Alnylam Pharmaceuticals, Inc Aktie

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.

Your next question is from Ritu with TD Cowen.

I wanted to ask about the gross to net pattern over 2026. Tolga, you mentioned mid-single digits. Is that going to be sort of a stepwise adjustment in Q1 and then flat through the rest of the year? Or is it going to be gradual? Basically, I'm asking are all the access discussions for the full year done? And also, if you can comment about per Salveen's question whether potential longer-term competitive dynamics are factoring into how you're thinking about gross to net over the year.

Maybe, Jeff, you start on the general gross net question and Tolga may have some additional perspective.

Yes, Ritu, again, the guidance for the U.S. market for pricing this year is a mid-single-digit net price decrease similar to what we did in '25, and that would be expected to be gradual over the course of the year rather than sort of all upfront in the first quarter, gradual.

Yes. And in terms of the '27 outlook, as we highlighted, it's really too soon for us to make any comments at this point. We don't know what that data is going to look like. We don't know what their label is going to look like. But what I can say is, given how well we're positioned in terms of Part B versus Part D, we believe actually we're really well positioned in terms of being able to manage our our growth. And in fact, if you think about the guidance that we provided or I should say, our objectives from 2030, we're ensuring that our 2030 CAGR growth of 25% certainly incorporates some of that thinking. We believe we're going to be able to preserve and increase the value of this category.

Your next call comes from Maury with Jefferies.

You commented a little bit on this at JPMorgan, but just wondering for the 5-year strategy, you've mentioned the select external innovation as part of the approximately 30% revenue R&D spend. Can you just elaborate on that? Should we anticipate additional partnerships like the Roche one with zilebesiran or other forms of licensing? And is there anything more on timing, size and scope of an external BD deal?

Yes. Thanks for that question. Look, I think it's important to highlight that we really are focused on our rich internal pipeline, which is truly spring loaded for growth. But given our strengthening financial position, it does make sense to start to become open to select innovation that could provide access to technologies and earlier stage medicines that are complementing our existing commercial portfolio and R&D pipeline. And I think it's important also to state that we have a very high scientific and financial bar both for our internal innovation but also as we look to assess opportunities externally as well.

Your next question comes from Tazeen with Bank of America.

You talked about the time that you could potentially launch at the beginning of the 2030s. I say, 2030-ish. How should we be thinking about the impact to your operating margin once that product becomes available -- and just practically speaking, even if it might have the better profile that you described of less frequent dosing, how long do you think it would take for patients to appreciate something like that vis-a-vis switching from AMVUTTRA to nucresiran when it becomes available?

So there are a couple of questions here. I mean I'll just reiterate maybe the remarks that I kind of made earlier, which is, I mean, we're really excited about nucresiran. We believe that if it's successful, which we have high conviction in is going to have a best-in-class profile, which is going to lead to swift patient uptake. And this is going to be without the royalty obligations for the nucresiran. So clearly, this will have a significant positive impact on our margins post 2030. And as I said, we're looking at potentially driving margins to the mid-40s by 2030.

And just to tag on to that. I mean, if you look at what consensus gross margins are for our business out to 2030, Tazeen, it's mid-70s. And I would say the vast majority of that is related to the royalty that we pay Sanofi. So that tells you about the opportunity to improve margins post 2030 if we have the kind of profile that we expect with nucresiran.

Next question is from Luca with RBC Capital Markets.

Congrats on the progress. Maybe if I can pivot to the pipeline, Pushkal, can you just talk a little bit about Huntington. Again, I'm assuming that maybe later this year, you'll show some initial pharmacodynamic data and the reduction in mutant [indiscernible] CSF, but we all know that Huntington is a relatively slowly progressive disease. So I'm assuming that the clinical data like cUHDRS is going to be pretty preliminary, would that be fair? And itself, are you willing to start the pivotal Phase III trial, we just target engagement data in hand? Or are you going to wait before doing so until you see a clear function sign there. So I guess the question is, maybe walk us through what kind of go/no-go decision to start a Phase III trial for Huntington.

Well, that's a great question, and thank you for asking a question about the Huntington's program. It's a program that we have high conviction for addressing what I think we all know is that is an incredibly devastating disease. But of course, a lot of that question, Pushkal.

Yes. Luca, happy to address it. As I mentioned, as you highlight, the unmet need in Huntington's, I think is undisputable. We're very excited about the approach we have. We have an siRNA that targets the overall Huntingon's protein, but specifically also target this exon segment that is thought to be necessary actually for disease propagation. And so we think we have a very unique approach. I think unfortunately, prior approaches haven't really addressed this. And interestingly enough, the one approach that does is the uniQure approach, and we've all seen some recent data coming from there that suggest potentially through natural history data, there may be a favorable trend there emerging in terms of efficacy.

So we're very excited about the approach. We're in a Phase I program right now in Huntington's patients where we're really trying to see convincing evidence of lowering of Huntington's as well as to safety. You'll recall that prior efforts in this space have been challenged because they can't get to high levels of knockdown beyond about 20%, and then they've been associated with safety concerns. And [indiscernible] increases cerebral ventricular enlargement, et cetera. So I think those are the first 2 things, Luca, that we're going to be looking for. Can we get to good levels of knockdown, we'd like to get to over 50% and can we do that durably and safely for a period of time.

As we've mentioned, we'll put out some data at the end of this year. You're right that I wouldn't expect a lot in terms of clinical data at that point in terms of cUHDRS. This is really relatively modest number of patients. And so -- but we're hoping that, that -- again, if we see those 2 signs. Then to your second part, look, this is, again, given the unmet need, this is a program we're very much going to try and accelerate as quickly as possible. We want to do that in a responsible way. But you look to us to see what -- anything we can do to bring this forward to patients as quickly as possible and keep you posted on that.

Your next question is Myles with William Blair.

Another one on the pipeline for obesity. Just what's the rationale for prioritizing the ACBR1c asset or the [indiscernible] for something like [indiscernible] in your Phase I trial? And then is the target product profile for that that's going to come out of that data? Is it something that's equivalent to what we're seeing from your peer in Arrowhead or are you going for something superior on the efficacy side?

Pushkal, that's one straight for you.

Yes. Thanks, Myles. So look, we -- I think we see a tremendous opportunity in the overweight obesity space and the diabetes space. I think GLP-1s have obviously revolutionize that space. But I think we all recognize there's a lot of unmet need to actually aid in weight loss, A1c reduction without the muscle loss and the tolerability issues that happened with GLP-1s. So we're bringing -- we have prioritized ACBR1c because both I think in our preclinical work, based on the genetics, preclinical models as well as, I think, some of the emerging data that you're seeing coming from Arrowhead. You see that ACBR1c appears to be the more potent target. And so we've certainly prioritized that. We are interested in [indiscernible], but we think ACVR1c is more interesting. I think I think the other point here I think is worth noting is that I think when you look at the Arrowhead and Wave data, I think there's questions about the monotherapy magnitude of weight loss that they can deliver.

And I think this is a space where we're going to have to be particularly thoughtful. I think we're uniquely positioned to be thinking about unique patient segments that we might be able to target, looking at unique combinations that can bring disproportionate benefit to patients within this space. So -- but that's the reason for prioritizing ACBR1c. And as I said, we expect to have some results to share at the end of the year.

Next question comes from Mike with Morgan Stanley.

Maybe I could ask a question just on cardiomyopathy and trends there particularly for market share. Obviously, you've had some great share gains in the second-line setting and also positive trends in the front line. Just curious, particularly in front line as we move through the year. Do you expect that -- those share trends to continue to increase?

Yes. No, we've been very pleased by the sort of broad and balanced kind of access that we're seeing, Tolga?

Yes. I mean, as you saw, Mike, in the data we shared, particularly around new-to-brand dynamics, we're approaching near parity with tafamidis and the goal was there to intent was to demonstrate that in a growing and increasingly competitive category, we've been able to make meaningful and rapid headway. Now in terms of '26, obviously, we have reiterated our full year '26 guidance. And what gives us the confidence is the continuous progress we're making in terms of first-line access, rising physician and patient preference and also importantly, healthy category growth. Those were the drivers heading into JPM, and we'll continue to see them strengthened. And that -- obviously, that momentum supports our outlook for '26.

And of course, we're going to be having our TTR webinar in at the end of March, which will be an opportunity. So when you think about how we're going to build this very exciting franchise for the future. Thanks for that plug.

Your next question comes from Ted with Piper Sandler.

Great. And just maybe digging a little bit deeper in terms of the external partnering, should we be more thinking complementary technology then from your comments earlier, Yvonne? whether that be delivery types or other RNA mechanisms?

Yes. No, I think that's absolutely correct. I mean we are looking at areas where there's good strategic fit, so opportunities are complementary to what we're doing. You touched on delivery. That's 1 potential approach to consider. We have a very exciting internal pipeline. So we're going to be very judicious about what exome innovation actually helps us accelerate our internal innovation and also complements our current portfolio. But Pushkal, do you want to add anything to that?

No, I think you've covered it, Yvonne. I think we're going to be looking at that landscape of things that are complementary from a technology perspective that help us bring medicines to more patients more rapidly.

Your next question is from [indiscernible] with Barclays.

Maybe just a big picture one across the sort of emerging early-stage pipeline, which programs are you most excited about? Or do you think are the most derisked? And then a second question, just you mentioned for the U.S., you expect a mid-single-digit net price decrease in 2026. What would you expect for 2027? Should we expect something similar or potentially more or less with a new competitor?

Well, I think it started off with trying to get to see what our favorite programs are, Pushkal?

Yes. I mean, Eli, I think like choosing between your children. So we've got some very exciting opportunities I think in terms of your question about which are most derisked, I think, look, obviously, nucresiran is about as derisked as possible. We obviously have no doubt, but TTR silencing aids in both polyneuropathy and in cardiomyopathy. And with that drug, we'll get to 95% silencing and twice year dosing. Zilebesiran has shown blood pressure lowering, compelling blood pressure lowering in 4 studies now of Phase I and III Phase IIs of increasing stringency on top of background medicines with a durable profile and there is a wealth as Professor Williams highlighted last year, ESC of data that suggests that continuous control of blood pressure should lead to outsized benefits in terms of cardiovascular outcomes. So I don't think -- I think that's fairly derisked.

I think as you look forward, we have a number of other programs where I think actually in the period of '26 and '27, we are going to get very compelling data that leads to derisking. If you think about data coming out on Huntington's, or as I just mentioned in my comments to Luca in CAA, and we will get some proof-of-concept data on a number of different programs in overweight obesity, diabetes and a number of programs that we actually haven't named. And then, of course, the plasminogen program, where we've already seen convincing data that we shared last year at R&D Day in terms of proof of mechanism that we're seeing clot stabilization, very strong genetics. So I think that's been significantly derisked.

And you see our confidence in there. We've kicked off on Phase II. We've talked about kicking off a second Phase II. And so we're moving rapidly with that program. So I'm excited about the opportunities that lie ahead. And as I said, a number of exciting potential to help patients and create value.

Yes, that's great, Pushkal. I think the really unusual story about Alnylam is actually we have a derisked organic product engine. And this gives us tremendous leverage, helping us to kind of accelerate the pace of innovation and allowing us to scale with this proven platform into what's going to be a multi-franchise growth company. And as Pushkal highlighted, there are a number of near-term opportunities for us to really turn these programs and important [indiscernible] for patients. Jeff, do you want to add any perspective?

Just on the pricing question, I think that Eli had asked about. Again, what we've said consistently, I think since we've launched in the U.S. with the cardiomyopathy and the labels, we've expected gradual net price reductions over time as the business scales. Again, we're entering year 2, right? And year 1 was mid-single-digit price decrease. That's what we're expecting in year 2 and I would say over the longer-term guidance that we've given, right, 25% CAGR, that's the expectation across the period at this point.

That's great, Jeff. And apologies when we get these multipart questions, sometimes the -- one of the question kind of slips off the list. Tolga, do you have...

Yes, I have a multipart answer as well. I mean, look, just to support Jeff's point, in terms of how anticipated new competition may impact the pricing. As we reiterated, first of all, we're really well positioned from an access perspective, we've established credibility and durability of this franchise in '26 and if you think about the potential emerging competition, we're already actually in that competitive field with the polyneuropathy indication. And we've been able to secure great access to the patients with limited co-pay.

So I think I would anticipate -- and obviously, we provided our goals for 2030, and that value growth of 25% [indiscernible] remains so we're comfortable with providing that perspective for '27 as well.

Good. Well, I hope we covered everything you asked. Next question, please.

Next question comes from Cory with Evercore ISI.

