Kymera Therapeutics Inc Aktie

Good day, everyone. My name is Michelle, and I will be your conference operator today. At this time, I would like to welcome you to the Kymera Therapeutics Third Quarter 2026 Results Call. [Operator Instructions] At this time, I would like to turn the call over to Justine Koenigsberg, Vice President of Investor Relations. Justine, please go ahead.

Good morning, and welcome to Kymera's quarterly update call, which will also include a discussion of the KT-579 Phase I Healthy Volunteer results. Joining me this morning with prepared remarks are Nello Mainolfi, our Founder, President and CEO; Terence Rooney, our Chief Medical Officer; and Bruce Jacobs, our Chief Financial Officer.

Following our prepared remarks, we will open the call for questions from our covering analysts. In order to have as much time for as many questions as possible, please limit your questions to one. If you would like to ask a question, please use the raise hand icon which can found at the bottom of your meeting window. A replay of today's call, including a copy of the corresponding presentation will be available in the Investors section of our website soon after the call concludes.

As a reminder, today's presentation will include forward-looking statements about our future expectations, plans and prospects. These statements are subject to risks and uncertainties that may cause actual results to differ materially from those projected. A description of these risks can be found in our most recent 10-Q filed with the SEC. Any forward-looking statements speak only as of today's date, and we assume no obligation to update any forward-looking statements made on today's call.

Before we begin, we have one housekeeping item. Starting next week, we will enter our previously planned quiet period ahead of our upcoming STAT6 data. As a result, we don't expect to provide additional commentary on our STAT6 program until we report those results.

With that, I will turn the discussion over to Nello.

Thank you, Justine, and good morning, everyone. Thank you for joining us today. This is a very exciting time for Kymera. We're seeing our scientific vision take shape across our pipeline of oral medicines to address serious inflammatory diseases with KT-621, our STAT6 degrader for atopic dermatitis, asthma and more and KT-579, our IRF5 degrader for lupus and potentially other autoimmune diseases. Together, they reflect our goal of developing medicines grounded in strong biology with the potential to reach many more patients than served by available treatments today.

I'll start today with an update on KT-621 as we approach its Phase IIb AD readout before year-end. I'll then briefly cover the rest of our pipeline before we turn to KT-579 Phase I results. Our STAT6 program continues to advance according to plans across both AD and asthma. As shown here, we've advanced KT-621 through a series of studies, building on what we learned at each stage to guide the next steps. In Phase I, we've evaluated KT-621 in more than 200 healthy volunteers and observing deep STAT6 degradation effects on downstream biomarkers and a favorable safety and tolerability profile. We then treated 22 patients with AD in Phase Ib, where we saw the first evidence of strong clinical activity in patients.

With each study, we've built a stronger body of evidence and further derisked KT-621, supporting its advancement into the ongoing Phase IIb studies. In the BROADEN 2 AD study, we're excited to report that we have completed the 16-week placebo-controlled portion of the study with the last patient just recently completing their final visit. We expect that the remaining activities to close out this portion of the study will enable us as planned to share the KT-621 Phase IIb data by year-end. At the same time, we're well into our preparation for the first Phase III study in AD, which we plan to initiate assuming both supportive data and alignment with FDA by middle of 2027.

Before we move to an update on asthma, as we have shared previously, patients that complete the full 16 weeks of treatment in BROADEN 2 are eligible to enter a 52-week open-label extension. Today, we're happy to report that 98% of eligible patients have enrolled into the OLE.

Now turning to asthma. Enrollment in the BREADTH study continues to progress as planned with top line results expected in late 2027. In total, these studies have already enrolled hundreds of participants, providing a robust data set to assess safety and efficacy of these exciting novel mechanism. And as a reminder, the BREADTH study also includes an open-label extension, which, together with the AD OLE are designed to further support our long-term safety database for regulatory requirements and the potential registration of KT-621.

As we approach the BROADEN 2 readout, I wanted to take a moment to put the opportunity for KT-621 in AD into perspective. As illustrated on Slide 7, published epidemiological reports show that there are approximately 6 million to 9 million people in the U.S. 12 years and up with moderate to severe atopic dermatitis. Despite this high prevalence, only an estimated 400,000 receive advanced systemic therapies, a penetration of only about 5% of the total moderate to severe patient population.

As we've been advancing KT-621, we've also been conducting market research to better understand the market dynamics of advanced systemic therapies. What we hear from both patients and prescribers is that the main reason for the limited adoption is that many patients don't perceive that their disease state justifies an injectable biologic or a medicine carrying a box warning. That perception creates a significant barrier to the use of currently available advanced therapies. Our market research tells us that patients and physicians want a safe, effective oral treatment.

In fact, when we ask what level of efficacy that treatment needs to deliver, we consistently hear that it does not necessarily have to match biologics. We have seen that opportunity play out in other markets. Otezla launched more than a decade ago with roughly half the efficacy of biologics and went on to become a multibillion-dollar franchise. More recently, Icotyde, despite efficacy that by cross-trial comparisons does not quite match IL-23 biologics is experiencing one of the strongest launches in psoriasis, bringing new patients to treatment in an already more saturated market.

Going back to KT-621, a safe and effective oral is what patients are looking for, and that is the profile we aim to deliver. Our focus is to serve the largest segment of moderate to severe AD population, those patients who are either untreated or in many cases poorly treated with nonsystemic therapies. If we're successful, we believe that KT-621 would have the potential to dramatically expand the number of patients accessing advanced therapies. All of that said and based on the preclinical and Phase I data we've generated so far, our scientific expectation remains that BROADEN 2 efficacy should land in the ballpark of what dupilumab achieved at week 16 as compared to what was reported in the SOLO 1, SOLO 2 trials, while recognizing the limitation of comparing results across studies.

Beyond KT-621, we're also tracking with expectations and time lines across our broader pipeline. Our partner program are both progressing as planned. Sanofi continues to advance KT-485, our second-generation IRAK4 degrader in a Phase I healthy volunteer study that is also expected to enroll HS patients.

And Gilead is advancing KT-200, our CDK2 molecular glue into IND-enabling activities with an IND planned for 2027.

With respect to our research pipeline, our undisclosed programs are tracking with our expectations. and to support our goal to advance in one program towards development candidate annually. Regarding the disclosure of our next program, given all that we have to share in the fourth quarter with today's KT-579 data and the upcoming KT-621 Phase IIb readout, we've decided to hold off on that introduction until next year.

With all of that said, before I turn the call over to Terence to share the IRF5 healthy volunteer data, I wanted to take a bit -- I wanted to talk a little bit about the importance of today's IRF5 data release. We have now successfully advanced multiple degrader programs from target selection and drug discovery through preclinical and into the clinic. This is, in fact, our seventh first-in-class degrader to enter the clinic. And today, we're sharing that we continue to demonstrate impeccable human translation. While each target and molecule is unique and must ultimately prove itself independently, this repeated execution is indicative of the positive and compounding effect of all our learnings and experience across our programs.

IRF5 itself is a highly compelling and genetically validated target that has historically been difficult to drug with conventional drug discovery approaches. And this study is an important first step in establishing our IRF5 thesis in humans. As you'll hear shortly, KT-579, which was well tolerated in this study, robustly degraded IRF5. Importantly, the potent IRF5 degradation led to meaningful reductions in multiple disease-relevant biomarkers. With this data in hand, we now plan to move the program with confidence into a Phase Ib lupus trial. The study is designed to establish whether KT-579 can demonstrate the biological and clinical activity we would expect based on this mechanism.

Overall, the KT-579 data represents another important example of our ability to target a highly compelling but historically undrugged target, in this case, the transcription factor. It also demonstrates our ability to translate our preclinical work into humans in a predictable and compelling way. We've now done this across multiple programs and with each success, we're building on a strong and increasingly repeatable foundation for selecting the right targets, developing differentiated degraders against them and efficiently translating those programs from discovery into the clinic.

I know everyone is eager to get into the data. So with that, I'll turn it over to Terence to walk you through the results. Terence?

