes increased Factor VIII levels and which leads to a higher risk for thrombosis. And obviously, if you can reduce the bleeding, you can reduce the iron deficiency. It's a virtuous cycle in that way.

But how we monitor these patients clinically, we don't -- when we treat these patients, we don't monitor things like D-dimer, prothrombin fragment and HHT because these are patients that are chronically bleeding. And so they're chronically going to be producing D-dimers and prothrombin fragments, and it's not helpful to monitor those over time because very frequently, they're elevated at baseline. We monitor these patients clinically. We do proper physical exams. We ask them proper questions. We educate them in advance of the symptoms and signs to look for and give them a low threshold to talk to us and reach out if they develop those symptoms or signs. And we also have a low threshold to do proper imaging to evaluate if somebody is potentially having an event.

The other part of your question, sorry, Pushkal, you mentioned the data -- so the data -- so why do I feel comfortable? I feel comfortable because we have real substantial body of evidence. And it's been -- Dr. Slingsby pointed out a lot of it. We have great data in patients with HHT showing no increased thromboembolic risk, multiple RCTs, multiple real-world evidence cohorts with over 100 patients followed for years, receiving 4 grams a day of tranexamic acid or aminocaproic acid that show no increased propensity for thrombosis.

We have studies in nonhuman primates. We have studies in mouse models with drastic knockdown of plasminogen showing no increased thrombin generation, no increased incidence of thrombosis. We have real world experimentation in patients with congenital plasminogen deficiency. People who have 5% or 1% of normal plasminogen levels, living their entire lives with these levels, followed for decades in a study called History, which is the major natural history study just published a large report in blood last year, no increased propensity for thromboembolism in these patients despite having very low levels for decades.

We have the U.K. Biobank data, which looked at over 50,000 patients, which was queried by 2 independent groups that came to the same conclusion. You could have reduction in plasminogen levels of any 5%, 90% from normal and no increased thromboembolic risk. So it doesn't get a whole lot better than that when it comes to the level of evidence that we're not really worried about thromboembolism. And let me tell you, it's not easy to anticoagulate these patients. It's not easy. So I have a very -- it's very important to me that when I'm using to treat my patients does not have a substantial thromboembolic risk. And it's important to note that right now, right, in HHT, the drugs that I do use for patients that don't qualify for clinical trials are things like bevacizumab and pomalidomide that have known thromboembolic risks, right? So -- even the bleeding is so significant that we're forced to use those drugs. So it's very, very reassuring to me the safety of plasminogen lowering as we've seen it in plasminogen inhibition, as we've seen it thus far.

That is super clear. Thank you for really reviewing all of that. I think that's super important. We've got a number of questions I wanted to clarify that.

Maybe we should then shift. We were excited about this approach. Martina, maybe this is to you. What data can we expect to see in the clinical readouts later this year? What does good look like in HHT and Von Willebrand? And then maybe John, you can speak to the Hunting -- the HHT data read through to the Von Willebrand disease, given we're going to see the HHT data first. Is that predictive of what we might see? And why do we start that first? And then will that be somewhat predictive of what we see in Von Willebrands. Martina, I will start with you there.

We are now excited to have complete data from our Phase I trial, and we will communicate these results later this year about our learnings of safety and pharmacology of ALN-6400 in-house volunteers. In terms of the HHT Phase II study, just to recap, that includes 48 patients with moderate to severe HHT treated with ALN-6400 or placebo over a 24-week double-blind period. Recruitment has gone very well attesting to the high unmet need in patients with HHT and also to the excitement of our investigators for enrolling patients in this study. And this study is really designed to tell us about safety and tolerability and show us how ALN-6400 can reduce nose bleeding and other improved on other hematologic parameters. And we expect initial Phase II results this year, and we plan to share the full data at a medical conference next year in 2027.

In terms of what wins would look like in these 2 parallel Phase II studies, the successful outcomes for both studies is to demonstrate that ALN-6400 is safe and well tolerated across these 2 indications. And in HHT Phase II, we'll be focusing on a reduction in bleeding, particularly in nose bleeding, but also the overall blood loss and the impact that has. And in our Phase II study and Von Willebrand disease, we are focusing on this reduction in menstrual bleeding, and we are also looking at reductions in other bleed types that these patients may experience also to inform our Phase III studies.

And I'll hand it over to John to comment.

So I mean I just want to go back to what I emphasized earlier, which is ALN-6400 targets liver-expressed plasminogen, which again is that central mediator fibrinolysis. And therefore, we really think that it has the potential, as Dr. Al-Samkari said, to work across bleeding -- blood -- bleeding disorders and also bleeding types. And so we do think that, Pushkal, to answer your question, what we see in HHT will be predictive of what we see in Von Willebrand disease. And we're very hopeful that we will have positive results in both studies.

We'll have to run them to see, but there's actually a lot of overlap between the bleeding types even within those 2 diseases themselves. So you see epistaxis or nose bleeds in patients with Von Willebrand disease, just like you do in HHT and you see other bleed types, heavy menstrual bleeding as Dr. Al-Samkari also emphasized. So we do think the one will be predictive of the other.

Fantastic. And maybe Dr. Al-Samkari, as a clinician, what's the clinically meaningful reduction or impact in these 2 diseases?

Yes. It's a really good question. So we've defined this in HHT an international consensus report that was published last year in an individual patients and improvement in epistaxis intensity, frequency or duration and we say or, but usually effective therapies affect all 3 of these domains of epistaxis, an improvement of 30% relative to baseline is a clearly meaningful improvement. That's what we call an epistaxis response. Between clinical arms of a study, we define the minimal clinically important difference of an improvement of at least 15% relative to baseline in one of these epistaxis parameters, which equates to about 50% of patients achieving that epistaxis response threshold, okay?

This is a difficult disease to treat. It is not easy. And so the -- and it's very, very clear that patients have significant improvements in their quality of life and in their overall blood loss when we achieve at least a 30% improvement. In Von Willebrand disease, an improvement of -- in the annualized bleeding rate of approximately 50% is what I would say would be a clearly meaningful improvement.

Very, very helpful. Let's shift. We're getting a number of questions around sort of just the market opportunity here and the value. So maybe, Christie, I'll bring you into the conversation. How are we thinking about the market opportunity in these 2 diseases? Can you speak to -- we got some epidemiology in our presentation, but can you just speak to what's the addressable proportion of those patients? And where do we see the value? How much is in these indications versus we've talked about a variety of other bleeding disorders, where does the value come from?

Yes. No, great question. And maybe just to pull through a couple of key themes. So on value, we expect significant value creation from these opportunities with combined blockbuster potential. And we expect these two first indications to really be the lion's share of value for the asset. I think a theme I've heard today is just the profound unmet need. If we think of HHT just to go through the numbers, obviously, 70,000 patients in the U.S., over 1 million globally, no approved therapies. And the reason why that's important in value, and I think it's been mentioned today, when there's no approved therapies that often results in not a strong urgency to diagnose. So naturally, from a value perspective, we see that as a market build opportunity. As treatments become available, there's increase in awareness, diagnosis and ultimately, utilization.

To dig a bit deeper on who would this be appropriate for? We anticipate ALN-6400 when thinking about HHT to be most appropriate for those patients that have moderate to severe disease with high clinical burden. We heard today of the profound clinical burden of this disease, and that's about 30% to 40% that meet this criteria. Now it's important to note the current criteria of severity is based on the epistaxis severity score, and that's based on, obviously, nose bleeds alone. Given the multi system bleeding disorder that this is, we expect that these measures will evolve over time, taking into account the full clinical burden and its increasing the opportunity.

For Von Willebrand, I'll be quite quick. This is an underserved market. From the numbers, we know 140,000 patients in the U.S., 3 million globally. But I think as Dr. Al-Samkari communicated, there is a gap. Yes, there's about 25% of patients treated in hemophilia treatment centers, but our internal estimates say upwards of 80% of those patients are eligible for prophylactic treatment and they're not getting it. The current treatments are very invasive. They're very time-consuming. They're very burdensome. I love the example of the patient with job and obviously, children, it's very difficult to take IV infusions 2 to 3 times a week.

So we know from other prophylactic markets like HAE and hemophilia the dosing frequency is a very, very strong commercial differentiator and basically shifts markets and unlocking significant value. So I think bottom line is significant value creation, combined blockbuster potential in both of these disease areas are just waiting for this next wave of innovation that we've seen in some of the other areas that we've mentioned.

That's fantastic. I guess a related question came in, which is people were noting that Incyte recently did a transaction in this space in Von Willebrand disease. Does that change our assessment of the opportunity here and for more innovation?

Not at all. If anything, another kind of external proof point or validation of the opportunity that we see. We really look forward to bringing forward this innovation at pace, and we do believe very strongly that our quarterly dosing profile especially in Von Willebrand disease is quite differentiated and again, unlocking significant value. So it's great to see others that recognize the opportunity that we're talking about today.

Great. And I think we just have time for 1 or 2 more questions. Maybe Dr. Al-Samkari for you, Christi, feel free to add if you do. But just can you -- why are the diagnosis rates so low for these HHT patients? Why are the treatment rates so low for the Von Willebrand disease patients? What's the diagnostic journey for these patients? Is there genetic testing? If you could just kind of spend a couple of moments to tell people and then why they are so low and where the...

Absolutely. So in HHT the Forest registry recently -- the recent publication right it taught us that in the United States, the average patient with HHT has clear signs and symptoms of HHT by age 16, but is only diagnosed on average at age 37, right? So over 2-decade diagnostic delay, which is really unacceptable. But the reality here is that it's a manifestation of the fact this is an inherited bleeding disorder that's progressive. So it gets worse as people get older and really adult docs and I'm an adult doc myself, so I will speak for us, right? We don't do the best job in the world as diagnosing inherited disorders. It really truly many people assume that the pediatricians have done that or are supposed to do that. And many children don't have that many -- that severe manifestations of disease. The most severe manifestations in HHT are really between ages 30 and 70. That's when things come up and these patients are adults.

And so I teach everyone now recurrent epistaxis in an adult if HHT and Von Willebrand otherwise because it's the most morbid potential cause of that. And quite frankly, usually ends up being the diagnosis. So why is it not -- why it is underdiagnosed? A lot of -- sort of fragmentation of care, number one. There are about 28 HHT centers of excellence in the United States, a number that is increasing. Not all of those centers are even funded by the government yet. That's changing. There are 145 hemophilia treatment centers for half the number of patients. Most states don't even have an HHT Center of Excellence yet.

But now starting in 2022, HHT has federal funding, that funding is going up and has already gone up and more and more HHT centers are being opened. And certainly, when we have approved therapies, that's if you build it, they will come kind of situation. But it's an educational gap. And that educational gap is something that the federal funding is explicitly addressing with that -- with funding for CME for docs and for centers to teach their surrounding community.

The diagnoses are -- that the under diagnosis rate is getting better. There's actually studies that have shown these huge increases and prevalence in the United States of HHT in the last 10 to 15 years, that's not because more patients have suddenly come down with HHT. It's because of increased diagnosis. And so this is really going into hyper speed right now. And I suspect that within the next 5 to 10 years, our under diagnosis rate will be down to 20% to 30% from the current 60% or so that it is today.

Why are so many patients Von Willebrand disease not adequately treated? It's because you either have -- you have a toy hammer or a sledge hammer. There's nothing in between, right? The toy hammer is the desmopressin. The sledge hammer is the prophylactic infusions. And so a lot of these patients are just kind of left in the middle and even a lot of docs feel like, well, your disease isn't that enough for 3 infusions of [ Will ] at every week it's not that, and it's too much for tranexamic acid and desmopressin. These patients sort of left in the middle. So I really think that the -- obviously, advances here will help to address that issue.

Very helpful. Thank you for clearing up. Clearly, a lot of room for improvement here. Hopefully, we can make a difference in that as we develop medicine. I think the last question that came in, we did get a number around what our Phase III plans are.

Maybe I'll start the first part, which is -- and what do we know about regulatory endpoints. So John, I'll -- so the preview, should speak a bit to what we understand about endpoints. I can just speak about the Phase III plans. I think we've highlighted in our presentation. Obviously, we're waiting for Phase II data first, and that's a clear milestone we need to get through, and we're anticipating Phase II initial results, as Martina said, at the end of this year for HHT and we'll plan to share those in early '27 at a scientific meeting. Von Willebrands, we -- that study is ongoing, and we'll wait to see. But pending positive results in HHT, we may start a Phase III next year in '27 and Von Willebrands to follow. But we'll give you more updates on that. But again, these are programs that we think given that the short timeline, we may be able to conduct fairly rapidly, again, assuming compelling efficacy and safety data along the way.

But maybe, John, you can just speak to where -- what the thinking is around what registrational endpoints might look like in these diseases?

Sure. Of course, Pushkal, I'll give a concise answer since I know we're short on time. So for Von Willebrand disease, I think it's pretty clear, as Martina said in the slide, the primary endpoint is expected to be ABR. There's a clear precedent in Von Willebrand disease. Trials that resulted in a marketed approvals for ABR to be used. So I think that's very clear, and that's what we'll use.

For HHT, there are no approved treatments, and therefore, there is less certainty. However, we are pretty convinced that because epistaxis is so important from a disease burden perspective to patients and to physicians that, that will be one component that we need to take into account. And again, we think we will have an impact on that in our Phase II study, but we have to show it. And then obviously, we also think that other things like red cell transfusions, IV iron infusion, health care resource utilization and anemia are also important things that we need to take into account when we're thinking about Phase III endpoints.

Fantastic. All right. Well, that -- look, I think that brings this to an end. I want to thank everyone for your questions who participate in the webinar, particular thanks John, Martina and Christi to each of you and especially Dr. Al-Samkari for sharing your insights as a treating physician to today's discussion.

This concludes today's RNAi Roundtable, and you can access the replay of the webinar and download the slides in the Capella section of Alnylam's website. The tenth season of the roundtable series continues on September 17, with this session on zilebesiran which has the potential to reduce the incidence of cardiovascular events by providing continuous control of blood pressure and then followed by a spotlight on ALN-HTT02, which aims to reduce the progression of Huntington's disease on October 26. Thank you all for joining, and have a great day.

Ladies and gentlemen, that concludes today's meeting. Thank you all for joining. You may now disconnect.

Great. Good morning. Thank you, everyone, for joining us. It's a pleasure to have with us the Alnylam team. With us is Jeff Poulton, CFO; and Pushkal Garg, Head of Development.

Maybe to start here, could you lay out your 5-year goals where you've talked about 25% revenue CAGR as well as 30% non-GAAP operating margin. Could you frame the contribution of AMVUTTRA relative to nucresiran in the context of that and the pipeline as it relates to the 2030 outlook?

Yes. Let me -- I'll sort of walk through the main categories of the goals that we rolled out earlier this year. We called Alnylam 2030. This is the fourth iteration of 5-year goals that the company has put out. And this has really, we think, been part of the story in terms of driving performance for Alnylam, both externally in terms of being really clear with the market about the areas that we're focusing our business, but also internally to make sure that the employees all are rowing in the same direction on the things that are important to us.

So the areas that we focus the goals on this year for 2030 were around leadership in TTR, which clearly is a big focus of the market. And we've defined leadership across the period in 2 ways, being the sort of peak revenue franchise in 2030 and also cumulatively across the 5-year period. That's how we're defining leadership. So that's the goal for TTR.

On the pipeline, this is really about driving diversification beyond TTR. And so we're very focused on advancing the pipeline to do just that by 2030. We've got a number of metrics. I'm sure Pushkal can go into these in more detail. But we're looking to have 2-plus new products that are either in the market or a line of sight getting to market that could be blockbuster type opportunities beyond TTR.

Again, that's really important to us to start driving longer-term diversification of the pipeline. And then some other things that are important to us are expanding into new tissues because we think that, in particular, unlocks a lot of very attractive opportunities. So we're looking at 10 tissues by 2030. And then just the breadth of the pipeline, we're looking to have 40 clinical programs by 2030.

And then lastly are the things that you touched on, which are really about how we're anticipating scaling the business financially. So we guided to a 25% top line CAGR, that's product sales, collaboration and royalty revenue. And I'll get to your question about nucre versus AMVUTTRA in just a second.

And then we also guided to non-GAAP operating margin of 30% across the period. And let me just touch on that for a second because I think that was an area where the market had to adjust a bit. The market was at a much higher rate by 2030. I think consensus at the time we guided to 30% across the period was more like 50% operating margins in 2030.

And with our gross margin profile through 2030, given the AMVUTTRA royalty burden, I mean, the market consensus is around 75% gross margins, very difficult for us to be at a 50% operating margin in 2030. And we're also investing heavily in R&D across the period to drive the R&D goals that I talked about to drive long-term diversification.

So back to the question about what's AMVUTTRA versus nucre, for 2030, that's primarily going to be AMVUTTRA just because of the timing of the Phase III studies that we're running for nucre right now. Again, Pushkal can get more into the details, but we have 2 Phase III studies for nucre. The PN study will be quicker.

We're looking at 2028 in terms of timing to market. And then we look at CN is likely at 2030. So the primary revenue driver is going to be AMVUTTRA across the period post 2030, assuming that we have a profile that we think we could have in terms of a best-in-class profile for nucre. That will drive long-term top line growth, but also importantly, unlock more margin. We talk about 30% through 2030. But with a heavy royalty burden on AMVUTTRA, we think that unlocks margin into the mid-40s post the launch in cardiomyopathy.

And how does external business development fit into your strategy here? Maybe walk through size, therapeutic area and potentially even expanding outside in terms of a different modality versus siRNA.

And I'll just touch on what we said about R&D investment, and I'll maybe let Pushkal talk a little bit more about the types of things that we might be interested in. The guidance on R&D reinvestment in the business as a percentage of revenue is 30% across the period. And that does include headroom to do business development. But I'll let maybe Pushkal take the question about areas of interest.

Look, we're really excited about what we have in terms of just a product engine and the probability of success that's associated with that, right? And so if you think about it over the past years, we've had over 50% probably the success of things we put into the clinic coming out on the other side. So our primary focus is going to be in our internal pipeline. We have about 25 drugs in development, and we'll have 3 or 4 new INDs each year as we go into new areas. So that's the primary focus.

But we also recognize there's a lot of innovation happening outside, and we now will have sort of really the financial wherewithal to be thinking about some of that, as Jeff outlined, as AMVUTTRA continues to grow. And so we are thinking about where we can deploy that capital.

A lot of that is going to be used where we do think about BD is where we're going to have a very high bar, right? Again, it's going to have to compete with internal programs. And so we'll make sure there's a strong scientific and economic basis for what we're doing. And we primarily see this not sort of to be confined to more or less early-stage assets that are actually going to either really help us advance whether it's on our delivery objectives, et cetera, or early-stage assets that synergize in some way with where we have a commercial business, right? And so I think those are probably the main areas where you'll see us focusing on for the next few years. But we're in no hurry to do it. We'll be -- kind of be very thoughtful about what we do.

And what will we see from the pipeline within the next 12 months? And what do you see from that -- from the overall portfolio as kind of the key levers of next growth beyond TTR?

Yes. So I think if you -- I'll maybe start with the second part, if you think we have got nucresiran that's obviously in the clinic now, and Jeff touched on that. That's moving. We have zilebesiran now, which offers continuous control of blood pressure, 2 injections a [ year ] reduce variability, improve adherence, restore nocturnal dipping. We think that will result in a real cardiovascular outcomes benefit. So that ZENITH study is underway and enrolling well. That's not going to read out until around 2030 time frame.

In the nearer term, we have a number of things that we're going to be seeing data on. We have our first metabolic disease asset going into the adipose tissue, ACVR1C or ALK7. So that's started. We think that's going to be a big driver of reducing visceral fat while preserving muscle mass. And we see the overall obesity overweight market evolving and subsegmenting quite a bit. And so we see a real role for that, perhaps as a monotherapy, certainly in combination with other therapies against a variety of metabolic health conditions.

We have an exciting program targeting Huntington's disease that's going to give us some data this year. We have a very unique approach that targets not only the mutant Huntington's protein, the full length, but actually this important isoform, the exon 1 fragment that I think really-- now is a huge consensus in the academic community is critical to the sort of propagation of these Huntington aggregates. And so we can specifically knock down both the protein and the transcript, both of which are believed to contribute to disease. And that's in contrast to prior approaches to silence Huntington's and other existing approaches. So it's a very unique way.

And so later this year, we'll have some exciting data, we hope, in terms of both knockdown, being able to get high levels of knockdown, infrequent dosing, good associated safety. And with those data, I think we'll be in a good position to actually move into more advanced pivotal trials. And so that's something we'll be updating on later this year.

And then the third big asset that we have is an exciting program that targets plasminogen. And that is an agent that has the potential to be a universal hemostatic agent. There's about 3 million [Audio Gap] treatments really for [indiscernible] disease. We don't have effective prophylactic therapies for most of these. And so what we're bringing forward is a drug that will be a few times a year and actually stabilize clots. And the beauty here is that the genetics and the preclinical data suggest it can stabilize clots without increasing the risk of thrombosis. The first indication we're pursuing is something called hereditary hemorrhagic telangiectasia, which causes bleeding through in the GI tract, nasal cavity, et cetera. And so we'll be able to look at bleeding data from that program later in the year.

Great. Maybe just pivoting over to your TTR franchise here. So in the context of the 2026 revenue guidance, how do you view the AMVUTTRA trajectory for the remainder of the year, including any other idiosyncratic items such as shipping weeks or ex-U.S. pricing adjustments, for instance?

Yes. So the guidance, as you said, for the year is $4.4 billion to $4.7 billion Q1 was held back both U.S. and ex U.S. by some phasing factors that will not impact the balance of the year in our international markets. We had a price reduction in Germany at the end of 2026 for the launch in cardiomyopathy, which has an impact on the existing PN business, obviously, unlocks a much larger opportunity.

But in the quarter, when you take the price reduction, it does have a headwind effect on the business. So our international markets were down $7 million between Q4 and Q1. We absolutely expect growth for the balance of the year in our international markets. We're now launched in the majority of, I would say, the major markets ex U.S., so Japan, Germany, the U.K. and Italy. We're continuing to work on opening up France and Spain, but we do, again, do expect growth for the balance of the year in our international markets.

In the U.S. in the first quarter, we grew about $60 million versus Q4. And the things that we had flagged that were headwinds for Q1 from a phasing perspective were the typical insurance reauthorization process, which we did see impact the business, particularly in January. And then with the way our product gets ordered and shipped and revenue booked, the number of Wednesdays in a quarter actually has an impact. And with the way the calendar fell, there were more Wednesdays in Q4 than Q1.

None of these things that I've just described will impact the rest of the year. In the U.S., the focus is really around 2 things to drive the business. First, I would say the foundation in terms of what we've accomplished to date, one is on the sort of preference side, what we see where physicians are using AMVUTTRA, right? And they've got 3 choices to make 3 options to treat these patients today. But where doctors are experienced with AMVUTTRA for cardiomyopathy, we have a leading share amongst those physicians. That's a good starting place for us.

Secondly, I think on the access side, we've done a very good job in establishing the opportunity for physicians to write the product and feel confident that the patients can get the drug. So from a payer perspective, we're at more than 90% of patients have first-line access to AMVUTTRA. That's terrific. The only part of the market where there are some steps in place is the commercial part of the market, but that's a fairly small part of this market.

Patients, majority of the patients, zero out of pocket, right? So it's not a financial burden for the majority of the patients. And then from a provider perspective, we've really done a nice job on the buy-and-bill side, both with the health networks, the hospital networks where we've got the drug on formulary.

And then for physicians that may be outside of those hospital networks where they don't want to buy and bill, there are infusion clinics. There's about 2,000 clinics in a network that we've created that make that where they can refer the patients to the clinic to do the buy-and-bill. So that's all in place. What we're really focused on for the balance of the year is first expanding the prescriber base.

Again, I talked about we have a leading share when physicians are using it. We want to drive more utilization into the part of the market where they're not using it today. So some of that's based on sales force targeting and really focusing more energy on docs that are not using the product yet. And then additionally, we are still starting to put a little more effort behind driving earlier diagnosis.