I guess it's related somewhat to what you were just talking about. But with the competitive silence or data, obviously expected this year, I'm interested in your latest views on the potential for that asset to attain a differentiated label based on their trial? And how you think about that having a potential commercial impact on AMVUTTRA if it were to actually be the case?

Okay. Well, I think there's a sort of both a kind of commercial and then also a development kind of perspective on that question. So I think, Tolga, you want to just make a few remarks and then we'll hand it over for Pushkal.

Yes. Before I turn it over to Pushkal, I mean, look, it's obviously difficult to assess the impact without seeing their data, and it would be premature to speculate on the specific role that you're going to play. That said, I think what's really important to highlight is this category remains very large and significantly underserved markets. Additional entrants will certainly help drive diagnostics and treatment rates, which we believe ultimately will benefit patients and expand the category. So from our perspective, we feel very well positioned. We have a head start given our rapid and deep and sustained knockdown profile, strong clinical data package and obviously convenient quarterly dosing. So maybe, Pushkal, you can...

Yes. I think, Cory, I think we are looking forward to seeing the results. Obviously, we don't have a magic crystal ball, we'll see what the results are. But I think our expectation is that the study will be positive. They've shown good knockdown that occurs over a period of some months. And so I would expect, and they have a large outcome study, both in monotherapy and in combination. So I would expect the results to be positive. I think we'll be on the lookout for a couple of aspects of this. First of all, obviously, we want to look at the safety profile that emerges. This is an ASO in a large population that's somewhat older and frailer. So it will be interesting to see how that emerges.

And then on the efficacy side, look, I think -- again, I think that I expect to see favorable impacts on the outcome parameters as we've shown with HELIOS-B with vutrisiran. I think there's some speculation that will they have a stronger signal, for example, in the combination because they'll have a larger number of patients on top of a background stabilizer. My hypothesis would be I don't see any reason why the treatment effect size we would be any different than what we've already established in HELIOS-B.

Now they may have a tighter confidence interval or stronger p-value in that subgroup, but in terms of the effect size, I don't expect it to be materially different, and I think so it would be consistent with what we saw. Your question is, I think, the most critical one, which is how is that going to impact the label and I would just point out that our label already shows gives -- provides data for both on and office stabilizer.

And it specifically points out that the treatment effects were consistent in both populations. And so we have a very broad label. So I don't know how -- I don't foresee how the label would be materially different based on the statistical significance in that one subgroup. But that remains to be seen. But that's how I would map it out.

Next question comes from Danielle with Truist.

This is Alex on for Danielle. Just a question on AMVUTTRA access in community centers. I guess do you have a sense of how much of the market is not currently accessible due to the high cost of AMVUTTRA and potential hesitancy to stock the drug. Just curious if you have a sense of what proportion of new diagnosis are coming out of the community centers versus what proportion of AMVUTTRA patients are actively being managed in the community settings.

Yes. I mean, let me just take that very quickly. As we highlighted, from a payer perspective, first and foremost, because I think you highlighted whether there's an access issue, we feel really well positioned from access standpoint again, the large majority of patients have first on access to AMVUTTRA and that's regardless of where those patients are. In terms of accessing the medication, as we highlighted, first of all, our experience is that it's very broad and balanced. And in terms of the community saving patients, we've been able to actually secure alternative site of care agreements where 90% of the patients already have AMVUTTRA injection within 10 miles their residences. And we are continuing to expand that network. But I think we reached actually that critical mass already within '25, and we obviously continue to work on that.

Well, I believe that was our last question. So I'd just like to thank everyone for joining us today. Clearly, 2025 was a remarkable year in which we delivered a blockbuster launch of AMVUTTRA in TTR cardiomyopathy. We made significant advancements across our pipeline and we achieve sustainable profitability. And as we begin this next chapter of our story, we look forward to executing on our 2026 goals and the broader 2030 strategy. to both accelerate innovation and scale impact. Thanks, everybody, who joined the call, and have a great day.

Ladies and gentlemen, this concludes today's conference call. Thank you for participating, and you may now disconnect.

Good morning, everyone. My name is Jess Fye, biotech analyst at JPMorgan, and we're continuing the 44th Annual JPMorgan Healthcare Conference this morning with Alnylam. Company had a lot of updates yesterday. I'm sure we'll talk about those.

We're going to start out with a presentation from the company's CEO, Yvonne Greenstreet, and then we're going to go into some Q&A. [Operator Instructions] But with that, let me pass it over to Yvonne.

Thank you, Jessica. Look, it's a real pleasure to be standing here as we launch this next exciting chapter in Alnylam's history. I'm Yvonne Greenstreet, the CEO of Alnylam, and I'm delighted to be joined on stage here -- maybe stand back a bit -- by my colleagues, Pushkal Garg, our Chief R&D Officer; Tolga Tanguler, our Chief Commercial Officer; and Jeff Poulton, our Chief Financial Officer. And of course, I'll be making forward-looking statements throughout my presentation.

Now as most of you know, Alnylam possesses a unique profile in the biotech industry. And what makes us so unique is that we have an established and sustainable innovation engine, coupled with commercial excellence. This has fueled our success to date, and we will continue to harness this to drive durable long-term growth. And it all begins with the leadership that we've established in RNAi with a proven organic product engine and a reproducible and modular process to developing our medicines that has resulted in outsized historical success .

We also have a high-yielding pipeline with over 25 programs in active clinical development. And in addition to success and leadership that we've demonstrated on the R&D side, there are now 6 Alnylam invented medicines on the market that are collectively generating multibillion-dollar annual revenue streams and treating hundreds and thousands of patients around the world through our global footprint. So these value-creating features give Alnylam a truly one-of-a-kind profile and frankly, one which is rarely seen across the biopharma landscape.

Since the company's founding in 2002, Alnylam has pioneered the RNAi and an important feature of our approach has been setting and not just meeting but exceeding pretty specific and ambitious long-term goals. Started back in 2011 when we set our Alnylam 5x15 goals, which to summarize, stated by the end of 2015, we will put 5 programs in clinical development. We delivered 7. We then followed that with our Alnylam 20x20 goals, where we said that by the end of 2020, we would have 3 approved RNAi therapeutics. We delivered 4.

Most recently, we've been working towards achieving our Alnylam P5x25 set of goals. And as we stand here having concluded 2025, I'm proud to say that our efforts have resulted in 6 approved products, and we brought RNAi therapeutics to about 0.5 million patients around the world who are on an Alnylam invented medicine. We also said that we'd expand our pipeline to over 20 clinical programs. We delivered over 25. Further, we said that over this period, we would achieve at least a 40% revenue CAGR, and we greatly exceeded that too at about 50%.

And finally, pending the formal announcement of our year-end results, which will happen in February, we are firmly on track to achieving non-GAAP profitability. Yes, and these strategic goals have guided us on our way towards achieving our vision of translating Nobel prize-winning science into a new class of medicines to transform human health. So let's double-click on some of the exciting highlights from 2025, which by all measures was a transformational year for Alnylam. And starting on the left, the key commercial and financial highlights include the landmark approval of AMVUTTRA for ATTR cardiomyopathy. And on a combined net product revenue basis, we generated nearly $3 billion, which represents a year-over-year growth of 81%.

On the pipeline and platform side, we initiated 3 Phase III studies. We expanded our clinical pipeline with 4 proprietary CTAs in addition to the 5 that were filed by our partners. And we developed and launched a best-in-class enzymatic ligation-based RNAi manufacturing platform, which we have termed siRELIS, and this will enable us to greatly expand our capacity and bring RNAi therapeutics to more patients around the world while reducing the cost of goods.

In our press release yesterday, we preannounced our net product revenues for the fourth quarter and full year 2025, delivering a breakout year with nearly $3 billion in combined net product revenues across our 4 wholly owned products. And of course, this was largely driven by the launch of AMVUTTRA in ATTR cardiomyopathy, which propelled our TTR franchise to achieve about $2.5 billion, doubling franchise revenue from the prior year and coming in more than $800 million above our original guidance.

So today, I couldn't be more excited to share our next ambitious set of 5-year goals for the company, Alnylam 2030 accelerating innovation and scaling impact. These goals rest on 3 strategic pillars. And I think you'll see these pillars are pretty consistent with what drove most of our performance in 2025. It starts with achieving global TTR leadership and building a durable TTR franchise. Specifically, we intend to lead the market in TTR revenue by 2030 and also cumulatively across the 5-year period.

We also plan to launch the best-in-class next-generation TTR silencer, nucresiran, first in polyneuropathy by the end of 2028 and then in cardiomyopathy by the end of 2030. The next pillar is growing through sustainable innovation. But most medicines today simply just slow the progression of disease. We want to do better than that and deliver therapies that prevent, halt or reverse disease. This includes delivering 2 or more new transformative medicines beyond TTR that have blockbuster potential. And if we include nucresiran, that makes 3 new transformative medicines.

We also aim to expand to 10 tissue types and build out a pipeline of over 40 clinical programs. In addition, we aim to invest about 30% of our revenues in non-GAAP R&D to accelerate organic internal innovation and selectively access external innovation. And the final pillar upon which our Alnylam 2030 goals rest is scaling with discipline and agility, where we plan to drive sustained profitable growth. And specifically, we aim to deliver 25% or greater total revenue CAGR through the end of 2030 and deliver an approximately 30% non-GAAP operating margin across the period.

Alnylam 2030 represents our strategy to become the leading science-driven, fully integrated global biopharmaceutical company and maximize the potential of RNAi therapeutics for patients. So let's dive a little deeper into the first pillar. Our aspiration is bold. It's to transform the experience for patients living with ATTR amyloidosis. And in the process, we're building global leadership and a flagship franchise for Alnylam. While diagnosis and treatment rates have improved, especially since the introduction of noninvasive diagnostics, most patients with ATTR cardiomyopathy remain untreated.

And so it's a large, rapidly growing and yet underserved category. And it's for this reason that we are driven to bring our RNAi therapeutic, AMVUTTRA to as many patients as we can as quickly as we can. We're therefore, incredibly encouraged by our early momentum. In just the first few quarters, AMVUTTRA's performance compared to the performance of some relative -- with some relevant specialty analogs suggests that we have the potential for a truly breakout launch. This speaks the cost of demand for new treatment options, the value of AMVUTTRA and our strong commercial execution as we continue to launch in ex U.S. markets, building global momentum, which will begin to manifest through 2026 and beyond.

We plan to share more details around AMVUTTRA launch dynamics in a TTR-focused webinar that we plan to host in March, but I'm going to give you a little preview. Impressively, within just a few quarters on the market, AMVUTTRA has already approached parity to tafamidis in share of new starts. But it's important to note that given imperfect data sources, which evolve over time, these numbers are estimates, but one thing is clear, we're challenging standards of care. And this -- I think it's really important to note that we are making great strides in establishing AMVUTTRA as a first-line treatment.

And it's the first and only approved treatment with an orthogonal mechanism of action, it's perhaps unsurprising that AMVUTTRA is the clear leader for the stabilizer progressor segment. This demand reflects health care professional and patient choice. It's also made possible by the broad access and patient affordability that we have been able to secure. Most payer coverage decisions are confirmed going to 2026 and a large majority of patients continue to have access to AMVUTTRA in first line, meaning no requirement to step through another treatment first.

And most patients pay $0 in out-of-pocket costs and 90% of patients can receive AMVUTTRA treatment within just 10 miles of their home, thanks to the broad network of health systems and alternate sites of care that administer AMVUTTRA. Bottom line, health care professionals and patients are choosing AMVUTTRA and access continues to remain strong. We'll continue to drive awareness and preference for AMVUTTRA on routes to our aspiration of global category leadership, but in addition to that, we're committed to reinvesting back into the category.

With so many patients still undiagnosed and untreated, we recognize our role in helping close those gaps. Our investments span evidence generation, education and awareness efforts, but also innovative collaborations to bend the curve on diagnosis rates, which include research collaborations, sponsorships, partnerships with medical societies and novel diagnostics programs. And we'll have more to share about these category growth driving initiatives at our upcoming TTR webinar in March and over the coming quarters.

And of course, we're also advancing nucresiran program. Nucresiran is our next-generation TTR silencer now in Phase III, and it has the potential to offer a best-in-class treatment experience for patients by providing rapid knockdown of TTR on the order of 95% with a biannual dosing regimen and to solidify our leadership for years to come. Assuming positive results from our TRITON Phase III studies and regulatory approvals, we expect to launch nucresiran first in polyneuropathy in 2028 and then in cardiomyopathy in 2030.