Thanks, Nello. It's a pleasure to join you all today to review the positive Phase I results for KT-579. As a rheumatologist by training, I'm particularly excited by what we've demonstrated with this program. The translation from the strong preclinical profile into humans is an important milestone and validates our confidence both in the biology and the potential of IRF5 degradation as we prepare to move KT-579 into patients. I'll start with an overview of the Phase I study design and the demographics of the healthy volunteers enrolled in the study. I'll then walk through the PD data, beginning with the depth and durability of IRF5 degradation in blood. Next, I'll cover the functional consequences of that degradation across 3 distinct IRF5-dependent immune pathways assessed using disease-relevant ex vivo stimulation assays. And finally, I'll review the safety profile observed and then discuss how the totality of these data inform our plans to advance KT-579 into lupus patients. As we've been saying for some time, primarily for competitive reasons, in some areas of the presentation, we're sharing only limited data.

As shown on Slide 12, the Phase I study was designed to characterize the safety, PK and PD of KT-579 following both single and multiple ascending doses in healthy volunteers. We evaluated a range of doses up to 600 milligrams in the MAD cohorts. In the SAD portion of the study, 8 subjects per cohort were randomized 6:2 to receive a single oral dose of KT-579 or placebo. In the MAD portion, 12 subjects per cohort were randomized 9 to 3 to receive once-daily oral KT-579 or placebo for 14 days.

While the primary objective of the study was to evaluate the safety and tolerability of KT-579, the study was also designed to establish proof of mechanism in humans. In both SAD and MAD, we evaluated IRF5 degradation across dose levels. And in the MAD portion, we also assessed the downstream functional consequences of IRF5 degradation using disease-relevant ex vivo stimulation assays measuring inflammatory biomarkers. Together, these endpoints allow us to address the key questions we set out to answer in the study. First, can we safely achieve deep and sustained degradation of IRF5 with KT-579? Second, does that degradation translate into the expected functional impact on IRF5-dependent biology. And as you'll hear today, the answer to both questions is yes.

Turning to Slide 13, the demographics of the volunteers enrolled in the SAD and MAD portions of the study. Overall, there were no meaningful imbalances in baseline characteristics that would impact our interpretation of the study results. Now before turning to the MAD degradation data, although it's not shown in this presentation, we did want to mention that KT-579 exhibited the predicted PK profile with dose responsive exposures in SAD and MAD cohorts. Additionally, while we generated degradation data across both the SAD and MAD portions of the study, we're only sharing the MAD degradation data here as repeated daily dosing most closely reflects the intended clinical use of KT-579.

Now looking at Slide 14, which illustrates degradation across MAD dose cohorts with data shown at day 7 and 14. The top 5 dose cohorts all reached median IRF5 degradation greater than 90% with saturation of degradation by dose level 3 with blood degradation achieving 94%. Importantly, while not shown, we also observed comparable reductions in IRF5 levels in skin, demonstrating target degradation in tissue as well as blood. Overall, KT-579 demonstrated robust degradation of IRF5 at or above levels predicted by our preclinical work in both the SAD and MAD. And this profile shows that the target remains continuously suppressed with once-daily dosing, providing sustained pharmacologic coverage of IRF5 expression.

Now in addition to degradation, we also assess the impact of IRF5 degradation on downstream biomarkers, which we believe is an important indicator of the potential biological effects. As a reminder, IRF5 has a role in the regulation of three major immune pathways relevant to several autoimmune diseases. These include, first, inflammatory cytokines. IRF5 promotes the production of key inflammatory cytokines by myeloid cells, including monocytes and macrophages. And when dysregulated, these responses can sustain chronic inflammation. Second, interferon response. IRF5 helps connect nucleic acid sensing with interferon production and associated gene expression responses. Dysregulation of this pathway can amplify immune activation and inflammation. And the third pathway is B-cell biology. IRF5 contributes to B-cell activation and pathways associated with plasma blast differentiation and autoantibody production. So this breadth of biology is an important feature of the IRF5 mechanism.

By degrading IRF5, KT-579 has the potential to modulate multiple interconnected drivers of inflammation through a single oral approach. Now to assess this biology in healthy volunteers, we use three orthogonal ex vivo stimulation assays that our team developed internally. These assays activate distinct RNA and DNA sensing toll-like receptor pathways and measure downstream changes in inflammatory mediators and gene expression. This allowed us to assess whether IRF5 degradation translated into functional effects across all three key areas. And in the following slides, we'll focus on the impact of IRF5 degradation demonstrated in each pathway. In each graph, we'll show the median of all KT-579 MAD dose cohorts combined compared to placebo.

So shown here on Slide 16, IRF5 degradation translated into deep and sustained inhibition of core inflammatory cytokines, including TNF alpha, IL-12 or 23 p40 and IL-1 beta. And as shown here, median cytokine reduction across all MAD cohorts combined ranged from 87% to as high as 94%. The kinetics of cytokine inhibition track with the kinetics of IRF5 degradation and the magnitude of the effect is consistent or superior to what was observed preclinically. These reductions are particularly encouraging as this is the core pathway involved in lupus through TLR7/8 and in IBD through TNF alpha and interleukin -12/23, two of our highest priority indications.

We interrogated the same inflammatory cytokine pathway more broadly with transcriptomics. The transcriptomics provide a complementary confirmation of the cytokine data, showing modulation of IRF5-dependent inflammatory biology. So anonymized, the heat map shows the changes in selected pathway genes with placebo and across all KT-579 dose cohorts at day 14 in relation to their respective pre-dose sample, while the graph quantifies the overall modulation of the gene set. We observed strong gene to protein concordance with genes like TNF alpha and interleukin-12 moving in the same direction as the corresponding functional cytokine readouts as described in the previous slide.

The second major axis we tested was interferon response, another important component of IRF5-dependent inflammation and a particularly relevant pathway in heterogeneous diseases. The effect on this pathway cytokine is particularly pronounced. We demonstrated near complete reductions in TLR7/8 stimulated interferon beta levels with the MAD dose cohort showing a median inhibition of 98%. Importantly, the transcriptional data independently support and extend this result, showing modulation results in broad coverage across key interferon pathway genes. And these data validate the pharmacology beyond the inflammatory cytokine pathway we showed in the prior slides, demonstrating that IRF5 degradation can translate into profound functional modulation of the interferon axis, which is well recognized as overactive in the biology of several autoimmune disorders, including lupus and Sjogren's disease.

Finally, as shown on Slide 19, the effects of KT-579 reach into the third major axis of IRF5, B-cell biology. Selected TLR9-driven transcripts are significantly modulated with KT-579, including key genes associated with DNA sensing and B-cell activation, again, important steps in the pathogenesis of autoimmune diseases, including lupus. In summary then, KT-579-driven IRF5 degradation translates into coherent functional modulation across three major pathways we set out to interrogate, inflammatory cytokines, interferon response and B-cell biology. And that breadth of pharmacology is one of the key takeaways from this first-in-human data set.

Okay. Moving to safety. KT-579 was well tolerated and had a safety profile comparable to placebo. As shown here on Slide 20, there were no serious adverse events, very few mild treatment-related adverse events, no adverse events leading to discontinuation of study drug or from the study and no clinically relevant changes in vital signs, lab tests or ECGs. There are also no imbalances in the rate of infections. It's very encouraging that KT-579 was able to robustly degrade IRF5 in blood and also functionally modulate disease-relevant biomarkers across 3 key immune pathways while demonstrating a placebo-like safety profile.

The Phase I data represents an important milestone for KT-579 for our IRF5 program and for Kymera. These results established important human proof of mechanism for KT-579. We've demonstrated that we can achieve deep and sustained degradation of IRF5 with an oral medicine with a favorable safety and tolerability profile. Importantly, we've also seen that IRF5 degradation translates into strong and encouraging downstream effects on the disease-relevant inflammatory biology. So taken together, this gives us increased confidence that we're achieving the profile we designed KT-579 to deliver and provide a strong foundation to move into patients.

As the program following our STAT6 efforts, IRF5 is yet another example of Kymera's ability to develop potentially transformational medicines for patients. So on that note, we now plan to advance KT-579 into its first patient study in lupus. Lupus remains an area of significant unmet need, where many patients continue to cycle through therapies without achieving adequate or durable disease control and treatment often requires combinations of immunosuppressive agents with meaningful safety and tolerability limitations. We see significant opportunity for a new safe and effective oral therapy.

Lupus is a compelling indication for this program given their strong genetic evidence linking IRF5 to lupus and IRF5 plays a central role in lupus disease biology. We've previously shown disease-modifying activity in multiple preclinical lupus models. And as you've seen today, we've now demonstrated exciting biomarker data suggesting a strong connection between IRF5 degradation and three important disease-relevant pathways. So this gives us a high degree of confidence in the underlying biology and a clear rationale for evaluating the impact of IRF5 degradation directly in patients.