We announced a partnership with a company called Viz.ai that has an AI algorithm that can get connected to electronic health records and review echo tests, right, both prospectively and retrospectively. And we'll run a pilot with them in 5 health networks to see if we can have success in driving more diagnosis. So those are the things I would say are highlights for the U.S. that will help drive more growth for the balance of the year.

And how are you thinking about the cadence of the ex U.S. launch and just the trajectory with regard to gross to net dynamics for the TTR drug?

Yes. I mean that's really on a market-by-market basis. Obviously, we're negotiating, I mentioned right now in France and in Spain. And look, the impact that, that will have on the business depends on ultimately where we land in terms of an agreed price. We have had some success in certain markets where we're priced at a premium to the existing standard of care in markets outside the U.S. And in other markets, it's more priced at parity. So that really is determined on a market-by-market basis based on negotiations with the local authorities.

And the U.S. net price decline?

Yes. We -- so I would say the story here has been consistent since the time of launch. We talked about a gradual reduction in net price over time as the business scales. Last year, that meant about a 5% net price decline versus 2024, and we've guided to something similar this year compared to 2025. And I think we're on track to -- that's the right guidance for the market.

Got it. Have you seen patients covered for tafamidis and AMVUTTRA combination use and in which segment? And maybe talk to evidence of cross management in Medicare Advantage.

We have seen some combination use. I think combination use is generally restricted in the commercial part of the market as well as the Medicare Advantage part of the market. That leaves the fee-for-service part of the market where there's no active payer management that are putting policies in place to restrict combination use.

And in the cardiomyopathy part of the market for us, that's probably about half of our business. And so we have seen and particularly in that segment of the market that there has been some combination use. Of course, we have data in our label, right? That's one of the subgroups that was studied in the HELIOS-B study, and we saw a consistent effect in patients that were on tafamidis as well.

And so I think that's been supportive of some of that combination use that we see ongoing. We think the more significant unlock for the combination opportunity in terms of timing happens when TAF goes generic and with Pfizer announcing recently the settlements that they've had with the generic filers that's middle of 2031, which from a timing perspective for us, given the design of the nucre study, which is largely going to be a combination study, and we think we bring that to market in 2030, that's probably a good timing for us.

You've framed that when you had Phase III data in ATTR-CM in second half could support combination use here. How are you thinking of positioning amidst payer and price dynamics as monotherapy and combination, especially in Medicare Advantage where we're cross managing as well.

Yes. I mean, again, I think what I talked about is that on the Medicare Advantage and the commercial parts of the market, they typically have policies in place today that do restrict combination use. So we're not seeing a lot of combination use in that part of the market. It's really more in the fee-for-service part of the market today.

And I don't think that will change significantly until, as I mentioned before, we get to the unlock on tafamidis -- tafamidis goes generic and then you've got a much cheaper option to do the combination with. That's what will really open up more opportunity for combination in our view.

And how are you thinking about just your pricing relative to the other drugs and there?

Yes. Look, I think there's -- we're the only drug in the Part B part of the market today. We're competing today against 2 stabilizers that are in the Part D part of the market that are at a lower price point than where we are. We're obviously waiting on the data from the AstraZeneca on this product. We -- our belief is that largely will also be a Part D product, although it sounds like they have some optionality between D and B. And so I'm not sure that, that's going to change anything when they come to market if it's predominantly a Part D product in terms of pricing dynamics for us. So we feel relatively confident about where we are right now from an access perspective.

Pushkal, do you want to speak to maybe your thoughts on how that trial will play out, both from the overall standpoint, but also in the TA/combo arm and whether that could actually be stat sig?

Yes. Look, I think they've got -- clearly, we know that molecule is effective, right? It showed good results in the PN population. And so here, they're doing an outcome study. It's about twice the size or a little bit more of HELIOS-B. So I think they're well set up to have a clinically important effect seen. I think if I had to benchmark, I would sort of say it's probably going to be more or less in the same size of treatment effects that we've seen already with AMVUTTRA and HELIOS-B. It's a little bit shorter.

So maybe they could have a little bit of a lower effect size as a result of that. But I think the fact that their population is so large still sort of sets them up, I think, for statistical significance. Now I think they've also announced recently some changes to the hierarchy of their endpoints.

How that's going to play into how far down the hierarchy they can get. It's hard for me to kind of prognosticate on that. But I think our going-in assumption is they're going to have an effective drug. It's going to be effective across the 2 segments of the population. The effect size will be in the range of what we've seen with HELIOS-B.

And so I think, again, we feel well positioned for AMVUTTRA and the fact that we already have a label that allows combination use. And again, as Jeff was saying, that we're following that up with nucresiran, which now is a much larger study, which is predominantly combination and we have both of those data sets at the time that tafamidis goes generic in 2031.

And for your next-generation TTR asset, nucresiran, for the Phase III CM study, do you believe the majority of patients will be on background stabilizer therapy? And what gives you confidence in the timing of events and the separation of the curves in that context?

Yes. So it is largely a combination therapy study. We expect there'll be some monotherapy use, but a lot of it will be on background stabilizer. And we kind of again designed this in anticipation of where we see the market evolving over time. We designed this with a lot of insights from HELIOS-B. So we have several hundred patients worth of combination therapy in that study. So we have really good individual level data to be able to understand what is the rate of sort of events that we can expect, what kinds of events, how they accrue, et cetera.

And so that gives us a lot of insight in terms of as we designed the TRITON-CM study with nucresiran. And it was using those insights that we kind of set the study up. We also recognize that it's likely, as we've seen successive clinical trials in this space that patients are getting diagnosed earlier, may be somewhat milder.

Enrollment has gone actually far ahead of schedule, and we've been really excited about that. It shows the real strong interest in this molecule. But we also, as somewhat predicted, saw that patients are a little bit on the milder side relative to what we saw in HELIOS-B. We had a predefined provision in the study to increase the sample size by 500.

And given the speed of enrollment, we pulled the trigger on that, and that's going to help us really accrue more events and compensate for the fact that maybe there'll be a somewhat lower event rate given the milder population. It's also an event-driven study. So obviously, we'll follow until we get enough of those events [Audio Gap] following that we, if anything, this increase in sample size a little bit sooner given the sample size. So we feel well positioned with that study.

Maybe a last question on the TTR side. But can you frame the size of the overall TTR market and your confidence in Alnylam's share here and where you expect these additional drugs when you antibody depleters and gene editing to ultimately fit in?

Maybe I'll start. I'll just say I'm going to repeat some things that we said on a TTR webinar that we did earlier this year around sort of our revised view of the size of the opportunity. We've talked about in the U.S., 200,000 or more patients and then globally, 500,000 or more. I think what's important is we're still very early in diagnosing and treating that patient population, right, that prevalent patient population. So we're probably around 20% of those patients are treated today. So there's a significant opportunity here to continue to drive diagnosis and treatment rates over time. But Pushkal, I don't know if you want to add.

Yes, I think as we think about treatments over time, look, this is a growing market. I think there's going to be a lot of space for multiple therapies in this disease area. I think -- we certainly feel very good about where the silencer class is, I think, going to evolve into being a foundational therapy, starting with AMVUTTRA, particularly when nucresiran comes along and to have sort of a twice-a year drug that gets to 95% knockdown, I think is going to be really great for patients.

But look, there's going to be continued innovation. The depleters are very interesting, right? We have 2 depleter studies going on now, large Phase IIIs. I think we'll see what those data ultimately look like. I think the conventional wisdom is these are somewhat cumbersome right now. They're IV. They're given monthly. I think there's several hour infusions.

And that they may be particularly used then for patients who are more advanced when they present sort of Class IV types of patients, Class III patients and really as a shorter-term induction approach to kind of clear some of the amyloid, hopefully, and then keep them on a backbone ideally of a silencer or perhaps a stabilizer depending on the physician and patient's preference.

So we look forward to seeing those data, and it will be interesting to see how that all plays out. But that's, I think, the conventional wisdom right now. I think in terms of the gene editing approach, look, I think it's a very, very interesting approach. I think -- and I'm sure there will be a segment of the population that may benefit from that or choose to opt that way.

I think the relative benefits compared to, for example, twice a year nucresiran that get you to 95% silencing, I think, starts to become a little bit more difficult to see where -- how that market evolves and given that we'll also have some challenges to figure out in terms of pricing and how that all works with a one-and-done therapy. So again, I think there'll be plenty of space for a number of players here, but we feel very good about what we're doing with both AMVUTTRA and ultimately with nucresiran.

As you noted earlier, you'll have data from 3 early-stage programs this year. Maybe starting with ALN-HTT. What's your confidence in that program in terms of the mechanism and the ability to achieve sufficient distribution here in Huntington's? And what's the bar for HTT knockdown?

Yes. So look, we're really excited about the program. We have, as we said, very strong genetic data and a lot of scientific data that's accumulating in terms of the specific way that we're targeting around this exon 1 fragment. In terms of delivery and safety, our C16 platform, and we put out now data on APP, which is the lead program in that platform.

Now we have, I think, over 18 months, 24 months of data out there suggest we can get to very high levels of knockdown over 70% with biannual dosing, and it's well tolerated. That's -- just to remind you, if you think about prior programs like Tominersen program against Huntington's disease, they got to about 25% or 30% lowering max, and that wasn't well tolerated.

They actually kept trying to have to reduce dose and space out dosing that early generation ASO. And so I think we feel good that our general approach and both now from human data from APP, what we've seen preclinically, where we can actually get very good biodistribution there as well in nonhuman primates and deep levels of lowering with infrequent administration and good tolerability.

So I think overall, the platform, we're very confident of in terms of the C16 platform. We have now multiple products that are in the clinic between us and our partners at Regeneron using that platform, and we've seen good safety, good knockdown and good biodistribution. I think we all have to have a little bit of humility going into an entirely new disease. So while we're very confident in the approach that we're taking scientifically, at the end of the day, we're going to generate data in patients to show that there's a clinical benefit that comes from that.

In terms of the target, I would say in general, I think the genetics and the preclinical data and sort of expert consensus which is if you get over about 50% knockdown, then we should be in a good range to sort of explore the therapeutic utility of that. So that's what I would be looking for.

And you have ACVR1C in obesity that's reading out as well. Maybe walk us through the strategy here with this asset and whether you would need to combine it with a GLP versus use it as a monotherapy.

Yes. Look, I think, obviously, the GLPs have transformed the entire space here. I mean it's -- but there are -- I think there still remains a fair amount of unmet need. We see the market segmenting over time, patients with various types of comorbidities, some patients who can't tolerate the GLPs are certainly at full doses.

People need to preserve muscle mass and you can't tolerate the risk of sarcopenia that comes from the GLPs. And so we're developing ACVR1C, where we think we have very strong, again, genetics and preclinical data that this can really specifically target visceral fat. And we know that visceral fat is the key factor in terms of cardiovascular morbidity and mortality, diabetes risk, et cetera.

And so what we're doing this year is this is our first adipose targeting program. We'll have data at the end of the year, primarily on knockdown, safety, but also some visceral fat data. And then we'll kind of come back and talk to you a little bit more about what we might be doing with this in terms of segments of the population, potentially in combination with GLPs, but potentially in combination with other agents as well where we think that we can really discern and make a meaningful impact on aspects of cardiometabolic disease.

You have your plasminogen knockdown program as well in bleeding disorders. Is there a benchmark that you see as meaningful with regard to reduction in bleeds in HHT? And you did recently initiate a study in von Willebrand disease and heavy menstrual bleeding. So maybe speak to the unmet need and rationale for these 3 programs.

So as I was saying earlier, this target really addresses it a protein called -- a liver protein called plasminogen, which basically leads to clot breakdown. It promotes fibrinolysis. And so by silencing it, we can actually have an antifibrinolytic effect and stabilize clots. And the beauty here is that you can actually hopefully stabilize clots, reduce bleeding without increasing the risk of thrombosis, which is what all the data would suggest.

And this mechanism is such that it really should work across a variety of bleeding disorders. So if you think about HHT, it's really a disease of vascular malformations that happen. If you think about Von Willebrand disease, which is really the most common bleeding disorder, HHT is the second most common bleeding disorder. It's really a platelet disorder, platelet aggregation. So we can attack bleeding disorders through a number of different mechanisms, all with this unifying approach that's downstream in the overall bleeding cascade.

So we picked these 2 because they both have a tremendous amount of unmet need. They're fairly prevalent with regards to rare bleeding disorders. As I said, von Willebrand is the #1 and HHT is #2. And they both -- HHT, there's no approved therapies. Von Willebrand, there are treatments that are available. They're primarily used for acute treatment, they're not really suitable for prophylaxis.

And what we're thinking about is a drug that would probably be given several times a year, subcu and really reduce bleeding risk. In terms of the magnitude of effect, look, I think it's going to vary a little bit. There's not just the number of bleeds, but there's the intensity of the bleeds that we want to reduce. If you think about HHT, for instance, there's patients who have bleeds, nose bleeds that last several hours a day that can be 3 to 4 days out of a week. The impact is devastating in terms of their ability to interact in social circles to go to school, to go to work. And so we'll be looking at all of that to characterize the efficacy of the drug.

Mivelsiran that's being studied here in Alzheimer's also cerebral amyloid angiopathy. Maybe help us understand the approach there and speak to the tau approach as well.

Yes. So lots happening in that space. So mivelsiran targets amyloid precursor protein, which is really the top of the cascade where all that amyloid is ultimately produced. Amyloid can actually come in a couple of forms, Abeta 40 and 42. And they -- some of that leads to Alzheimer's disease. Actually, the AB40 is actually involved in a disease, a closely related disease called cerebral amyloid angiopathy, where the amyloid deposits in the blood vessels of the brain cause them to become brittle and it's the second leading cause of hemorrhagic stroke, this disease CAA.

So we have a Phase I that's been going on in early onset Alzheimer's disease. We've reported out on that. We've seen great levels of knockdown tolerability. We've started the CAA study. We have a goal that we've announced this year to complete enrollment in that study. It's a 200-person study by the second quarter of this year. And that will set us up to have data end of '27, early '28 time frame.

And there, we're looking at bleeds. We're hoping to see bleed reduction. On the Alzheimer's side, we actually just -- I think it just got posted today, announced a small Phase II study in Down syndrome Alzheimer's disease. We think that this approach is going to be most effective in somewhat of a preventative setting, getting in early in disease and start stopping amyloid deposition. And it's also important because it can reduce both intracellular and extracellular amyloid as well as all the various isoforms of amyloid that form without increasing the risk of ARIA.

And so this Down syndrome population is actually -- the mechanism lines up very nicely. Trisomy 21 is the belief that actually the overexpression of APP in that setting is what actually leads to the Alzheimer's disease, which is 100% penetrant in Down patients. If they live to about 40 to 45 years old, which the majority now do, there's about 50,000 such patients about 90% to 95% of them -- and so we think our approach can be a benefit to that population. So we're doing a study there. And the learnings from there will also then inform approaches into the sporadic AD population as well.

As you touched on, there's also advances happening on the tau side. Biogen has put out some top line data suggesting that with their ASO, they may be seeing some benefits in terms of cognitive dysfunction -- cognitive function. And we have an siRNA that we're bringing forward that's in Phase I development against tau as well. And so we look forward to seeing those data. And then that will open up for us a little bit thinking about how we bring that molecule forward in Alzheimer's potentially as a monotherapy, potentially we can think about combination approaches. So really, we think we're really well set up as we kind of think about the next stage of innovation in the Alzheimer's space to make some progress.

Perfect. Jeff, it looks like you're on track for investing 30% of revenue in R&D.

I think we'll have the opportunity to do it, right? And again, importantly, what that's about is driving long-term top line growth also beyond TTR, which we think is critical and the time is now.

Yes. Perfect. Well, with that, thank you so much. Really...

Thank you.

Good morning. I'm Tazeen Ahmad. I'm one of the senior biotech analysts at the bank. It's my pleasure to have our next presenting company with us, Alnylam Pharmaceuticals. Sitting up here on stage with me is Jeff Poulton, who is, of course, Chief Financial Officer.

Jeff, welcome back to Las Vegas. Thanks for making the trip.

No, I always make the trip to Vegas. I'm always here for this one. So I appreciate the invite.

Yes. We have to continue the tradition. So maybe we can start off with a quick overview of the company in case anyone in the room isn't as familiar with Alnylam and its platform.

Yes. I mean we're a 25-year-old company. It was founded based on Nobel Prize winning science. RNAi is really a new modality that we've developed. It was a long haul to figure out some of the delivery challenges with the technology. But over the last 6 or 7 years now, they figured that out, and we've had a steady stream of products launching into the market. We've built the commercial side of the business, which I know we're going to talk a lot about here in the fireside chat.

We've transitioned the company from being a loss-making company to now being a profitable company. And we've put out new 2030 goals earlier this year to kind of provide a picture of where we think we're taking the company over the next 5 years. We think there's a lot of top line growth ahead. And importantly, now that we're profitable and we've got a real nice trajectory on the top line, we have the ability to significantly invest in the pipeline, which we're taking the opportunity to do because we want to be more than just a TTR company. That's an incredibly important franchise for us, and we intend to invest in that, but we want to be able to grow beyond TTR. And this next 5 years from a pipeline perspective is really about setting up that foundation so that there is growth beyond TTR. So there's a lot to be excited about here, I think.

We agree. So let's talk about AMVUTTRA, which is the key topic of...

Yes.

So you launched the product last year. In fact, it was this time last year, we were sitting here with early innings of the launch. So now we're comfortably into a few quarters. You have -- the sell side had to raise estimates for last year just because of the pace with which sales grew. You have now provided 2026 sales guidance for AMVUTTRA in particular, the range is $4.4 billion to $4.7 billion.

Yes, it's total TTR, it's almost all AMVUTTRA...

[ AMVUTTRA ]...

But just to be clear. Yes. Yes.

And so that's healthy growth over what you reported last year.

Yes. Yes.

And you talked about very early in the year, some of the dynamics that would be impacting 1Q.

Yes.

So now that 1Q is reported and behind us, you've reiterated guide. Maybe talk to us about what you're seeing that's giving you confidence that you could at least reiterate guide given 1Q's growth wasn't necessarily as robust as previous quarters?

Yes. Maybe I'll start there just to recap what we reported and what the kind of pushes and pulls were on Q1 and then talk about the -- we reiterated and why we're confident in our ability to achieve the guidance.

So we reported a couple of weeks ago, we did $910 million in revenue for TTR, which is 150% plus growth year-over-year. We didn't launch until CM in Q2 last year. So obviously, a huge amount of growth compared to Q1 last year.

Relative to the quarterly growth, that's what you're sort of mentioning in terms of lower growth, right? So we did -- in Q4, we did $134 million of TTR growth compared to Q3. And when we were on our year-end call, we talked about Q1 was going to be lower growth than what we delivered in Q4 for a number of reasons. One, outside the U.S., we are actually guiding to a reduction in revenue in TTR from Q4 to Q1, about $25 million is what we said to expect. And a lot of that was going to be driven by pricing in Germany.

So as we launch in new markets outside the U.S., where we've expanded the label to include CM, we are likely adjusting price downward from where it was for PN, right? We've been on the market outside the U.S. in PN for 5 years. And so as you bring the price down to launch in CM, it has an impact on your existing PN business because we got one price for the product.

And so given the size of the market in Germany and given the price adjustment and the size of the price adjustment, that was what was creating the headwind in Q1 because that price adjustment hit right at the end of the fourth quarter, so really impacted Q1.

Now the result in international and Q1 was a little better than down 25%. It was down 7%. The impact in Germany was what we expected. So we did better outside of Germany than what we had anticipated. And a couple of things. One is the CM launch in Japan, which is the first market that we launched in outside the U.S. lapped about middle of last year, is going very well. And actually, they did better in Q1 than what we had anticipated around CM volume. So that was good.

And then the PN business, which is still the main driver outside the U.S. is we're just starting to get going in CM. The PN business is performing well, and that was a little better than we anticipated. So that's why international did a little better than we expected.

In the U.S., we grew $59 million in Q1. We had grown $111 million in Q4. And when we talked about Q1 being a little bit compressed in terms of quarter-on-quarter growth, there were a couple of things that were impacting the U.S. One is insurance reauthorizations, which is pretty typical seasonality for these high-priced meds. And we did see that play out if we looked at demand, meaning shipments to patients for -- to get the injection as well as start forms, which is kind of the prescription or the start to get patients on therapy. It was slower early in Q1 than it was as we were exiting Q1. And so we do think the fact that the offices had some administrative burden earlier in the year was impacting things.

And then the other thing that we highlighted for the U.S. is just the way the product gets ordered and shipped and revenue booked. We have a closed distribution network where we've got one major distribution partner that about 80% of the volume flows through. They order every Monday, every week on a Monday, product ships Tuesday, revenue books on Wednesday. So to the extent that there's a different number of Wednesdays when you're comparing growth across periods, that can have an impact. It just so happened with the way the calendar fell that Q4 last year had 14 Wednesdays and Q1 had 12. So all that, I would say, generally played out like we expected.

So now to your point, we reiterated the guidance. To hit the midpoint of the guidance, we need to average $150 million of growth a quarter the rest of the year. We just did $50 million, $52 million, right? So there needs to be a step-up in growth for us to achieve that. Ex U.S., like we're not going to have this dynamic that we had in Germany, the rest of the year. So we absolutely expect international is going to be contributing to that $150 million in growth on a quarterly basis for the rest of the year. So that will be beneficial to us.

And then in the U.S., we definitely expect a step-up in growth. I think, first of all, I would say the foundation that we've established in the last 12 months or so, particularly around access and logistics around Buy and Bill, we've really reduced the friction. I think first from a payer perspective, we've got about 90% plus of patients that can access AMVUTTRA first line, which was a huge debate as we were coming into the launch. So there's no friction there in terms of patients getting access to the product when the doctors decide to put them on AMVUTTRA.

Patients, the majority of the patients have $0 in out-of-pocket co-pay. So that's not a particular burden that's preventing access to the medicine. And then as it relates to Buy and Bill on the provider network side, we've done a very good job in the health systems that treat a lot of these patients to get AMVUTTRA on formulary, again. So when the doctors write it, the product gets filled.

And we've also created a sort of pretty broad network of third-party infusion clinics, which is really important for a Buy and Bill drug. We've got a couple of thousand clinics that patients could access around the U.S. And that puts most patients within 10 miles of an infusion clinic. And where that's important is if you have a doctor, let's say, that's in the community that's not experienced with Buy and Bill and they don't want to do it, they don't have to Buy and Bill. They refer the patient to the clinic to get the drug administered, they can still treat the patient.

And so we've done that very well. So that foundation is really strong. What we have to do, obviously, now to drive performance for the rest of the year is drive demand, right? And one of the things that we talked about on the call is what we're seeing so far a year into this is when you get a physician to try AMVUTTRA for the first time, it leads them to prescribing more AMVUTTRA. And that doesn't matter if they start in second line or if they start in first line, they use more of the product.

So if we look across the physician universe that's using AMVUTTRA today. We actually feel very good about the share that we have there, but we want more physicians to use AMVUTTRA, right? This is obviously a market that we've launched into -- in the last year, where Pfizer was the only game in town for 5 or 6 years, and that has been the standard of care. So it takes time to change that.

And so from a tactical perspective, commercially, we are really focused now on getting to physicians that are not writing AMVUTTRA at all today and doing the hard work to get them to experience it because we think if we can get them to use it for the first time, they'll use more of it. And that's really going to be critical to the performance of the business for the balance of the year. So that's something I think that we will report on quarterly as that prescriber base and how it's expanding because that's a big focus for us right now.

Okay. So we're halfway into this quarter, can you share any qualitative feedback on what you're seeing?

No. I mean it's -- we're not going to -- I'm not going to comment specifically on Q2. Again, I do think the things that I just highlighted in terms of our expectations of what's going to drive stronger growth the rest of the year are things that we remain confident in, but I'm not going to provide any specifics to this point on Q2 performance.

So it's more based on the confidence that you have in reiterating the guidance. That's the reason for the question.