The next pillar is growing through sustainable innovation, where we aim to deliver therapies that not only slow disease but prevent halt or reverse course of disease. And this rests upon the truly unique innovation engine that has driven the sustainability. This is a modular process that we utilize to catalyze long-term growth. And of course, at the core of this engine is the Nobel Prize winning science of RNAi, and we're going to leverage our leadership and expertise here to continue to invest in the power of human genetics, where we now have access to more than 2 million lives through various biobanks to uncover new genetically validated targets to sustain our pipeline and leadership for the future.

To expand the delivery of RNAi therapeutics into 10 or more major tissues by 2030 and to enhance the fundamental attributes of siRNAs and advance our capabilities with continued platform requirements. As I said, Alnylam is unique. And here, we've a demonstrated track record of success. We believe that the seamless integrated approach enables us to do all of this with high quality and probability of success at scale. And this has helped us build out this robust and high-yielding pipeline, industry-leading pipeline, that you can see here across rare, specialty and prevalent indications and spanning multiple therapeutic areas.

I want to highlight a few of these programs, which represent the next wave of transformative medicines, each of them with multibillion-dollar potential. These include programs that span the cardiovascular metabolic space, neuroscience and hematology. Zilebesiran targets angiotensinogen with the aim of achieving continuous control of blood pressure. With just 2 doses a year, zilebesiran could address significant unmet need for over 60 million patients with uncontrolled hypertension who are at high cardiovascular risk.

We're also advancing assets for metabolic disease, which represents a substantial global unmet medical need. And we see a compelling opportunity to address significant gaps in treatment left by GLP-1s. ALN-4324 targets GRB14 with the potential to be a novel insulin sensitizer for patients with type 2 diabetes. And ALN-2232 is our first RNAi therapeutic directed towards an adipose target ACVR1C, with the potential to lead to durable and fat-specific weight loss.

Turning to neuroscience. Mivelsiran targets amyloid precursor protein for the potential treatment of cerebral amyloid angiopathy and Alzheimer's disease. Mivelsiran has the potential to prevent amyloid deposition, both in the vasculature of the brain to prevent the life-threatening clinical sequelae of cerebral amyloid angiopathy and in the parenchyma of the brain to impact the progression of Alzheimer's disease. ALN-HTT02 targets the Huntington gene to reduce the progression of Huntington's disease.

Our exon 1 targeting approach has the potential to lead to deep and widespread lowering of HTT in the brain. With over 100,000 symptomatic Huntington's patients globally, this also represents a multibillion-dollar market opportunity. We look forward to sharing initial Phase I data in the second half of this year. ALN-6400 targets plasminogen to address a wide range of bleeding disorders. There are over 3 million people in the U.S. alone estimated to be living with an inherited bleeding disorder.

The first indication we're pursuing is hereditary hemorrhagic telangiectasia, affecting approximately 70,000 in the U.S. Our Phase II trial in HHD patients is already underway, and we also plan to start a Phase II in a second bleeding disorder later this year. Now since our founding in 2002, we pioneered the RNAi revolution, solving hepatic delivery, proving the platform. This has resulted in 6 approved RNAi therapeutics. We intend to build on this foundation as we drive towards our vision for 2030 and beyond.

We plan to accelerate innovation and build on our competitive advantage by delivering to 10 or more new tissue types and utilizing potential combinations and polygenic approaches. We'll also look to continue our leadership in platform enhancements while selectively pursuing complementary modalities through business developments. Now let me conclude with our 2026 guidance and goals. In our press release yesterday, we provided 2026 net product revenue guidance. Specifically, we're expecting total combined product sales between $4.9 billion and $5.3 billion, driven by our TTR franchise guidance of $4.4 billion to $4.7 billion or 83% growth at the midpoint.

And really, what this does is indicate our strong conviction in the opportunity and reflects robust growth and excellent commercial execution. Let me now turn to our 2026 pipeline goals, which will drive our next phase of growth. We've got an exciting year lined up in which we expect 4 clinical data readouts advancing 3 Phase III studies, initiating 3 Phase II studies and filing 3 to 4 new INDs. But of course, it's not just about this coming year. We're building Alnylam for the future. We believe we have a generational technology, which has the impact, the possibility of impacting potentially millions of patients.

And our Alnylam 2030 strategy positions us for continued long-term growth and becoming the leading high-science global biopharma company. And as we look out over the next 5 years, if we achieve our aspirational goals, this is what we believe the profile of the company could look like in 2030. We expect to deliver substantial impact for human health around the world across a diverse range of diseases, as I said, potentially helping millions of patients. By 2030, we aspire to be generating well over $10 billion in annual revenues, driven by multiple blockbuster products and enabled by a best-in-class commercial organization.

We plan to maintain our industry-leading pipeline by continuing to reinvest in programs with the potential to transform human health. We also expect to substantially increase our manufacturing capacity and lower our production costs to support our rapidly expanding pipeline and commercial portfolio. Moreover, we want to be a company recognized for our commitment to social responsibility. If we do all of this, we believe that we will build substantial value creation for shareholders.

This is our vision, and thank you for your continued support up to this point in our journey. We hope you share the excitement that we have for building a leading global biopharma company and transforming human health. And we truly believe that we're in the early innings of RNAi and the best is yet to come. Thank you.

Great. Thanks for the presentation. [Operator Instructions] We spent a lot of time kind of going through those 2030 goals. What gives you the confidence to kind of lay out sort of these ambitious targets today?

That's a really great question, Jess. Now as I said, we we have this history. We have a 15-year history of setting these long-term 5-year goals. And the reason why we do this is that it really helps rally the organization. It creates focus. It creates accountability. And as you've seen, we've got a track record here. We have met or exceeded every single set of 5-year goals that we've delivered and most recently, piece of it by '25.

And we've built our next set of 5-year goals based on what has been an incredible year in 2025, where we've seen real momentum across the business in R&D, in commercial, in manufacturing. And so we feel that we have in our hands the opportunity to really impact human health and are going to set ourselves these bold goals on that journey. And I think it's important to say that we've set the goals, but we also have plans to ensure that we're going to be able to deliver them.

And when you're kind of setting goals that far out, how much buffer do you bake into kind of long-term targets like that?

So I'm not sure that's the right way to think about it actually because what we're trying to do here is set goals that are ambitious, okay, but that we feel we have plans that will allow us to achieve those goals. So by definition, it's not about buffers. It's about understanding the underlying assumptions behind our business and then developing goals that provide us with the potential to really impact patients across a broad range of diseases and build a substantial business. But Jeff, you may want to talk a little bit more.

I mean the only thing I'd add to that is, I think the goals are probably almost more important for internal purposes than they are for external because of what Yvonne has touched on that the organization is very accountable. So when we establish something like this, the desire sort of to galvanize the organization to drive that performance is real. I mean that's why we've continued to do these 5 sets of goals. So that's how we think about it. It's really about driving performance.

And then turning to the 2026 guidance you provided, specifically on the TTR franchise. Can you just talk a little bit about the AMVUTTRA drivers like underlying that guidance and how they may be similar or different from last year?

Sure. Look, '25 has been an exceptional year for us. As we shared with you, if you look at the fundamentals of the market, we really set up an exceptional business where we're gaining preference in market share, underpinned by the very much untapped market demand and the growth that continues to go from a category perspective. So in light of that, we obviously would like to be able to continue to build that market preference.

And what you'll see is where we're actually going to be accelerating the growth opportunities as well. So we want to be able to increase more diagnosis rates as we are actually continue to differentiate the product that's already been well received, both by payers, physicians as well as actually from the patient's perspective. So we just need to continue to elevate that and as we are growing the category.

So with AMVUTTRA writing, it sounds like you're seeing both in the academic and community settings. What are you kind of learning about prescriber behavior or patient characteristics in the different channels? And how do you use that information to kind of maximize frontline use?

So when you look at the fundamentals of the business and why we think it's actually very strong is because it's balanced, durable and there's a depth to our business, both from academic centers as well as from the community centers, the business that we're driving is more or less the same in terms of the quality. And what's also really important for us is how the community physicians and academic centers are experiencing the prescription.

Are they getting easy access? Are there patients actually being able to access the medicines and getting their injection conveniently? What's been the experience both in the academic centers and the community centers once the product is actually being used. And when we look at that across the board, we see a very similar dynamic. And what's, I think, really important for us, and you've seen in the numbers is to drive first-line preference. And that has been going really well. We're being very competitive, and we need to continue, obviously, that journey. So just the bottom line is it's a balanced business, and we're really not seeing a one particular patient type that's preferring one or the other.

What's your latest thinking on what eventual tafamidis generics will mean for the AMVUTTRA business?

So we've heard from Pfizer that tafamidis is losing patent protection 2028 in the U.S. From an Alnylam perspective, this isn't really a big deal for us. We're already approaching parity to tafamidis, as I described in my presentation. And actually, the real potential impact of tafamidis going off patent is that it really unlocks the opportunity for combination use. And when we think about AMVUTTRA, we have all that we need in this regard. I mean, we have data from HELIOS-B, which shows benefits in combination with tafamidis. It's on our label. And so we think that the introduction of generic TAF will actually likely accelerate a little bit of combination use.

Within that 2026 TTR guidance, how should we think about the contribution from international cardiomyopathy sales? And maybe you can expand a little bit on your expectations for price outside the U.S. where you've kind of commented a little bit before?

Yes. No, that's a really great question. Jeff, do you want to take that?

Yes. I mean I'm happy to take the question. The expectation is as we launch in markets ex U.S., you're not going to have split indication pricing. Price will likely come down, which will have an impact on the existing polyneuropathy business. Over time, the volume growth in the cardiomyopathy parts of these markets will more than offset that. But in 2026, it likely means you're not going to see an acceleration of growth outside the U.S. relative to the growth that we saw in 2025.

What are you guys going to be watching for in the eplontersen CVOT data coming out this year?

Yes. And obviously, we're waiting for the data to be released. But Pushkal, why don't you take that one?

Yes. I mean, look, we'll obviously be watching. I think we want to see the efficacy. We also want to see the safety, right? This is an ASO in a large, older population. I think we want to understand what the safety profile looks like as well. As we kind of think about the readout, just, it's probably also -- as we kind of think about, okay, how does -- it's another silencer type of mechanism in the disease. We kind of look at what we've established with HELIOS-B, which is 85% knockdown, 30% plus reductions in all-cause mortality, comparable reductions in hospitalizations. We're seeing some evidence of disease reversal on cardiac MRI, and we're seeing benefits on extracardiac manifestations like GI, et cetera, with 4 times a year dosing.

So I think when we look at the profile that's going to emerge for eplontersen, I think I would -- my instinct is that it will be somewhat similar to that. I don't expect it to be materially different. That said, I think there's been a lot of discussion around, well, they've got a larger population of patients on combination and is that going to mean anything. And I think as Yvonne just alluded to, we already have established benefits in combination using HELIOS-B, which is now reflected in the label. So while they may have greater statistical precision around that estimate, I don't expect that, that's going to result in a materially different claim, for instance, because we already have that established HELIOS-B, as Yvonne mentioned.

Maybe just building on that, I think we're going to have a head start as well. And I think we've demonstrated in the PN market segment, but we've been able to maintain a leading market share compared to eplontersen in the polyneuropathy indication. So we feel we're well set up with the data that we have for HELIOS-B and looking forward to seeing the data come out of CARDIO-TTRansform, but as Pushkal said, we don't believe it's really going to change the game.

And what about for nucresiran? What are the most important differentiators from AMVUTTRA? And I guess, how do you think about the transition or maybe like coexistence of that product with AMVUTTRA?

Yes, nucresiran is a really important opportunity for the company. And that's why we're really expediting development and delivering the PN indication, hopefully, by 2028 and CM in 2030. But Pushkal, why don't you speak to the specific...

I can speak to the profile and then Tolga, you want to speak to the -- how we're going to bring it forward. I mean I think we're very excited about nucresiran. As Yvonne highlighted in her presentation, we can get about 95% knockdown with nucresiran, AMVUTTRA delivers about 85%. That's going to lead to more patients getting that deeper level of knockdown, which we think is a benefit both in polyneuropathy as well as in cardiomyopathy, less variability, so more patients getting there.

It's twice a year dosing. So we think it's going to offer greater patient convenience. And so at the end of the day, our hope is that this will really be now the new sort of standard of care for patients with this disease, where we need to hit them strongly with the best available therapy. Tolga, do you want to comment on this...

Yes. I mean the only thing I would add is our ambition for 2030 obviously includes nucresiran, which we're really excited about. It's the target -- the product profile is really exciting. In terms of how the switch is going to happen, it's probably too soon for us to really articulate that. We've obviously managed through ONPATTRO and AMVUTTRA, although they're not exactly the same. And again, we're really excited about nucresiran, and we hope to be able to -- once the product is in our hands, we're going to be able to provide a lot more clarity around how the category is going to be developed.