The planned Phase Ib study will allow us to begin answering the next important questions, whether IRF5 degradation and downstream biology we observed in healthy volunteers carry through to patients with lupus and whether KT-579 can affect the disease pathways that are active in those patients. In healthy volunteers, we measure pathway effects after stimulating blood samples ex vivo, while in patients we'll be able to assess those effects in the setting of active disease as well as look for early signs of clinical benefit. We view this as an important next step for the program and towards establishing IRF5 degradation as a potentially new therapeutic approach for patients with autoimmune disease. Here's a snapshot of the Phase Ib study designed for the trial, which we've named LUMORA.

We plan to enroll approximately 30 patients with SLE randomized 2:1 to KT-579 or placebo and treated for 16 weeks. Oral corticosteroid background therapy is permitted. In fact, our upcoming oral presentation at the American College of Rheumatology Conference demonstrates that KT-579 shows significant activity alone or in the presence of background therapies in preclinical lupus models. The Phase Ib will evaluate the impact on inflammatory cytokines, interferon signatures, B-cell subsets and other key immune pathways implicated in lupus. And we'll also explore measures of lupus disease activity, including changes in mucocutaneous and musculoskeletal symptoms that patients experience. In this small Phase Ib study, those measures will help us look for early signs of clinical activity alongside the safety and biomarker results.

So with that, I'll turn the call over to Bruce.

Thanks, Terence. Turning to our third quarter results. I'll quickly walk you through the income statement shown here. As expected, we did not recognize any collaboration revenue in the third quarter. And as a reminder, we do not expect additional collaboration revenue for the remainder of 2026 as the milestones and our previous deferred revenue under our collaborations with Sanofi and Gilead were fully recognized as of the second quarter.

In terms of operating expenses, reported R&D expenses for the quarter were $128.5 million. Excluding approximately $10.9 million in noncash stock-based compensation, R&D expense was $117.6 million, an increase of 8% compared to the second quarter of 2026. Reported G&A expenses for the quarter were $18.7 million. Excluding approximately $7.9 million in stock-based compensation, adjusted cash G&A expense was $10.8 million, a decrease of 14% compared to the second quarter of 2026. We ended September with cash, cash equivalents and investments of approximately $1.6 million, providing a runway into 2029 and positioning us to continue to execute on a number of important value-driving milestones over the coming years.

Our financial position gives us the resources to advance both our wholly owned programs into and through their next phases of development. Specifically, it allows us to complete the KT-621 Phase IIb study in asthma and to take KT-579 through our planned Phase Ib study in lupus. We also expect to fund the KT-621 Phase III studies in AD in the initial stages of the Phase III development in asthma within our current runway. Alongside these clinical priorities, we'll continue to invest in our research pipeline and build the capabilities needed as we move towards later-stage development and commercialization. We believe this puts us in a strong position to execute our plans while remaining disciplined in how we deploy capital.

I'll pause here, so Nello can provide a few closing comments before we open the call to questions.

Thank you, Bruce. To wrap up, we have an important milestone ahead for KT-621, building on the compelling profile observed in Phase I healthy volunteers and patients with AD. In dermatology, we expect Phase IIb AD data by year-end, as I've said earlier. Subject to those results and regulatory discussions, we plan to begin Phase III development by mid-2027. And that planning is already well underway. In respiratory, our Phase IIb asthma study is ongoing with data expected in late 2027. As for KT-579, today's results are an important step for that program.

In healthy volunteers, we saw evidence that degrading IRF5 can modulate multiple disease-driving pathways. Along with the safety and tolerability profile observed in this study, these findings support our plans to advance KT-579 into patients with lupus by early next year. We also plan to expand beyond lupus and we'll be sharing more on our broader development strategy next year. These programs are emblematic of our strategy to build a world-class pipeline of wholly owned immunology programs that are directed at fundamental disease pathways with the potential to have large patient populations.

In closing, I want to thank the study participants, investigators and our team for making all of this progress possible. With that, we'll open the call for questions.

[Operator Instructions] Our first question comes from Brian Cheng from JPMorgan.

On the Phase Ib LUMORA trial design, I'm curious how you're thinking about the bar for success there? And any color in terms of which doses you would pick to move forward into this study, just given that it's interesting to note that you're already saturating at dose level 3. And just one tiny question at the end is any opportunity for patients to also taper off steroids as well?

Thanks, Brian. So I'll take a little bit of the question, then I'll pass it to Terence, who's our expert. So I think it's important to remember that the goal of this study is to demonstrate for the first time that in patients where there is disease, is obviously disease and we believe this pathway activation, we can modulate the biology of patients with the drug, obviously, without the need of ex vivo stimulation. So it's really demonstrating for the first time that IRF5 is relevant in the disease biology of lupus.

With that, I'll let you, Terence, maybe talk about some of the other specific goals that we have. I just want to touch a little bit on the dose. So as you pointed out well, Brian, again, we're so proud that in other first-in-class targets, that's never been drugged before we've been able to do it robustly, safely and showing probably better-than-expected biomarker outcomes.

We have many options in terms of doses, right? Because we've shown preclinically that 85% is actually enough to drive the biology. And you saw all of our doses at more than 85% degradation. So we will continue the mystery around the dose for now. But obviously, we have several options, and we'll pick the one that we believe will allow us to answer that question well.

Terence, on the Phase Ib, maybe you can add more color.

Thanks, Brian. The success criteria. So obviously, we'll look to recapitulate degradation in the setting where the target is active and much more highly expressed than in healthy volunteers. And then downstream with that, we'll look for movement of relevant biomarkers in those three key pathways that we discussed in the healthy volunteer study, inflammatory biomarkers, interferon response and B-cell biology. We'll be able to do that without having to artificially stimulate the pathway ex vivo. We also have the opportunity, obviously, to also look at clinical outcome measures. And so we'll take heat of that, too. Zero taper, I think, was your final question. We'll get into a little more detail around trial design at a later date when we launch the trial and post clinical trials, et cetera. But I think it's fair to say that across lupus studies these days, the expectation is that taper is incorporated design.

Our next question is from Thomas Smith from Leerink Partners.

Congrats on all the progress in these very nice IRF5 data. Just with respect to the IRF5 degradation, just wondering if you could comment on how much intrapatient variability you observed. Were there any patients who didn't achieve at least that 80% threshold you were aiming for? Was there any difference in serum versus skin? And then I was also wondering if you could just comment on some recent data we've seen from the TLR7/8 class and how that maybe influences your thinking around probability of success in an indication like lupus.

Okay. So I'll take the first two. I do want to encourage people to try and focus on one because if you have three one, we're not really doing one. This is for future questions.

So on the degradation, I mean, if you look at our graph, the slides should be up on our website, by the way, to everybody listening, so you should be able to see it. Our degradation profile as now for -- this is the sixth program we show data for is always extremely robust and consistent. Our error bars are extremely small. So there are no outliers in the degradation profile in our patient, in the subject in our study. The difference between blood and skin is minimal, if any. The IRF5 expression in skin is extremely low. In fact, we actually did not set the expectation around skin because actually, we thought we weren't going to be able to measure it. But we have an amazing team here that has developed unique assays some of which we're not sharing because they are assets that we've invented and we want to protect as well. But we were able to actually measure even very low expression level, we were able to robustly reduce with this drug. So that was another important milestone.

There was a question around the competitive landscape, Terence, do you want to make your commentary?

Thanks, Thomas. I'd say the TLR 7/8 direct inhibition gives us confidence in probability of success. But of course, this mechanism goes beyond just TLR7 and 8. So that I think is a good guide for us too. I'm really looking forward to interrogating that profile in lupus patients very, very soon.

Our next question is from Derek Archila from Wells Fargo.

Congrats on the data today. So more of a market question in terms of atopic dermatitis, but kind of the beyond opportunities for KT-621. So I was wondering if you could help quantify how the atopic dermatitis market may expand with the introduction of a safe and effective oral. And I guess the bigger question is, could you expect similar expansions in other indications like asthma, COPD and so on?

Yes. Thanks, Eric. So actually, this gives me an opportunity to also make another point, which sometimes we forget to do, which is KT-621 potentially the first effective oral for type 2 diseases is something that has never actually been accomplished before. So not only we can focus on AD in a minute, not only this is a drug for AD, but it's a drug that will or should, I should say, be treating all comorbidities.