Yes. I mean -- we remain confident in our ability to achieve the guidance, which is why we reiterated. Obviously, Q2 is going to be important. We'll be halfway through the year. We need to see that growth inflection from Q1 and I'm sure people are going to be very interested to see that.

Do you expect Q1 to have similar dynamics on a go-forward basis?

Probably some of these things like the insurance reauthorization point, I think, is an issue. And that's a bit of a learning probably just because the volumes are more than when we were in PN only that became a little more apparent what the impact on the business was. That's something that I think that will be something every year that we'll see.

Ex U.S., as we get launched in all markets for CM, that dynamic that we had in Germany, that's not going to recur, right? We're launched in Germany now, the U.K. and Italy and Japan. The other major ex U.S. markets that we're still working on to open up access are France and Spain. They'll either be by the end of the year or early next year. So we'll have a lot of that pricing ex U.S. dynamics behind us, and it will really be about driving volume on a go-forward basis.

In general, what type of price discount do you have to take ex U.S.?

It differs by market, right? And it depends where the PN price is. And look, the way this works in most markets outside the U.S. is they will look at your package of clinical data that they'll compare it to the products that are in the market for the same indication. They'll assess whether or not the data is -- looks like better efficacy, similar efficacy and then they'll obviously benchmark your price to those existing products.

So typically, we're launching somewhere around the tafamidis price in these markets, and that's lower than where we were. Again, we were in -- a much rarer, much smaller part of the market in PN. And so price is coming down, but it really does differ market-by-market depending on where the PN price and what the benchmark is for CM. But generally speaking, we're adjusting downward as we launch in CM.

Okay. This market is getting more crowded...

Yes.

For the second to launch, there's ATTRUBY, which is the -- another stabilizer. I think during 1Q, there was a lot of conversations at least with investors about the fact that it looked like it continued to increase its momentum throughout the quarter. Can you talk about the potential differences relative to how that gets reimbursed versus how AMVUTTRA gets reimbursed as to why that's not necessarily the way of comparing?

Yes. I mean I don't know that I'm going to talk a lot about ATTRUBY and their performance and it may or may not what might have impacted that. I mean when I look at -- I think they've done well. I think the launch to me looks consistent in terms of the amount of revenue growth that they've had quarterly. But I don't know that I'm going to get into a sort of a comparison of reimbursement dynamics in Q1 that may have been different for them because I'm not able to speak to that.

Okay. Now if you think about the next data catalyst that's been in the space, that's going to be for Ionis and AstraZeneca and they have a silencer. They were the third ones to go into pivotal. So they took their time to design a big study...

Yes. I think they learned a little bit from the others that went before them. Yes. Yes.

Yes, for sure. So relative to HELIOS-B, they had a bigger study.

Much bigger.

It was -- they were able to stratify based on different patient populations. I think people are particularly interested in seeing what the effect will be when you add a silencer on top of the stabilizer.

Yes.

So can you talk about the different scenarios and the outcomes you think that would be impactful for Alnylam. So there's obviously the blue sky where it looks good and it looks good in all the subgroups. How should we interpret that as to potential if at all pressure on AMVUTTRA?

Yes. I mean I think our expectations are that's going to be a successful study. As you said, it's a much larger study. So there's obviously -- than HELIOS-B was. So there's a powering benefit there. I mean they're more than 1,400 patients. We were 650 patients. And you're right, my understanding is the design of the study has about half of those 1,400 patients are on background TAF. So that's going to be a pretty robust data set in combination.

And in comparison, in HELIOS-B, we had about 40% of the patients that were on background TAF at the start of the study, so 250. So they got a much larger data set there. So the powering is different than what we had.

Look, I think there is a lot of discussion about that. And if they hit in the overall study, which we think they will, and then they hit in that subgroup as well and they have a statistically significant result there, is that going to give them a benefit commercially? We don't think so. We actually do have data in combination in our label, right, because that was a prespecified subgroup. And the results were consistent in that subgroup like they were across all subgroups that were studied in HELIOS-B.

And so physicians -- some physicians are using it in combination today, likely as a result of the data that we have in the label. So if they hit a statistically significant result in that study, our view is that will be sort of viewed as a class benefit, right? And we would get some benefit from that.

There's not a huge amount of combination use going on today. There's some, and that's largely because payers are -- have policies in place, certainly on the commercial side and the Medicare Advantage part of the market, they all have policies that restrict combination use, right, to manage costs.

In the fee-for-service part of the market for us, which is 40% to 50% of our volume, there are no policies that are written to restrict it. So that's probably where we're getting some combination use reimbursed today. But we think the broader unlock for the combination opportunity is when TAF goes generic. And now we've got more clarity on the timing of that, obviously, with the settlements that Pfizer's recently announced. That looks like that will be middle of 2031 before that big unlock occurs.

And that's when I think there's going to be a different dynamic in the market likely and how these products are used together, right? And so we can talk a little bit more about that, too, in terms of some other things that we're working on that might also position us perhaps even more strongly than the way AMVUTTRA is positioned for combination use down the line.

Yes. So we've done survey work on this. It's pretty consistent that doctors feel the best outcome over time is to combine stabilizers with silencers. As you've mentioned, I think the feedback has generally been that silencers are probably not that different from each other that if the study ends up working for one silencer, the interpretation would be that you would have similar efficacy across all drugs in that class.

So we agree on the view that -- and this is probably going to be in the 2030s and after that you see an increase in combination. But to the point you just made, maybe we can talk about some of the efforts that you're undertaking now that could position the company well for that later on.

Yes. So we've got -- look, we're -- we view ourselves as a leader in TTR, and we're investing in this franchise, I think as a leader would do. So we've got a third-generation product that's in the clinic right now, 2 Phase II studies, one for PN and one for CM, this is vutrisiran, right? And this drug has the promise of being a better drug than AMVUTTRA and hopefully better than WAINUA as well.

In terms of knockdown, we see in the Phase I study that we get to 95% knockdown. AMVUTTRA is more like mid-80s. And actually, the spread, the variability around that 95% is tighter than the variability around the 85%. And we know, particularly on the PN side, when we get deeper knockdown, it leads to better efficacy in the disease. And so we're hopeful that this study because of the deeper knockdown is going to show better efficacy. So that's kind of point one.

Point two, with this product is it's got longer duration. So this is a once every 6-month subcu administration. AMVUTTRA is once a quarter. WAINUA is once a month, right? So that would give us a real convenience advantage from a patient perspective. And we absolutely know patients would much prefer fewer injections than more. And so that would be positive to uptake.

And then lastly, from an economic perspective for us, this is pretty meaningful that there's no royalty burden on this product like we have on AMVUTTRA, which is close to 30%, given that there's a tiering of 15% to 30%. But given the tiering and the size of the commercial opportunity, like the weighted average is going to be pretty close to 30%.

And so just to touch on the -- what that could mean for us economically and sort of margin-wise longer term, we've guided with our Alnylam 2030 set of goals to have operating margins around 2030 -- I'm sorry, around 30% across the period out to 2030. That's weighed down by the gross margin because of the royalty we own on AMVUTTRA that's about 75% across the period.

So if vutrisiran delivers on this promise, right, of having better efficacy, more convenient and we get that into the market, that's going to be a very attractive profile, and I think it's going to drive nice uptake. And that really then unlocks a much lower gross margin and more significant operating margin post 2030. And we've talked about it, we see a clear path to mid-40s on operating margin. So this is an important product for us.

But let me talk a little bit about, again, the study, the CM study that we're running for that program, vutrisiran. We expect that's a study that -- it's an outcome study. And one of the things that we did with that study, and this is frankly, learning from HELIOS-B was rather than a time-bound endpoint, we've got an event-driven endpoint there, right? So that we sort of were more comfortable with the powering in the study as a result of that because patients are becoming diagnosed earlier and earlier, kind of less advanced in the disease, event rates are lower. So we've got an event-driven endpoint. I think that makes us feel good about the powering.

One of the things that we just announced on the Q1 call is that we've decided to increase the size of that study. We initially announced it as about a 1,250-patient study. And in the protocol, we had given ourselves the option to upsize that by 500. And we chose to do that and announced that on the call. The reason we announced it when we did is because the enrollment is going very, very well on that study. And we didn't announce it and make this decision pretty soon. That study was going to complete enrollment very soon to 1,250.

So we've decided to upsize the study. That's mostly around managing time risk with the study because it's an event-driven study and the patients that we're enrolling in the study are milder, similar to HELIOS-B, maybe just a little bit milder, but there's uncertainty around event rates and how long will it take once you get it fully enrolled to hit that number of event -- endpoints. And so having more patients in the study obviously gives you an opportunity to accrue more events faster.

So we feel actually -- even though we've upsized the study and we've got a little bit more enrolling to do, our confidence level in 2030 is higher. And that -- now that we know when TAF is going to go generic to have that product in the market that will have a huge amount of combination data, like that's largely going to be a combination study. We'll have enough monotherapy patients in the study as well to have that part of the label. But that's mostly a 1,750 patient going to be a combination study.

And so we'll have that data. We'll have -- we're assuming that the study -- the events accrue the way we think they will. We'll have that product in the market before tafamidis goes generic now given the timing of that. And again, if this becomes largely a combination market, that's good that we're going to have that product positioned in the market before TAF goes generic.

So we're excited about that. And I think that was a meaningful change. I don't know that the market completely understood what we did and why. So I wanted to be clear about that. That's mostly about managing time line risk in the study and getting to the number of events that we need to have to complete the study. And I think the fact that it's enrolling as rapidly as it is, is a very good sign.

Okay. So you talked about making this available and that could be attractive for patients. How are you thinking about switching patients from AMVUTTRA to nucre when it does come out?

Yes.

How would the dynamics of that work?

I mean -- I talked about the potential for the profile having -- this is a progressive fatal disease. So if we have efficacy data that looks better, than the existing silencers that are in the market. I think that's going to drive uptake, added to the fact that if it's twice a year rather than 4x a year or 12x a year, I think it's going to drive -- it's going to be an attractive profile for patients. And I think that will drive a lot of uptake for us.

Okay. Maybe another question about near-term competition. Assuming that Astra has positive data that -- they apply and then they launch next year, what is the concern that they might try to use price as a way of trying to gain traction in the market?

Yes. I mean they're -- today, they're a Part D product. They're not in the market for CM. They're in the market for PN. And in the U.S., they're actually priced higher than we are. I think, close to 10% higher.

We're already competing against 2 Part D products, both stabilizers, and they're both at a lower price point than we are today. And I talked earlier about access for us. That fact that there's 2 products on the market that are at a lower price point has not impacted our ability to get AMVUTTRA to patients on a first-line basis, right? More than 90% of patients have access to it.

So I don't think having a third Part D product that's at a lower price is actually going to change the dynamics that we're dealing with today and meaningfully impact access to AMVUTTRA. So again, we feel comfortable with the access dynamics at this point in time. I don't think that's going to change dramatically when they launch.

Okay. And then on discontinuations, are they tracking in line to what you would expect?

Yes. This is one of the things I believe that's underappreciated in the value of our medicine. We've got adherence and compliance on our drug that are more than 90%. And generally speaking, the biggest reasons why patients discontinue taking the therapy is because they pass away, right? This is a fatal disease ultimately.

And I think when you compare that just in general to patients that are on products that require them to take daily pills or sometimes -- in the case of one of our competitors, twice a day to take pills, patients even with these kinds of diseases are not compliant, right? And we have the benefit of very good compliance.

I think partly because it's fairly convenient once a quarter, which aligns with physician visits that they have. I think one of the things that we also do very well is we've got a patient services hub that supports these patients and is actively working with patients to make sure that on a quarterly basis that they're getting access to the medicine that they need. But ultimately, that can lead to better outcomes just being compliant.

And so I think that's a big advantage for us, and that's something that we're going to continue to really focus on to make sure that patients are staying on the drug. And obviously, patients staying on drug and getting it every quarter also has a beneficial impact to us in terms of consistent revenue.

Okay. So let's talk about the rest of the pipeline. So maybe just remind us of what data updates do you expect from the earlier pipe...?

Yes. I think we've got 3 readouts in the second half of the year that are worth paying attention to. Maybe we'll start with our Huntington program. This is a program that we're -- that's in a Phase I study that we're developing in partnership with Regeneron.

We've got an exon 1 targeting approach here. We're running a Phase I study that's primarily looking at safety in PK/PD, like how much knockdown can we get. We think for a variety of reasons, we believe we may have the right approach here to treat this disease. But what we really want to learn from this study, frankly, is what level of knockdown can we get hopefully, safely and form a dose that we would then take forward into a study that we would really be looking at efficacy. So we'll have that initial data in that program later this year.

Our bleeding disorder program that's targeting plasminogen, and this is a program that we think could ultimately be a pipeline and a product type opportunity where we have the ability across a variety of bleeding disorders to sort of improve clot stability with the genetics on this particular target without increasing the risk of thrombosis. And there's hundreds of bleeding disorders that very few of have treatments today.

The first indication that we've got a Phase II ongoing right now is in a disease HHT. I'm not going to pronounce it because I'll get it wrong, but that will have a Phase II readout that's a proof-of-concept readout where we're really looking at -- we're looking at the number of nose bleeds in that study. So we'll have that in the second half of the year.

In addition to we have an ongoing Phase I study in healthy volunteers. We'll have some additional data. We're actually expecting to start second indication Phase II with that same therapy this year. And so we'll actually do a -- we're going to do an R&D type webinar on this program later in the second quarter. So pay attention to that. We'll put some news out on that. I think this is an important one that the market probably isn't as educated on as we would like them to be. So we're going to spend some time talking about the product as well as the market opportunity that we see for that later in Q2.

And then...

Do you know how many -- sorry to interrupt you, but how many HHT patients are there?

I think in the U.S., from a prevalence perspective, the number is about 70,000. Now all those patients aren't diagnosed and treated today. There are actually no on-label treatments for this disease today. This is one of the things I think that we'll educate on in the webinar in terms of what's the burden of treatment associated with this disease. It's a pretty horrific disease in terms of impact on quality of life. And so we think it's an interesting opportunity. So more to come on that in the second quarter.

And then the last thing, I think, from a readout perspective is our initial obesity program, where we're targeting adipose tissue to go after ACVR1C. So this will -- again, this will be early Phase I data where we'll get PK/PD information, and we'll have that by the end of the year as well.

And how big is that opportunity?

I mean, obesity is huge, right? But this is lots of questions about some of these targets and some of the competitors have these about how much monotherapy weight loss can you get? How would you position these? Would these be monotherapy? Would they be combination? I think more to come on that in terms of our perspective on that.

Okay. And then last question on cash.

What was that?

The balance sheet?

Yes. I mean the good thing is I don't have to think about that quite as much as I used to. We ended the year with around $3 billion in cash, and we're going to start adding cash to the balance sheet as we go now that we're profitable, which is a nice position to be in.

Questions about capital allocation and that has start to come up more and more as you start to see a bigger cash balance. And we've talked about the priorities right now are 100% TTR launch and continue to invest appropriately behind that to drive demand. So that's a priority.

And then on innovation, certainly, internal innovation is the priority, but we have talked about starting to add external innovation into the mix as well. So I do think business development is an area that we will focus and we will start to spend some dollars on external innovation as well, likely earlier stage things. I think in particular, one of the areas that we're looking for some help externally is on delivery, right? We're trying to get to 10 tissues by 2030, and there's a lot of interesting innovation going on across the industry in delivery. And so that could be an area that we would invest from an external innovation standpoint.

Okay. And that's potentially near term, but if you see something...

Yes. I mean we're building the -- I would say we're building the BD muscle now. We've hired a new Head of BD in the last 6 months, and she's helping us build that team internally and sort of build the muscle on how you do these things. So we're starting down that path.

Okay. Perfect. With that, we're out of time. So Jeff, thank you.

Thank you.

[indiscernible] time with us.

Appreciate it.

Thanks, everyone, for joining.

Hello, and thank you for standing by. My name is Ian, and I will be your conference operator today. At this time, I would like to welcome everyone to the Alnylam Pharmaceuticals Q1 Earnings Conference Call. [Operator Instructions] I would now like to turn this call over to the company. Please go ahead.

Good morning. I'm Christine Akinc, Chief Corporate Communications Officer at Alnylam, with me today are Yvonne Greenstreet, Chief Executive Officer; Tolga Tanguler, Chief Commercial Officer; Pushkal Garg, Chief Research and Development Officer; and Jeff Poulton, Chief Financial Officer.

For those of you participating via conference call, the accompanying slides can be accessed by going to the Events section of the Investors page of our website, investors.alnylam.com/events. During today's call as outlined in Slide 2, Alnylam [indiscernible] our introductory remarks and provide some general context. Tolga will provide an update on our global commercial progress. Pushkal will review pipeline updates, clinical progress and upcoming milestones, and Jeff will review our financials and guidance before we open the call to your questions.

I'd like to remind you that this call will contain remarks concerning Alnylam's future expectations, plans and prospects, which constitute forward-looking statements for the purposes of the safe harbor provision under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those in our most recent periodic report on file with the SEC.

In addition, any forward-looking statements represent our views only as of the date of this recording and should not be relied upon as representing our views of any subsequent date. We specifically disclaim any obligation to update such statements. With that, I'd like to turn the call over to Yvonne. Yvonne?

Thanks, Christine, and thank you, everyone, for joining the call today. The first quarter of 2026 demonstrated continued strength of the business and represents the type of execution that will drive continued growth at Alnylam. Our leadership in TTR amyloidosis was on display, having achieved over $900 million in total net revenues from AMVUTTRA and ONPATTRO combined. We also entered into exciting new collaborations that we expect to drive TTR disease awareness and diagnosis and improve overall care pathways for patients.

On the R&D side, we continue to progress our deep pipeline of investigational medicines, including the presentation of impactful data for vutrisiran and [indiscernible] at ACC. We also initiated a Phase I trial of ARN-2232, which is our first adipose directed RNAi therapeutic and targets ACVR1. And on the financial front, the more than $1 billion in combined net product revenues generated in Q1, Alnylam's first quarter, exceeding the threshold in our history an important milestone.

We're also reiterating our full year financial guidance, reflecting continued confidence in the AMVUTTRA launch and the strength of our overall portfolio. [indiscernible] of biotech with a differentiated model built on a proven durable innovation engine and strong commercial execution, positioning us for sustained long-term growth. As the leader in RNAi therapeutics, we have established a modular reproducible approach to drug development and a product engine that has consistently translated scientific innovation into successful method. This high-yielding platform, combined with our outsized historical probability of success relative to the industry will be key to driving future growth. That capability is reflected in a deep pipeline of more than 25 programs currently in clinical development with continued expansion into new indications and therapeutic areas along with evolving platform capabilities.

Lastly, today, there are 6 Alnylam invented medicines that are collectively generating several billion dollars in annual revenues reaching hundreds of thousands of patients around the world. My colleagues will outline for you the commercial, R&D and financial progress we made in the first quarter of 2026. All of this progress builds our momentum towards accelerating innovation and scaling our impact as we look to deliver on our recently announced 5-year vision Alnylam 2030.

These ambitions are anchored in 3 strategic pillars. The first is to establish global leadership in TTR while continuing to build a durable franchise. Our second pillar focuses on growing through sustainable innovation where we aim to deliver therapies to not only slow the progression of the [indiscernible] but prevent halt or of asset. And the third pillar is scaling with discipline and agility to enable durable profitable growth. Taken together, our nylon 2030 represents our strategy to become the leading science-driven fully integrated global biopharmaceutical company and to maximize the potential of RNAi therapeutics for patients.

With that, let me now turn the call over to Tolga for a review of our first quarter commercial performance. Tolga?

Thanks, Ivan, and good morning. I'm pleased to share our continued progress in bringing Alnylam's therapies to patients globally. Q1 was another strong quarter of commercial execution and marked our first quarter exceeding $1 billion in product revenue, Specifically, we delivered $1.03 billion in combined net product revenues, up 121% year-over-year and 4% over Q4 2025.

While our TTR franchise continues to be our primary growth engine, we continue to see consistently strong performance in our rare disease business. So let's start there. Our rare disease portfolio continues to deliver meaningful impact for patients and consistent performance for our business. We generated $126 million in rare disease net revenue up 15% year-over-year. Growth was driven by increased patient demand, partially offset by higher gross to net deductions across U.S. and international markets.

Now turning to our TTR franchise. One year into the ATTR-CM launch, Alnylam continues to show strong momentum. Global TTR net revenues reached $910 million in Q1 and up 6% from Q4 and 153% year-over-year. In the U.S., TTR revenues grew 9% versus Q4 and more than 230% year-over-year. reflecting continued growth in patient demand. The $59 million in U.S. revenue growth over Q4 was achieved despite fewer Q1 shipping weeks and customary insurance reauthorization dynamics earlier in the year, anticipated headwinds that we shared with you on our February earnings call.

Access remained broad, pull-through was strong and adherence exceeded 90%. Outside the U.S., revenues declined $7 million from Q4, primarily reflecting our previously announced updated pricing in Germany following the ATTR-CM launch, but grew 35% year-over-year. Importantly, international TTR revenue outperformed our Q1 expectations shared in February, primarily due to continued strength in Japan, where our CM launch execution remains on track with leading analogs as well as strength in PN performance across our international markets.

This strength provided more balance to the quarter than anticipated as we did see the expected headwinds from the price adjustment in Germany. We remain confident in our 2026 TTR revenue guidance as we continue to expect more substantial quarter-over-quarter growth in TTR revenues, both in the U.S. and across the world over the balance of the year. As we move into the next phase of U.S. ATTR-CM launch, our focus is grounded in the strong foundation established in 2025.

First, physician preference and utilization. Alnylam's clinical profile has driven a strong and compelling first-line positioning with strong preference demonstrated by physicians who have experience using it; second, access and affordability. Our access has improved versus 2025 and continues to be durable with over 90% patients covered with first-line access and most facing 0 in out-of-pocket costs. Third, side of care infrastructure. We built a robust provider network designed to deliver a seamless patient experience. These fundamentals enabled a highly differentiated launch with rapid uptake and strong utilization across lines of therapy.

Importantly, our initial success has shown that physician experience with Auto leads to deeper and sustained use over time. As highlighted during our TTR investor event, moving forward, we're focused on the following 3 indicators of continued launch success. First, prescriber base expansion. We've already built a large and expanding base with more than 1,200 unique new U.S. prescribers since last March.

When we look at prescribing trends on an individual health care professional basis, we generally see that initial utilization of AMVUTTRA by a new prescriber is relatively balanced between first and second lines of therapy. Second line use is being driven primarily by moving that prescribers existing base of patients progressing on stabilizer on to AMVUTTRA, either a switch or combo therapy. Over time, as the existing base of stabilizer patients is transitioned.

We generally see that prescribers new second-line scripts reduced to a normalized level. Importantly, health care professionals experience with AMVUTTRA breeds a greater number and proportion of new scripts in the first-line setting. So our experience with AMVUTTRA has translated into a durable preference, and we also see significant opportunity coming from expanding the number of prescribers. We will do this by increasing engagement with physicians who don't yet have experience with AMVUTTRA, reinforcing the role of AMVUTTRA across the full patient journey and maintaining seamless patient access.

Second, sustained category growth. ATTR-CM remains significantly underdiagnosed and undertreated with an estimated 200,000 patients in the U.S. and more than 80% of still untreated. We are addressing this gap directly as part of our TTR leadership agenda, advancing practical, AI-enabled partnerships to facilitate earlier diagnosis and treatment. Collaborations with [indiscernible] others as well as support for an initiative with American Heart Association, or embedding AI diagnostics into real-world care pathways, expanding patient identification, and accelerating access to therapy.

Third, [indiscernible] and persistence supported by quarterly dosing and actual patient adherence. Pushkal will share some more color in a moment, but recently presented real-world data demonstrate greater than 90% adherence to vutrisiran over more than a 2-year period. This profile translates into [indiscernible] patients and by extension into sustained revenue which is central to any long-term growth outlook.

Online's global footprint is enabling strong execution on international market access for Aura reflected in a series of positive reimbursement milestones across key markets. In Europe, we're seeing favorable health technology assessment outcomes and reimbursement momentum, including recent launches in Austria, the U.K. Switzerland and Italy, supporting broader patient eligibility and more streamlined treatment pathways.