And just I think also important to note that this really gives us a durable franchise. So we are committed to patients with TTR amyloidosis. We're committed to continuing innovating for these patients. And it really gives us a sort of durable long-term growth franchise here.

Just one comment here on nucresiran and the importance of it financially. From a margin perspective, we've guided to 30% operating margins through 2030. Nucre, we're talking about CM launch 2030. That will really drive a margin enhancement post 2030, assuming that we've got a successful product launch.

Okay. So the nucre transition could be sort of like a tailwind for the 2035...

Very soon, very soon after 2030. I don't think we'll need to wait to get to 2035 for us to see the impact.

The royalties -- the average royalty that we'll be paying on that is going to be high 20s. So if you can obviously switch that business from AMVUTTRA to nucresiran where you won't have the royalty burden, I think it should substantially benefit our margins.

So I guess, put differently, the 2030, 30% operating margin does not really reflect much of a transition?

Correct.

No, you won't get that in this period. It's really beyond this period, right? Because the CM launch is really what would unlock that.

Another element of that long-term guidance. When you talk about expanding into 10 tissue types, what sort of -- what counts as an expansion into a new tissue? It looks like you've brought something into the clinic or you've got preclinical proof of concept? What sort of...

Yes. This is a really important part of our strategy because we believe that the expertise and experience that we've built up in working in the RNAi field for more than a couple of decades now really helps us come up with strategies for accessing additional tissues. And that's why we set the target at 10 each tissue that we unlock, think about it acts as a value multiplier for the business. But Pushkal, maybe you want to talk a little bit specifically about how we're thinking about the different tissues?

Yes, absolutely. I think -- look, I think it's important to note, RNAi is an evolutionary concerned process. It's in every cell of our body. It's in every tissue of our body. And so if we can deliver into a particular tissue like we did in the liver now that we've done in CNS with our colleagues at Regeneron, that opens up now a wealth of possibilities. And so in terms of new diseases to go after or new targets to pursue. And so we've identified and we'll be pursuing at least 10 tissues that we want to get into where we think that there is a preponderance of disease as well as a preponderance of genetically -- genetic targets that we can pursue to ameliorate that disease.

As Yvonne said, that then allows -- that's a value multiplying concept for us where we can go after in that tissue, but also start to think about multiplexing across tissues, right, to really address polygenic and more complex chronic diseases. In terms of what counts, we've talked about -- what we're really talking about is things that are either in the clinic or sort of IND-enabled at that point. That's really what we're looking for through NHP studies, et cetera, so that we have a strong confidence that they're going to work...

So for the ALN-HTT data coming up, can you talk about what would represent success in that update? What would be kind of especially exciting when you unveil those results?

Yes. I mean, I think ALN-HTT is an incredibly exciting program. I don't think I have to describe the harness nature of Huntington's disease, which has been described as ALS and Parkinson's and Alzheimer's altogether. It's a devastating disease. We've got a unique approach, which I think is now being really supported by the academic science, which is targeting this exon 1 fragment is felt to be necessary to have an effect on this disease. We've been going through Phase I studies.

So we'll be sharing some data later this year. I think -- look, there have been, unfortunately, for the patient community, real setbacks with past programs that have looked this disease where they've actually had some deleterious side effects. So first and foremost, we want to ensure that we get good deep knockdown as well as good safety.

And that's really what the primary focus is going to be. Obviously, over time, we'll be looking at other measures, biomarkers and clinical measures of efficacy. But the first and foremost is we want to make sure that we have a safely administered drug that really does what we're hoping to from a pharmacology perspective and allows for infrequent dosing, we anticipate probably twice a year.

And maybe turning to mivelsiran. What are the data for that product that you're kind of most excited about so far? And what should we look for in the next update?

Yes. I mean I think this kind of connects again to what I just talked about with Huntington's disease. What's really remarkable is that in the few years, we've now taken the C16 delivery platform, and we're able to now actually have these discussions about how we can affect these really horrendous diseases, which I think kind of only imagined just a few years ago, right? And so with mivelsiran now, that is -- targets amyloid precursor protein, and we're really bringing that forward for 2 different indications. One is a blue ocean opportunity, which is cerebral amyloid angiopathy, the second leading cause of hemorrhagic stroke. We've got that in the Phase II study, which is enrolling well. But that's really a potential blockbuster and really entirely blue ocean.

And then we'll be coming forward with our plans in Alzheimer's disease shortly in terms of how we're going to pursue that indication. So these are very exciting opportunities. Again, what's amazing is we want to share more data in terms of the levels of knockdown that we're achieving, the safety that we're seeing now with some patients on drug for over 2 years. And then again, we'll start to share some data over time in terms of biomarker imaging, et cetera, that gives us confidence in this approach.

With our last minute, what would you flag to investors as the next kind of most exciting upcoming pipeline data readouts look out for?

I think -- look, I think as Yvonne highlighted, we now have 25 programs in the clinic. We're putting 3 to 4 molecules in the clinic every year. So there's going to be really a steady sort of flow of data coming out of the pipeline. We've highlighted a few things that we're going to share about some Huntington's data that we've talked about, some data on plasminogen, some data on ACVR1C for overweight and obesity.

But I think there'll be more data as well over time. Understandably, we're keeping some things a little closer to the chest these days than we may have in the past. It's getting competitive out there, but you can see that we're incredibly excited about what we have in our hands and continue to build an amazing portfolio across a range of diseases.

Yes. And Jess, if we think about where we are as a business, we could not be more excited about what's ahead. Thinking about the growth trajectory with AMVUTTRA, we doubled TTR revenues this year. We set ourselves some bold guidance to be the market leaders by revenue by 2030, and all the business fundamentals are strong. So we're very excited about driving that through.

Pushkal has talked about this very rich pipeline with a number of really important and exciting multibillion-dollar opportunities that we're going to be prosecuting over the next few years. And so we really have a business that is humming and we're going to use this 2030, 5-year set of goals to really accelerate our innovation and scale our impact and hopefully have significant impact on human health and build, I think, what is already a remarkable business, and we're determined to become the leading science and biopharmaceutical company.

Great. Well, thank you.

Hi, everyone. My name is Maurice Raycroft, and I'm one of the Biotech Analysts at Jefferies. It's with great pleasure that I'd like to welcome the Alnylam management team. We've got Yvonne Greenstreet, the CEO; and Tolga Tanguler, the Chief Commercial Officer. Thanks so much for joining us today. And maybe to start off, it's been an exciting launch for you guys in the cardiomyopathy space. Maybe for those who are new to the story, if you can give a brief intro to Alnylam and talk about the launch so far.

Yes. I delighted to and really pleased to be here at Jefferies. I think it's becoming kind of an incredibly important meeting on the calendar. So delighted to be here. So, Alnylam, the leading RNAi company based on Nobel Prize-winning science, and we have been able really to build an extraordinary company over the last couple of decades, with respect to bringing forward 6 marketed products in a fairly short clip and build a very exciting clinical pipeline of over 20 programs and then all underpinned by what we believe is a very productive innovation engine that's going to continue to deliver new medicines actually for decades to come. And as we think about the company going forward, there are really 3 areas that we are absolutely focused on.

The first is achieving TTR leadership. We'll talk about it more, but we've had a terrific start to the AMVUTTRA cardiomyopathy launch, and that really is just the beginning. We believe that we'll be able to achieve leadership with respect to TTR over the coming years by bringing forward a medicine AMVUTTRA that we believe has the potential to be standard of care and then following that up with the next-generation program, which is called Nucresiran, which really provides us durability for this TTR franchise out until the 2040. So really establishing a leadership position in TTR, point number one.

Point number two is the opportunity that we have to grow through innovation. Built off the pipeline that we currently have, which has, we believe, the potential for 3 or 4 blockbuster transformative medicines that we're moving forward as expeditiously as possible to patients and an outsized probability of success from our R&D engine.

And the third aspect that we've been focused on has been around our financial performance, growing revenues, but also building a pathway to becoming profitable as a company through really disciplined capital allocation, carefully prioritizing our pipeline and making sure that we're building a company that has all the foundations to continue to grow for decades to come.

Got it. That's a great intro. And 5 years ago, you set up the P5x25 goal and have achieved that as envisioned. What comes next for Alnylam over the next 5 years? And what are your top priorities?

I just want to say a few things about the P5x25 goals because setting goals has been an incredibly important part of Alnylam and who we are. Every 5 years, we really focus on what we believe that the company could achieve for the subsequent 5 years. And we've done this for 3 times now. And each time we've either met or exceeded the very audacious goals that we set for ourselves.

And the reason why we do this, it's really important is actually it aligns the whole company, it focuses the whole company. It gives us a very clear pathway to what we're trying to do together. And I think by going out there and committing that to investors, I think also just strengthens the commitment that we have to achieving these goals.

So pleased to say we really are on the cusp of delivering what we call the P5x25 goals, which refer to number of patients on RNAi therapeutics, the number of products that we have on the market, the size of our pipeline, our revenue performance and importantly, a commitment to achieving sustainable non-GAAP profitability within the period. And we really are literally on the cusp of being able to declare victory. So I couldn't be more excited about what we've been able to achieve together over the last 5 years.

And it's now time to start to think about what might be around the corner. So I'm not going to say too much on that at this point in time, but we will commit to being able to deliver an exciting set of objectives for the company that will serve the needs of patients across a range of diseases, but we will also commit to value creation for investors. So we're very excited about what's to come. And I just want to finish by saying, in my mind, that's actually one of the most exciting things about Alnylam.

Yes, we've had an incredible trajectory over the last couple of years, but we really are in the very early innings of what RNAi therapeutics can deliver to patients. And as I look forward to the future, really the best is yet to come.

Got it. It makes sense. And for those goals, we'll probably learn more at the beginning of next year. Is that fair to...

Yes, we will probably have something to declare, and I hope you'll stay tuned for that.

Understood. Okay. So let's dive into AMVUTTRA, in our ATTR cardiomyopathy. It's off to a great start. Are you providing any more granularity on how many patients are currently on therapy? And how sustainable is this U.S. ramp up?

So we're not really speaking to specific patient numbers at this point, but I will say the launch has gotten off to a terrific start. What we said as we were preparing for the launch that a very important first step was to unlock the opportunity for AMVUTTRA to be available in the 170 health care systems that account for about 80% of prescriptions for patients with TTR amyloidosis with cardiomyopathy. And in the first quarter of launch, that was Q2 this year, we actually more or less achieved that and achieve that more rapidly, we unlock that opportunity more rapidly than we had believed possible.

And essentially, that allowed us to raise guidance kind of at Q2 because essentially we brought forward the revenues for the subsequent part of the year. So that was a really good start to the launch. And in the last quarter, we are really pleased to have actually doubled patient volume demand. And I think that's a substantial achievement that we're very proud of, thanks to the very good work that Tolga and his team are doing. And we've been able to grow the business, therefore, not just expanding the number of health care systems that we work with, but actually deepening the opportunity for patients to be prescribed AMVUTTRA in these health care systems. And I think that speaks to a couple of things.

I think, one, it speaks to the strength of the profile that we have developed for AMVUTTRA with HELIOS B. I think it also speaks to the fact that we haven't really had any access barriers to patients receiving AMVUTTRA. Patient affordability is good with a large number of patients having 0 out-of-pocket costs. So we really have set up, I think, a tremendous foundation for the AMVUTTRA launch. And really, I think what we're seeing is just continued momentum with broad and balanced utilization prescriptions coming from both academic centers, community centers, physicians that have prescribed AMVUTTRA historically, but also physicians that are prescribing for the first time. So I think really good signals as we think about building this durable TTR business over the subsequent years.

Tolga, anything else you want to add?

No. I mean the only point -- really nicely covered. Look, I mean, if you take a quick step back, the fundamentals are all there, right? If you think about it, this is a devastating disease. It's very fast progressing. So doctors really want to do something about it. And if you lose the cardiac function, you never take it back. So there is a sense of urgency in treatment. And yet, it's still underdiagnosed. So when you look at the category growth, the category growth is really accelerating as soon as newcomers come into play.

And last but not least is exactly what you alluded to, it's execution. In execution, we looked at how we want to be able to make sure that the access is there. And remember, this is a category where we like to call, we had a running start. We've obviously had a good track record on Polyneuropathy. We understood the category, but we had to expand and we had to approach it differently. That's where the whole access to these centers was very important. And that's, I think, was one of the reasons why we've done so well in our first launch quarter. But in the second quarter, as Yvonne indicated, the what I see is a very healthy uptake. So this balanced and broad patient uptake suggests to us that this kind of growth is very sustainable.

Got it.

And obviously, this allowed us to increase guidance again after Q3, which we were pleased to be able to do. And I think, again, underscores the momentum that we believe we have around this launch.