One of the main reasons for dupilumab's success is not only the robust efficacy and pretty amazing safety profile, but it's the fact that it's the preferred option for most doctors because it treats comorbidities that most patients have when they have any one type 2 disease. So that is something that we often forget to remind, but I just wanted to take the opportunity to remind this is a unique drug also because of it.

Now when we go back to your point about -- we had a slide today earlier in our presentation that there is millions of patients with moderate to severe AD in the U.S. we said this is actually a publication. This is not our numbers. And another data that is not ours, but it's a fact it's about 400,000 are on systemic therapy. So the opportunity here that we have with the potentially the first effective oral drug is to expand the market of patients that are sitting on the sidelines because they're not comfortable with the idea of taking an injectable biology. So we think this would be transformative almost regardless of where exactly the efficacy profile will land, although as we said, we expect it, obviously, to be in the ballpark. And that could be applied as you were implying to other diseases where actually either -- there's -- mostly it's not only biologics, for example, asthma or diseases where there's only one drug or two drugs.

If you think about EoE, only injectable drug for so far only Dupixent, we probably have [ Kizeen ] we assume approved relatively soon. CRS, again, these are dominated by injectable drugs that are not what people are looking for. So we believe that the opportunity here, we continue to make the case. It's not so much that we will have to compete with biologics, which I'm sure we will do as a highly competitive team here, but it's actually about expanding the market to new patients.

And even in psoriasis, as you've seen with Icotyde recently, a much more mature market, 60% of new prescription for Icotyde are new patients, which is pretty impressive for a market that has been built for now almost 15 years.

Our next question is from Geoff Meacham from Citi.

This is [ Nisam ] on for Jeff. So looking at today's data from KT-579, are there any elements that most strongly support development beyond lupus, maybe like in IBD, Sjogren's or RA?

Yes. Maybe I'll let Terence take this question, and then I might add one thing at the end.

Thanks. So genetically, there are strong genetic links to each of those diseases for IRF5 overactivity. So that gave us confidence as a starting point. From the data today, obviously, we looked at those three pathways proinflammatory cytokines, type 1 interferon and B-cell biology. And you can draw threads between each of those and rheumatoid arthritis and/or Sjogren's disease or IBD. So just as an example in IBD, obviously, in the pro-inflammatory cytokine panel, things that we looked at included TNF alpha and Interleukin-23. Each of those has been successfully targeted as monotherapies and recently in combination. In Sjogren's disease, it's well recognized as an interferonopathy with strong interferon signature, and we saw good damping in type 1 interferon in today's readout. And finally, it's also well recognized as a B-cell-driven autoantibody-associated disease, and we saw signals there too. So I think we've got good evidence of a broad waterfront of opportunity.

Yes. The only thing I would add, thanks, Terence, is that the lupus LUMORA study, which is bound to start soon, you should expect it to be one of multiple patient studies that we plan to initiate around this program with KT-579.

Our next question is from Mike Ulz from Morgan Stanley.

Congratulations on the data as well. Maybe I could just ask a follow-up just on the upcoming BROADEN-2 data. Just given you completed the last patient visit in the study, just wondering if you can share any thoughts on baseline characteristics and how that might impact our thinking when we try and do cross-trial comparisons to the Dupixent Phase III studies.

Yes. Thanks, Mike. I mean, as we've said in the past, we're trying to just preserve all the patient baseline characteristics as well as obviously the data when we report the data later this year before year-end, as we said. The only new update we gave today in our remarks was around the percentage of patients that went from the 16-week study to the OLE just because we have completed that study and now the study is officially in an open-label extension. And we said that of the eligible patients, 98% enrolled into the OLE. That's the only comment we're going to make around that study. And then the next update will be when we share the data. Thanks you. Next one.

Our next question is from Biren Amin from Piper Sandler.

Congrats on the IRF5 update. Maybe a question on KT-621 and BROADEN-2. What measures did you take in the trial to mitigate against high placebo response, which typically we've seen that historically in other AD studies.

Yes, Biren, thanks for the question. I'll let maybe Terence take this one.

Thanks, Biren. So the priority of the company in enrolling that study was to focus on quality rather than speed. Hence, it was actually a particularly pleasant surprise that the study enrolled a couple of quarters early. Measures included careful site selection, careful investigator selection, control of factors that can sometimes drive placebo response rate like previous medications or concomitant therapies coming into the trial, careful patient selection coming in, including some fairly novel measures to assure that patients had atopic dermatitis, that it was moderate to severe.

So despite that tight filter, as I say, there was a lot of enthusiasm. The trial enrolled approximately two quarters early. Some of that enthusiasm, I think, came from appetite for a safe, effective oral in the space, comfort with the pathway, a high-touch approach by the team and a transparent scientific disclosure. We're really looking forward to disclosing the results very soon.

Thanks, Biren. Next question. I'm doing the operator as well today.

Our next question is from Alex Thompson from Stifel.

Maybe another on BROADEN-2. What should we expect in terms of data beyond sort of the primary and key secondary endpoints as it relates to subpopulations like those with comorbid asthma and as well as biomarkers? Anything there would be helpful.

Yes. Thanks, Alex. Obviously, we don't have visibility into the data yet. So it's really hard for us to commit like 100% to -- beyond what we've already said. I think the goal of the first disclosure is to ensure that we share all the data that we believe is material to obviously the company and to investors to assess the safety and efficacy profile of the drug. Some things that we believe are additional interesting scientific information that are not critical, we love to keep them for eventual presentation and publication. So that's kind of the overarching philosophy. I think once we'll share the data, we'll be able to then explain what's in there and what will come at a later point.

Our next question is from Faisal Khurshid from Jefferies.

Just wanted to ask maybe a little bit different of a question. With regards to your degrader platform, can you talk to us -- there's like some interesting like extracellular degrader programs and platforms that are out there. Can you talk to us about whether that's something that is kind of like within the Kymera repertoire? Or is that something that you could be interested in going into in the future?

Yes. Thanks for the orthogonal question. So let's say -- so I think what -- so let me explain what we're very good at. I think we're the best at is I think identifying the right targets for the pathology, identifying small molecule, highly specific ligand for novel targets, making exceptionally well behaved and specific degraders and I think designing and executing so far early- to mid-development studies in immunology. And obviously, that sounds like status quo, but actually that's really hard to do all in a completely novel company.

Another thing that we're really good at is any type of heterobifunctional molecule chemistry. So that obviously could incorporate by just nature of the business, extracellular degraders, these LYTACs, obviously, molecular glues. And so we, as a curious and well-financed company, we look at other contiguous technologies as well. What I would say is that I find it extremely hard to develop a technology, let's say, an extracellular degrader solution that is not oral, meaning I think the power of heterobifunctional molecules is the ability to make these drugs oral drugs that can replace or expand beyond these injectable biologics. I don't think you're going to see us making extracellular degraders that are injected because I don't think we -- there is a need for that. There are other technologies that can track extracellular proteins much more efficiently or even now probably a lower cost than other technologies. Thanks for the question. Next one.

Our next question is from Jeff Jones from Oppenheimer.

Again, congrats on the really striking data. As far as Phase III planning for 621 beyond AD and asthma, just any updates on your thinking around additional indications and programs there? You've disclosed some thoughts previously, but just if there are any updates to your thinking?

Yes. Thanks, Jeff. Great question. I'll try and address this quickly. So our goal is to launch KT-621 in all indications that we believe are relevant to type 2 inflammation. In terms of priority indications are the ones that we believe there is the highest unmet need and opportunity for an oral drug to change the landscape. So those go beyond AD and asthma. I think we want to have that conversation post the BROADEN-2 data so that at some point early next year we can share a bit more comprehensively what our late development plan is because that will be obviously highly dependent on the upcoming data readout. Next question.

Our next question is from Brian Abrahams from RBC Capital.

This is Kevin on for Brian. So on the Phase Ib lupus study, will you enroll both interferon high and low patients? And for later-stage development, do you think there is value in focusing on interferon-high patients, should the effect be sort of more pronounced there?

Terence?

Thanks, Brian. Thanks for the question. We will enroll both interferon-high and low patients. It's premature at this stage, I think, to focus on a biomarker-driven subset. Obviously, we're well aware of interferon-high and its potential for controlling placebo response rates in lupus trials. But just harkening back to the mechanism of action here, obviously, the MOA includes what goes well beyond just interferon inhibition. So at this stage, we're in learn mode. We'll enroll a well-controlled, well-defined lupus population, but not necessarily tightly focused on just interferon-high.