Taken together, these developments reinforce the growing global recognition of the value of AMVUTTRA and positions are slow to expand patient reach around the world. With that, I'll turn things over to Pushkal.

Thank you, Tolga, and good morning, everyone. Alnylam undoubtedly has one of the most robust pipelines in biotech with over 25 clinical programs, spanning multiple therapeutic areas across rare specialty and prevalent indications, representing a tremendous opportunity to improve patient health and create value in the years ahead.

Over the next few moments, I'll double-click on some of these programs to highlight some key near-term value drivers in the pipeline. In support of our ongoing efforts to demonstrate AMVUTTRA's unique profile that we believe supports first-line use, we shared new data on the drug's impact on patients with ATTR-CM at the recent American College Cardiology Annual Meeting. As Toga briefly mentioned, a retrospective cohort study of approximately 4 years of real-world data in patients with transthyretin-mediated amyloidosis indicated high adherence and persistence to vutrisiran treatment. Over the treatment period, greater than 93% of patients were adherent to vutrisiran, defined as 80% or more days covered by vutrisiran and over 85% remained on therapy for more than a year.

These data stand in contrast to the low adherence and persistence we've seen with many oral therapies and support the potential for vutrisiran's clinical trial benefits to translate into a real-world setting. In another analysis, we looked at diastolic dysfunction, which is known to be prognostic of poor outcomes in patients with ATTR-CM. The post-hoc analysis of HELIOS-B assessed outcomes at month 30 in patients who had evaluable diastolic dysfunction grades, DDG at baseline. There were 3 key findings.

First, higher DDG at baseline corresponded with adverse outcomes in ATTR-CM in the HELIOS-B study. Second, vutrisiran was associated with a lower risk of worsening DDG and compared to patients receiving placebo. And finally, vutrisiran reduced the risk of all-cause mortality and cardiovascular events during the double-blind period, irrespective of patients' baseline DDG. Together, these data continue to underscore the differentiated and substantial impact of vutrisiran in ATTR cardiomyopathy. We also continue to advance our next-generation TTR [indiscernible] in the TRITON Phase III program. As a reminder, interim Phase I results with nucresiran demonstrated greater than 95% mean TTR knockdown and were supportive of a twice-yearly dosing regimen.

TRITON-CM is a randomized double-blind events-driven outcome study of nucresiran versus placebo. We initiated the study last year and are encouraged by the very strong interest we've seen from both investigators and patients who wish to participate. As a result, enrollment is proceeding faster than expected. In addition, and as anticipated, the patients enrolling in this study have somewhat milder disease on average, than those enrolled in HELIOS-B due to greater disease awareness and earlier diagnosis around the world.

Our study already includes a built-in safeguard against potentially low event rates in that it is event-driven. In other words, we will continue the study until we have enough endpoint events to ensure sufficient study power. Today, we are announcing that we will take advantage of the fast pace of enrollment to utilize a prespecified option in our protocol to expand enrollment by approximately 500 patients or from 1,250 to about 1,750 in total. This increase further mitigates the risk of low event rates, while maintaining or potentially even accelerating time lines for this important study.

Given the rapid pace of enrollment and the anticipated accrual of endpoint events we still project to launch by 2030, assuming positive data and regulatory approval. In addition, the TRITON-PN Phase III trial in hereditary ATTR polyneuropathy is also ongoing and if successful, has the potential to support approval in this indication by 2028.

As we look ahead to the next period of R&D evolution at Alnylam were guided by our new Alnylam 2030 set of 5-year goals specifically the pillar of growth through sustainable innovation. As a reminder, we've committed to delivering at least 2 new transformative medicines beyond TTR with blockbuster potential. We also anticipate achieving RNAi delivery to at least 10 tissue types with over 40 programs in the clinic by the end of 2030.

And lastly, we aim to invest approximately 30% of revenues in non-GAAP R&D through this period to support our next wave of medicines. We're on our way to achieving these goals and look forward to many clinical readouts in the coming quarters and years to unlock these transformative programs, which will propel Alnylam into its next phases of growth.

As for 2026, we plan to share updates from across the pipeline as outlined here. In the first half of the year, we expect to complete enrollment in the Capricorn 1 Phase II trial of mevelsiran in cerebral amyloid angiopathy and to initiate a Phase II trial of [indiscernible] in Alzheimer's disease. We're also on track to initiate a Phase II trial of ALN-6400 in a second bleeding disorder. In addition to these study milestones, we also look forward to several clinical readouts from 3 different programs in the second half of the year.

For ALN-6400 in bleeding disorders, we plan to share Phase I data from healthy volunteers in Phase II results in patients with hereditary hemorrhagic tolangictasia. We also plan to share Phase I data for ALN-HTT02 in patients with Huntington's disease and ALN-2232 in development for obesity and weight management. Within our robust pipeline are several programs, each with multibillion-dollar potential that we believe represents the next wave of transformative medicines. ALN-6400, which we believe has potential application across a wide range of bleeding disorders, [indiscernible], which has the potential to reduce the risk of cardiovascular events by providing continuous control of blood pressure and ALN-HTT which we are starting to treat Huntington's disease are among the many opportunities in our pipeline that may improve human health and accelerate growth in the years to come.

Given these are novel therapeutics that have the potential to change the practice of medicine, I'm excited to announce that we will be discussing each of these programs in greater detail during upcoming webinars starting this summer. Those of you who have followed Alnynam for a while may recall our RNA Roundtable series in which we spotlight key pipeline programs of interest in discussed disease areas, treatment landscape, unmet needs and the differentiated impact possible with RNA therapeutics. We'll be using a similar format to deep dive into each of these programs and outline the opportunities this summer. Stay tuned for more details in the coming weeks. With that, let me now turn it over to Jeff to review our financial results and 2026 guidance. Jeff?

Thanks, Pushkal, and good morning, everyone. I'm pleased to be presenting a summary of Alnylam's first quarter 2026 financial results and discussing our full year guidance. Let's begin with a summary of our P&L results for Q1 2026. The Total global net product revenues for the first quarter were more than $1 billion or 121% growth versus Q1 last year, driven by the continued uptake of AMVUTTRA and ATTR cardiomyopathy. We achieved $910 million of TTR revenue in the first quarter, a $52 million increase versus Q4, consistent with the Q1 phasing expectations we discussed on our year-end earnings call in February. For the first quarter, collaboration revenue was $82 million or a 17% decrease compared with the same period last year. The decrease was primarily driven by a $30 million milestone payment received from [indiscernible] in Q1 2025.

Royalty revenue for the first quarter was $49 million representing an 85% increase compared to the first quarter of 2025, driven by higher global [indiscernible] sales. Gross margin on product sales was 80% for the first quarter representing a 5% decrease compared with Q1 last year. The decrease in margin was primarily driven by increased royalties on AMVUTTRA as higher revenues in 2026 and resulted in an increase in the average royalty rate payable to Sanofi compared with the same period last year.

Additionally, a quick reminder that the royalty rate we pay Sanofi on sales of AMVUTTRA resets each calendar year. As a result, as AMVUTTRA's sales increase over the course of the year, we anticipate that the average royalty rate on sales of AMVUTTRA paid to Sanofi will increase, resulting in a decrease in quarterly gross margin on product sales over the course of the year.

Our non-GAAP R&D expenses of $335 million increased 39% compared to last year, primarily driven by the costs associated with our ongoing 3 Phase III clinical studies including the Xenith cardiovascular outcomes trial for zalbisiran and the TRITON-CN and PN studies for nucresiran. Beyond the pivotal programs, we continue to increase investment to support important programs for bleeding disorders, Huntington's disease and CAA as well as early pipeline investment to deliver new INDs.

Non-GAAP SG&A expenses of $283 million increased 36% compared to last year, driven primarily by investments in support of the AMVUTTRA ATTR cardiomyopathy launch in the U.S. and in the international markets as well as increased employee compensation costs and other scaling investments to support the organization. We achieved non-GAAP operating income of $339 million, which represents a more than 4x increase compared to last year, driven primarily by the strong top line results that I previously highlighted.

We continued to deliver profitability on both the GAAP and non-GAAP net income basis in the first quarter, which represents our third consecutive quarter of both GAAP and non-GAAP profitability. Finally, we ended the first quarter with cash, cash equivalents and marketable securities of $3 billion compared with $2.9 billion as of December 31, 2025. The primary driver of the increase in cash during the quarter was our strong operating performance.

Now turning to our full year guidance. Today, we are reiterating our 2026 guidance as presented during our last earnings call, and as summarized on our guidance slide. Notably, on TTR revenue, as Tolga previously highlighted, our guidance continues to reflect an assumption of significantly higher quarter-on-quarter revenue growth for the balance of the year in order to achieve our $4.4 billion to $4.7 billion TTR product sales guidance.

Let me now turn it back to Christine to coordinate our Q&A session. Christine?

Thank you, Jeff. Operator, we will now open the call for questions. To those out then, who would like to ask you to limit yourself to 1 question each and then get back in the queue if you have additional questions.

[Operator Instructions] Our first question comes from the line of Ritu Baral with TD Cowen.

So Tolga, I wanted to ask you a little more about your comments around first-line use and second-line use. You said that they were balanced, and I believe you mentioned that use improves with experience. And then you said something about second-line use reducing to normal levels. What is that sort of experience that you're seeing? Is it that doctors are starting with second line? And then with increased exposure and experience willing to start patients on first-line or are they starting on first line? And how much does your detailing sort of detailing contribute to it or combination therapy contribute to it as well.

There's quite a lot in that question, and we'll try to plan to unpack it as we go. But just before I turn it over to Tolga, I mean, just kind of reiterate our confidence really in the fundamentals of the AMVUTTRA launch. And we're really pleased with the progress that we've made as we march towards achieving our goal of TTR leadership by revenues through this next period. But Tolga, let's dive a little bit into resides.

Sure. No, I think it's an important dynamic and happy to expand more on that. So what we're really describing is the natural evolution of second-line dynamics as the launch progresses. As new prescribers begin using AMVUTTRA, essentially initial utilization is typically balanced between first and second line. early second-line use is obviously driven by physicians treating patients progressing on stabilizers. They had these patients that were already progressing in the last 5, 6 years. and they were waiting for a product with essentially in our target of mechanism of action. So over time, as those patients have transitioned second-line volume normalizes. At the same time, what we're really excited about is the growing physician experience has been leading to increased adoption in the first-line setting. I think that's a really important element to highlight. So we see this as a really positive and expected progression that you would see the early in the launch dynamics. Today, the business is modestly way towards first line. while second line remains an important and ongoing contributor to growth. And obviously, we are -- [indiscernible] we're talking makers of action, we are the -- we have the highest share in that respect. But what's also important is this is a gradual shift in mix as physicians move from early adoption to more established prescribing patterns. And from a strategic standpoint that you asked, -- our focus remains on strengthening first-line positioning, which in turn supports both broader and more durable utilization, including second line given our differentiated product profile. So for us, the key driver from here is really going to be about expanding the prescriber base, bringing more physicians into the AMVUTTRA experience, which we consistently see that translates into deeper and early line use over time.

Our next question comes from the line of Paul Matteis with Stifel.

I was wondering, Jeff, if you could try to help do some math for us on the call as it relates to the headwind this quarter from selling weeks? I know you talked about 2 [indiscernible] weeks, but I think that might be related to 1 specific. And then conversely, maybe if there was any sort of inventory headwind or benefit this quarter and sort of when you net out and take a step back, how would you sort of simplify for us what we're seeing in terms of actual demand growth from 4Q to 1Q for AMVUTTRA in the U.S.

Great. Thanks for the question, Paul. Look, good question. I think Q1 played out generally in line with our expectations in the quarter. If you look at the U.S. results, $59 million in growth. That was primarily demand-driven. There was some positive inventory impacts in the quarter, but that was offset by pricing, which is continuing to trend in the direction that we expect. Just to remind you on the things that we talked about impacting the quarter, insurance reauthorizations in the U.S. were part of the story. And we did see that. I mean, if we look at demand and start form generation across the quarter. January was the lowest, and we saw sequential improvement in February and March. So that played out as we expected. And then you hit on the ordering patterns, yes, that's correct. The number of Wednesdays in the quarter actually does make an impact in terms of comparisons quarter-to-quarter just because of the way the ordering works in the U.S. So the way things work in the U.S. for us is there's one wholesale distributor that we work with that drives about 80% of the volume. They order every week on Monday in the U.S., product ships on Tuesday and inventories received and is recognized on Wednesday. Just the way with the calendar fell last year and then into this year, there were 14 Wednesdays in Q4 last year and 12 in Q1. So that contributed. Look, if you looked at the TTR growth last year in the U.S., it was $111 million and again $59 million in Q1. So I think, again, this all played out as we expected.

I just wanted to clarify on the selling weeks. We have that dynamic at like close to an 11% sequential headwind. Is that an exaggeration of [indiscernible] dynamic or kind of roughly where we should be modeling it?

Yes. Again, I'm not going to get into maybe the specific detail on that, Paul, per your question, but it did have an impact and which was one of the reasons why we flagged it on the call in February. Just thinking about going forward, right, for Q2, there will be 13 Wednesdays. Q3 will have 14 in and then Q4 will have 13, right? And so over the course of the year, there's 52 Wednesdays, but that's how they're going to fall. So again, it's one of the things that drives confidence in our view in terms of growth going forward, higher levels of growth. on a quarterly basis going forward in the U.S.

If I could add in terms of the -- how the quarter should be characterized from a demand perspective, it was really largely driven by demand. So we did have some inventory benefit, but that was really offset by the gross to net adjustments. So net-net, this was really about demand growth.

That's spot on. Thanks for providing some color to the quarter. I mean, we were really pleased to be able to maintain patients how well the authorizations went, how patients were able to kind of get access with our commitment to make it as easy as possible for them. So we're seeing kind of good progress from 2025 to 23.6%.

Our next question comes from the line of Tazeen Ahmad with Bank of America.

There's a study coming up for a competitor who has the [ silencer ]. I think there's a lot of eyes on the portion specifically related to adding that [ silencer ] on to a stabilizer. So I wanted to get your thoughts if that portion of the study proves to be robust, is there any reason to think that a result like that would not have been replicated with Ambu you had designed that trial. And looking ahead, how do you think physicians would interpret that type of data? Would that be specific to the target set? Or do you think it would be validating for silencers overall?

Thanks, Tazeen. Maybe I'll take a question. Tolga may have something to add as well at the end. Yes. Look, I think we're obviously looking to see the cardiac transform results as they come out. I think we're expecting a little later this year based on the announcements yesterday. But I think as it relates to the combination portion of that study, yes, it's -- they've got an upsized portion in that study. And we fully expect that, that study will be positive and that those results are positive. The reason we believe that is because we have the HELIOS-B results which have already shown that the silencing mechanism is effective in monotherapy and in combination therapy when it added on a background of stabilizer. We saw strong results in that category. It was not powered specifically for that group, but we saw additive benefit that was commensurate with the benefit we saw as a monotherapy. And that was realized then in the product labeling as well, where it was recognized that there was equal effectiveness on or off [indiscernible] and that's captured in the take in the label. And so we're obviously able to communicate that appropriately with prescribers and Tolga can talk more about that dynamic. So I do expect that they'll see a [indiscernible] benefit there, but I think it really just enhances and further validates the signal that we've already seen with this drug. The other thing I would just mention is that we talked today about the nuu study with TRITON-CM. And that is going to -- as we've talked about before, be primarily a study adding on top of patients who are on a stabilizer. And with today's announcement, I think we'll have perhaps the largest experience coming out of that study. So a very, very rich data set showing the benefits of adding a silencer on top of a stabilizer. So I think we're looking forward to those results as well. So I think we're very well positioned, both for how treatment patterns are today and how they're going to evolve over time. But Tolga, you have anything to add.

Making a kind of commercial comment [indiscernible] here, too. I think you've kind of focus very well on how we think about apron. But I think it's worth referencing our success in the PN indication. I mean, I think as you have seen in PN, there are 2 real dynamics that works in our favor. First and foremost, obviously, we have a significant. We had a significant lead time when an air plant came out in PN. And what you now see is we have a pretty robust and durable market share in terms of new patient starts over 75%. And then the good news is the category continues to grow in PN. And when you actually translated into the CM, which is a much larger obviously category, when you have a deeper, more durable and sustained [indiscernible], which we already have AMVUTTRA, it's going to be only advanced by nucresiran, hopefully. We are really well positioned given the lead time that we have. And again, from a label perspective, we already have a combination use in our label. We really feel good about another study actually confirming some of the benefits of the silencer class.

Our next question comes from the line of Konstantinos Biliouris with Oppenheimer.

Congrats on the quarter. Maybe I'd like to reverse [indiscernible] question and ask about the scenario that cardio transform sales to show an effect under the [indiscernible] cobalt nurse can demonstrate an effect under the stabilizer silence combo. Do you think that your competitor will be able to leverage [indiscernible] will be specific to nucresiran because of the potency and the durability of the drug.

Yes, there's a lot of scenarios there to work through. I appreciate the nature of your question. I don't know that I can answer it directly. Look, I think Again, I think there are commonalities between the plan approach and what we're doing in that they both knock down TTR, although at the same time, they are different molecules and they use different mechanisms. We use in our AI mechanism, they use an ASO mechanism. They're knockdown tends to happen a little bit longer over time based on the data that I've seen published, whereas we get to higher levels of knockdown a little bit earlier. So I think it's really difficult to sort of prognosticate all the different scenarios. I think maybe they'll see an effect. Maybe it's not static. I don't know. I don't want to speculate at all. but these are different molecules, but there are overlapping areas. And I think as we get the data sets, there'll be some inferences made in terms of where we can connect the dots and where there are maybe unique aspects of the molecules or study designs, for instance, that may have contributed. Our studies are event-driven for instance. And so we may -- that may give us, as we've talked about, additional insurance and help with powering of the studies overall. So Again, I think we'll wait to see how those studies pan out. But I think we feel very good based on the HELIOS-B results, our patient level insights that we have from those studies and the detailed data we have in terms of how to design TRITON-CM and to establish its success. And so we feel very good about that. And that is why -- part of the reason we had talked about the sample size increase as well today.

It's great. I think we are quarterly subparts regimen as well for AMVUTTRA provides additional differentiation. I think that's one of the reasons why we think such good adherence to [indiscernible] as well as, obviously, the compelling clinical profile that we provide.

Our next question comes from the line of Salveen Richter with Goldman Sachs.

With regard to AMVUTTRA, how are you thinking of the trajectory in 2026 post the headwinds that played out in 1Q? And in particular, could you just comment on the ex U.S. pricing dynamics in Germany and elsewhere and whether those have stabilized yet or are still ongoing?

Question is referring to the ex U.S. picture. I think talk clearly, you'll answer that, but I just want to say how pleased we are with the progress of our launches ex U.S. Tolga touched on this in his prepared remarks. And I think it's a testament, actually, to our pricing and reimbursement organization that we've been able to to move forward with a number of AMVUTTRA-CM launches in Europe and in Japan. Tolga you want to comment on pricing.

Sure. Thanks, Salveen, for that question. So let's unpack that a little bit in terms of our ex U.S. pricing dynamics. And we touched upon this in our earnings call, the prior earnings call. And obviously, it's worked out better than what we had anticipated. That was primarily driven by our Japan launch progress. That's going really well as well as obviously the robustness business in RPN. But if you look at the rest of the year, I think the way we should be thinking about it is when we launched the CM indication in markets outside the U.S., it does typically involve a price adjustment for our which can have an impact on the existing RPN business space. The magnitude of that impact obviously varies by market, primarily driven by the size of the price adjustment and the relative scale of that business, existing business. In that context, that Germany did represent the most significant impact in Q1 across all our international markets. And importantly, this was obviously a deliberate and expected step in expanding into a larger opportunity. Over time, the CM volume more than offsets the impact of the initial price adjustments on the PN base. And a helpful way to think about this is a mix shift. We're effectively trading a smaller, higher-priced segment for access to a significantly larger patient population. And then the mix evolves, the overall value of the market will expand. And what does this mean for the rest of the quarter is we expect this to become a net positive growth for starting in Q2, building throughout the year and contributing incremental on a full year basis. I think what we had said is essentially, the contribution of growth is going to be about the same, net-net as ex U.S. did contribute last year.

Our next question comes from the line of Cory Kasimov with Evercore ISI.

Apologies for asking another one related to cardio transform but assuming that doesn't factored out positively, how do you think about the evolution of pricing as another silencer enters the picture, especially given the Part B versus Part D dynamic? Is there any reason to think that pricing could materially change? Or is the PN experience applicable and CM in this case as well?

Look, it's never a good idea to speculate your competitors' pricing. But what we've seen so far is -- we've done really well in '26 in terms of how we've been able to actually increase our first-line access with payers. We anticipate that to continue. Payers are taking this disease very seriously and price sensitivity right now is not really in the works as we've seen and been able to demonstrate that. Currently, Yvonne slightly more premium than our product annual on an annual basis. What we've seen so far, and they had priced it after us. I think they're also seeing how the pricing is working. We don't really anticipate any significant shift in the moment. And of course, we have been managing this very, very thoughtfully and monitoring it very carefully.

Our next question comes from the line of Ellie Merle with Barclays.

In your prepared remarks, you commented on how second line use is reduced to a normalized level. But can you comment on the trends you're seeing in the first line. Are you seeing a steady number of naive starts or an acceleration in the number of naive starts. If you could just help characterize what you're seeing there, that would be helpful.

You touched on that Tolga, but maybe to add a little bit more color.

Yes. I mean I think what's really exciting is what we've been seeing consistently is that once physicians initiate patients on [indiscernible], utilization deepens shift towards earlier using over time, and that really strengthens our first line. So early adoption is largely driven by treating patients progressing on stabilizers in the second-line setting and the opportunity is to work through prescribing natural evolves toward a greater proportion of first-line use. Therefore, we feel very good about so far how we've been able to managing this. And essentially, our aspiration is to continue to grow that first-time use by expanding our prescriber base.

Our next question comes from the line of Jessica Fye with JPMorgan.

I was wondering if you could touch on how -- if at all, the recently announced Pfizer settlement for [indiscernible] impact, how you think about the TTR [indiscernible] looking out over the next several years.

Yes. Great question [indiscernible] timely. Look, I think we've been rather consistent in how we've been characterizing that our growth outlook is really not dependent on the timing of a generic entry in the stabilizer class. We do expect the impact on our TTR outlook from the settlement to be rather limited. Just to remind everyone, this remains a significant underserved category with a large proportion of patients untreated. And we know that nearly half of those patients that are on a stabilizer continue to progress and they do in need of an [indiscernible] mechanism of action. Importantly, demand for Anbutra reflects a fundamental shift towards treating this disease added source which we see as durable and independent of pricing dynamics within the stabilizer class. We also believe that the TRIDENT CM study positions us really well to generate a robust data package for [indiscernible] supporting continued leadership in an evolving treatment landscape. Today, we're really well established with broad first-line access, strong patient affordability growing physician preference and well ahead of any potential LOE considerations. So taking it all together, I think we feel very well positioned to sustain growth through both continued on but adoption and frankly, the advancement of our next-generation pipeline.

Our next question comes from the line of Luca Issi with RBC Capital Markets.

.

. This is Shelby on for Luca. Yesterday, AstraZeneca printed a pretty meaningful miss for TTR and we know is actually down 35% Q-over-Q. So I guess from a competitor standpoint, is Alnylam a net beneficiary of that miss in PN. And then maybe bigger picture, could you walk us through your latest thinking on the competitive landscape here in the U.S., especially given the Medicare Part B, Part D dynamic and with the [indiscernible] syringe coming for [indiscernible]

Yes. I mean, look, I think it is customary to see some softening in the first quarter of the dynamic. When I look at our numbers throughout our -- we had certainly seen that, but that tends to actually recover in March, and we've always been able to post a good growth based on our base based business. So I think you guys should raise that question with them. What we know is even before the CM indication, we have been able to establish a very strong new patient market growth -- market share upwards of 75%, while the category continues to grow. So we are very pleased with that experience, and we certainly have every plan to replicate that success in the landscape as well. When it comes to Part D and Part B, look, I think we're really well positioned in terms of how we've been able to provide that access. The fact that our product is a quarterly subcutaneous injectable meets very nicely with the cadence of how those patients actually visit those offices. And it's -- and by the way, again, we've been able to expand our actually access nearly 90% when it comes to overall access and over 90% in terms of first-line access without any step edits with 0 patient out-of-pocket costs. those dynamics not only been secured but also improved versus last year. And that's, again, a testament to the product profile as well as actually a testament to the payers who really understand this disease and they leave up to the physician and their choice in how they want to manage this category.