Got it. Okay. All helpful. And for the types of patients you're getting on therapy, maybe talk about the naive patients that are going on drug versus second-line patient, progressors and how that could evolve over time?

No, look, I think what we're really pleased about actually and Tolga touched on this, is a broad and balanced utilization across all patient segments. I mean, our focus from the very beginning was to make sure that we're able to establish AMVUTTRA as a first-line therapy for patients because we believe as a progressive and devastating disease, it's really important to start to have -- physicians have the opportunity to start AMVUTTRA in patients as first line. And given the very strong data from HELIOS-B, we have a profile that we think is resonating physicians. And we're certainly earning a very healthy share of the first-line opportunity.

And we also have another source of growth, which is the second-line opportunity. So, patients that are progressing on stabilizers that need an alternative therapy. And I think it makes perfect sense to us that in that scenario, and it's about 50% of patients that progress despite treatment with available therapies that many physicians, most physicians are probably going to reach for AMVUTTRA as an orthogonal mechanism of action to provide benefits to those patients as second-line.

So really pleased with our position across both first-line and second-line. And our focus remains making sure that physicians understand the benefits. So what we find is that more physicians understand the details of HELIOS-B study, which is a very rich study, the more compelled they are to prescribe AMVUTTRA first-line. So we couldn't be more pleased with the mix of business that we're getting.

Got it. And for the types of patients, are you getting information from the real-world launch, I guess, on a regular basis, informing you about these frontline versus second-line and then also mixed patients as well.

Do you want to speak to that?

Yes. I mean Look, first of all, as Yvonne indicated, when I look at the first-line patients after a short 6-month period, we're already inching ahead as the second most preferred option. And as Yvonne indicated, given that our orthogonal mechanism of action, we're clearly the right address in terms of second line. We're really not even competing there. We're getting the lion's share. When you look at the type of patients we have, and that's also, again, very encouraging. You're getting some early patients. You're getting patients that are maybe diagnosed in the later stages of their disease. When I look at the community centers, we're getting a lot of those. There was a lot of debate whether those patients will actually have the sort of the Part B patients that are they going to be able to come in, outside of the centers of excellence. We're absolutely seeing that.

So that's why I think we keep referring back to broad and balance because that's how you want to be able to sustain the level of growth. We're not actually seeing a one specific type of patient or one specific type of doctor that are preferring our drug over others. We're seeing this nice rise of broad range of patients coming into treatment.

And one of the questions we get more is like are we seeing much in the way of combination use. And I think we're seeing a little combination use. But I think as we said over a year ago that probably the combination opportunity would not really truly open up until their generic stabilizers available just given the cost of administering 2 medicines at the same time. And we feel really well positioned for that in the future because with the HELIOS-B data, demonstrated additive efficacy on top of tafamidis. And so when tafamidis goes off patent, which we believe is going to be in the 2028 time frame, we do believe that the obvious kind of combination is going to be with a generic TAF and with AMVUTTRA. So we're well situated for that scenario as and when it arises.

Got it. you think that could get pulled forward a little bit, the combo use just with what you're seeing...

We're seeing a little modest, I'd say, modest combo use, modest combo use.

Got it. And maybe jumping ahead a little bit, but the AstraZeneca, Ionis study that's reading out second half of next year, what could potential impact of that study be if they show stat benefit on top of stabilizers?

I mean, look, that's a good study, and I'm glad there's more data that's going to be generated on this. As Yvonne alluded to, if you look at the HELIOS-B data, you have already have background, starting 40% in the baseline and over 50% in the -- at the end of the trial that already demonstrated that stabilizers were leaving efficacy on the table. And when we communicate this and discuss this data set with the physicians, they actually appreciate this and they understand that this is more or less of a class effect. Now I think what we see is given that their size and our HELIOS-B trial was never really powered to actually demonstrate a significance of p-value. So what we anticipate coming out of the eplontersen study is probably you're going to see a little more tighter results in terms of the confidence interval. But at the end of the day, magnitude effect, there's no reason why we should see any real differentiator. And that's actually what the KOL community also sees.

And if you look at sort of how we've been actually competing in our polyneuropathy One could argue that, look, I mean, we have maintained 70% of new patient share and the category continues to grow. So I think given that the diagnosis rates continue to grow, I think this is going to be a good addition in terms of the armamentarium for the physicians to have another option, but we believe we're going to be able to maintain our leadership, which obviously we've had 18 to 24 months head start in terms of CM data.

I think that head start is really important. I think there are also some aspects of differentiation, which we believe that patients -- physicians will understand over time in terms of kind of rapid the regimen, AMVUTTRA given quarterly, et cetera. So we think that we'll be able to maintain this momentum. And importantly, in a rapidly growing kind of category, where it's probably more about voices, more voices coming to the table to educate physicians in order that patients can be able to be diagnosed more quickly and more often.

And I think one of the things we're trying to also make sure we're establishing the differentiation is by generating a lot of real-world evidence. So you've seen at AHA, we've had some really exciting data that we generated that actually shows signals of reversal. We have shown a GI data, which we thought actually was helpful, but we saw incredible traction with the physicians, how excited they were because essentially it impacts quality of life. So a lot of this data that we're generating through outcomes is going to be really important as we continue to differentiate the product.

Got it. And you mentioned under diagnosis earlier in a lot of rare disease type situations, companies talk about underdiagnosis, but I think it's a major issue here that doctors are focused on trying to -- and I guess, where do you see some of the improvements in diagnosis rates going and some inflection points?

So I think it's a really important question because we know that the sooner patients are diagnosed and they get treated, the better outcomes they have. So clearly, it's very important for patients that diagnosis rates continue to increase. I mean, as we think about this market, what we've said historically is that there are probably about 300,000 patients around the world with TTR with cardiomyopathy, probably about 150,000 in the U.S., but only 20% of those patients are diagnosed. We do see real opportunity though for continued acceleration of diagnosis, given it's become so much easier for physicians to diagnose this disease with the ready availability of scintigraphy at low cost.

We see diagnosis just continue to grow over time. So I think this is a market that we don't think is a flash in the pan that's going to grow for kind of 1 or 2 years and then peter out. We really see this as an opportunity to be able to continue to educate physicians, get more and more patients diagnosed and more and more patients treated. So this is a market that's going to grow for years to come. That's why actually our second-generation opportunity is so important. Maybe we'll come back to that later.

Yes. Yes. We will -- maybe just one other question just about the academic centers being familiar with the buy-and-bill strategy and community centers, maybe less so. Maybe just talk about the rollout there and...

Yes. No. I mean, I think, again, this is one of the sort of exciting insights that we were able to capture, especially in the second quarter of the launch. We're actually getting great traction in community centers. It's -- more than half our business is coming from those community centers because they are well equipped, frankly, to be able to do buy-and-bill. And they are seeing -- even their satellite centers of these academic centers are embracing this. So we really have not seen any challenges.

Now in those centers that they may not have the buy-and-bill capability, we actually establish what we call these alternative side of care. Essentially, these are infusion centers across the United States. We've had contracted over 2,000 of them, which essentially puts about 90% of our patient population within 10 miles of distance so that they can have access to. And we've actually gained great success through that.

Got it. Okay. And also briefly, I just wanted to ask on EU reimbursement. I'm wondering just what the status update is there on pricing, even though you've already got established network for polyneuropathy.

Yes. I mean, look, we've established ourselves quite well in Europe with -- we were -- just to remind everyone, we were -- we have been competing with tafamidis in polyneuropathy, and we had upwards of 90% market share in that particular indication. Obviously, with the new indication, it opens up a new round of negotiations -- and Germany is a soft launch where we're still negotiating our final pricing, and we would see the uptake after that negotiations are concluded. Now in Japan, we actually have already concluded that negotiation. And when I look at the -- some of the analogs, it's actually one of the best launches in the Japan market in this type of category where you see a rare specialty category. So uptake is already happening. And the rest of Europe and Germany, you would see more of a mid- to late '26 story, and we'll obviously update that accordingly.

Do you see what the price is in Japan?

No. But obviously, we've been able to -- look, a lot of considerations taken into account, including the larger volume of CM, that's going to -- this whole volume price dynamic, we have to watch out for that. So you're probably not going to see a direct impact of the ex U.S. markets contribution to our markets rapidly, but we actually don't anticipate a significant slowdown because we think we can manage the volume accordingly, when we are managing the price.

Got it. Okay. And let's talk about Nucresiran.

That's really exciting.

Next-gen drug. You're in 2 Phase III studies. Maybe provide a status update on that.

I mean we couldn't be more excited about the opportunity that Nucresiran is going to provide to patients. Think about a medicine like AMVUTTRA, which has got a terrific profile. You get TTR knockdown of around about 85%. With Nucresiran, we're looking at kind of upwards of 95%. And we feel that increased knockdown actually has benefits to patients that will probably play through into improved outcomes for patients. We've seen that in our polyneuropathy studies. We've seen that in other amyloidotic conditions.

So the hypothesis here is that with this better knockdown, okay, we're going to achieve better outcomes, and it's going to be in a regimen that's not 4 times a year, but it's twice a year. And it's also going to be free of the royalties due to Sanofi Genzyme. So we think there's a lot of reasons to be excited for Nucresiran from a patient perspective, but also from a corporate profile perspective over time. We're delighted that we've kicked those studies off. So we've got 2 studies, one is called TRITON cardiomyopathy. That's an outcome study because we really believe that if we're going to bring the next generation of opportunity to patients that we need to deliver outcomes, that obviously takes a little bit of time. It's an event-driven study, in about 11,000 patients. So it's a large -- sorry, 1,200 sorry. So it's a large study.

It's about twice the size of HELIOS-B, but we'll be able to come to market with a compelling profile. We're thinking roughly in the 2030 time frame. Enrollment is going very well because obviously, we have a really strong track record in executing on TTR studies. So that's TRITON-CM. And then we've also imminently kicking off TRITON-PN, which is our polyneuropathy study, and that's got a creative study design, really borrowing from the learnings of study that we earlier did with HELIOS-A and this is a fast-to-market strategy where we're looking at a much smaller study and being able to bring this to patients in the 2028 time frame. So both those 2 studies, we're really excited about them and moving forward as we can.

Yes. Okay. And we haven't talked a lot about the rest of your pipeline, which you've got a lot going on there. Maybe a couple of quick questions for Huntington's disease. There's a lot of interest there. Maybe just provide a status update on what time lines could look like.

Yes. So if I think about our kind of clinical pipeline, I mean, just to say that we've got what we believe are a number of blockbuster opportunities that will bring transformative medicines to patients. We've got Zilebesiran for hypertension. We've got a raft of CNS programs, Mivelsiran for cerebral amyloid angiopathy and Alzheimer's and then a very interesting program that if you have time, it's worth taking a look at, which is ALN-6400, which we are positioning as a universal hemostatic agent with really strong genetics behind it and could actually be a pipeline and a product, if you like, if we think about the numbers of bleeding disorders that we could go after.

But really to come back to Huntington's, we couldn't be more excited because this is a devastating condition. It's -- the unmet needs probably surpass kind of many other diseases that we can imagine. And we have in our hands what we believe is a program that could really impact the course of -- for these patients. It's got a mechanism that knocks down the full-length Huntington protein, but also the exon 1 fragment. We think that's differentiating. We've been able to deliver deep and broad distribution in the brain.

And importantly, the safety and tolerability is encouraging thus far with what we've seen with our C16 platform. And it's likely to be administered just a couple of times a year intrathecally. So we kicked off the Phase I study, and we're really looking forward to be able to bring that forward as quickly as we can.

Got it. We're excited to see data from that. So we're out of time. Maybe in closing, if you -- we're going to get your goals probably beginning of next year, our guess, but maybe highlight the key catalysts ahead investors should be focused on.

Yes, we've talked about Huntington's. I think that's something that you should actually really be focused on watching the program, the progress there. We'll be updating data from our Alzheimer study in due course. But really, I mean, the message that I want to leave this audience with is that we have rapidly growing AMVUTTRA revenues, which requires us with the opportunity to continue to invest in this very rich and high-yielding clinical pipeline as well as continue to move forward INDs on an ongoing basis as we access all the major tissues in terms of delivery of our siRNA. So a really exciting kind of year ahead, and you'll hear more about it as we get into '26.

Sounds good. Thanks, Yvonne. Thanks, Tolga. Thank you for joining us.

All right. Good day, everybody. My name is Ash Verma, I cover SMID-cap biotech and spec pharma here at UBS, and welcome to UBS Healthcare Conference. And next company, really excited to present Alnylam Pharmaceuticals. And I have Jeff Poulton, who is the CFO; and John Vest, who is the Senior Vice President of Clinical Research. Thank you, guys, for joining us.