Yes, I agree, Terence. And more importantly, because we want to learn whether there will be a different biomarker response based on heterogeneity of baseline. So I think at this stage, it's very important to be more open-minded than not. Next one.

Our next question is from Andy Chen from Wolfe Research.

This is Jason on for Andy. We just had a quick question on the PD for IRF5. Did the data suggest any flexibility in dosing frequency or rapid reversibilities if any safety issues emerge?

So our drugs, as you can see even from the biomarker responses, when you stop dosing, the degradation, obviously, the target comes back to baseline in a few days. And you can see it again in the biomarker response glucose kinetics is very similar to the degradation as Terence said. So I think we know how to obviously dose this drug, what doses we need to adopt. We personally, I should say maybe I personally don't expect that we'll have to react to some emerging adverse event based on mechanism. But even if that was the need of cessation of dosing, again, these drugs' half-life are in the hours, not in the days. And so you can see a reuptake of pathway signaling relatively quickly. So we're not concerned. Next one?

Our next question is from Morgan Lamberti from Goldman Sachs.

This is Morgan on for Andrea Newkirk. On IRF5, how are you thinking about the translation of biomarker reduction in healthy volunteers to lupus patients in terms of whether you would expect to see similar or greater reductions? And then how should we think about the safety or the ramifications of achieving greater than 90% IRF5 degradation, just if there's any specific AEs you're monitoring there?

So maybe just quickly, I'll try to answer and then Terence can help me. So just remember, the ex vivo cytokine activation is, let's call it an artificial pathway activation. And this allows us to measure in the absence of IRF5 how much pathway inhibition you see when you have a robust activation. So the fact that we're able to practically inhibit fully the pathways with IRF5 degradation is telling you that this target is central to this pathway activations when we use the stimuli. I think in patients, you obviously have this pathway activated, but not with this type of stimuli. There is obviously disease-driven stimuli that might be often that would be probably less robust than this. And so it's always difficult to be able to predict. I think the fact that we can block them fully gives us confidence that no matter what the stimuli is in patients, we should be able to see robust pathway inhibition.

What was the second part?

Safety.

The safety. Terence, do you want to take that?

Yes. So thanks, Morgan. I think we expect to see movements in all three key pathways unstimulated in lupus patients, some of which are obviously clinically validated in that disease, including type 1 interferon and B-cell biology. On the safety side, we've been encouraged by the safety profile seen preclinically before this study and particularly encouraged by the preliminary safety data we've seen here in Phase I, including a lack of any signal with respect to infection. We'll continue to watch carefully, but so far, so good.

Yes. We know that there is -- there are redundancies in the IRF5 family. So while -- I mean, we'll have a watchful eye. We're not concerned about the long-term safety of this drug. Next one?

Our next question is from David Hoang from Deutsche Bank.

Congrats on today's IRF5 data. So before you head into the quiet period ahead of the BROADEN-2 readout in AD, I just wanted to ask you, could you remind us what is your view of in the ballpark of dupi for endpoints like EASI-75 and IGA 0/1? And then in terms of the scenarios that could occur, knowing what we know about STAT6 biology, is there a scenario where 621 could outperform dupi at 16 weeks?

Yes. Thank you. So I mean, the reason why we continue to talk about this ballpark is because for all the data that we have generated so far for more than half a decade, we've seen that blocking IL-4 and 13 with an upstream biologics or blocking IL-4 and 13 with a STAT6 degrader seems to block whole downstream signaling in a similar way. So that's where our thesis hypothesis comes from. The other aspect is if there are differences between the 2 drugs, obviously that could be driven by many things. It could be -- obviously, these are different technologies, small molecules and antibodies. It's still an intracellular versus extracellular target. But it's difficult for us, high priority to determine the impact of these nuances on the clinical effect that we will see.

With regards to the design in the ballpark, it's actually -- I'm trying to define unscientifically something that is also unscientific. So cross-trial comparisons are technically not doable and they have an inherent flaw in the approach. And so it's impossible for me to tell you exactly what the numbers should be that we should be looking at. But I think for people that are students of the space, you should be able to have a reasonable interpretation when you see a data set across several endpoints between two studies that are run a decade apart. So you have to look at the placebo rates, you have to look at the absolute treatment effect, you have to look at the consistency across endpoint.

And at the end of the day, it actually does not matter because we're not trying to replicate dupilumab study. We're trying to develop one of the most exciting oral drugs for type 2 patients that is right now in clinical development. And the important thing is that we demonstrate safety, efficacy and tolerability. I know that there's a lot of focus on comparisons, and we will do that comparison too. I'm not trying to be a purist here, but I'm just trying to say that actually the important thing is that we deliver on the profile that we believe will be commercially successful. And for the scientific curiosity, there are many tools that one can use to compare trials that will all be wrong, but will give us a sense of what it would look like. This is the definition of ballpark, what I said in the past 2.5 minutes maybe. Next one?

Our next question is from Tyler Van Buren from TD Cowen.

Regarding BROADEN-2, should we expect to see itch data with the initial release? And can you discuss the potential to differentiate there given the IL-31 reductions observed? Our KOLs have recently brought this up in discussions.

Yes. We plan to have itch data, of course, itch, sleep itch, quality of life. These are actually important measures of how well the drug is actually serving patients. If you do market research, the #1 complaint for patients that are actually on therapy continues to be itch. So with regards to differentiation, it's hard for me, and obviously, I should be the most biased person in the world for the STAT6 program. It's hard for me to over-index on the IL-31 data. It's great that we saw IL-31 blood reduction with -- in the BROADEN study. This is the Phase Ib. It is also true that hasn't been measured by others. There was a study with dupilumab in Japanese patients where they didn't see a reduction of IL-31. But again, we're 10 years apart. We have an amazing translational medicine team under Terence's guidance. I think that it's probably more likely that we're just better measuring than we are different biologically from Dupixent. But anyway, we'll know soon. So we'll definitely share the data. Next one?

Our next question is from Jeet Mukherjee from BTIG.

Congrats on the data. It almost seems you guys make degraders of this quality in your sleep now. My question was just focused around the KT-579 Phase Ib lupus study. Could you just elaborate on some of those exploratory endpoints? And what would tell you that you have a clinically differentiated profile here for KT-579?

Terence, you want to take that?

Sure. Jeet, I assume you're referring to the exploratory clinical outcome measures. We look at all of the usual lupus clinical outcome measures, including composites like SLEDAI and BILAG. We look at the individual components. And obviously that will sit alongside the biomarker data, which are the chief focus of the study. And we'll take the whole set of data together in making our decisions downstream with that.

Yes. I want to add two things. So first, the reason why we make drugs in sleep is because we don't sleep. So we actually can make drugs effectively. That's a joke, by the way.

And then on the other thing, I just want to remind everybody, the study is not powered for clinical endpoints. That's why we say that we're -- they're more exploratory than the usual exploratory. So everything Terence said, obviously I agree. But just remind everybody, this is a small study, a biomarker focus to understand the biology in the right clinical context of IRF5 degradation. But obviously, it's a 16-week study. So we'll keep an eye on any move on clinical endpoints, understanding that, as you guys all know, placebo rates in lupus are high. And so we're going to be careful on how we interpret those data set. Next one?

Our next question is from Jasmine Fels from Barclays.

Jasmine on for Ellie Merle. So congratulations on the IRF5 data. I wanted to ask a little bit more about dose selection and dose response. So can you characterize the dose response you saw across the different MAD cohorts for the ex vivo stimulation biomarkers? So do you see a similar trend of degradation for the saturation at dose level 3? Or was there a wider range of dose response across the different biomarkers?

Yes. Thank you. It is a great question. So to be honest, the reason why we're not sharing what we usually share, Terence said it earlier, is we want to retain some competitive advantage over the fierce competition that we've seen increasing over the past few years. We feel with KT-621, we probably caught the market too much. Actually I shouldn't say the market, our competitors. And so we're trying to be a bit more thoughtful. So the reason why we're not sharing, let's call it, the dose response on biomarkers because I personally don't want to share what is the level of IRF5 degradation to that leads to the optimal biomarker changes that we're seeing. So we have a really good understanding of what is the dose we need to use and that dose selection has been based on what we think the level of degradation and what we know the level of biomarker changes are. And for now, we're going to leave it at that.