Our next question comes from the line of Myles Minter with William Blair.

This is John on for Myles. Maybe just switch gears just a little bit. Just wondering where you're seeing [indiscernible] competitive landscape along with some of the next-gen complement CD19, [indiscernible] or FcRn. And any thoughts as to why more [indiscernible] combo therapy didn't result in better efficacy there?

No, we're clearly pleased with the progress of [indiscernible] in patients with MG. The results were really quite supportive of use of this disease. [indiscernible] any additional perspectives you'd like to add?

No. Look, I think I guess I'd just echo what [indiscernible] said. I think we're really excited that Regeneron has advanced [indiscernible]. I think the data in myasthenia are incredibly compelling that they've generated. We think this is going to be [indiscernible] and expect this will be a formidable drug for these patients where there's a lot of unmet need I think the detailed questions in terms of the market and the opportunity, I think we should leave for our colleagues over there, but we will end and its opportunity to help patients.

Our next question comes from the line of Paul Metteis with Morgan Stanley.

And maybe just a follow-up on the generic [indiscernible] question. Would you anticipate increased combo use in the frontline setting? Or would that be more of a second-line setting effect? And then do you think you need the data from nucrisaran combo to kind of accelerate that. Or do you not need that?

Yes, Mike. Look, I think as I explained, we've been able to establish ourselves as a first-line treatment over 35% in a short 9 months since the launch of the third entrant. That really is the fundamental question in a way how the market is going to be unfolding. In respect to combination use, as we had shared before, there are physicians who prefer to have a second line use in a switch or combo. And if that were to happen so far, we haven't seen any significant headwinds. We don't really speculate on that, how payers are going to be managing that. I think one step goes generic, certainly, that dynamic will evolve. And I think obviously, [indiscernible] will we'll be in a great position given the data we're generating. We already also do have combo data in our label as well as, obviously, physicians have been experiencing it already over a year. So what we, again, appreciate the fact that it's how we got out of the gate in terms of our launch dynamics, and we continue to maintain that posture.

Yes, absolutely. I think the key point here is that, as you said, our fortunes aren't tied to the generalization of the stabilizer class and we're quite excited about the TRITON-CM designed for [indiscernible] deliver a very robust data package to support the evolving treatment landscape. I think we've come to kind of our last question. So I will just wrap up by thanking everybody for joining us today. think we're off to a good start in 2026. And as we maintain momentum with the ongoing launch of [indiscernible] Ampoxin ATTR cardiomoprathy. We also continue to deliver significant advancements across our really quite exciting and deep pipeline of innovative therapy 6. Thanks, everybody. All the very best.

Ladies and gentlemen, that concludes today's call. Thank you for joining us. You may now disconnect. Have a good rest of your day. Goodbye.

Good morning, everyone, and thank you for joining us today. I'm Tolga Tanguler, Chief Commercial Officer at Alnylam, and I'm thrilled to be hosting today's webinar to update you on our leadership journey in delivering transformative therapies for patients living with ATTR amyloidosis.

This past Friday marked one year since AMVUTTRA was approved in the U.S. for patients with ATTR cardiomyopathy, a pivotal milestone for Alnylam that has launched us into a new era of growth. We've built a strong foundation through years of disciplined execution and are rapidly advancing toward leadership in TTR. So how do we get here? In 2018, with ONPATTRO, we introduced an entirely new class of medicine, RNAi therapeutics that silence disease at its source, bringing a transformative option to patients with hereditary ATTR amyloidosis with polyneuropathy.

We have continued to build on that foundation with AMVUTTRA, which launched in '22 for the same indication. And exactly 1 year ago, we expanded into ATTR cardiomyopathy population, which while still an orphan indication, is far more prevalent than hATTR-PN. We're now driving strong adoption across that larger patient base, and we're just getting started. We continue to accelerate AMVUTTRA uptake across the world. We're advancing our next-generation TTR therapy, nucresiran, with the potential to further raise the bar.

And as announced today, we're investing in cutting-edge capabilities to enable earlier diagnosis, better coordinated care and sustained long-term outcomes for patients. The strategy is clear: lead with science, reach patients still untreated or progressing on stabilizers and deliver durable impact for patients and value for shareholders.

Following last year's approval of AMVUTTRA for ATTR cardiomyopathy, supported by the compelling results from the landmark HELIOS-B trial, we moved quickly to drive adoption and ensure seamless patient access. Execution has been strong, enabled by our deep experience in TTR and the strength of our commercial and medical teams. That execution is translating into results. Now we more than doubled revenues for our TTR franchise in '25 versus '24. We beat and raised our guidance twice over the course of the year, and we're guiding to a further 83% growth in '26 at the midpoint.

This momentum reflects both the value AMVUTTRA is delivering to patients and physicians and the strength of our commercial capabilities. Today, we'll focus on how we build on this momentum to shape the future of ATTR treatment by expanding diagnosis, advancing innovation and continuing to raise the standard of care in an increasingly dynamic and competitive landscape. And before we begin, I want to acknowledge the ATTR patient community. It is a privilege to work alongside physicians, patients and their families as they navigate this complex disease and to bring forward therapies with the potential to meaningfully change the course of their lives.

I'm joined today by our key commercial and medical affair leaders who are at the center of this progress, including Mark Soued, Senior Vice President, Head of U.S. and TTR Lead; John Kennedy, Senior Vice President, TTR Franchise Commercialization Lead; Dr. Sameer Bansilal, VP TTR Disease Area Lead; and Christine Akinc, our Chief Corporate Communications Officer, who will join us to moderate the Q&A.

Let me briefly walk you through how we will shape the future of ATTR treatment and how it connects to our path to leadership. I'll start with our cardiomyopathy launch, what we've learned, how that momentum is building and how we're applying those insights to scale and strengthen our leadership position. Mark will then step back and frame the broader opportunity in ATTR amyloidosis, including the significant number of patients who remain undiagnosed and untreated. Dr. Sameer Bansilal, will build on that with recent data reinforcing AMVUTTRA's differentiated clinical profile and how that translates into compelling value proposition for patients and physicians.

John and Mark will then focus on 2 defining potential future dynamics for the market, increasing competition within the TTR silencer class, where we've already demonstrated our ability to compete successfully in the hATTR-PN setting and the transition of stabilizer class with tafamidis loss of exclusivity. They will outline how we are positioned to continue to compete and grow through both.

And finally, John will bring it together with how we're planning to drive category growth, expanding diagnosis, increasing access and reaching more patients at scale. For the Q&A, please submit your questions through the webcast dialogue box. As a reminder, we will be making forward-looking statements. Looking at pace of AMVUTTRA's launch in cardiomyopathy, we're seeing strong early momentum. In 2025, performance was driven by our U.S. launch and the initial rollout in Japan, both demonstrating uptake that exceeds relevant specialty analogs. That momentum is translating into real scale.

More than 12,000 patients now treated globally across our TTR franchise, a large and expanding prescriber base, including more than 1,600 unique U.S. prescribers since launch last March, and this is clearly reflected in our financial performance. Since launch in cardiomyopathy, we have delivered $2.1 billion in total global TTR revenues, and we're guiding to $4.4 billion to $4.7 billion in 2026, underscoring our confidence in continued growth.

As we look ahead, it's important to start with what enables that future, the foundation we built in 2025. Our early success in cardiomyopathy reflects deliberate execution against the core fundamentals required to build a durable franchise. First, physician preference and utilization. AMVUTTRA's clinical profile has driven a strong and compelling first-line positioning with strong preference among physicians who have experience using it.

Second, access and affordability. Innovation only matters if patients can access it. Leveraging our experience in this space, we've secured durable first-line access for approximately 90% of patients with the majority paying 0 out of pocket. And our access is broader than it was in 2025, allowing us to reach more patients.

Third, site of care infrastructure. We've built a robust provider network to enable efficient administration. Today, around 90% of U.S. patients can receive treatment within 10 miles of their homes. These are not short-term metrics. They are the foundation for sustained growth. They position us to scale within a therapeutic category that continues to expand meaningfully.

If you look more closely, we can see the momentum unlocked through disciplined execution against these fundamentals. As a third entrant in ATTR-CM, competing against a legacy standard of care, we achieved an average approximately 35% new-to-brand market share across the first 3 quarters of launch. That's a clear signal of unmet need and willingness from both physicians and patients to adapt a new treatment approach.

Importantly, we're seeing consistent patterns emerge that will guide how we scale from here. First, experience drives preference. Physicians who gain experience with AMVUTTRA increasingly choose it as their first-line therapy for new patients.

Second, utilization drives depth. As physicians build confidence, they expand use, treating more patients and choosing AMVUTTRA consistently in their practice. Third, patient choice is reinforcing adoption. Patients are well informed and asking their physicians for AMVUTTRA, now the most requested brand among surveyed U.S. TTR patients who express a treatment preference.

With these dynamics, our foundational pillars in place, our focus now shifts to the next unlock, expanding the breadth of our prescriber base. That is a key driver of growth and a metric we will hold ourselves accountable to as we scale to the next phase of launch. To double-click on the first learning that experience drives preference, we're seeing clearly that experience with AMVUTTRA reinforces physician confidence and drives further adoption.

As with any new therapy, entering a competitive and established market, physicians begin with a set of practical considerations, particularly around access, affordability and efficacy. And from that perspective, real-world experience with AMVUTTRA has been highly favorable. It has broad access. Most patients pay 0 out of pocket, and it has a highly differentiated clinical profile that resonates with physicians, especially when they start using it. And as we now focus on expanding the breadth of prescribing, bringing more physicians into that experience, we're confident this will continue to drive deeper utilization and sustained growth over time.

Importantly, -- all of this is unfolding within a large and rapidly expanding U.S. treatment category. We now estimate nearly 200,000 ATTR-CM patients in the U.S. alone with more than 80% still untreated. What we're seeing is a category where the treatment volume is continuing to accelerate. As expected, increased focus and competition are driving diagnosis and treatment. The U.S. treatment category grew 56% annually in '23 and '24 with only a single approved therapy.

With the addition of a second stabilizer and the introduction of AMVUTTRA, the first and only silencer in ATTR-CM, U.S. category growth accelerated to 77% in '25. We expect this strong trajectory to continue in the U.S. as diagnosis expands and more patients are treated. We are well positioned at the center of that growth, combining a differentiated approach, strong execution and increasing physician adoption.

With that, I will turn it over to Mark, who leads our U.S. business, to outline the opportunity ahead and how we intend to capture it.

Thanks, Tolga, and I'm thrilled to be here today to discuss the opportunity ahead. Let me start by framing the ATTR-CM opportunity. Today, we're updating our latest understanding of global epidemiology. ATTR-CM remains a significantly underserved disease category. We estimate there are roughly 200,000 patients in the U.S. living with ATTR-CM. And importantly, more than 80% of those patients remain untreated.

Globally, we estimate approximately 500,000 patients are living with ATTR-CM. At the same time, awareness of the disease continues to increase meaningfully. Since 2019, we've seen prescription volume in the category grow, reflecting improvements in diagnosis, greater physician awareness and ultimately, more patients being treated. Taken together, these dynamics highlight both the substantial unmet need that still exists and the momentum already underway in expanding treatment across the ATTR-CM landscape.

To better understand how the category can continue to grow, it's helpful to look at the opportunity across 3 key patient segments. First, of the nearly 200,000 patients living with ATTR-CM in the U.S. today, approximately 80% or 160,000 remain untreated. This is up from the 125,000 patients that we estimated at our TTR Day in October 2024.

Second, we estimate that approximately 15,000 patients per year are new to treatment. That means you have an inflow of about 15,000 new starts every year, and that's a constantly refreshed number. And this is up from the 10,000 or so that we estimated in October 2024. And third, there is a meaningful opportunity among patients currently receiving stabilizer therapies who unfortunately continue to progress. There are some observational data suggesting that as many as half of patients on a common stabilizer, suggesting roughly 15,000 patients today fall into this category, representing an important population where physicians are increasingly evaluating additional or alternative MOA treatment options.

And this is up from the between 8,000 and 13,000 that we estimated in October 2024. Together, these segments illustrate the multiple avenues for continued category expansion, driven both by new diagnosis and optimization of treatment for patients already on stabilizers. And these categories will continue to grow in number over time.

Finally, it's important to consider how diagnosis itself is evolving. So prior to the availability of effective therapies, ATTR-CM diagnosis and treatment rates were extremely low. Around 2% of patients were identified before the first treatment options became available. As awareness and treatment options expanded, diagnosis and treatment rates have improved meaningfully. And looking forward, we believe diagnosis and treatment rates will continue to increase substantially based on benchmarks from other diseases such as MS or PAH or AFib, diagnosis rates reach around 70% over time as awareness, screening practices, clinical guidelines and the treatment landscape all evolve.

So with additional therapies entering the market and a growing focus from the cardiology community, we believe the ATTR-CM treatment category is still in the early stages of formation, creating a significant opportunity for continued growth over the coming decade. We'll talk later about how we are stepping firmly into that leadership role and ensuring diagnosis and treatment rates do indeed improve for the patients who depend on it.

So stepping back, we believe the ATTR-CM category remains in the early stages of its development with significant opportunity ahead. Today, nearly 200,000 patients in the U.S. are living with ATTR-CM. The majority remain untreated even as diagnosis improves and awareness expands. And when we look across the opportunity from the large untreated population to newly diagnosed patients entering treatment each year to patients progressing on stabilizers, we see multiple pathways to help patients in need and sustain AMVUTTRA's growth with durability.

And importantly, if diagnosis rates ultimately evolve towards levels we've seen in other cardiovascular diseases, the number of patients actively treated could actually increase substantially within the decade. So in short, we believe ATTR-CM represents one of the most significant remaining opportunities in cardiovascular medicine to improve diagnosis and expand treatment options for patients who are largely underserved today.

You'll hear more about what we're doing to grow the category later on in today's presentation. But with that context on the size of the opportunity and how the category is evolving, I'll now turn it over to Dr. Sameer Bansilal, who will walk through AMVUTTRA's clinical value proposition. Over to you.

Thank you, Mark. That clearly highlights the opportunity in ATTR-CM. The next question is, what defines clinical value and how does vutrisiran stand apart? From a clinical perspective, I'll focus on the data and the experience that matter most for cardiologists and patients. My name is Sameer Bansilal, I'm Vice President, Global Medical Affairs, TTR Disease Area Head at Alnylam.

I'm also a practicing cardiologist at the James J. Peters VA Medical Center in the Bronx. Over the course of my career, I've worked as a clinical trialist and outcomes researcher at Mount Sinai, NYU, Brigham Women's Hospital and the Harvard School of Public Health. As clinicians, our goal is simple. We want our patients to live longer, better lives and remain on therapy long enough to realize those benefits.

Historically, it has been difficult to achieve all 3 simultaneously. With their RNA silencing platform at Alnylam and continued commitment to ATTR-CM patients, we believe we have the opportunity to deliver across each of these goals. We ask cardiologists who treat TTR patients, what attributes matter most when selecting a therapy for patients with ATTR-CM. What you see on the left side of the slide is the rating for the patient outcomes that are most important to them.

Their top priorities include reducing mortality, reducing cardiovascular-related hospitalization and having a positive impact on patients' quality of life. What you see on the right side is the cardiologist rating of vutrisiran on these attributes. And as you can see across the board, for the outcomes that are most important to them as they make choices for their patients, AMVUTTRA rates very highly for mortality, for hospitalizations and also quality of life. So let's take a closer look at all 3 of these in terms of the data that drives these high ratings.

To start, let me walk you through the clinical rationale and evidence supporting our expectation that this therapy can help patients live longer, the mortality data. In the HELIOS-B trial, during the double-blind period and the extended follow-up during the open-label extension, vutrisiran has shown a definitive and increasing benefit on all-cause mortality to nearly 40% in the monotherapy population. When identified early and treated as we did in HELIOS-B, vutrisiran has the potential to bring patients close to their estimated age-adjusted mortality, which is remarkable for a disease that the survival rate over 5 years was extremely low only a few years ago.

A patient's experience with the treatment is often undervalued in our system. But in reality, it's one of the top priorities for patients and cardiologists treating them. How patients feel day-to-day matters. It can influence things like being able to take a walk with a friend or play with grandchildren. It matters to patients, and it directly influences treatment decisions. That's where targeting TTR production at its source makes a meaningful difference for patients. Gastrointestinal symptoms are one of the most common and burdensome extracardiac manifestations of ATTR-CM, affecting the majority of patients, whether hereditary or wild-type, with prevalence rates reaching as high as 70% in some populations.

In HELIOS-B, we saw that patients treated with vutrisiran have self-reported 40% fewer of these symptoms and depending on the specific GI side effect, as much as 65% lower incidence. What is noteworthy because we inhibit the protein at source, the lower incidence of these extra cardiac manifestations were observed early and the difference grew over time. This is in contrast to the effects noted with stabilizers. How are we impacting mortality and morbidity? What is the relevance of this inhibition at source?

One specific proof point that is unique to vutrisiran, and this is important data from the National Amyloidosis Center in the U.K. is that we have been able to show in HELIOS-B with serial cardiac MRI imaging in the monotherapy population, we observed not only a reduction in the amyloid burden, we also see that translate into improvement in structure and function. In fact, when we compare regression of amyloid protein, as noted in the LV mass change here and paralleled by ECV and multiple other measures, we see amyloid regression in 22% patients in the vutrisiran group in contrast to over 2/3 of patients progressing in the placebo arm.

The improvement in LV stroke volume is quite striking and has not been previously seen in terms of an improvement in myocardial structure and function. And we do believe that this is due to the innovation at source. These are both observed in a small subset of patients, and we continue to study these measures in ongoing and future studies. Patients can only realize these benefits if they take their medicines correctly, well and for the long term. Another noteworthy feature of vutrisiran is its once every quarter health care professional administered dosing, which is associated with a persistence and adherence profile that is quite exceptional.

We have previously shown in real-world analysis of hereditary ATTR peripheral neuropathy patients that quarterly HCP administration represents a significant benefit, and we see a meaningful difference as it relates to vutrisiran persistence and adherence versus old stabilizer therapy. Similar data in the ATTR-CM population will be presented at upcoming congresses. Finally, we are continuing to expand the evidence base to further strengthen AMVUTTRA's differentiation and support sustained growth.

Building on the strong clinical foundation established by HELIOS-B, we are continuing to generate real-world evidence through the DemonsTTRate observational study now enrolling globally. We are capturing a range of patients, and we'll be able to not only look at further clarifying the benefit, effectiveness and safety of vutrisiran as a first-line therapeutic, but we shall also be able to look at comparative and combination treatments as patients accrue.

Let me wrap up with what I just shared with you in terms of what this all means for patients through outcomes that align with what clinicians prioritize most when selecting a therapy. With vutrisiran, we are able to help ATTR-CM patients live longer to the point of them living nearly as long as they would without this disease. With this TTR inhibition at source, vutrisiran mitigates extracardiac adverse effects while positively impacting cardiac structure and function.

And then finally, the reason we think this happens quite consistently across the board with vutrisiran is our once every 3-month dosing. And with that, we have been able to get to more than 90% persistence and adherence over more than a two-year period. And that's all translating into the benefit, which we hope to capture in an observational study and many other studies that we are launching.

With that, I will hand over to John Kennedy.

All right. Thank you, Sameer. I'm John Kennedy, Senior Vice President, TTR Franchise Commercialization Lead. Let me shift to the competitive landscape within the silencer class and how we think about sustaining leadership going forward. We're competing against eplontersen in the hereditary ATTR polyneuropathy category today. And that experience has shown us 2 things. The first is that the category expanded. Our volume growth continued unabated and the total treatment category grew.

And the second, we maintained leadership. More than a year after competitor entry, we maintained about 70% share of new starts and more than 80% of the total market share. And we established this preference for AMVUTTRA before having the cardiomyopathy approval, meaning we were competing effectively before the benefit of label expansion. This reflects the strength of AMVUTTRA value proposition, including the favorable access dynamics that Tolga referenced, the adherence and persistence that Sameer mentioned and the customer preference built during our lead time.

And we believe these dynamics are all transferable to cardiomyopathy as well. Another consideration when thinking about the silencer landscape is how these therapies are used alongside stabilizer therapy. AstraZeneca has focused their commentary on the combination data they expect from CARDIO-TTRansform. But remember, HELIOS-B showed consistency of AMVUTTRA treatment effect with or without tafamidis background. We have the data. It's reflected in the label. And in fact, we're already seeing meaningful volume of use in combination and in the real world.

That means customers are gaining experience using combination mechanism of action, and we'll be able to continue generating even more data from real-world data sets. So if CARDIO-TTRansform demonstrates the benefit of dual mechanism of action approach, that would corroborate what we've already seen and bolster the case for even more combination treatment. Now it's not surprising there's been conversation about what CARDIO-TTRansform will show. And in fact, our market research has shown that the large majority of cardiologists believe favorable combination treatment data will support a broader class effect.

Again, it would corroborate what we've already seen from HELIOS-B. And ultimately, when clinicians reach for a silencer, they're looking for depth, duration and consistency of knockdown. Today, AMVUTTRA delivers on that with the fewest doses per year. And of course, our next-generation candidate, vutrisiran, is designed to extend that durability even further into the future with greater than 95% knockdown in just 2 doses per year.

Finally, we've also heard questions relating to pricing or access implications with a new silencer competitor that will be covered under pharmacy benefit. But remember, today, we're already competing against 2 ATTR-CM medicines, both covered under pharmacy benefit. And we know AMVUTTRA has excellent access, approximately 99% coverage overall and 90% coverage in first line and the majority of patients paying $0 in out-of-pocket cost for AMVUTTRA. So from an access perspective, we believe AMVUTTRA is already well positioned within the current coverage environment. Having another pharmacy benefit medicine in the mix does not change the calculus.

So pulling it all together, competition in the silencer class is a net positive for the category and for patients. ATTR cardiomyopathy remains significantly underdiagnosed and undertreated and increased attention in the disease ultimately expands awareness and accelerates category growth. We're already competing today in the silencer class in the hATTR polyneuropathy market. Competition has expanded that category. And despite that competition, we've retained clear leadership.

But ultimately, when physicians choose a silencer, they're looking for depth, duration and consistency of knockdown to drive meaningful outcomes for patients. We're well positioned to sustain differentiation with AMVUTTRA. Additionally, our next-generation candidate, nucresiran, is positioned to extend that leadership even further.

With that, I'll turn it over to Mark to speak about the second competitive event in ATTR-CM, the genericization of the stabilizer class. Mark?

Thanks, John. Okay. Let me now turn to the anticipated genericization of the stabilizer class, specifically tafamidis. Importantly, our trajectory is not dependent on the timing of tafamidis' loss of exclusivity. AMVUTTRA's differentiated profile is already driving demand and shaping physician preference today, and we expect that momentum to sustain and build both before and after the stabilizer class transitions.

And as we think about how the market may evolve, we see several dynamics that we believe will support sustained growth for AMVUTTRA. First, we are already seeing meaningful traction against the incumbent in new patient starts despite entering the market several years later. Within just a few quarters of our U.S. launch, AMVUTTRA has delivered steady share gains in new starts, reflecting growing physician and patient interest in differentiated upstream silencing. Importantly, that early adoption is translating into preference.

Among physicians with experience using AMVUTTRA, we're seeing a clear shift towards selecting it for new patients, and this dynamic is critical. As preference builds, then it's driving demand and establishing that foundation ahead of tafamidis' LOE positions us well for sustained growth over the long term.