Nice to be here.

Yes. So a lot of excitement around the story. It's been one of the best performers on XBI in the last 2 or 3 years. Maybe if you can just give me a little bit of a sense on key highlights coming out of third quarter earnings, and then we can get into more.

Yes, there's obviously still a lot of focus right now on the cardiomyopathy launch in the U.S. We got approval right at the end of the first quarter. So we've now got 2 quarters under our belt. In Q2, we did $150 million in CM revenue in the second quarter, raised guidance on our second quarter earnings call and then doubled that in Q3. So we think we did $300 million in CM revenue in the third quarter and also upgraded the guidance a second time for the full year, driven by the TTR business. So we raised guidance at the midpoint by $275 million. And so really pleased with the early momentum that we're generating in that business. And I know you're going to have other questions about that. But that's been the focus, I think, for the company this year in terms of what investors have really focused their questions on.

Yes. Got it. Okay. So just maybe like big picture, I mean, you have been providing these 5-year goals, right? So in 2025, if you can like give us an update on where we are.

Yes. It's -- this is something that I think that's unique for Alnylam, and this has gone on for 15 years now. So the current set of 5-year goals that ends at the end of this year is the third iteration. And it's really been something that company has done to put bold goals out into the public marketplace that then really focus the organization to really drive performance and be very accountable for the goals that we put out. When the company has done this again, 3 times now, we've achieved the goals that we've set out every time. So that's kind of how we think about this when we put these goals out.

The P5x25 set of goals was really about establishing Alnylam over this period as a leading biotech company. And I think based on where we are now almost at the end of '25, we've achieved that. There were 5 goals: patients, 500,000 patients on an RNAi therapeutic; products, 6 commercial products that have come out of our research laboratories in the market; pipeline, 20 clinical programs. And then 2 financial goals, one around top line growth across the period. The goal was for a 40% CAGR across that 5-year period. Based on the guidance that we've given from -- for this year, we'll well exceed that goal. And then the last one was around profitability that we had guided to get to non-GAAP profitability within that 5-year window. And based on the guidance we've given this year, we're going to achieve that as well. So I think we feel very good about the performance against those 5-year goals.

Next question is, will we do it again? And I do think that we will at JPMorgan roll out a new set of goals that we'll be looking out to 2030.

And like for 2030 goals, like is the focus going to be revenue, margin or EPS? Like how does that start?

Yes. I don't want to steal the Evan's thunder. That's obviously something that she'll do at JPM. But I think the sort of the general areas that those goals will focus on are not going to come as a surprise to people. I think one will likely focus around TTR leadership and how do we define that across the 5-year period. We'll look at the pipeline in terms of progressing the pipeline to generate confidence that there's growth beyond TTR. So how would we think about that across the next 5 years? And then lastly, what you're asking about is how will the financial profile of the company evolve over that time period, likely both sort of top line as well as what would the margin profile look like? Those would all likely be things that we'll be talking about at JPMorgan.

Got it. Got it. Yes. I know you mentioned that like you always think about kind of putting ambitious goals out there, right? And 2030 consensus for the Street, actually, like I was just looking at it before getting on here, it's pretty decent place to begin with already with the $10.5 billion in revenue and a pretty substantial margin profile. Like I mean, maybe if you can -- to the extent that you can comment on that and just like qualitatively, what are the elements that you have to achieve that?

I mean I think that's what the goals will focus on in terms of expectations across the period, right? Again, from a financial perspective, I think we'll be talking about top line expectations as well as how the margin profile will emerge as we've now just become profitable and kind of how profitable, how fast will the company become? I think that's what will want to guide people on.

Great. So yes, in terms of the dynamics for the launch then, so can you give us a sense of like what are the drivers behind this acceleration?

I think the thing that went better and faster than we expected, and this was really what we talked about for the second quarter call was around access. So this is a buy-and-bill drug. So there were a couple of things that we were really focused on as we got the approval and launched the drug on the provider side, so those that are actually purchasing the product, administering it and then getting reimbursed for it. There's about 170 health systems. So think of these are networks of hospitals where the vast majority of these CM patients are being treated. We had to get the drug on formulary at these health systems to enable those health systems to start ordering the drug. And we, generally speaking, completed almost a vast majority of that in Q2 and now completely done in Q3. That went faster than we had anticipated. We had been talking about the revenue trajectory as being a second half of the year story before we launched. So that was one very early unlock that enabled faster revenue trajectory.

And then the second component of access is around the payer side. And what you have to do is work with the payers to get policies in place to enable access to the drug. And we've done that very effectively as well. So for the most part, we've got first-line access to the drug. We're not seeing a lot of step edits where you have to go through another product to get access to AMVUTTRA. It's a heavy Medicare population. It's about 80% Medicare split evenly between fee-for-service and Medicare Advantage. And then a smaller part of the market is commercial. But from a payer standpoint, we're really pleased with that first-line access for the product because that's really how we're positioning the product as a first-line product. It's a progressive fatal disease. Physicians have choices to make in terms of what product do I put the patient on first. And given the nature of the disease, we're making the case to physicians that this should be the product that you reach for first. And again, from an access perspective, they have the ability to get the patients on it as a first-line choice.

All right. So there, like just like you said, like second quarter in the launch, like where is most of the focus coming from the patients? Like is it first line as you're seeing? Or is it -- what's the mix like?

Yes. I mean, right out of the gate in the second quarter, there was a larger portion of the initial kind of prescriptions or start forms that were coming through in the U.S. that were second line. So there probably was a little bit of waiting for the product to be approved where maybe patients weren't doing well on the existing therapies where there was a pretty quick sort of switch to AMVUTTRA. But over the course of the second quarter, that first-line versus second-line source of business really balanced out and then that continued through the third quarter. So we're really seeing growth and equal growth, I would say, in terms of sources of business from both first line and second line. And I do think that positions us uniquely among the 3 products that are in the market that we've got a good source of both first-line growth as well as second line growth. So that's what we really have seen now for 2 quarters in the U.S. Good balance.

Yes. I know just like early in the launch, there's a lot of different dynamics that can be at play, like one of the things about the combo use for like how much of that are you seeing?

Yes. I mean that's predominantly monotherapy, which is what we have expected just given the cost of putting 2 drugs like this together. There is some combo use, and there's interest in that. But from a payer standpoint, they're going to make that pretty restrictive, I think, until we get to a point where you get a generic product in the market, which right now, I think the expectation is the end of 2028 in the U.S. is when we'll likely see a tafamidis generic. That will likely unlock the opportunity for more combination therapy at that point. We're seeing some of it today, but it's primarily still monotherapy.

Got it. Okay. I think -- so you have the volume growth pretty significant lined ahead of you. And sometimes when these like new market formation, I think there is a tendency that investors are kind of worried about like is there a pricing degradation that can happen going from here? So effectively like what happened with GLP-1s in the last few years, right? So I'm trying to understand like on the TTR side, is that something that is possible? Like where does the gross to net like go in the long run?

Yes. I mean I think what we said when we launched where we -- on the approval call for the cardiomyopathy indication, we talked about leaving list price where it was in the U.S. So no change. But we did anticipate net price gradually coming down over time as we ramp volume for the business. And I think for 2025, what we talked about specifically was we expected a mid-single-digit year-over-year price decline for the TTR business. We're on -- I think we're on track to sort of deliver that.

I mean the volume opportunity is so significant in CM that is price is coming down gradually, which I do think will be the sort of the general direction that this will go. The volume opportunity obviously more than offsets what you're giving up in price. So that's the way we're thinking about it right now. We feel good about '26. I mean most of these payers have kind of got policies locked in for '26 and what I described for '25 in terms of broad first-line access, we anticipate that to be the case for '26 as well.

So it's kind of the continuation of the same trend that we are seeing in '25?

I think that's -- our expectation is gradual reduction in net price over time as the volume in our business continues to ramp up.

Right. And then the other aspect of this, just if you can talk about like the Part B versus Part D dynamic on how that shakes out different.

Look, we've -- I've talked already about the success that we've had on the payer side, right, both on the provider and the payer side. We've unlocked the provider side where we've got the drug on formulary. So these hospital networks have the ability to buy and build a product now. We've talked about on the payer side, the success that we've had in getting policies written that enable first-line access. One of the things I think that's unique that Alnylam does that's enabled some of that on the payer side are value-based agreements that we have in place across all of our products, but we've extended those for cardiomyopathy as we're launching in CM.

And essentially, what that does is that it gives the payers confidence that the patients are going to -- what they're paying for, they're going to get because if the patients stay on the drug, there's no rebate. If the patient starts on the drug and then drops off, discontinues, then rebates kick in. Payers really like that for a rare disease, high-priced product like this that what they're paying for, they're going to get the benefit of because they're worried about the downstream costs if these patients are not staying compliant to the drug. So we're given a commitment from a compliance perspective. And I think that's been part of the story that's enabled the access that we have.

Got it. And then just in terms of the competing dynamics so between the 3 products that you talked about, yes, like where is the -- is it ultimately like expanding the pie? Or where are you taking share?

Yes, I think the expectation is that over time, as you've got more voices in the market that you are going to see accelerating growth. It's probably a little early to say precisely that that's happening, but we do expect that, that will happen. Look, we're very focused on that first line positioning right now, and I think we're competing very effectively there. I think the second line business is going to come for us. But again, both of those right now are sources of growth for the franchise, which is the place that we want to be.

Great. Excellent. So with that, I'll switch over to you, John. Maybe just if you can talk about the next-gen science here and maybe give us an idea like where we are in the development cycle?

Yes, sure. So I mean, look, we're obviously absolutely thrilled with the profile of AMVUTTRA, but you're asking about nucresiran, which is our next generation, and we really think we can take things to the next level with that. Based on the results that we had in our Phase I study with nucresiran, we're highly confident that we'll be able to achieve upwards of 95% TTR reduction compared to we get about 85% with vutrisiran. And we're also anticipating very low interpatient variability, meaning that the vast majority of patients will reach that -- those high levels of knockdown of 90% plus. And this is with a twice annual dosing treatment regimen.

So we're really, really excited about that based on everything that we've seen. We know in the hereditary TTR polyneuropathy space, lower TTR reduction drives better outcomes. And this has also been something that's observed consistently in other forms of amyloidosis like AL amyloidosis, where the deeper you can knock down that pathogenic protein, the better the outcomes are. So it's certainly our hope not only that we'll achieve this profile, achieve more convenient dosing for patients, but we believe that will drive better outcomes. So we're really excited. We've already kicked off our TRITON-CM. So this is an outcome study in ATTR cardiomyopathy. And we are in parallel initiating a study in hereditary TRITON-PN. So as a study in hereditary polyneuropathy, and we're off to a great start. So we're very excited about this.

Yes. Maybe just on TRITON-CM. Yes, great to see that start. Like where are you on the enrollment progression? And like when can we expect the top line for that?

Yes. I can't comment in detail on enrollment, but we're pleased with where we are. We're leveraging our now vast experience in this space in operationalizing these studies around the world. We're capitalizing on that experience, and we're really pleased with where we are. But I can't comment too much on exactly where enrollment is at this point of time. We've guided that we would anticipate launching this in CM in the 2030 time frame and that the hereditary PN is an opportunity for early to market that we can bring that based on that study design. More streamlined approach that we can bring that to market a year or 2 earlier.

One, I mean, one of the benefits of this financially is that there's not a royalty burden on the third-generation product. And so if the product has the profile that John described in terms of better efficacy, better outcomes, combined with the more convenient dosing, we would think that this would be a business that we could switch fairly quickly as we launch into the market. And that from a gross margin and obviously, a bottom line perspective would really allow us to expand, we think, margins fairly quickly for the company. So this is an important one for us.

Yes. Like as these trials are progressing, is there any like competition that you see from the new product launch? Or like are you able to enroll patients in the study irrespective of the...

Yes. That's a fair question. Again, I would point to the experience we have here. We know how to run these studies. We know how to enroll them, and it's a big world. And certainly, we will take that into account in our footprint and where we are and how we roll out that study, but we're really comfortable.

We're targeting 1,200 patients in this study globally, right? We did -- we talked about patient numbers at Q2. We think we put 1,400 CM patients in the second quarter just in the U.S. on therapy. So it's -- the market is big, right? So I do think that we're going to be able to enroll the study without having much of an impact at all on the commercial opportunity that we're seeing.

Yes. Got it. And then just in terms of the design of these studies, if you can talk about that a little bit, like what effectively for CM and PN, what is the construct of the study? And what type of patients are you essentially looking for?