Our next question is from Seamus Fernandez from Guggenheim.

Congrats on the IRF5 data. The question that I have on IRF5 and maybe at some upcoming meetings would be the potential links of the robust biomarker effects that you're seeing targeting IRF5 and some of the data that we're going to learn coming out of ACR, particularly as it relates to Sjogren's disease. Terence, what would you be looking for from other disease states given this sort of B-cell versus T-cell dynamics, CD40 ligand versus APRIL/BAFF and the opportunity that you see in other disease states from some of those learnings.

Thanks, Seamus. I think Sjogren's is a really good indication for the target. There's a lot of unmet medical need in Sjogren's, yet no approved advanced therapies. The biology is a good fit. We've got good genetic links between IRF5 and Sjogren's risk. And some of the pathways are clearly activated. So for example, we know Sjogren's to be a highly high interferon flavored disease. And we know that B-cell targeted therapies have shown efficacy, including one that's hopefully on the cusp of approval out of Novartis. So I think we're very encouraged that Sjogren's could be a good indication and one we're carefully considering.

Next one, we'll try and accelerate. I'm being told we're being too slow, so...

Our next question is from Tazeen Ahmad from Bank of America.

A couple of questions. So for this big data update that you have upcoming, as it relates to safety, in particular, for conjunctivitis, what if you don't see any instance of it? Because I think mechanistically, it should be something to expect. But if at this juncture, you're still not showing it, how should we be thinking about what that means? Could that differentiate from other treatments, for example? And then secondly, can you just give us a sense of what the top catalyst for 2027 in your mind would be as we think about next year and beyond?

Thanks, Tazeen. I love that we haven't gone through the biggest catalyst, but we'll talk about the next one. So the next one, let's start with your second question. Obviously, we have big data with asthma, which will be a huge catalyst to initiate multiple Phase III programs in asthma and other respiratory indications. So that from where we stand today is probably the biggest data set of '27. We have other things that we will be sharing more in the near future. But I think for now, I would say this year -- next year was supposed to be both AD and asthma. AD has moved this year. So this year is AD, next year asthma and other things.

On your question about conjunctivitis, the mechanisms, as we've always said, biologically is coherent with IL-4 and 13 biology. So I've said for a couple of years, we expect to see conjunctivitis. If we don't see it, obviously we could talk about potential reasons for it. But again, as we're seeing, we're close enough and we'll have that conversation than what we see [indiscernible]. Next question?

Our next question is Mayank Mamtani from B. Riley.

Mike on for Mayank. Congrats on the quarter and the data. When you report for BROADEN-2, will you break out IAE using the same conjunctivitis and keratitis clusters from DP label? This is just so investors can kind of compare KT-261 with like-for-like?

And also considering that Nemluvio is kind of seen as the itch benchmark, how do you think KT-261 compares to Nemluvio when it comes to itch?

I think for both questions, we'll know soon. I mean we -- I don't know the data to know what's going to be put with what. But for sure, we will present the data in a way that, as I said earlier, everybody should be able to assess the efficacy and the safety of the drug as well as whether there has to be any comparator way of looking at also safety, we'll do it in the way that is interpretable.

With Nemluvio, it's not a very active drug, but it does have an impact on itch by IL-31. We do have also a downstream effect on IL-31. I'm not sure Nemluvio would be our competitor, let's put it this way. But we'll see. The data will come up soon.

Our next question is from Xiaochuan Dai from UBS.

Congrats on the IRF data as well. So you noted a similar IRF reduction in skin and blood. So I'm just curious how does the skin tissue data give you confidence that the peripheral blood IRF degradation will be a reliable surrogate for target engagement in disease relevant tissues in lupus potentially IBD?

Well, the reason why we always look for a noncentral tissue and skin really is the only thing we can look at in healthy volunteers is to, again, derisk the distribution and degradation profile of the drug beyond the central compartment. So I'm a big believer through, again, 10 years of work here that skin is actually the hardest tissue to degrade targets in. And that's why we always measure it because we know that if you degrade in skin, you're probably going to be fine for the rest of the body. We also have preclinical data that shows that we can consistently degrade this target in all the relevant tissues. So this was just an additional validation of our profile.

Our next question is from Srikripa Devarakonda from Truist Securities.

Congratulations on the data. So you accelerated your atopic derm program because of the great high level of demand that you saw. Are you seeing similar demand with asthma program as well? And has that led to increase in enrollment rates? And if not, why do you think there is a difference? And how predictive do you think the endpoint, the FEV1 endpoint is of eventual exacerbation benefit?

So I'll take the first question, so we can move more quickly. So we are seeing the same level of enthusiasm in AD as we have in asthma. The main difference is that in asthma, our inclusion/exclusion criteria are much more strict. And so the screen failure rate is much higher, and that's what determines how quickly or not quickly we're enrolling the study. Next question.

Our next question is from Joseph Holden from Canaccord Genuity.

This is Joe Holden on for Edward Nash. I just wanted to see if you could provide any guidance on expected R&D expenditure into 2027 given KT-579 Phase I in lupus and the expected Phase III program in AD. Congrats on the data.

Bruce?

I'll just be brief because we don't give explicit guidance, but I would guide you to the runway, which is into 2029. And you should see, I would say, increases in operating expenses that are gradual but consistent to get you to the point that you're into 2029. Obviously, the expenses will accelerate as we start the Phase III study in AD, which we guided to by mid-2027. So we are also adding significantly to the team in preparation for those studies as well. So those will be the biggest factors in driving the cash year-over-year, I'd say, use of cash in '27 and beyond.

I believe this was the last question. I want to thank everybody for attending the call and also staying to 9:40. Please take the opportunity to check out our website. The slides are there. We're very excited about where we're going with now two very exciting first-in-class programs in patients. And so we're happy to follow up with any of you in the next couple of days apparently, but not beyond. Thank you.

All right. Good morning, everyone. Thanks for being here on day 2 of the Morgan Stanley Global Healthcare Conference. We're very excited to have the team from Kymera here for this session. Let me just get a quick disclosure out of the way. For important disclosures, please see the Morgan Stanley research disclosure website at www.morganstanley.com/researchdisclosures.

All right. So with that, welcome, guys. And earlier this year, you celebrated your 10-year anniversary as a company. You're approaching another set of milestones now. So before we dive in, can we maybe give the audience a bit of an intro on the company and your degrader programs?

Yes. So first of all, thanks for having us. So yes, the idea when we started Kymera in May of 2016 was there is tons of biological data tying disease-causing protein to diseases. And we've really lacked the right technology to address many of them. And while we make so much progress with oligo-based therapeutics and obviously, injectable biologics and traditional small molecules, there was still a big gap. And I would argue there's still a big gap.

Only, I think, 20%, 25% of the proteome has been drugged. And so we saw this new small molecule-based modality called targeted protein degradation as a means to expand the number of targets we can go after and ideally, obviously, fulfill some of the key unmet needs that are still out there. And so as people that might have heard about protein degradation is this modality that uses the ubiquitin-proteasome system, which is the cellular machinery responsible for protein homeostasis and directs against disease-causing protein.

So we have focused -- we focused in the past -- over the course of the company in different areas across initially oncology and immunology in the past 6 years, focused really almost solely in immunology. And the idea was, again, at a high level, quite simple, lots of pathways have been validated in immunology, lots of extremely successful drugs have changed lives of millions of patients around the world. These are almost only, if not mostly injectable biologics.

And so we found these opportunities to go downstream of these biologics intracellularly with oral degrader molecules to provide what we believed for the first time, really specific directed therapies that could deliver the best risk-reward profile for patients with immune inflammatory diseases.

So our wholly-owned programs are a STAT6 degrader, which is downstream of IL-4 receptor alpha, the target of Dupixent, which is, I believe, today, the #1 prescribed drug in immunology.

Another program that we're very excited about is IRF5 with KT-579, which is another undrugged transcription factor downstream of highly validated pathways in many immune inflammatory diseases. We have many other preclinical programs that we haven't disclosed yet, and we have a couple of partnerships, one in immunology with Sanofi and one in oncology with Gilead.

Okay. Great. So I thought maybe we'd start kind of in reverse order with that Sanofi partner program that's directed at IRAK4. So that program goes back to the early years of Kymera. Like you said, partnered with Sanofi. Can you talk about the discovery and preclinical efforts around that candidate? What were the specific issues you were looking to solve for?