The second important consideration is access. If you look at the U.S. payer mix in ATTR-CM, we should not assume that genericization will lead to universal step edits for AMVUTTRA. In fact, it will not. For patients already on treatment at the time of tafamidis' LOE, we expect continuity of care to remain the priority, meaning many patients will continue therapy without payer disruption. It's also important to remember that in Medicare fee-for-service, which is our single largest payer segment and represents approximately half of our business today, AMVUTTRA is covered to label with no step edits, and we would expect that dynamic to continue following tafamidis' LOE. Again, this segment represents nearly half of our business today.

Of course, it's possible we'll see step edits, particularly in the commercial segment of the market. But even when there is a step edit today, we've seen that when a doctor and a patient determine that AMVUTTRA is the right treatment, patients can usually access it, whether through appeals or a relatively rapid progression through a step. And let's not forget that many ATTR-CM patients may progress on tafamidis and therefore, require a switch or add-on treatment. And because of AMVUTTRA's orthogonal mechanism of action, we are well positioned to address that need.

This leads to another important opportunity following tafamidis' LOE, which is the potential to more fully unlock dual mechanism treatment strategies. Cardiologists are already accustomed to adding on and combining therapies in cardiovascular disease. This is how they practice. As John spoke about earlier, as the body of clinical data supporting silencing therapy continues to grow, including evidence emerging from studies like CARDIA transform, we expect increasing confidence in combination approaches using both stabilization and silencing.

At the same time, the availability of generic stabilizers could significantly reduce the cost of dual MOA treatment, making these strategies more accessible in clinical practice. And so taken together, this creates an environment where AMVUTTRA will play an increasingly important role. So when we step back, we believe AMVUTTRA is extremely well positioned in a post-LOE environment. We're already building first-line demand and physician preference today years ahead of anticipated genericization.

We expect durable access across key payer segments with continued need for therapies that offer an orthogonal mechanism of action. And the tafamidis LOE may actually accelerate adoption of dual-MOA treatment strategies, supported by a growing body of clinical data. And so taken together, these dynamics reinforce what we believe is a sustained opportunity for AMVUTTRA growth.

And so let me turn it back over to John to discuss how we'll accelerate our investments to drive category growth.

Thanks, Mark. So let me close by focusing on the opportunity ahead to further accelerate growth in ATTR-CM. We've already talked about the strong momentum in the category, but we see a clear opportunity to build on that and do it in a deliberate, focused way. As we continue to scale, our role as a category leader is not just to participate in the growth, but to help shape it, expanding diagnosis, increasing treatment rates and ultimately helping more patients.

We think about the diagnostic journey, there are really 3 stages: awareness, suspicion and diagnosis. Diagnostic tools already exist. Nuclear scintigraphy provides noninvasive, accurate and accessible confirmatory diagnostic test. So that's not really the primary barrier. The real opportunity is earlier recognition of disease, which requires much greater awareness and clinical suspicion upstream. So more patients are identified and diagnosed sooner. By increasing recognition of the disease and improving identification of these patients, we can help ensure more patients reach confirmatory testing and ultimately receive appropriate treatment. And that's where we're investing.

The first pillar of our strategy is expanding patient awareness and engagement, including our direct-to-consumer efforts. We're already driving meaningful interest from patients today. Now if you're not one of our target audience, you may not have seen our ad, but I can tell you, our target audience is seeing it and is working. Already today, we're the most requested ATTR-CM therapy by patients.

Second, we continue to expand the HCP prescriber base across cardiology and heart failure specialists. We've talked about the breadth of prescribing. We'll continue to increase that just as we have so far in our launch. We're built to cover the potential of the market with our field force, and we're engaging more physicians. The third pillar of our strategy is advancing AI-enabled diagnostic technology, importantly, with an emphasis on practical implementation.

We're partnering with nationally recognized organizations to identify patients earlier in the course of disease. So earlier today, we announced a set of strategic collaborations designed to accelerate earlier recognition and improve care coordination for ATTR-CM patients. One of these is our collaboration with Viz.ai, a leader in AI-powered disease detection and care coordination.

Together through the AWARE study, we're developing ATTR-CM care pathways at 5 large U.S. integrated health systems, integrating FDA-cleared Echo AI algorithm with electronic health records designed to help clinicians identify patients earlier in the disease and guide appropriate diagnostic evaluation and referral. The pathway will coordinate care across cardiology and heart failure teams. This AWARE study is the first multisystem prospective implementation study designed to evaluate how AI-enabled screening can be incorporated into real-world clinical workflows and improve diagnostic time lines and care coordination.

The initiative will help generate real-world evidence to inform broader scalable adoption across health systems in the Viz.ai network. The goal is simple: identify patients earlier and connect them to care before potentially irreversible disease progression occurs. The fourth pillar of our strategy is to enable end-to-end health system engagement, working directly with the large integrated health systems to improve care pathways.

So also announced today, we're working with the American Heart Association to strengthen systems of care for ATTR cardiomyopathy. This 3-year initiative will convene a national learning collaborative of multidisciplinary health systems to evaluate current care pathways and identify ideal models of care for diagnosis and managing ATTR cardiomyopathy. Participating centers will assess processes across diagnosis, referral, treatment and follow-up to improve coordinated care and patient outcomes.

We'll disseminate insights generated through this program nationally to enable broader adoption of effective care models. Now remember, we're already engaging approximately 190 accounts that drive about 80% of ATTR cardiomyopathy patient volume. With our new collaborations, we believe we can strengthen ATTR-CM care delivery across the health care system nationally.

Finally, we continue to expand global access for AMVUTTRA to ensure that patients around the world have access to this important therapy. We've launched in Japan and Germany and more recently in Austria and the U.K. We continue to advance additional regulatory submissions and pricing and reimbursement negotiations to expand access in markets around the world. So stepping back, the opportunity in ATTR cardiomyopathy remains significant. We're establishing leadership with AMVUTTRA a differentiated therapy, and we're building strong physician and patient preference.

We're investing to accelerate diagnosis all while expanding access globally. So taken together, we believe these efforts position us to continue driving meaningful growth while improving outcomes for patients living with ATTR cardiomyopathy.

So with that, I'll turn it back to Tolga.

Thank you, John. As you've seen today, Alnylam is well positioned to continue driving long-term growth with our TTR franchise. This is enabled by a treatment category that is underpenetrated and rapidly growing. All told, by 2030, we could see upward of 75,000 patients being treated for ATTR-CM in the U.S. alone. It will be a competitive market, but one in which AMVUTTRA is poised to stand out and be the revenue leader in TTR by 2030. We're confident in our ability to achieve that goal, driven by continued focus on these 3 key foundations we discussed earlier, driving differentiation preference, knowing that experience drives utilization, ensuring seamless patient access and affordability and setting up a broad care network.

With these elements in place and helping to deliver remarkably strong results out of the gate, we look forward to unlocking the next phase of launch. As we look ahead, we're focused on scaling what we built, driving sustained category growth, expanding our prescriber base and maximizing the strong adherence and persistence we're already seeing. These are the key drivers that will shape our next phase of growth. What you heard today is a plan for leadership in a category with tremendous amount of opportunity.

We're advancing the field with continued investment in TTR, including our next-generation therapy, nucresiran, which has the potential to raise the bar. We're also investing in new technologies to identify patients earlier. All of this with the goal of continuing to bring real transformative therapies to patients at scale. As you can tell, we're incredibly excited about the opportunity ahead.

So with that, let's head to our Q&A session.

Good morning, and thank you, Tolga, Mark, Sameer and John. So we'll now begin the Q&A portion of our webcast today. So just as a reminder, please enter your question in the dialogue box in the chat and we will get to as many as we can in our 20-minute session. Just as a quick reminder, the focus of today's session will be the presentation that was delivered earlier today, and we will hold any questions related to quarterly progress for our Q1 call. So with that, let's go to our first question. We have a number that have been queued up at this point. So you said a lot about expanding the prescriber base. Can you tell us who has prescribed so far? And are all the former PN writers?

Great question. Indeed, we are focusing on that. Before I turn it over to Mark, let me point out the fact that what's really great about this first year of learning is the fact that once doctors experience AMVUTTRA, they really enjoy it. They use it. So there are no real hurdles in terms of prescribing the drug and they start seeing the results. And therefore, what's really left is to continue to differentiate the asset as well as to continue to expand the prescriber bases. So Mark?

Yes. No, I think you said it well. I mean if we look at our prescriber base today, it's quite broad and balanced. And actually, 75% of our prescribers today for AMVUTTRA are new prescribers. And so as Tolga said, once they get experience with AMVUTTRA, we found that there's actually a preference adult for AMVUTTRA. And so that's why it's really important that we continue to expand that prescriber base, and we use that to essentially unlock the next wave of growth.

Great. So let's go to our next question. What do you expect your share of the 75,000 treated patients in TTR in the U.S. to be in 2030? And can you translate that into a peak revenue number for us?

Yes. So what we've done, Christine, is obviously, we guided the market for '26 revenues, which is at midpoint, over 80%, anywhere between $4.4 billion to $4.7 billion. That obviously is built on the great momentum that we've been able to build in 2025. Now in terms of the 75,000 number, one other key aspect of this is obviously our 2030 ambition. We certainly look forward to being the leader in terms of revenue by 2030 and 75,000 number has been incorporated into that. Maybe JPK, you can actually expand on that.

Yes, absolutely. I think you talked about some of the core elements. So we did provide TTR guidance for 2026. That's robust growth. And for the 2030 aspirational goals for the company, obviously, we did provide some commentary about TTR. So one component of that was to achieve leadership share of revenues for the category by 2030 and across the period. And then the second component that we talked about was our total revenue for the company would grow at about 25% CAGR over the period of time between now and 2030.

Now that's total revenue for the company, so more than TTR alone. But again, consider TTR is a significant driver of it. So that gives you a sense of the potential that we see. And again, it's all grounded in how many patients there are in the U.S., unfortunately, still untreated today. There's significant opportunity. We're seeing momentum. That's great, but there's still a lot of opportunity ahead.

Super. And we actually have a 3-part question for our next one. So are you seeing any changes in step-through requirements as a part of restrictions to first-line AMVUTTRA? And how are payer discussions going for 2027 policies? What gives you confidence in your ability to maintain this level of first-line access beyond 2027?

Yes. So as Head of U.S., Mark, you'll probably need to take this one. What I'll say is, look, there has been -- this has been a hot topic. Since we actually had our first event on investors with the TTR back in '24 in October, there was a lot of debate about are we going to be covered? What the burden on the co-pay for the patients is going to be? Are we going to be step edited? So in '25, obviously, we've been able to demonstrate that we got great coverage, nearly all patients actually not having any co-pay. And '26, in fact, the numbers have been actually better in terms of our coverage. So maybe, Mark, you can give additional color on that.

Yes. So indeed, in October '24, and I think leading up to the launch, there were a lot of questions. And at that time, I think we shared our expectations for favorable access based on AMVUTTRA's clinical profile, but also based on the dynamics between Part B and Part D. And our expectations have become reality. Today, we have over 90% of patients with confirmed first-line access. The majority of patients pay $0 out of pocket. And that, by the way, is with 2 Part D competitors in the market.

And so as we look ahead and we sort of see and think about how this is going to unfold, all those fundamentals remain the same. That's regardless of whether another Part D competitor comes into the market. And I'll point out that today, we are competing with WAINUA in polyneuropathy, and we have virtually unrestricted access I mean, one other point here to think about as we think ahead is also the LOE of tafamidis. And if we think about what that means, we believe that's actually a tailwind. We'll see the price of tafamidis come down.

We think that will help unlock combo usage, which I think this is something that a cardiology community would want to do. And so bottom line is we think we're very well positioned from an access perspective. And we actually think that those dynamics that allow us to have that access today will persist into the foreseeable future.

No, you covered it very nicely. I think this is going to continue to be an ongoing effort on our side. But looking ahead, we're very confident about how we're going to be actually be able to manage that.

Thanks, Dr. Tolga. So while there is no universal definition of progression, what are some of the common guideposts or indicators that physicians are citing as meeting the bar for combo therapy or switching patients to AMVUTTRA?

Yes. So maybe, Sameer, you should take that as the only clinician in the panel of today. Go ahead, please.

Yes. Thank you, Tolga. That's an important discussion, really draws a lot of interest in the clinician and the academic community. While there are guidelines on both sides of the Atlantic, I think the more we speak to clinicians and researchers, the answer is always the same. This is as much art as it's science. At the end of the day, we have to talk to our patients, and we have to bring our clinical judgment in. And that's driven by multiple variables, which come from the guidelines in terms of imaging biomarkers and other clinical outcome measures.

I would say that I think far more important, even though there are data from health systems and observational data that point to nearly 50% progression with stabilizers, the broader need is really to identify these patients early because this is a very progressive disease and treat them with an effective agent. I would argue in this case, vutrisiran has shown very definitive data that we can really help bring down everything from mortality to hospitalizations and more.

That's nice capture. What's really excited about -- exciting about this first year is also being able to see that now doctors do have an option, an [indiscernible] mechanism. And therefore, I think we've been able to really help physicians to start identifying those patients early and as they progress, and therefore, they can actually end up being with AMVUTTRA.

So we've gotten a few questions about the collaborations that were announced earlier today. So can you tell us about these collaborations? And do these collaborations give you access to new or different patient segments that you're not currently penetrating today?

John, I'll have you take this one. But let me say a few words. First of all, we're really excited about these collaborations, and there will be more to come. And the point of this is we did lay out that we -- 2030 is our goal for leadership, and we're acting like leaders. And a leader does actually what others don't, which is set up the right ecosystem, making sure that we're actually connecting the dots to make sure that more patients are getting treated as the awareness and options are continuing to increase. So John?

Absolutely. So these are a couple of initiatives that have already announced today. And yes, we're very excited about. The most simple terms, this is about increasing diagnosis and ideally, the timeliness of that diagnosis and then facilitating care coordination. So bear in mind, we already know the numbers. Unfortunately, too many patients are overlooked, not diagnosed and/or not treated. And unfortunately, for many patients who are diagnosed, it happens later than it likely should.

And so this is really about facilitating timely and accurate diagnosis for more patients. Now you asked a question in there about specific segments. What I would say is if we look at the utilization of AMVUTTRA so far in the launch, it's been broad and relatively balanced, whether it's wild-type or variant patients across the spectrum of disease severity, academic center or community, we're seeing broad and balanced utilization. So it's not really about unlocking a specific segment per se, but more just increasing diagnosis, ideally timely diagnosis so more patients can find their way to appropriate treatment.

Can you expand on the meaning of the 35% of new-to-brand starts? Does this mean that AMVUTTRA is 35% of all new patient starts?

Yes. So look, we're incredibly excited about the number itself, given the fact that as a third entrant to this category, under less than 12 months, we've been able to actually essentially secure about 1/3 of the net new patients into -- for AMVUTTRA. That's quite remarkable. Those of you who may be familiar with how the market dynamics work. But I'll have Mark maybe expand on that, how that number is calculated. What does it really mean?

Yes. So that's new-to-brand Rx -- and to your point, Tolga, that captures the totality of the patients that are coming on to AMVUTTRA. I think having 1/3 of all those new starts within 9 months of launch actually is pretty impressive. So I think we're very happy to see that. It's very encouraging. I think it speaks to AMVUTTRA's clinical profile and also, frankly, to a once-a-quarter HCP administered therapy, which allows for validated adherence and ensure that the patients actually get the medicine to get the efficacy. And so now the goal is to really unlock this next wave of growth, as I mentioned before, and really expand that prescriber base.

Great. Thank you. We've gotten a couple of questions about the CARDIO-TTRansform study. So if AZ shows statistically significant results in the combo arm and lower the price, how will you compete? And conversely, if CARDIO-TTRansform does not hit stat sig in the subgroup of patients on background TAF, -- how do you expect greater restrictions from payers? And how would this potentially impact your commercial strategy?

So it's a 2-parter. I'll have Sameer, who is himself a trialist, expand on what we expect from CARDIO-TTRansform, and then I'll have John comment on the latter part of the question. What I'd like to say is, look, as we laid out in terms of our silencer strategy, there's nothing new essentially. In terms of our label, in terms of our data set and the experience that we're already building with patients and physicians both, we're already establishing AMVUTTRA.

And given it's actually unique profile, deeper knockdown and longer duration, we're already highly differentiated in this class. But let me turn it over to Sameer and maybe he can expand on what we expect and how we're going to continue to compete.

Absolutely, Tolga. Thank you. Again, let me, first of all, remind everyone, I think for HELIOS-B almost 2 years back, in our primary paper, we showed very clearly that vutrisiran provides benefit regardless of tafamidis as a background therapy. So that's our anchor data on combination therapy. That is the data that is available today. We have shared that broadly in multiple roundtables that many of us, in fact, led personally. And I would say in those conversations, the data resonates.

So people already know of this data that vutrisiran in combination with tafamidis does provide benefit from that perspective. I would say that I think when you start thinking about what happens with CARDIO-Transform, we have had those conversations as well. And I think the belief set is only going to be that it's a class effect. And that's our best guess at this point based on what we expect with CARDIO-Transform later this year.

Yes. So one of the question there was about what do we expect for pricing and access. And I had shared some of those thoughts earlier today. So just restate it. If you think about it, already today, we're competing against 2 pharmacy benefit covered products. And you see the AMVUTTRA access, it's really unencumbered. We have about 99% coverage, about 90% of that is in first line with the majority of patients paying $0 out-of-pocket cost. So we don't really see a dynamic that changes here. And I think the other thing I'll go back to is instructive to think about the experience that we've had in hereditary ATTR polyneuropathy.

So don't forget, we've been competing against the silencer already today. In polyneuropathy, way past a year of competition with another silencer, we saw 2 things happen. Number one, the category expanded. More patients were being treated. And the second is we retained leadership. So obviously, we do know that competition is generally helpful for the category. And at the end of the day, when a physician is reaching for a silencer, they're looking for that knockdown profile. AMVUTTRA today delivers about 87% mean reduction in TTR with 4 doses per year. Nucresiran, which is still a development candidate, promises to have the potential of delivering 95% knockdown with just 2 doses per year. So again, we're well positioned for the competition.

Great. What should we expect as far as quarter-over-quarter growth for the remainder of 2026?

Yes. So as you highlighted, it's a good question, but it's a question that we're not going to be able to answer, and we'll actually address this in the Q1. But what I can tell you is this, -- we've laid out our guidance at JPM. And what we laid out was due to a couple of facts. One is we could see how the product is performing competitively. We can see how the category is growing very -- in an accelerated fashion. And last but not least, we have concluded our '26 negotiations with the payers.

And all these 3 important dynamics were green. And that gave us even further confidence to actually provide it a guidance that's over 80% in midpoint to $4.4 billion to $4.7 billion for a year. And that's building on over 100% growth that we've been able to achieve in '25. And we're very confident that we're going to be able to continue that progress. And in Q1, we'll discuss more of the details on the Q1 and what you'll obviously see for the remainder of the year, how we intend to meet and hopefully exceed that guidance.

Great. We've actually gotten a number of questions about the TAF LOE. So I'm going to ask a couple of parts to this one question here. So when do you think TAF will goes generic? And what does that actually mean for AMVUTTRA? Is the availability of a generic alternative going to be a headwind for all players in the space as payers will step at a generic TAF first or it will be a tailwind as it would unlock combo use? And then how do you weigh the potential headwind of first-line access versus a tailwind on combo use?

That's a long question. Exactly. Well, look, I'll have Mark address this. And he, I think, did a phenomenal job in the way he laid out how we're going to compete against the potential genericization of the stabilizer class. What's great about where we are today, though, is it really doesn't matter because essentially, we have an orthogonal mechanism of action that have already established its competitiveness in less than a year. So whether TAF go generic by end of '28, that's what Pfizer has stated or one may speculate that it may happen later. It really doesn't matter in the way we are competing. But maybe in terms of the granular detail, Mark, you can provide more perspective.

Yes, yes, I will say. So Pfizer has publicly stated they expect the U.S. LOE for TAF to be in late 2028. And we think we're really well positioned, to your point, Tolga, to continue to manage AMVUTTRA in that era. There's strong demand, as I just shared a moment ago in terms of our NBRx. There's strong demand for AMVUTTRA, and that's because it's a therapy that knocks down TTR at the source and we're seeing that physicians and with patients that really resonates.

Additionally, I'll just reiterate, we have strong access today, right? As JPK pointed out, over 90% first-line coverage, 99% total coverage. Most patients pay 0 out of pocket. We expect those dynamics, those fundamentals to persist post TAF LOE. And so we really see the TAF LOE, frankly, as a tailwind because we think this unlocks the ability for physicians and for patients to use combo therapy if they want. I'll remind you, as Sameer pointed out, that we show from our HELIOS-B results similar effect with TAF or without TAF. And we'll see what the AZ WAINUA data look like, but that's almost certainly going to provide a tailwind for the category. And so at the end of the day, our fortunes are not tied to whether TAF is generic at the end of '28 or not. We do think this is an unlock for the class big picture. And so we look forward to it.

So how do we think about phasing of ex U.S. TTR revenues as you roll out across additional geographies?

Sure. First of all, look, we're quite excited because we're a company that is obviously despite its early stages of commercialization, has been a global organization, and we have footprint across the world. And we've been able to commercialize first ONPATTRO and then later AMVUTTRA with the PN indication quite successfully.

And as we move forward with making this product available across the world, we're going to actually have important steps. As you already know, we shared that Japan launch is going extremely well, even better than most analogs and other launches regardless of the therapy area. And we also did indicate that in Q1, we're going to see a little bit of a headwind given the fact that we're actually going to make a price adjustment to further compete in the cardiomyopathy, which has a much larger prevalence.

Now that softness in Q1 is good news. It's good news because essentially, we're building up volume that's going to be able to actually overcome some of those headwinds in the full year. John, you already shared with the slide that how those rest of the world launches are going, starting with, obviously, Japan, Germany. Can you give a little more context?

Yes, absolutely. So again, Japan well underway, great momentum, excited about that. Germany. We started with the provisional launch while we are working through the pricing reimbursement process, but now that's underway. And you're spot on in that Q1 will reflect the new negotiated cardiomyopathy price in Germany. And so for the PN volume in Q1, there's an adjustment, but we'll more than make up for that in growth. Bear in mind, the prevalence of cardiomyopathy is tenfold greater than polyneuropathy.

So we'll make up for that in volume growth after the initial transition. And then today, I shared that we've also launched in Austria and U.K., and we have several other countries staggered throughout the remainder of this year and into next year. So the goal is simple, bring AMVUTTRA to as many countries as we can as fast as we can. In terms of the revenue contribution, it will be more kind of back half of the year weighted just given these transitional dynamics, but tremendous opportunity we continue to move forward.

Thanks, John. So what are the AMVUTTRA persistence adherence you see in real world for ATTM-CM (sic) [ATTR-CM] so far? And how do you anticipate these evolving over time?

I'm so glad somebody picked up on the adherence point because as I closed the presentation, there are 3 key metrics, along with, obviously, our other metrics that we've been talking about. There are 3 key metrics that we're going to be updating -- the Street. One is obviously the category growth. The other one is adherence rate. And essentially, what we're going to make sure is that our highly differentiated product profile comes across very clearly. So with that, John, do you want to was it Mark? Yes, sorry, yes, take it. Sorry.

Yes. So just building on your point. So if we think about polyneuropathy, we've seen adherence rates in the 90% range, upwards of 90% -- and we're starting to -- obviously, it's early days here on cardiomyopathy, you need enough time to measure adherence, but we're seeing very similar numbers in terms of cardiomyopathy. So an important point here, though, is obviously, with cardiomyopathy, that tends to be an older patient population. And so sadly, there are more of those patients that expire over time.

It's still a small percentage, but obviously, that's on an increasingly large patient base. And so that's why coming back to the bigger question here, that's why we think AMVUTTRA really has a compelling and frankly, advantageous profile in terms of once quarterly HCP validated -- HCP administered and validated dosing where you're ensuring that the medicine gets into the patient.