Yes. Let me start with the CM study. That's as Jeff said, that we're targeting about 1,200 patients. This will be placebo-controlled. Importantly, and these are patients with ATTR-CM, so both hereditary and wild type. There will be no restriction on stabilizers in the study. So we would certainly anticipate and we've designed the study with the anticipation that the large majority of the patients will be on background of stabilizers. But we're -- our anticipation here with the global footprint, we'll be able to thoroughly characterize the experience with that drug, both in combination with the stabilizer as well as the monotherapy experience.

It's going to be an event-driven outcome study. So we'll run until we've got the requisite number of events to be highly confident that we'll achieve our primary endpoint. And the way that the dynamic in that space has happened, we'd anticipate that these patients will -- as we saw with HELIOS-B, which was reflective of a contemporary population with disease that's more reflective of what's out there today, patients a little bit milder on lots of background therapy, we'll continue that trajectory in TRITON-CM so that we're able to characterize this in today's patients.

Got it. Okay. And then you also have some data that you reported for zilebesiran. So for that, this KARDIA-3 study, right, just overall, like I wanted to understand like what are the key highlights from that and how the physician feedback has been?

Yes. And I would encourage everybody -- but I'll certainly comment, but I would encourage everybody to go and it's on our website. You can see the cast from the ESC Congress and the KOLs who are luminaries in the hypertension space who presented, there really paint this picture well. We are really excited about this, and we believe that the prescribing physicians out there share this excitement for this to really redefine paradigm of how hypertension is treated. And I'd point to a couple of key things here.

Number one, this addresses the issues around adherence that we see with hypertension. A big, big problem in this space is that patients -- there are effective therapies out there, but patients don't take them with a high pill burden and having to do it every single day. Here, we have a profile where we'll be able with the twice annual subcutaneous injection to have tonic control of blood pressure, which is point two, that with currently available therapies, there's more variation both throughout the day, diurnal variation and over time as well, we're able here to have clamped control of blood pressure over time.

And then just what we see in the population that we'll be looking at in the ZENITH study, which is our outcome study, we've kicked off patients who are on a background of at least 2 antihypertensive medications, including a diuretic, we're seeing 8 to 10 millimeters of blood pressure reduction, which is certainly 5 millimeters or greater is very clearly associated with the benefits and outcomes that we're looking at. So collectively, we really think we have an opportunity here to not just impact the patients with this disease, but to completely redefine the way people think about treating it.

Got it. Maybe just like coming back to you, Jeff, I think for the next 5 years, there's 2 different dynamics at play, right? So hopefully, you get the next gen in the market by 2030, let's say, and then you also have the tafamidis IP going away. So in terms of like what you see the impact of that on AMVUTTRA from like a revenue standpoint and when do you start to sort of convert the patient? So you have a few different dynamics here. Like maybe if you can talk about like how do you think that will play on?

Look, I think we're confident in the durability of the TTR franchise that we've got to be able to sort of grow through that period when taf would go generic. I do think that at that point that the market will likely start to pivot more towards a combination market. I think we've got some really interesting data actually in the combination setting, which John can probably speak to from HELIOS-B that does show up in our label. And so I do think that would be supportive of using the product that way at the point in time where the payers will allow more of that. And John also described for the third-generation product that the design of that study is largely going to be on top of a stabilizer. And that will be a much larger study than HELIOS-B and likely will allow us to have a specific claim associated with that. So I think we're well positioned to grow through that period given the profile of the product that we've got that would support using it in combination with a stabilizer.

Great. Yes. A couple of other pipeline questions. And before that, I'll just ask for the audience in the room, if you have any questions, feel free to send them or through the QR code, and we can take them over. But just some of the early stage pipeline. So mivelsiran, so this is just kind of the status on the Alzheimer's and CAA, like where are we on that? And what's the next step?

Yes. So mivelsiran, which targets amyloid precursor protein, really exciting program, which is currently in the clinic for both Alzheimer's disease as well as CAA, cerebral amyloid angiopathy which is a leading cause of hemorrhagic stroke. And we released data from our Alzheimer's disease program earlier this summer, multi-dose data, very encouraged with what we're seeing both in terms of target engagement and the pharmacodynamic profile, where with twice annual -- every 6-month dosing, we're seeing profound and sustained impact on the target protein and very importantly, also encouraged with the safety profile of the drug. So that's -- we're moving on there. I don't know that we can comment on when we will release data from that next.

But then I think also just to highlight that we're also in the cerebral amyloid angiopathy, and this is a real blue ocean scenario. There's really nothing to offer these patients. And again, it's a devastating cause of hemorrhagic stroke, and we're really excited about that opportunity as well. We have what we think is a differentiated approach and profile here. APP is genetically validated as being important -- fundamental importance in both of these diseases. With our approach, we're able to knock down both intracellular and extracellular components of this protein, which is differentiated from, say, antibody approaches to treating Alzheimer's disease where you can only get at the extracellular protein. So we'll update as U.S. results become available, but really excited about the progress we're making here.

A tough area with a lot of room for innovation there. So exciting opportunity. And then I know like the HTT02 in Huntington disease, so that's another one. So yes, if you can talk about like what's the differentiation that you're trying to draw from that and where we are?

Yes. Again, as with the APP programs, this HTT is just -- there is hard to think of a disease with a more devastating consequence and greater unmet need than Huntington's. And we have what we believe, again, is a really differentiated approach. Our exon 1 targeting strategy, we're knocking down not only the full-length Huntington's protein, but also a shorter segment HTT1a variant of the protein. And it's -- we believe it's a hypothesis that targeting both of these is going to be fundamental to unlocking the full potential of the drug. We're in the clinic. And I guess I would -- I probably can't comment specifically on when we'll update. We have at some point next year at a scientific congress we'll update on the results of that Phase I study. .

I think in terms of differentiating, maybe just to point to a couple of other things, though. We are able to broadly penetrate all regions of the brain as opposed to some of the other -- I suppose the uniQure's frequently a question we get that's targeted to a very specific region of the brain. So we believe that we're going to be able to both widely target different areas of the brain and also based on what we've seen in clinic so far, optimistic that we'll be able to push knockdown of the drug. Some other competitor programs have run into platform toxicities as they've tried to get to deeper levels of their pharmacodynamic effect. So we think we can really push and test this therapeutic hypothesis with this compound. We're very optimistic.

Got it. Yes. I mean you do have a bunch of different early phase trials going on, right? Like I mean, outside of the ones that we talked about, like which ones do you think you're most excited about?

One thing I would highlight is ALN-6400. This is -- we're targeting plasminogen that we believe has the potential to be a universal hemostatic agent. So we talk about this as the potential for a pipeline and a product. We've disclosed that we'll be starting by the end of this year. We've disclosed our first or initial disease, HHT or hereditary hemorrhagic telangiectasia, which, again, is a devastating disease with a very large unmet need. But based on our preclinical data, what we've seen in the clinic to date, we're optimistic that this concept could be applied across a wide range of bleeding disorders with the potential to achieve hemostasis without increasing risk of thrombosis, which is the -- that's sort of the holy grail in treatment of bleeding disorders. So that's one.

And then also just to speak about we had highlighted, I believe, at our last R&D Day, our ambition that we would be in every major tissue by the year 2030, and we're well on our way to first of 2 new tissues adipose with ACVR1 as well as our muscle programs. We haven't disclosed the targets or indications there, but we're well on our way in getting into the clinic in both of those new tissues within the next few months. So we're very excited about that. More to follow on the muscle program and other tissues over time.

Good stuff. Great. So any closing remarks, Jeff, from you?

I think you wrap it up. You've covered the sort of the key focus areas, and we look forward to laying out that kind of the 2030 equity story at JPMorgan.

Great. Excellent. Thank you guys for this. And yes, very excited for your future and looking forward to keeping in touch.

Thank you.

Thank you.

Good morning, ladies and gentlemen, and welcome to the Alnylam Pharmaceuticals 3Q 2025 Earnings Conference Call.

[Operator Instructions]

Also note that this call is being recorded on Thursday, October 30, 2025. And now I would like to turn the conference over to management. Please go ahead.

I'm Christine Akinc, Chief Corporate Communications Officer at Alnylam. Good morning ladies and gentlemen and welcome the 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 on Slide 2, Yvonne will offer some introductory remarks and provide general context. To will provide an update on our global commercial progress. Pushkal will review pipeline updates and clinical progress, and Jeff will review our financials and guidance, followed by a summary of upcoming milestones 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 purpose of the safe harbor provision under the Private Securities Ligation 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 of any subsequent date. We specifically disclaim any obligation 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's Q3 results announced this morning demonstrate the exceptional progress we are making across all aspects of the business. As we continue to evolve into a top-tier bisect company, our focus remains on these 3 core pillars that we believe will drive sustainable growth and value creation for years to come. The first is TTR leadership. The AMVUTTRA launch delivered another strong quarter. It's still early, but we're very encouraged by the progress and dedicated to establishing long-term leadership in TTR.

Next is growth to innovation, focused on the potential multibillion-dollar opportunities within our pipeline, and an R&D engine positioned to deliver sustainable innovation and value creation for many years to come. The third element is strong financial performance, with robust top line growth and disciplined capital allocation, providing us with the opportunity to sustain profitability going forward. And of course, all of this is underpinned by a best-in-class team and our award-winning culture. The quarterly results announced this morning represent strong execution on each of these fronts. Our commercial performance was driven by TTR franchise revenues of $724 million or 135% year-over-year growth, with growth largely attributable to the AMVUTTRA CM launch in the U.S., where we achieved total TTR revenues of $543 million, representing 194% year-over-year growth. As Tolga will describe, the broad and balanced uptake in the second full quarter of launch drive an approximate doubling of TTR cardiomyopathy revenue compared to the prior quarter.

In addition to these commercial results, we continue to advance our leading pipeline of RNAi therapeutics. Two new Phase III trials are getting underway. The ZENITH Phase III cardiovascular outcomes trial of zilebesiran in hypertension has initiated and the TRITON PN study of icrisiran in hATTR-PN will be initiating shortly to complement the TRITON CM study that was initiated last quarter. We're also excited by earlier-stage pipeline advancements in bleeding and neurologic disorders. And with regard to financial performance, our third quarter results show continued growth with $851 million in total net product revenues, up 13% year-over-year. As a result, we've again increased our total net product revenue guidance for 2025 and from the range of $2.65 billion to $2.8 billion, to a revised range of $2.95 billion to $3.05 billion representing an increase of $275 million or 10% at the midpoint, underscoring our confidence in the AMVUTTRA TTR CM launch and our other commercial products for the remainder of the year. Now with our Alnylam piece of is by '25 era concluding soon.

We're thrilled by this incredible execution over the past 5 years, reflecting tremendous progress on these ambitious goals. This is indeed a strong foundation on which to build our next phase of significant growth. and we look forward to harnessing this momentum. 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. Following an exceptional Q2 continued on [indiscernible] strong trajectory of growth and execution. We delivered $851 million in combined net product revenues representing 103% growth year-over-year and 27% growth versus the prior quarter. Our TTR franchise remains the primary growth engine. And we're also seeing continued momentum in our rare disease business.

Let me start there. More than 5 years after launch, our rare disease portfolio continues to deliver meaningful impact for patients and steady performance for our business. In Q3, the rare portfolio achieved $127 million in sales, up 14% versus Q3 2024, driven largely by ongoing patient demand. While the timing of orders in our partner markets created some short-term shifts, the overall trajectory remains strong. I'm proud of the focus and dedication of our rare disease and partner teams who continue to reach patients with these 2 transformative medicines globally, even as much of the organization focuses on the TTR growth opportunity. With that, let's review the TTR highlights. Q3 was another exceptional quarter for our TTR franchise, continuing the strong launch trajectory we saw in Q2.

Global TTR net revenues reached [ $72 million, ] up 33% versus the prior quarter and representing 135% growth year-over-year. This performance was primarily driven by an increase in U.S. patient demand with an increase in U.S. channel inventory more than offset by an increase in U.S. gross to net deductions. It is worth noting that the increase in gross to net deductions primarily impacted ONPATTRO, reducing U.S. reported Q-over-Q growth in our hATTR-PN business relative to our recent quarterly run rate. In the U.S., net sales for our TTR franchise grew 42% quarter-over-quarter and 194% versus Q3 2024, reflecting continued robust adoption following the AMVUTTRA-ATTRCM label expansion. Before we provide further color on the U.S. launch, let me quickly share the ex U.S. dynamics. Outside the U.S. revenues grew 13% versus the prior quarter and 46% year-over-year, underscoring continued global momentum. Further, international AMVUTTRA ATTR-CM launches are anticipated across 2026, following the completion of local pricing and reimbursement reviews.