Well, I haven't studied IRAK4 since 2023. So that's a very interesting, exciting way to start. So we started with the program with the idea of going after one of these key, again, undrugged nodes in immune-inflammatory diseases. In this case, IL-1, IL-18 -- IL-17 sorry, biology, a pathway that had actually upstream extensive validation. We had IL-1 biologics, even more recently from AbbVie that had some exciting data in HS. We had -- initially back then, IL-18 had some mixed data, but more recently, we've seen some interesting data from IL-18 in AD.

We have recently seen some really amazing data of IL-33 from AstraZeneca in COPD, probably one of the most exciting data set of the year, I believe, in that area.

So again, between then and now, we've seen these cytokines have impact across many diseases. IRAK4 is the central node downstream of those cytokines and responsible for the signaling. So it was actually an obvious target that has been pursued by many in the industry going after the catalytic function. We demonstrated that there was a scaffolding function that required a degrader instead of a small molecule inhibitor.

And obviously, we advanced our first-generation degrader, KT-474 through Phase II. And then as a part of the collaboration with Sanofi, we decided to focus on the second-generation degrader, which is a superior molecule that now entered recently Phase I.

Okay. Great. And I guess maybe just kind of given the experience with the IRAK4 program, what have been kind of learnings that you've been able to leverage across the broader platform?

Yes. I would say the biggest learning and actually one of the reasons why we have decided to invest further and if not almost solely in immunology was driven by the early translation of IRAK4 degradation in healthy volunteers. And we saw that what we had studied preclinically, kinetics of degradation, safety, predictability of safety, predictability of degradation kinetics across different tissue types gave us the confidence that one can develop reliably degraders in immunology. We were the first company to do so back then.

And so that's, I think, a big learning, even the, let's call it, the platform translation and fidelity thereof. And then the second part was actually how important specificity is to successful drugs in this space, how important dose selection becomes, how important the distribution of the molecule and the impact of that distribution has on the profile of the drug. And so this allowed us to develop this new generation of degraders.

I would call 474 a first-generation degrader molecule with pros and cons and things that we learned from. And then this allowed us to invest and learn and optimize these degraders. And so I think KT-621, 579 and even 485, which is our second-generation IRAK4 degrader, have benefited from what we learned, and these are way better molecules than our first molecule.

Can we spend a minute maybe just on design of the Phase I study for 485, what the objectives might be there and how they could confirm further development?

Yes. So there's not a ton we can disclose given that this is a program run by Sanofi. But I think it's also, I believe, on clinicaltrial.gov by now. It's actually a quite creative Phase I study that has healthy volunteers and HS patients. The healthy volunteer portion is a more traditional SAD and MAD study with some interesting biomarkers. Again, we unfortunately can't go into it. And then there is an HS, let's say, proof of mechanism portion at the back of it. Obviously, we look forward to seeing the data when they are generated.

Okay. Great. And you touched on it, but I guess just kind of given the interesting data we've seen in certain type 2 indications you talked about, but then non-TH2 targets in atopic derm like IL-18. I guess, whether it's specifically for 485 or other potential shots on goal in the space, where do you see a product like this potentially fitting into standard of care for a disease like atopic derm?

To be honest, we're so focused on KT-621. This occupies less than 5% of my mind. given that that's a wholly-owned program. It's probably the best program in immunology today. And so I think what Sanofi and we, to some extent, do with IRAK4, it's not center of our mind right now. What I will say is there are opportunities. I would probably say AD is not probably the best place for IRAK4. But I think HS is an interesting place. I think asthma, COPD are exceptionally interesting places.

But again, because we don't control it, although we're trying to influence and given where we are with our programs, we don't spend a lot of time on it.

Makes sense. All right. So switching to, like you said, the program that occupies, I think, most of your and investors' attention, obviously, KT-621, your oral STAT6 degrader. Maybe just some numbers around the unmet need that you could solve for here. How big could the opportunity be?

Yes. Look, I think this is -- thanks for the question because this is probably the most underestimated aspect of the program. I think the mistake we all made, and we used to make it in the past. Now, we don't really have many excuses to still make it. But we always think about Dupixent. Dupixent is a $25 billion drug. And so we can take a fraction of that. And that's actually the wrong way to think about the opportunity here.

Actually, the opportunity here is that these diseases -- and we can start with AD first, but asthma, COPD, EoE, chronic rhinosinusitis with nasal polyps, CSU, et cetera. I can come up with 9 at least. These are diseases that actually have been put on the map in many, if not in most cases, by the work that Regeneron and Sanofi have done with dupilumab, meaning that they provided a solution to diseases that were not either well characterized or well treated.

And so, as a result of that, these are still under-served patients, mostly because one drug for as great as the drug can be, can never serve all patients, especially when it's an injectable drug. So let's use AD because it's easier. And let's use the U.S. market because we're here. So there is about 6 million to 9 million patients with moderate to severe AD, depending on the publication you read. So this is not our number. This is market research.

And let's say, for the sake of argument, I'm going to use 8 million -- I like a full number. So there's 8 million patients with moderate to severe atopic dermatitis. The patients that are today on advanced systemic therapy, which means Dupi, Lebri, RINVOQ and a couple of others are roughly 400,000 patients. So there is about 5% penetration of this advanced systemic therapy onto the moderate to severe patient population.

So the question we asked when we did this market research is why is there such a low penetration? Other companies will come up with different numbers, but these are actually unbiased numbers that are out there. So the answer that we get from patients and prescribers is the feeling, the perception that they're not severe enough. Again, I'm not saying they're actually from an EASI score. I'm saying from a perception, they're not severe enough to want to be on an injectable biologics or an oral drug with black box in the case of RINVOQ. So that's like the big barrier.

And then we ask the next question is, what type of drug would change that behavior and the answer is a safe, effective oral. So I think the opportunity for KT-621 is to build a market that is multiple of what these injectable biologics have built. And so I don't want to come up with numbers because it just doesn't make sense. You can come up with any numbers. But that 400,000 patient number is a $25 billion market.

So think about if we increase the penetration from 5% to 10%, from 5% to 15%, from 5% to 25%. And it's not just 621. I think we need more drugs to expand the number of patients, but we believe our drug is best positioned to be first-in-line, post-topical to serve as many patients as possible. So that is probably in the realm of no other drug that is being developed today, either in immunology or outside of immunology, maybe besides obesity, which is a whole different world.

Right. And maybe just help us get up to speed on 621's clinical profile. Specifically, how did the preclinical work translate to the clinic? How is the drug's profile shaping up? Dupixent clearly is the right comparator. But within the context of Dupixent, how did that preclinical translate to clinical? And then what's the drug's profile versus the key comparator?

Yes. Maybe I'll start with the preclinical-clinical translation. I'll let Terence comment on the -- let's say, forward-looking drug profile. So I would say that scientifically, when we disclosed this program in January of '24 -- it seems like 10 years ago, but it was only a couple of years ago. And we've done work for more than half a decade on this target. And the fascination we had is what I was saying earlier is that -- actually, there aren't many programs or there haven't been in the past either of a downstream transcription factor that has such a one-to-one direct relationship with a receptor. And so we felt the STAT6 beautifully could replicate IL-4 and 13 biology.

And so we've done so much work and some of it hopefully will be published soon on mechanistic understanding of STAT6 degradation versus IL-4 receptor blockade, how does the biology play out. And what we've seen preclinically and early clinically is this consistency of IL-4 and 13 blockade with a STAT6 degrader that is comparable to what we've seen with receptor with dupilumab. But maybe Terence can comment more on the clinical profile, et cetera.

Yes. So a comprehensive preclinical package put together that showed that the asset completely and exclusively degrades STAT6. And of course, we've put together a nice biology package building on what's already there in the literature that STAT6 completely and exclusively serves the signaling of IL-4, 13. So many transcription factors serve multiple masters. STAT6 is extremely focused.

So this provided a rationale to develop 621, which moved into clinic in healthy volunteers in the last couple of years and at a range of doses ranging from a little over 1 milligram a day up to 200 milligrams a day, we have a nice biomarker that allows us to directly measure degradation of the target STAT6, both in blood and in tissue. So we saw that the asset can produce near complete degradation of the target in blood and in tissue at doses -- most doses over 1 and a bit milligrams a day.