And with nucresiran, as JPK pointed out, there's an opportunity there to have every 6-month dosing, which I think will be even more compelling. So anyway, this is something we're going to report on regularly as we've committed to. But so far, things look pretty similar in CM as they were in PN.

We have a number of questions that have come in, but we have time for one last question. So what are some of the channels you're using to reach patients to become the most requested treatment?

That's a great question. Who's going to take that one?

I mean what I'll say is patients and physicians, we know they're very involved in their treatment. And they're very active, especially in cardiomyopathy. And we use a number of means. We certainly do a lot of direct-to-consumer, and that may be with television, that may be with social, that's with search, that's with radio. And what we've seen is that it really works. And patients are asking for AMVUTTRA now very regularly.

In fact, what we've seen in our Q4 research is that AMVUTTRA is the most requested brand by physicians, which is -- which tells you something. And you may be wondering why don't I always see the ads on television. That's because we have a more targeted approach to actually placing the AMVUTTRA advertisements where the patients really are. And so we've seen it working. And we also have an in-house patient services organization that includes nurse educators that are able to engage directly with patients in an appropriate manner. And so I think all of those things help to ensure that patients are educated. Do you want to add anything to that, John?

I think maybe I'll just point to some of the initiatives that we have at scale. So we talked about some collaborations that have been announced. One of these, just to give another example, is this sponsorship of American Heart Association initiative, which really brings together a consortium of organization health provider accounts that are integrated systems. And it's really designed to identify what are these best practices for engaging customers so that we can actually work through the diagnosis and the care coordination process as efficiently as possible. So that's working at kind of a system scale, which complements some of the work that you're talking about in terms of direct patient engagement or physician engagement as well.

What's really exciting about -- thank you guys both. What's really exciting about this category is you've seen the growth has already been pretty robust when Pfizer alone actually introduced the first option available. And now it has significantly accelerated with the addition of AMVUTTRA. And part of the reason is not only actually communicating and creating awareness with the physicians, but also actually communicating directly with these patients.

Patients are really aware of this disease once they're diagnosed, and they are actively engaged in their treatment. That's where we see actually a clear preference for AMVUTTRA. But more importantly, before -- as John actually laid out, before the diagnosis, there is a longer period of suspicion and awareness. And this is the part where I think we've been playing a very important role. And clearly, again, we have a very targeted, very selective approach to reaching those patients. And once we do, I think our narrative really resonates with them, and this is one of the reasons why you see the results that you see today.

Great. That's all that we have time for today. Thank you to our speakers and to everyone who joined us on the webcast. The replay will be available on our website later today, and we look forward to keeping you updated on our progress on our next quarterly earnings call. Have a great day.

All right. Thank you, everyone, for coming today. This is to the TD Cowen Healthcare Conference and the fireside chat for Alnylam Pharmaceuticals. I am the covering analyst Ritu Baral. And with us from Alnylam, we have Kevin Fitzgerald, CSO; and Jeff Poulton, Chief Financial Officer. So guys, welcome. Thank you for being here. Let's start with AMVUTTRA because that's where every conversation of mine starts. And the revenue growth drivers, sustainability of growth specifically. How are you guys describing the key drivers behind AMVUTTRA's recent revenue growth? And how sustainable is this trajectory not just through 2026, but beyond?

Yes. Thanks for the question. I'd say there's probably 2 or 3 fundamental things that underpin our confidence in the growth going forward. One is just the growth of the category in general. This is an underdiagnosed, undertreated disease. We think probably you're at about a 20%, 25% treatment rate today. And if you look back 2 or 3 years when there was only a single therapy in the market, it's been growing fairly consistently the last several years, about 40% a year. We do anticipate that you're going to continue to see robust growth on a go-forward basis. Now you've got 3 players in the market.

You're talking about treatment or diagnosis.

We're just talking about market growth, treatment...

Treat...

Treatment, right? More patients coming onto therapy. And that 40% growth in treated patients over the last several years has been with one therapy in the market. What's been the standard of care, Pfizer's product. And you've got 3 companies in the market today, all investing behind disease awareness and driving treatment rates. And so that should be something that we have a lot of confidence in that that's going to continue to grow at a brisk pace. So that's one. Second is market access, which, as you know, Ritu, was a pretty significant debate prior to our launch in terms of being a Part B med, Part B buy-and-bill drug with a higher price than the other Part D products that are in the market.

How is that going to work for Alnylam. We're in the second calendar year of the launch today, and I would say it's worked very well. We have 90%-plus percentage of patients today have access to AMVUTTRA is a first-line therapy. And so we have not seen access be a headwind for the brand, and we don't think that is going to change over a period of time. And so -- but we'll continue to stay focused on that. Payers and plans have the ability on an annual basis to look at policies. We feel very good about 2026 in terms of access to AMVUTTRA.

And then lastly, of course, is preference, right? Market share, right? What's going to drive the brand first in the first-line part of the market, which is really where we have been very focused since launch is driving preference for AMVUTTRA. It's a progressive fatal disease and patient should be on the best, most potent therapy as early as they can. We think based on the data from HELIOS-B that we have the ability to argue that AMVUTTRA should be the treatment of choice. We shared some share data at JPMorgan through the end of the third quarter that showed our share in the first-line part of the market sort of mid- to high 20s. That's really been a focus for us...

And has that been increasing since then?

I mean we haven't given data for beyond the third quarter, but we feel very good about the positioning of the product in the first-line part of the market...

Was that your internal target, that level? Or are you continuing to see more room for growth...

Yes. I mean I don't think we put out a target. I mean what we've put out in terms of forward-looking information is on 2026 revenue guidance. We guided for the franchise $4.4 billion to $4.7 billion, which would be 83% growth at the midpoint, which would be more than $2 billion in revenue growth on a year-over-year basis. And then longer term, at JPMorgan with the Alnylam 2030 guidance that we put out, we did put a total revenue CAGR out over that period of a 25% total revenue CAGR. And that's not only product sales, that's collaboration revenue and royalty. But certainly, the biggest driver of that revenue CAGR over the period is going to be the TTR franchise. So again, I think that speaks to the confidence that we have in terms of the positioning of the product and the ability of that product to drive durable long-term growth for Alnylam.

As we think about commercial focus, is it really on expanding the first-line percentage and seeing that number?

Yes. I mean I think if we're success -- we think if we're successful in the first-line part of the market, which is the largest segment, that's where you have the opportunity to get access to the most patients. If we're successful there, then that we think will support also success in the second-line part of the market. And we've been very successful since launch in the second-line part of the market. But we've really been focused on driving that first-line share. That's been the focus.

How has payer contracting evolved and step edits now that you're a growing line item and therefore, are payers starting to pay attention.

I mean we've got '26 payer policies that are all set, and we have not seen any...

But not permanently, so they can always...

Every year, they have the ability to do this, but the '26 plans have been set, and there hasn't really been any change from '25 to '26 in terms of access to AMVUTTRA. Again, we're more than 90% of the patients today have access to AMVUTTRA in the first-line setting...

With no step edit.

No step edits. Again, maybe we should just talk about the payer mix. I mean this is a -- given the nature of the disease, this is a heavy-Medicare population. So it's probably about 80% of the patients that are on AMVUTTRA, whether that be for polyneuropathy or for cardiomyopathy, are Medicare patients. And then that Medicare part of the market is split roughly 50-50 between fee-for-service original Medicare part of the market and Medicare Advantage. And just as a reminder, in the original Medicare part of the market, there's no payer policies. There's no management of that part of the Medicare market. So that's obviously a very good segment for us in terms of access.

The fee-for-service.

Yes. The fee-for-service, there's no policies. There's nobody managing that part of the market. The Medicare Advantage, which is really where there was a lot of debate, I think, coming into the launch...

They do cross-manage the B and D.

Very, very little. I mean we have seen very little. Look, I think from a systems perspective to cross-manage B and D is challenging for payers. And so we've seen very little of that in the Medicare Advantage part of the market. So that's almost all first-line opportunity. The smaller part of the market is the commercial part of the market. So that's what's 15%, 20% -- and that's where we did anticipate some cross-management between B and D, and we've seen some of that, right? So that's where the steps are, right? That's where the majority of the steps are in the commercial part of the market. But again, that's a smaller part of the market.

What kind of step edits and what sort of documentation?

I mean it varies by plan, right? In terms of what you have to provide to work your way through the step. And look, we have the ability to support patients and offices when there are steps in place, but it really does vary by plan. There's not a single approach to how those steps are put in place.

How do you assess the midterm competitive threat from WAINUA? I mean, it's not near-term, that data is later this year -- the Phase III...

Yes. Look, this is -- I think one thing that's good with more competitors is what we talked about earlier that this is still largely an underdiagnosed and undertreated patient population. So the more voices that you have, the more it drives those things, and that can be good for everybody that's in the space. So I think I'd start there, number one. It's hard to comment too much further until we see their data. I mean I think there's a few things that -- number one, I'd say is just in terms of the -- how rapidly we knock down TTR, we probably have an advantage there in terms of time to get to there...

So a potential differentiator.

It could be -- I mean, we're going to have to see the data in terms of whether or not that translates into efficacy, but that's one. I think we're going to be very interested to look at the safety data in that study. I mean there's been renal tox issues with ASOs in the past. This is clearly a different molecule. But this is a -- in the cardiomyopathy setting, this is an older, frailer population. So it's going to be interesting to see if there are any safety signals there that could have an impact. In terms of how these products are dosed, we're once a quarter dosed, we're Part B, right? So that's physician administered their Part D once a month. So 4 times a year versus 12, majority of patients would prefer fewer injections to more injections.

You can get our products at home. You can have it administered in the home. So that's one differentiator. And then lastly, I think maybe it's instructive to look at what's happened in the polyneuropathy space since they came into the market. So in the U.S., they launched in polyneuropathy at the start of 2024. And if you look at the growth of our PN business prior to their launch, post their launch, you really didn't see any change in the trajectory of the polyneuropathy business.

And I think what's happened over time is, with the second entrant in the polyneuropathy part of the market in the U.S. The pie started to expand faster, just as what I said before in terms of another voice, but we're getting majority of that business. We probably have gotten 70% of the new patient starts since they launched in polyneuropathy. So that leadership position that we have, that kind of firmly established position was very helpful in polyneuropathy. We believe that we're going to have a similar situation in the cardiomyopathy part of the market with the head start that we've had on them.

One thing you've been able to do to really lock in that PN market was contracting, whether it was -- I'm still not sure, but I inferred there was certainly ex-U.S. contracting, national orders, national pricing in place. Is that something that you -- is that a strategy you can adopt for cardiomyopathy, whether U.S. and ex-U.S.?

Yes. I mean we're not doing any contracting in the U.S. today per se, right? So I don't think that, that's going to be part of the plan going forward in terms of competition with WAINUA ex-U.S., again, the dynamics are obviously a little bit different around sort of pricing and access than they are in the U.S.

Patient sizes as well. But...

Yes. I mean the polyneuropathy part of the market has been -- it is a much more mature market outside the U.S. because tafamidis got approved outside the U.S. for polyneuropathy and really built that part of the market. That didn't happen in the U.S. And so we were really building the polyneuropathy market in the U.S. with ONPATTRO many years ago. So the dynamics are just a little bit different in polyneuropathy, U.S., ex-U.S.

How do you hope next-gen will evolve into the TTR landscape? This is nucresiran -- and how is enrollment in TRITON.

Yes. I mean we're early days, but I would say enrollment is on track in terms of the plans that we had, and we're really excited about this opportunity. This is a next-gen, so uses different chemistry and allows us to dose less frequently. So we're looking at twice a year dosing, so once every 6 months and deeper knockdown and I would say sort of less variability around that deeper knockdown. So our belief is that, that could translate to better efficacy. We're looking at 95% knockdown versus mid-80s knockdown. And again, TRITON spread around 95% than it is around 85%.

So do you think that's going to end up representing sort of a linear improvement in outcomes?

Again, I think it's hard to say. I think the best data that we have, and looking at deeper knockdown and what efficacy benefits that you see, is in polyneuropathy on mNIS+7. And we do see certainly a relationship with deeper knockdown leads to better efficacy. So I think we're hopeful that we'll see that. We've got 2 studies underway with nucresiran, 2 Phase III studies right now, a polyneuropathy study that is very similar in design to what we did with HELIOS-A and that will read out.

With the same APOLLO-A control arm?

Yes. Yes. And that would be a 2028 launch is the expectation. And then we've got an outcome study for cardiomyopathy that's largely going to be a study that's going to be run on top of tafamidis, much bigger study than polyneuropathy study. This is about 1,200 patients...

What percentage do you think is going to be on top of.

Most will be on taf, right? And I think...

Like 80%, 90%...

I don't think we've put out a percentage, but it's certainly going to be mostly going to be on top of taf. And I think, look, the confidence level that we're going to have a successful study there is based on what we saw in the combination subgroup in HELIOS-B, where we actually saw very good efficacy on top of tafamidis. And actually, that's one of the things that we think sort of speaks to the potency of our mechanism of action that on top of tafamidis, which is 40% of the patients in HELIOS-B, we saw really good efficacy on every endpoint in the study, right? So it certainly seems that the stabilizers are leaving some efficacy on the table. So we've designed the cardiomyopathy nucresiran study with -- in terms of assumptions around powering with really good data from HELIOS-B to support the assumptions that we're making.

Going back to WAINUA for one second, just reminded me of something. One thing that the WAINUA developer has been saying is that they -- based on the design of the study -- they will be able to show stat improvement on all outcomes, I believe, all cardiac outcomes versus taf background. And you have similar data, but not exact data. Can you -- if they're saying that's their differentiator, what do you have to?

And they've got a powering -- their study is powered, right? They've got 1,400 patients in the study, 50% of those are the tafamidis subgroup. So it's a much larger study. We had 40% of the patients in HELIOS-B; it was 655 patients in total, 40% were on taf at baseline, so a much smaller sample size. So they've got a powering advantage, right? So I think our expectation is that they will show stat sig in that subgroup. Now we have data in our label on that subgroup of patients.

It's a different endpoint, but yes.

I mean the primary endpoint is very similar, right? And we have data that shows in that subgroup that there was an advantage. It's in the label, and that should be supportive of physicians using that product in combination. We are seeing some combination use today. That's more restricted, I would say, from a payer standpoint, and we don't think that, that will open up more broadly until path goes generic. But look, we think that based on that data that we can compete in that part of the market when combination therapy becomes more open from a payer standpoint.

And the nucresiran study that we talked about earlier is powered, right? In that patient population on top of tafamidis based on the way we've designed that study and the cardiomyopathy readout and launch would be expected in 2030. So we feel comfortable that we're going to be able to compete effectively even in the combination part of the market, first with AMVUTTRA based on the data we have and then certainly with vutrisiran to follow.

So last question on TTR before we move to Kevin in the pipeline. How do you see nucresiran in terms of how we model things? Are you looking at it as sort of continuation of market expansion and sort of keeping the growth going? Or at that point, in 2030, are we looking at sort of duration of franchise as an asset and sort of consolidation?

Yes. I mean I think it will consolidate the TTR business if it has the profile that we think it will, meaning patients would certainly prefer to be on a less frequently administered product, particularly if we have efficacy that looks like it has an advantage. So I do think it will consolidate the TTR business, which is going to be very good for us from a financial perspective.

Margins perspective.

No royalty burden. We've talked about 30% operating margins through 2030 and then the ability to really expand to probably at least mid-40s with a successful nucresiran launch. But I think it will also continue to grow the franchise longer term. Like again, this is a large rare disease that's undertreated today. Beyond 2030, there's still going to be plenty of opportunity to keep driving penetration rates deeper. And I think nucresiran will position us to continue to not only consolidate the AMVUTTRA business, but continue to grow the franchise overall beyond 2030.

With that, we're going to move to the pipeline and the biggest topic that I get talking to investors about the pipeline. This is what I call my airport lounge bar conversation when we're all delayed on flights. What asset in the pipeline should we be focusing on now? What's an internal priority for Alnylam amongst the myriad? I mean this is the downside of having such a rich pipeline, right? Where do you focus? What's the next lever?

Let's talk about the pipeline in general -- zilebesiran. So here's we'll talk about the cardiometabolic franchise in general. We've got zilebesiran for blood pressure. We've got GRB14, which is for diabetes, right? And then we have recently put in the clinic ACVR1c for obesity. So we'll start with zilebesiran, and we can also talk a little bit about how you might combine some of those. So zilebesiran is this product that literally takes blood pressure down and holds it there, right? And so what we know similar to how it's linear between lowering LDL cholesterol and outcomes, blood pressure, if you lower it and keep it down, you do better on outcomes.

And in fact, when we looked at the human genetics, the variability in blood pressure, if you go up and down, say you are taking your medication, you're off or it wears off and you spike in blood pressure, it's those spikes actually that are bad for the blood vessels. So overall, the profile of something that comes down unique in the industry and keeps your blood pressure low, we think, is really, really exciting.

And we're in a Phase III outcome trial to show that, right? That over time that, that benefit accrues right? So we're very excited about that program. If you look in GRB14 there hasn't been a new novel insulin sensitizer in years, right? And so there's a program where the human genetics is clear that if you lower this protein, you actually prevent that Type 2 diabetes. And so I think it's an insulin sensitizer and that it controls the level of the insulin -- of the insulin receptor itself.

Where are we getting...

We're in Phase II. So we're going to look for data in diabetics by the end of the year.

By that proof of concept -- and that endpoint, you're just looking at HbA1c or like fasting glucose...

No, we're also doing clamps actually.

Clamps.

Both. So there's a subpopulation where we're doing -- we have our program targeting plasminogen, which that's a program where, again, the human genetics, we set out looking for something that could be a universal hemostatic agent without thrombotic risk. So as you look across the targets that people have chosen over the years, most of them genetically carry thrombotic risk because when you change that pathway more towards clotting. So this particular target, plasminogen, what we found profoundly was that individuals could lower the rates of bleeding without a thrombotic risk. And so now we're in a number, there's about 3 million or more patients that have bleeding disorders and only a small segment of them with hemophilia really have treatments. And so we're very excited about -- we've gone into HHT.

What percentage does that -- like non-hemophilia bleeding disorders?

It's the majority of...

It's like 95-plus million. Okay, 90-plus percent -- of that 3 million.

Yes. 3 million.

3 million.

So we started out in an indication HHT, which these individuals actually have fragile blood vessels. And so they bleed constantly, so they can have nosebleeds that last for 2 hours...

What's the particular prevalence for HHT?

There's about -- we probably think between 40,000 to 90,000 of those individuals, and they -- a lot of them actually need to have transfusions. And so this is not just they bleed from their gums. And so we're in a Phase II trial. They're now in patients. And so again, we'll be looking to have data by the end of the year around how that's impacting them. And then we're filing in a second indication that we haven't yet named.

You've discussed some additional indications. Can you walk us through those in the market?

Well, so again, there's a number of them. There's things like hemophilia, right? There's things like von Willebrand disease. There's a couple of others that are smaller. And so we're going to walk through them because we think that this really is going to have benefit in all of those patients.

How do you think of the development path for this asset? Is this something where like you could have 2 trials in similar -- or different, but similar disease populations that could support an approval for the drug?

I mean I think we're going to do for -- the good news is that a lot of the readouts are sort of binary, right? So you have really hard outcomes, which is bleeding, no bleeding. And so as you walk across them, we'll probably do somewhat standard trials in some of them. And as you get to the more sort of the less prevalent diseases, you might think about something like a basket trial.

You have a Phase Ib Huntington's trial with [ HTT02 ] reading out in the second half, too. Can you walk us through those key endpoints and how you see the interpretation of that mechanism evolving, given the overlap of the mechanism with gene therapy and efficacy [indiscernible] data?

Yes. So let's start out with Huntington's devastating disease. And we are going in with a very specific mechanism, which is that we're hitting this thing called exon 1, right? So there's exon 1 and there's the full length. So this is a disease where you have both of those playing an important role. So you really want to hit exon 1. And it wasn't known in the field for a long time that exon 1 was important.

But now as this has evolved, it's very clear that exon 1 is part of that disease. And so we have unique mechanism here where we have an RNAi that targets that. It took us a little bit extra time to actually figure out how to do that, but we've got a really nice molecule that does that. We're in Phase I. We're looking at lowering in patients, have data by the end of the year that will look at safety of that molecule as well as a degree of lowering and we're looking for something maybe 40%, 50%. That's where the field thinks there'll be significant benefit for...

40% to 50% knockdown...

Knockdown. And so I think the uniQure data -- I don't like to comment on other people's data, it was a very small trial -- but I think if anything, that if you sort of read the tea leaves, it does look like that's the only other thing out there that's an exon 1 mechanism. I mean it maybe seemed to have some hints. I think the FDA has come back and said they want to see a bigger controlled study, but that's...

Putting the landscape together and if you do target this 40% to 50% knockdown for the next study, speculating, obviously, on contingent data, but speculating how long do you think you need to treat before you start moving the endpoints that FDA cares about?

I mean I'm not going to speculate on our Phase II design, but I think we're still looking at the data. There are natural history studies that are coming out of the progression of the disease. There are neurological endpoints that you're going to want to look at, but we're in the midst of sort of figuring out exactly how long and what those endpoints should be with all the KOLs.

In our last few minutes, I want to talk about next 5 years and long term. This is the conversation that I have with the generalists that are really looking on the long term. Are you going to be focused on maintaining and growing profitability or more on pipeline development and expansion into new therapeutic areas? I mean you guys used to be the R&D engine. You had a huge pipeline and absolutely no profits. And a huge R&D budget, which you reined in from some of your first few years, we've had that conversation. So how is that balance evolving?

Yes. This is where I think the Alnylam 2030 set of goals that we shared a couple of months ago is really helpful because I do think it sort of gives a picture of where we're going. Just to recap, I mean, that's really focused on 3 things. One is leadership in TTR, which we talked about earlier. Two is about, frankly, expanding the pipeline and creating opportunities to grow durably beyond TTR. We can talk about that more in a second. And then it's really about how we're going to scale the business financially. So we talked about the top line growth expectations, right? We set a 25% CAGR.

And then we provided our view of operating margins across the period, and we're looking at 30% across the period. So let me walk through that because there were a lot of questions about that. And frankly, we anticipated that because the market, if you looked at consensus going into JPMorgan and you look out 5 years, the market's expectations in terms of profitability were frankly much higher. They were at about 50%, actually better than 50% operating margins.

And that's really, really difficult, if not impossible, with the gross margin. With the cost and the royalty. Yes. Our gross margins are at about 75%. So to have operating margins of 50% when you're frankly starting at 75%, but that just doesn't leave enough room for investment in SG&A and R&D to be at that level. So we needed to be really clear about that with the market. And one of the things that we clarified is how we intend to invest in R&D across the period, and we did set a goal of 30% of revenues reinvested in R&D.

We think that's a prudent allocation of capital. Kevin talked about a lot of the things that are in the pipeline today that are going to drive that growth in the years ahead. Primarily, this is going to be focused on internal innovation. And again, I think that's smart given the success that we've had with the platform and the approach that we've taken historically in terms of how we use genetics to drive targets and things that we bring into the clinic. That's not going to change. We're very focused on opening up new tissues, right? We've got a goal to be in 10 tissues by 2030.

And maybe the harder R&D goal that we gave, very specific goal was to have 2-plus new therapies either in the market or line of sight to being in the market that can drive substantial growth that are beyond TTR, right? Really, we're really focused on trying to -- we're focused on protecting and growing TTR, but we want to make sure that we can diversify the business. And so that's why we've selected 30% as the place that we see the right investment rate to drive that kind of growth in the pipeline and innovation across the period.

So speaking of potential in-licensing, how -- like what therapeutic areas are you looking into? Or is it going to be more of a technology delivery focus thing to.

Maybe I'll clarify what we said about business development, and then I'll let Kevin maybe comment further on the types of things that we might be interested in. So that 30% reinvestment rate of revenues into R&D, we said primarily is going to be driven by internal, right? R&D. So our focus on RNAi. We said that we would start to add selective business development into that mix. That's included in that 30% reinvestment rate. So we do think that we will start to look at external innovation as...