Having said that, we're particularly pleased with the early progress in Japan where the CM launch is advancing well and tracking in line with leading launch analogs, a strong validation of AMVUTTRA's profile and first-line potential. In Germany, launch activities remain in the early stages as final reimbursement decisions continue, and we're encouraged by how the product differentiated profile is resonating at key treatment centers. More broadly, our international performance reflects the continued strength of our hATTR pull neuropathy legacy business, which remains robust despite new competition. Broader engagement in the category is expanding awareness and diagnosis, ultimately, benefiting patients and reinforcing Alnylam's leadership role in shaping the field. Building on our global presence, we're positioned to extend our momentum as AMVUTTRA ATTRCM launches expand worldwide. Now let's turn to the U.S. on AMVUTTRA ATTRCM launch which recently completed its second full quarter and continues to build momentum.

In Q3, our U.S. TTR franchise across both PN and CM indications, delivered $543 million in net product revenues representing an increase of approximately $160 million versus the prior quarter. If we assume steady and consistent growth of $50 million quarter-over-quarter in the pulmonaropathy-based business, then we estimate the CM indication represents approximately $300 million of net product revenues this quarter. or doubled from Q2. This reflects sustained launch momentum in AMVUTTRA ATTRCM with patient demand roughly doubling compared to Q2 and as awareness and physician adoption continue to grow. Our strength is built on 3 key pillars as part of our launch strategy. First, health system setup. It is not complete. Nearly all of our 170 priority health systems are now using AMVUTTRA, driving broad utilization, combined with our extensive treatment site network, roughly 90% of the U.S. patients can receive their AMVUTTRA treatment within 10 miles of [indiscernible] anywhere in the U.S. and meaningful milestone and accessibility.

So again, the health system setup is effectively complete. As such, we plan to no longer report on this launch enabler on future calls. Second, access remains strong. Payer coverage is broad and nearly all patients have access to AMVUTTRA as a first-line treatment option, meaning these patients have no step edits. Of similar importance most patients pay 0 out of pocket. Finally, with health system setup and access and affordability in place, we are focused on treatment choice and the profile of our AMVUTTRA continues to resonate. We're seeing broad and balanced adoption across new diagnosed patients and those progressing on stabilizers in both academic and community settings. Subscriber growth also remains robust. Having reviewed the 3 strategic pillars, we're executing and delivering on them. Patient demand roughly doubled quarter-over-quarter, reflecting strong, sustained momentum for the AMVUTTRA-ATTRCM and U.S. launch.

In summary, it is still early in the journey, but the results to date highlight the substantial long-term opportunity ahead and underscore our strong positioning for leadership in this expanding underserved TTR category. Looking ahead, the majority of ex U.S. launches are expected to begin in 2016 as pricing and reimbursement processes wrap up, extending our global reach and providing a measured contribution to launch momentum. We continue to invest in the TTR category, advancing science, enhancing patient experience, and building a durable foundation. Pushkal and the R&D organization are leading that chapter. With that, I'll hand it over to you. Pushkal?

Thank you, Tolga, and good morning, everyone. In support of AMVUTTRA's strong launch in ATTR-CM, we continue to share new data from the HELIOS-B study that further underscore the unique and compelling profile of this medicine with the aim of cementing AMVUTTRA as the treatment of choice for patients with ATTR cardiomyopathy. To that end, as shown on the left, at ESC, we presented new data from HELIOS PE that demonstrates the sustained benefits of vutrisiran through up to 48 months, which includes 12 months from the open-label extension. Specifically, as compared to placebo, which substantially reduced the risk of the composite of all-cause mortality or first cardiovascular event by 37% in the overall population and 42% in the monotherapy group.

More recently, at HFSA, as shown on the right, we shared important new data from the double-blind period demonstrating that vutrisiran treatment was associated with a lower rate of gastrointestinal adverse events versus placebo across the overall vutrisiran monotherapy and baseline tafamidis treatment groups with reductions of 37% to 49%. This observation is quite important, so that suggests vutrisiran may reduce GI symptoms, which as you can see from the placebo data, we're seen in approximately 40% of patients. These symptoms arise from the multisystemic nature of ATTR cardiomyopathy and are a major source of concern for patients with this disease. With these continued insights from HELIOS B, we're excited about the prospects for RNAi therapeutics to become the standard of care in TTR amyloidosis. Nucresiran, our next-generation silencer may offer even greater TTR knockdown with subcutaneous biannual dosing is now being evaluated in the TRITON Phase III program. We announced last quarter the initiation of the TRITON CM trial in cardiomyopathy patients. Today, I'm happy to share additional details about the TRITON PN trial in hereditary TTR polyneuropathy patients, which we'll be initiating shortly. This will be an open-label trial of Nucresiran in approximately 125 patients with hATTR-PN. Patients will be randomized 4 to 1 to receive either nucresiran dosed every 6 months, or to a reference arm of vutrisiran, dosed every 3 months. The primary endpoint is the change from baseline in the modified neuropathy impairment score or mNIS+7 at month 9 in the nucresirian par as compared to the placebo arm from the APOLLO Phase III trial of patisiran.

You might recall that this is essentially the same study design we utilized in our HELIOS-A pivotal study of vutrisiran in hATTR-PN, which led to its initial approval in that disease setting. We expect top line results from TRITON PN in 2028 look forward to sharing additional details as the trial gets underway. Now moving on to another exciting program. We made great progress this quarter with our zilebesiran program in hypertension. This program represents an amazing opportunity to address some of the major shortcomings of existing antihypertensive therapies. By targeting angiotensinogen upstream of the RAS cascade we believe we can help more patients get to goal, not only in terms of the quantity of blood pressure lowering but also the quality of blood pressure control, reducing blood pressure variability, improving adherence, and restoring nocturnal dipping. Ultimately, we believe continuous control of blood pressure will drive long-term improvements in cardiovascular outcomes. At ESC in August and shown on the right, we shared results from the CARDIO II Phase II study.

As you can see, treatment with zilebesiran resulted in clinically meaningful reductions in [indiscernible] is tolled blood pressure in patients with uncontrolled hypertension and high cardiovascular risk at the month 3 primary endpoint with continuous control sustained through month 6. Moreover, the treatment effect was further enhanced in a biologically based enriched subgroup of patients. With these results, Cardia I met the objective of informing the design, patient population and dose for the global Phase III cardiovascular outcomes trial, Zenith. Zenith is a cardiovascular outcomes trial that will enroll approximately 11,000 patients to evaluate zilebesiran at a dose of 300 milligrams given every 6 months compared to placebo in patients with uncontrolled hypertension with either established or at high risk for cardiovascular disease on 2 or more antihypertensives. The endpoint is a vent trip with a minimum follow-up of 2 years, and we expect to launch, assuming a successful study and regulatory approval around 2030.

I'm also excited to share an update today on our ALN 6400 development program. ALN-6400 targets plasminogen, and we believe it has the potential to be a universal hemostatic agent that can address significant unmet needs across a range of bleeding disorders effectively becoming a pipeline and a product. Plasminogen is a genetically validated target, high circulating levels are associated with increased bleeding. And conversely, individuals with loss of function variants have reduced rates of bleeding. Importantly, loss of function is not associated with the increased risk of thrombosis. As we believe that by lowering plasminogen with ALN-6400, we potentially can slow down the process of fibrinolysis thereby stabilizing clots and preventing bleeding without increasing the risk of thrombosis. Today, we're announcing the first indication we'll focus on with ALN-6400, hereditary hemorrhagic tolangictasia, HHT. HHT is the second most common inherited bleeding disorder, affecting individuals of all ages. 90% of HHT patients live with recurrent nose bleeds which can be severe and life-threatening and many experienced gastrointestinal and heavy menstrual bleeding as well.

And importantly, more than half of patients face iron deficiency anemia. So this is a burdensome condition and from one for which there are very limited treatment options. Importantly, we've already demonstrated initial proof of mechanism for this program in healthy volunteers in Phase I. On the right are the results from an ex vivo assay of fibrinolysis from our Phase I study and shows in the top panel without ALN-6400, clot formation represented by the dark blue area quickly dissipates. Whereas with ALN-6400, there is an antifibrinolytic effect as represented by the dark blue area, which extends for a much longer time, and this effect is maintained after 43 days. We've now moved ALN-6400 into a Phase II trial in HHT patients and look forward to providing updates as this program progresses. We also continue to advance new programs into clinical development building a pipeline that has the potential to drive sustainable growth and long-term value creation.

Today, for example, we announced the initiation of a Phase I trial of ALN-5288, which targets MAPT or TAO for Alzheimer's disease and potentially other rare [indiscernible] . The trial will evaluate the drug safety, tolerability, pharmacokinetics and pharmacodynamics in adult patients with Alzheimer's disease. With that, let me now turn it over to Jeff to review our financial results and upcoming milestones. Jeff?

Thanks, Pushkal, and good morning, everyone. I'm pleased to be presenting a summary of Alnylam's Q3 2025 financial results and discussing our full year upgraded guidance. Let's begin with a summary of our P&L results for Q3 2025 compared with the same period in 2024. Total product revenues for the quarter were $851 million or 103% growth versus 2024, driven by 135% growth in our TTR franchise, primarily from the continued strong performance of the U.S. launch of AMVUTTRA and ATTR cardiomyopathy. Collaboration revenue for the quarter was $352 million, representing a $294 million increase when compared with last year. The increase was primarily due to revenue recognized under our collaboration and license agreement with Roche, including $300 million of milestone revenue associated with the dosing of the first patient in our ZENITH Phase III cardiovascular outcomes trial with [indiscernible] .

Royalty revenue for the quarter was $46 million representing a doubling compared with last year, driven by higher [indiscernible] sales as Novartis continues to successfully grow the product globally. Gross margin on product sales was 77% for the quarter, compared with 80% in the third quarter of 2024. The decrease in margin was primarily driven by increased royalties on AMVUTTRA as higher revenues in 2025 resulted in an increase in the royalty rate compared with last year. For the fourth quarter, our gross margin on product sales is expected to decrease as the applicable AMVUTTRA royalty rates increased further, driven by higher expected sales of AMVUTTRA. Our non-GAAP R&D expenses of $310 million increased 23% compared to last year, primarily driven by costs associated with the initiation of multiple Phase III clinical studies including the Zenith Phase III cardiovascular outcomes trial for zilebesiran and the TRITON CM Phase III study for ducrisiran.

Our non-GAAP SG&A expenses of $263 million increased 35% compared to last year, primarily driven by increased headcount and other investments in support of the AMVUTTRA-ATTR cardiomyopathy launch in the U.S. Our non-GAAP operating income for the quarter was $476 million, representing a $507 million increase compared with last year, driven primarily by strong top line results both in product sales, a well's revenue from collaborations as previously highlighted. We continue to be pleased with the progress we are making towards achieving our non-GAAP operating profitability guidance in 2025. We ended the quarter with cash, cash equivalents and marketable securities of $2.7 billion compared with a similar amount at the end of 2024. Cash for the quarter was impacted by our refinancing in September. We raised more than $600 million via the issuance of new convertible notes, which was more than offset by the use of $1.1 billion of cash to repurchase a large portion of our convertible senior notes due in 2027.

Additionally, we also entered into a $500 million revolving credit facility, providing a new source of flexible liquidity if necessary. Now I'd like to turn to our financial guidance for 2025 and where we are increasing our net product revenue guidance driven by the strong U.S. launch performance of AMVUTTRA and ATTR cardiomyopathy with specific details as follows: we are increasing our net product revenue guidance from a range of $2.65 billion to $2.8 billion to a revised range of $2.95 billion to $3.05 billion representing a $275 million or 10% increase from the midpoint of the prior guidance to the midpoint of the updated guidance. The combined full year growth compared to 2024 is an 82% increase at the midpoint of the guidance range. On a franchise level, the guidance is broken down as follows: we are increasing our total TTR guidance range from $2.17 billion to $2.275 billion to a revised range of $2.475 billion to $2.525 billion, representing a 12% increase at the midpoint.

We are reiterating our guidance range for our total rare franchise of $475 million to $525 million. We are also narrowing the range of our non-GAAP operating expense guidance to $2.15 billion to $2.2 billion as we expect to end the year at the upper end of our original 2025 operating expense guidance. The remainder of our financial guidance, including collaboration and royalty revenue and non-GAAP operating income remains unchanged. Turning now from financials to our key remaining goals for 2025. As Pushkal mentioned earlier, the TRITON TN trial of nucresiran and hATTR-PN will initiate shortly. We also expect to initiate a Phase II trial of [indiscernible] in Alzheimer's disease. 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 dialed in, we would like to ask you to limit yourself to one question each and then get back in the queue if you have additional questions.

[Operator Instructions]

First, we will hear from Salveen Richter at Goldman Sachs.