And that's within the 30%...

It's within the 30%, right? We've left ourselves headroom for external innovation in that 30% -- so maybe I'll let Kevin talk about sort of our approach and how we might think about external innovation.

Yes. So I'd say I'm a drug hunter, right? So in a lot of ways, you're looking for both things that can enhance your technology, right? So what's...

Delivery...

Well, either delivery or a modality that maybe you can combine, right? With an RNAi. So as you start to think about things like that, there are -- for instance, our cemdisiran program with Regeneron for certain indications, it's an antibody with an siRNA, right? So you can get very creative about how you take RNAi as a foundation and maybe add something to it as well as if you start to think through delivery to 10 different tissues, there may be somebody that has a delivery modality that they're using for something else that you can repurpose for delivery to RNAi.

Any favorite therapeutic areas or strategic approach to therapeutic areas? I mean, you've obviously evolved from like an orphan company to targeting much larger indications. TTR is incredibly cuspy if you look at models on whether it's orphan or not. Your partner programs are large. And are you looking for commercial synergies for the marketing force as you look at?

I would say as we look at assets internally and externally, if there's something that fits within a franchise or a therapeutic area. It gets a little bit of weight. I think on the other hand, I'm always looking for what could be the next franchise right? So we're going to be very opportunistic. If there is another large indication where there's high unmet medical need where we think we can really make a huge difference, we'll go there.

And there is the willingness to spend on the SG&A in the midterm.

Yes. I mean I think external opportunities that we're looking at, probably earlier stage is probably much more likely at this point. Again, we've given a pretty robust top line growth expectation across the period. So we don't need to buy near-term revenue. So it's more likely that we're going to see things that are earlier in development that we've been investing internally...

With that, we are a little over time. Thank you, guys. Thank you, Jeff. Thank you, Kevin.

Thank you.

Good morning, ladies and gentlemen, and welcome to the Alnylam Pharmaceuticals Q4 and Full Year 2025 Earnings Conference Call.

[Operator Instructions]

This call is being recorded on Thursday, February 12, 2026. I would now like to turn the conference over to Christina Kensch. Please go ahead.

Good morning. I'm Christine Akinc, Chief Corporate Communications Officer at Alnylam. With me today are Yvonne Greenstreet, Chief Executive Officer; Tolga Tanguler, Chief Commercial Officer; Pushkal Garg, Chief Research and Development Officer; and Jeff Poulton, Chief Financial Officer.

For those of you participating via conference call, the accompanying slides can be accessed by going to the Events section of the Investors page of our website, investors.alnylam.com/events. During today's call, as outlined in Slide 2, Yvonne will offer introductory remarks and provide some general context. Tolga will provide an update on our global commercial progress. Pushkal will review pipeline updates, clinical progress and upcoming milestones, and Jeff will review our financials and guidance before we open the call to your questions.

I would like to remind you that this call will contain remarks concerning Alnylam's future expectations, plans and prospects, which constitute forward-looking statements for the purposes of the safe harbor provision under the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including those discussed in our most recent periodic report on file with the SEC. In addition, any forward-looking statements represent our views only as of the date of this recording and should not be relied upon as representing our views as of any subsequent date. We specifically disclaim any obligations to update such statements. With that, I'll turn the call over to Yvonne. Yvonne?

Thanks, Christine, and thank you, everyone, for joining the call today. Alnylam possesses a truly unique profile in the biotech industry, underpinned by our established and sustainable innovation engine, coupled with commercial excellence, driving durable long-term growth. We're the leaders in RNAi therapeutics with a proven organic product engine and a reproducible and modular process for developing our medicines that has resulted in outsized historical success rates. We also have a high-yielding pipeline with over 25 programs currently in active clinical development. And there are now 6 Alnylam invented medicines on the market that are collectively generating several billion dollars in annual revenues and treating hundreds of thousands of patients around the world. This broad execution across all areas of the business was clearly evident in 2025, which was a transformational year for Alnylam.

In terms of commercial and financial performance, we achieved a landmark approval of AMVUTTRA for ATTR cardiomyopathy and driven by the success of that launch, delivered nearly $3 billion in combined net product revenues, which was 81% growth compared to 2024. Importantly, we met or exceeded all of our ambitious Alnylam [indiscernible] 25 goals. And with today's announcement, we can now officially declare that we have achieved GAAP profitability for the 2025 full year and expect to sustain profitability going forward.

On the pipeline and platform side, in 2025, we initiated 3 Phase III studies and expanded our clinical pipeline with 4 proprietary CTAs in addition to the 5 that were filed by our partners. We also developed and launched a potential best-in-class enzymatic ligation based RNAi manufacturing platform called siRELIS. We believe this platform will enable us to greatly expand our capacity and bring RNAi therapeutics to more patients around the world while reducing the cost of goods. While 2025 was a defining year for the company, we're now focused firmly on the future, harnessing our success to accelerate innovation and scale impact. To that end, we're excited to have recently shared our new set of 5-year goals on Alnylam 2030. And these goals rest upon 3 strategic pillars, starting with achieving global TTR leadership while building a durable TTR franchise. We aspire to lead this market in revenue by 2030 and across the period and to launch nucresiran in 2028 for polyneuropathy and 2030 for cardiomyopathy.

The next pillar is growing through sustainable innovation where we plan to deliver 2 or more transformative medicines beyond TTR that have blockbuster potential. We also aspire to achieve delivery of RNAi to 10 tissue types and have a pipeline of over 40 clinical programs by the end of 2030. The high-yielding platform and outsized historical probability of success, combined with our rigorous and disciplined approach to portfolio management. We believe this is the right place to focus our efforts and resources, and we expect to invest approximately 30% of our revenues in non-GAAP R&D across the period to accelerate organic internal innovation and selectively access external innovation.

Given our expertise and leadership in this space, we believe this is a prudent allocation of capital that has the potential to deliver significant growth in the future. The final pillar of our 2030 goals is scaling with discipline and agility to drive sustained profitable growth. This includes striving to achieve over 25% revenue CAGR through the end of 2030 and to deliver a non-GAAP operating margin of approximately 30% across the period. It's important to note that this operating margin goal is only through 2030, which is the year we aim to achieve regulatory approval for nucresiran in ATTR cardiomyopathy. And if the nucresiran is successful in demonstrating the best-in-class profile that we expect, we believe it would drive swift patient uptake and given the lack of any royalty obligation for nucresiran potentially drive our operating margins to the mid-40s post 2030. Through these goals, I hope you can appreciate that we're building on Alnylam for the future, delivering continued long-term growth, underpinned primarily by our RNAi innovation platform. With that, let me now turn the call over to Tolga for a review of our commercial performance. Tolga?

Thanks, Yvonne, and good morning, everyone. It is a pleasure to show how we're continuing to bring Alnylam's transformative therapies to patients around the world. Q4 represented another quarter of strong growth for Alnylam. We delivered $995 million in combined net product revenues representing 121% growth year-over-year and 17% growth versus prior quarter. While our TTR franchise remains the primary growth engine, we're also seeing continued momentum in our rare disease business.

Let me start there. Our rare disease portfolio continues to deliver meaningful impact for patients and consistent performance for our business. In Q4, our rare franchise generated $136 million in net revenue, up 26% versus the same period last year, driven by increased patient demand and favorable order timing in partner markets. As a result, GIVLAARI and OXLUMO together became a $0.5 billion franchise in 2025, reflecting continued growth, more than 5 years post launch.

With that, let's turn to the TTR highlights. Q4 was another robust quarter for our TTR franchise, continuing the strong launch trajectory we saw in Q2 and Q3. Global TTR net revenues reached $858 million, up 18% versus the prior quarter and representing 151% growth year-over-year. In the U.S., net revenues for our TTR franchise grew 20% compared with Q3, '25 versus 222% versus Q4 2024. The quarter-over-quarter growth was primarily driven by a continued increase in U.S. patient demand, partially offset by an increase in gross net deductions and an unfavorable inventory channel impact. Outside the U.S., revenues grew 13% versus the prior quarter and 47% year-over-year, underscoring continued global momentum. We continue to be very pleased with the early signs in Japan, roughly 6 months into the CM launch as we continue to track in line with leading launch analogs in the industry. In Germany, we recently aligned pricing for AMVUTTRA for the ATTR-CM opportunity, reflecting the significant larger prevalence of the CM indication relative to polyneuropathy indication. As expected, this will create a modest near-term impact on total TTR revenue in Q1. But importantly, it positions us to compete effectively and participate in a substantially larger CM market in Germany.

As we have previously mentioned, we anticipate launching AMVUTTRA for ATTR cardiomyopathy in additional international markets throughout 2026 following the completion of local pricing and reimbursement reviews. As we continue to launch across ex U.S. markets, we are building global momentum that we expect to carry through 2026 and beyond. Finally, our international performance reflects the continued strength of our hereditary ATTR polyneuropathy legacy business, which remains robust despite competition. Broader engagement in the category is expanding awareness and diagnosis, ultimately benefiting patients and reinforcing Alnylam's leadership role in shaping the field.

Now let's turn to the U.S. ATTR-CM specific dynamics. Looking back on 2025, our confidence in the size growth and continued underpenetration of the ATTR-CM category has been reinforced. Despite approximately 40% volume CAGR over the past 6 years, the majority of patients with ATTR cardiomyopathy remain untreated. Against that backdrop, we are highly encouraged by AMVUTTRA's early momentum. In its first few quarters, performance relative to relevant specialty analogs supports the potential for a breakout launch, reflecting strong customer demand, the value of our AMVUTTRA's differentiated profile and disciplined commercial execution.

When we look at the early launch data, what's most encouraging is not just the pace of uptake, but where AMVUTTRA is being used and why? First, AMVUTTRA is rapidly establishing itself as an important choice in new treatment starts. By just the second quarter post launch, AMVUTTRA approached parity with tafamidis in share of new starts based on available estimates. While these available data will continue to evolve, the early signal is clear. prescribing dynamics in ATTR-CM are shifting.

Second, we're gaining traction in first-line patients, establishing AMVUTTRA as a first-line option remains our strategic priority, and we're making meaningful progress. In parallel, AMVUTTRA has quickly become the preferred option for stabilize and progress their patients consistent with its differentiated and orthogonal mechanism of action. Third, this momentum is underpinned by broad and durable access. Following completion of our '26 payer policy discussion, we can look ahead with increased confidence to even broader patient access for AMVUTTRA in 2026 versus last year.

Over 90% of payers now provide first-line coverage with the large majority of patients able to initiate treatment without step-through requirements. Most patients incur 0 out-of-pocket costs and approximately 90% can access treatment within 10 miles of their home, supported by a broad, well-established network sites of care. As we enter '26, we remain clear-eyed about where we are. The ATTR-CM launch is still in its early stages, just 3 quarters in, and there is important work ahead. At the same time, we have established the foundations for durable growth. underpinned by a strong value proposition, broad access and steadily increasing customer demand.

Looking forward, we see meaningful opportunity to further expand the category by improving diagnosis and treatment rates. And we are investing accordingly through targeted efforts in education and awareness, evidence generation and diagnosis enablement to ensure sustainable long-term impact for patients. We look forward to sharing more details at our upcoming investor webinar where we will mark the 1-year anniversary of AMVUTTRA's USFDA approval for ATTR cardiomyopathy on March 24, 2026, and highlight our progress for patients and the long-term growth and durability of our TTR franchise.

With that, I'll hand over to Pushkal.

Thank you, Tolga, and good morning, everyone. As Yvonne highlighted earlier, 2025 was indeed a year of substantial pipeline progress and platform innovation for Alnylam. First, we initiated 3 Phase III studies in 2025. Zenith is our event-driven cardiovascular outcomes trial for zilebesiran in patients with uncontrolled hypertension at high CV risk. We aim to enroll approximately 11,000 patients and have successful plan to launch around 2030. Triton-CM is our event-driven outcome troughed for nucresiran in ATTR-CM. Approximately 1,200 patients will be enrolled in this study with launch also expected in 2030, if successful. And Triton-PN is an open-label study of nucresiran in approximately 125 patients with hereditary ATTR polyneuropathy, if successful approval in this indication is expected in 2028. We also expanded our clinical pipeline, taking 4 new Alnylam-led programs into the clinic, ALN-2232, our first RNAi therapeutic directed to an adipose target, ACVR1c, with the potential to lead to durable weight loss, particularly reduction in visceral fat that is associated with poor cardio-metabolic health; ALN-5288, carding MAPT, or tau, for Alzheimer's disease and other rare tauopathies and 2 new programs for which we are not yet disclosing details to 2 competitive reasons, ALN-4285 and ALN-4915.

Our partnerships also continue to generate progress for 5 new partner-led programs entering the clinic in 2025 across a range of indications with significant unmet need. We're also excited for our partners at Regeneron. We remain on track to submit a U.S. regulatory application in the first quarter for cemdisiran in generalized myasthenia gravis with potential approval anticipated later this year or early 2027. And finally, as Yvonne mentioned, we also launched -- we also launched siRELIS, our proprietary enzymatic ligation manufacturing platform. As a result, we ended 2025 with a pipeline of over 25 clinical programs, spanning multiple therapeutic areas across rare specialty and prevalent indications, representing a tremendous opportunity for improving patient health and creating value in the years ahead.

Among these many programs, there are several that represent the next wave of transformative near-term RNAi therapeutics from Alnylam each of which has multibillion dollar potential. In the cardiovascular metabolic space, we're excited about zilebesiran, targeting angiotensinogen with the aim of achieving continuous control of blood pressure with just 2 doses per year. For metabolic diseases, we see compelling opportunities to address substantial unmet medical need in gaps in treatment left by GLP-1s in both overweight obesity and type 2 diabetes.

And in neuroscience, Mivelsiran targets amyloid precursor protein for the potential treatment of cerebral amyloid angiopathy and Alzheimer's disease. APP is a genetically validated target for both of these diseases and CAA, in particular, represents a blue ocean opportunity. ALN-HTT02 employs a unique exon 1 targeting approach with the potential to address Huntington's disease, a disease with no approved therapies through deep and widespread lowering of the Huntington protein in the brain. And in hematology, ALN-6400 offers an exciting opportunity for a pipeline and a product, targeting plasminogen to address a wide range of bleeding disorders with a unique approach that has the potential to reduce bleeding without increasing the risk of thrombosis.

Our first indication is hereditary hemorrhagic [indiscernible] which affects approximately 70,000 patients in the United States. We'll share important updates across many of these programs over the year, as outlined in our 2026 pipeline goals. In the first half of the year, we plan to complete enrollment in the CAPRICORN 1 Phase II trial of nivelsiran in patients with CAA and initiate 3 Phase II trials. The first of these has already been achieved, which is a Phase II study of ALN-4324 for patients with type 2 diabetes. The study is now actively enrolling patients, one for revelsiran in patients with Alzheimer's disease and another for ALN-6400 in a second bleeding disorder. Importantly, we expect to have clinical derisking data this year on several of the programs I just mentioned. Specifically, we expect to share Phase I and II results from the ALN-6400 program and Phase I data on both our Huntington's and ACVR1C programs in the second half of the year. And with that, let me now turn it over to Jeff to review our financial results and 2026 guidance. Jeff?

Thanks, Pushkal, and good morning, everyone. I'm pleased to be presenting a summary of Alnylam's full year 2025 financial results and providing our comprehensive financial guidance for 2026. Let's begin with a summary of our P&L results for the full year. Total global net product revenues for 2025 were nearly $3 billion or 81% growth versus 2024, driven by a more than doubling of revenue in our TTR franchise primarily from the strong performance in the U.S. following our Q2 launch of AMVUTTRA and ATTR cardiomyopathy. These full year results were more than $800 million above the original 2025 product sales guidance we provided last year, a testament to the strength of our ATTR-CM launch performance. For the full year, collaboration revenue was $553 million or 8% growth compared with 2024 and included a $300 million development milestone in Q3 associated with the dosing of the first patient in our Zenith Phase III cardiovascular outcomes trial for zilebesiran. Royalty revenue for the full year was $174 million, representing a 90% increase compared with last year, driven by higher LEQVIO sales from Novartis. Gross margin on product sales was 77% for the full year representing a 4% decrease compared with 2024. The decrease in margin was primarily driven by increased royalties on AMVUTTRA as higher revenues in 2025 resulted in an increase in the average royalty rate payable to Sanofi compared with the prior year.

Our non-GAAP R&D expenses of approximately $1.2 billion increased 17% compared to last year primarily driven by costs associated with the initiation of 3 Phase III clinical studies, including the Zenith Phase III cardiovascular outcomes trial for zilebesiran and the TRITON-CM and PN studies for nucresiran. Non-GAAP SG&A expenses of approximately $1 billion increased 22% compared to last year, primarily driven by increased investments in support of the AMVUTTRA ATTR-CM launch in the U.S. we achieved full year non-GAAP operating income of $850 million, representing a $755 million increase compared with last year, driven primarily by the strong top line results that I previously highlighted. I'm also pleased to share today that we achieved profitability on both a GAAP and non-GAAP net income basis, both in the fourth quarter and for the full year 2025 and more than delivering on our [indiscernible] by [ '25 ] non-GAAP profitability goal.

I'd like to take a moment to thank the Alnylam employees who made this milestone possible through their active engagement and scaling our business with discipline over the past 5 years. Finally, we ended the year with cash, cash equivalents and marketable securities of $2.9 billion compared with $2.7 billion at the end of 2024. The primary drivers of the $200 million increase in cash during the year include improved operating performance and proceeds from the exercise of stock options, partially offset by net proceeds utilized during our convertible refinancing in Q3.

Now I'd like to turn to our financial guidance for 2026. Starting with net product revenues, we are reiterating the combined net product revenue guidance for AMVUTTRA, ONPATTRO, GIVLAARI and OXLUMO that we communicated in our JPMorgan press release dated January 11, 2026. We anticipate combined net product sales for our 4 commercial products will be within a range of $4.9 billion to $5.3 billion, representing combined full year growth compared to 2025 of 71% at the midpoint of the guidance range or more than $2.1 billion in growth. On a franchise level, the guidance is broken down as follows: Total Rail, $500 million to $600 million, representing full year growth compared to 2025 of 10% at the midpoint of the guidance range. Total TTR, $4.4 billion to $4.7 billion representing full year growth compared to last year of 83% at the midpoint of the guidance range. As Tolga noted in his prior comments, it's still early days in the ATTR-CM launch but we are pleased with our initial momentum and the strong fundamentals which support the long-term growth potential of our TTR franchise. As we highlighted at the JPMorgan conference, the 2026 TTR product sales guidance is underpinned by 3 key assumptions: First, we anticipate U.S. TTR category growth will remain brisk and consistent with prior years. Second, in the U.S., we continue to expect a modest decrease in net price as our CM business continues to scale. Specifically, we forecast a mid-single-digit net price decrease for AMVUTTRA in 2026.

Third, given the impact on our polyneuropathy business associated with lower CM launch pricing in international markets, we expect international TTR revenue dollar growth in 2026 will be consistent with 2025. I'd also like to provide some color on Q1 phasing assumptions associated with our full year TTR revenue guidance. For Q1, we expect considerably lower quarter-on-quarter TTR revenue growth compared with the $134 million of TTR growth that we delivered in Q4 '25. The lower growth expectation in Q1 is driven by a variety of factors, including the following: First, unlike in Q4, when our international markets contributed $23 million in quarterly TTR revenue growth, we are expecting an approximate $25 million reduction in Q1 international revenues with the primary driver of the decrease attributable to our CM launch in Germany where our AMVUTTRA pricing was adjusted downward in late Q4, as Tolga previously mentioned. For the balance of the year, we expect our international markets will return to quarter-on-quarter growth as the impact of increasing volume outweighs reduced price.

Second, in the U.S., we expect more modest quarter-over-quarter TTR growth in Q1 compared with the USD 111 million of quarterly growth achieved in Q4 due to fewer product shipping weeks in Q1 and the expected impact of annual insurance reauthorizations. Beyond Q1, we expect higher quarterly growth for the balance of the year in the U.S., and we remain confident in our full year TTR product sales guidance.

Now returning to our full year 2026 financial guidance. Our collaboration and royalty revenue guidance range is $400 million to $500 million, representing a decrease of 38% compared to 2025 at the midpoint of the guidance range driven by the onetime $300 million zilebesiran development milestone achieved in 2025 that I previously mentioned that will not recur this year. We expect the collaboration revenue associated with our partnerships with Roche and Regeneron as well as LEQVIO royalties from Novartis will drive the majority of our collaboration and royalty revenue this year.

Our guidance for combined non-GAAP R&D and SG&A expense is a range between $2.7 billion and $2.8 billion, with the midpoint of the range representing 26% growth versus 2025. Growth drivers for R&D expense this year include increased investment in clinical studies including the continuation of pivotal Phase III studies for zilebesiran and nucresiran as well as early pipeline investment to deliver 3 to 4 new INDs and support expansion of delivery into new tissues. Growth in SG&A will primarily be driven by ongoing launch activities to support AMVUTTRA for ATTR-CM in the U.S. and select international markets. Let me now turn it back to Christine to coordinate our Q&A session. Christine?

Thank you, Jeff. Operator, we will now open the call for questions.

[Operator Instructions]

[Operator Instructions]

One moment for your first question. I have Paul with Stifel.

Okay. I was wondering if you could just comment on what you're seeing so far in 2026 in terms of new patient adds and the mix of first line for vutrisiran versus tafamidis switches and how you see that evolving over the course of this year and what's assumed in guidance?

Yes, that's a great question. I think it's important just to underscore how pleased we are with the AMVUTTRA launch so far. Coming out of the gate strong, we're building towards an analog beating launch and really building a long-term franchise that's incredibly important. And all the fundamentals are in place to drive continued AMVUTTRA growth, which I think is underscored by our 2026 guidance on our 2030 goals. But Tolga, maybe you will speak specifically to -- yes, I mean, how you're seeing the market.

Thanks, Yvonne. Look, as Yvonne highlighted, what really drives our confidence in reiterating the guidance is really is the fundamentals. If you think about it, we've actually improved our first-line access. We're clearly seeing a strengthening physician and patient preference and even more importantly, continued category growth with more patients entering the market. Those trends were in place heading into JPM and have continued to build, and that's why we remain confident in the year.

Your next question is from Salveen with Goldman Sachs.

If I could just follow up on the confidence here and the guide for the year for the TTR franchise. Just speak to the the choppiness that we're seeing coming out of the scripts for the first quarter to date? And then how you think about the pricing dynamics as you look to a new potential market entry this year or next year as well as kind of the growth dynamics in Europe?

Yes. So let me take the pricing question first. We feel very well positioned from an access standpoint for this year. The large majority of patients have already first-line access without required petites and most patients are continuing to pay 0 out of pocket, partly supported by our value-based agreements and in fact, utilization within those agreements have been rather minimal to date.

In terms of on our pricing, our net price declined mid-single digits in '25 and our '26 guidance assumes a similar mid-single-digit decline. And that dynamic is fully integrated into our outlook. Now in terms of '27, it's obviously too soon for us to be able to provide specific guidance, but we felt really well positioned as we enter '26.

Your next question is from Konstantinos with Oppenheimer.

Congratulations on the strong year. A question on seasonality from us. Have you seen any seasonality during the fourth quarter, potentially patients who push the injection to the next quarter because of the holidays and whether this will be a tailwind for the first quarter of 2026.

Maybe Tolga, a question for you. I mean I think we spoke to Q1 phasing and that's actually kind of very typical in the industry. But Tolga, do you want to...

Right. So I would actually really step back and start thinking about rather than on a monthly fluctuations looking at the quarterly -- the total growth of this category. If you think about the historically, while quarterly growth has fluctuated, the longer-term category trend has been one of robust and really well sustained growth. On the order of about 40 plus over the past several years. So even within Q4, we've seen momentum improved as we exited the quarter. Now, as Yvonne highlighted, Q1 has been rather specific for across the industry in terms of the seasonality. We're certainly seeing some of that, but we believe that from that seasonality is really not impacting the underlying momentum that we're building in the category.