So this provided a rationale to complete a single and multiple dosing studies in healthy volunteers and bridge that into patients with disease. So we conducted a Phase Ib study called BroADen, where we took 22 patients with moderate to severely active atopic dermatitis and dosed them with either 100 milligrams or 200 milligrams once a day. And those data were shared at the American Academy of Dermatology earlier this year. And the idea was to see if that degradation story and particularly the relationship between dose and degradation in tissue would replicate in disease where there's much more STAT6 activation.

And what we saw was that it was and each of those doses produced complete degradation in blood and in tissue. But of course, we then had the opportunity to look at downstream biomarkers and even downstream of that disease activity in skin and downstream of that disease activity or features of disease activity in people who also had related type 2 diseases. And the whole thread lined up. So biomarkers like TARC and eotaxin that are type 2 related and downstream of degradation moved as you would expect for an advanced therapy asset blocking the type 2 pathway.

Disease activity improved in line with what you would also expect in skin. And as we just presented at the European Respiratory Society in Barcelona a week or 2 ago, people with -- a proportion of people who had asthma saw movement in biomarkers and PROs and people with allergic rhinitis also saw improvement.

So as Nello said, while the biology seems to tell us that there's a very reasonable reason to expect that this would produce efficacy exactly in line with the most efficacious advanced T2 biologics. The market is telling us that, that would be great, but it's not necessarily what the market needs for a successful offering for human health or indeed for business case.

Okay. Great. And I think for a Phase Ib data set, I think the handicapping on biomarker degradation and what would be viewed as good data for the Phase Ib, you guys clearly surpassed the very high bars that were set. But I guess in terms of what you saw in the Phase Ib and potential for that to translate to a larger study in running BroADen-2 at this point. How confident are you in the translation, specifically in atopic derm from a smaller data set to a larger one?

I mean this is a once-in-a-lifetime program. I think you have a great molecule, very well behaved, highly specific with pristine safety preclinically and through the end of Phase Ib, biology that is congruent with what we understand of this pathway. So this is probably as confident of a translation that one can have going into this Phase IIb data. There is not a lot of surprises here on how things have evolved to date.

So obviously, I don't know what the number will be, the numbers will be. But again, we've seen consistently over the past few years that every time we ask the question, is STAT6 degradation sufficient to block IL-4 and 13 in a disease relevant manner, the answer has always been yes. And so I think we're going into this Phase IIb study expecting that we'll see the type of efficacy that first, we've seen in Phase Ib and that we've seen also with dupilumab in the past. Again, you can't really do cross-trial comparisons, especially if you're a decade later.

But I think that's why we keep saying we expect it to be in that ballpark because that's what the biology has been telling us for years and years and years. Now again, we keep saying the market is telling us we don't need that. That's great, but we still expect to be in that ballpark.

Right. You said there haven't been surprises, maybe biologically, I think you guys certainly surprised the market with pace of enrollment into the Phase IIb. So maybe just describe what you've seen in terms of interest amongst patients and investigators relative to expectations when you were at trial initiation stage. And we've talked about expanding the population of addressable patients to potentially include milder disease. Any early signals of that as you enroll patients?

So first, let me say, we're not expanding to milder patients. I want to be sure and repeat again that what I talked about earlier, about 5% penetration is still in the moderate to severe population. And so the drug will be -- if everything works out, obviously, we believe first line post first-line post-topical drug for all moderate to severe patients.

So with regards to what was the excitement that we saw, I mean, I think there are 3 -- maybe 3, 4 main reasons. One, as I mentioned, even based on the market research that we've done, there is a huge amount of excitement, and we've seen this in both AD and asthma actually for an oral drug by patients. There is a level of understanding comfort and knowledge of investigators about this pathway.

Obviously, Dupixent has been dosed to children as young as 6 months old. So obviously, this is not the same target, but it's the same pathway. And so there is a level of comfort with this pathway, which obviously we will have to continue to earn with our own data. And then I think we had exciting early data, both the Phase Ib, the healthy volunteer, the preclinical data for the sciency-focused investigators on our study.

And then I think the team have done an amazing job being extremely high touch. We visited all countries and met almost every single investigators and show the passion and the rigor that we use to run our studies. And so all of those things have come together to have basically hundreds of patients that wanted to enter a study. And obviously, we're limited by our protocol.

Right. Okay. Great. And you talked about kind of the ability to compare to older studies. I think one area of concern amongst developers that comes up is high placebo rates that have been seen in atopic derm studies. I guess between the enrollment criteria and study execution, can you talk about how you're managing that risk in BroADen-2?

Yes. Maybe, Terence, do you want to take that?

Yes. So I think since the early days of dupi and the very first program emerged into atopic dermatitis, in the advanced therapy space. It's not that dissimilar to other disease areas. You could pick rheumatology or gastroenterology. When the first therapies arrived, there was very little available. And therefore, placebo response rates tended to be extremely low because patients and providers had low expectations of what might be possible. And then time went by, expectations went up, patients were better treated.

So the proportion of people with very severe disease who were available to enter programs went down. People had still moderate to severe disease, but perhaps less severe and more moderate as a proportion. So you see this across multiple therapeutic areas as more treatments become available and the field matures.

So sure, in atopic dermatitis, placebo response rates in trials have generally crept up over the years. But in our view and in my view, not in a catastrophic way, there have been multiple recent programs that have read out over the last year, even this calendar year with pretty respectable non-problematic placebo response rates. It's true that a couple of years ago, there had been a couple of programs that experienced very problematic placebo response rates, but perhaps there were specific reasons related to the design and execution of those programs.

So, in our own study, we nonetheless remain paranoid about this problem and put in place a variety of measures related to the design and execution of the trial to try and control it. So that range from selecting good and experienced sites, careful training of those sites I would say high-touch oversight of the kinds of patients who were allowed into the program. We haven't disclosed the specific measures, but we had some pretty interesting innovative measures to make sure people actually had atopic dermatitis and actually had moderate to severe atopic dermatitis.

We made sure that a couple of the things that occasionally and typically trip you up the placebo response didn't happen. Typical things would be making sure that medicines that they had been on beforehand that they were allowed to be on remain stable or medicines that they had come off beforehand that they weren't allowed to be on had come off at a reasonable interval before coming in. And then the final thing I would say is that the team at both ourselves and our CRO partner have a very high-touch approach as we're executing the study, maintaining oversight of things like rescue medications and other concomitant therapies, again, things that influence response rates.

So the proof will be in the pudding very soon before the end of this year. We look forward to the readout, but we think we've done everything reasonable. And we also think that generally in atopic dermatitis, while placebo response rates have crept up, it's still very possible to extract a nice signal from the noise.

Okay. Great. And I want to make sure we touch on safety. Safety has been extremely clean so far. It does seem like investors wouldn't be surprised given the mechanism and given prior experience with dupi of some conjunctivitis or eosinophilia cases popped up with longer-term dosing. But I guess how stringent is the safety bar in your mind?

I mean for AD, we know that, as I said, what are patients looking for safe and effective oral. So safety is key. And I think we've been fortunate and we'd be good at, I think, selecting and making the right molecule with the right profile. And again, we look forward to seeing how that translates into longer duration and much bigger patient population. And I've always said, I believe after these two big Phase IIb studies that both have open-label extension, we'll know almost fully the safety profile of this drug.

I think this Phase IIb are much more derisking for what the totality of the package and in some programs, you might need Phase III data for, I think, would be hugely derisking because of the global setup, the open-label extensions, the generally large N -- so we'll know soon as we continue to derisk safety.

Okay. Speaking of, I guess, you talked about potentially moving into Phase III next year. I guess what questions could be answered from the BroADen-2 data that could inform Phase III design potentially, whether it's dosing or...

Yes, dose for sure. We'd love to take one dose. I mean I'd love to take one dose only to Phase III. It's cheaper and faster. Yes, I think -- and then obviously, you also learn about the profile of the drug, which are the endpoints that the drug might be doing better than others and how you use them in your hierarchy for Phase III. But these are all kind of technical things that we'll solve along the way. I think the biggest -- obviously, it's the efficacy and safety and then the dose selection for Phase III.

Okay. And then maybe just lastly on BroADen-2, the efficacy measures potentially being kind of in that ballpark of Dupi. We get the question, like which endpoints matter? The biomarkers still matter in this readout as much as maybe EASI and vIGA? Like how are you thinking about kind of the hierarchy of endpoints there?

Yes. I mean I think if -- in these type of studies, biomarkers are helpful to tell the story, but I don't think they're going to be the story, right? I think this is about impact we'll have on patients. So we -- I think the endpoints in this day and age for atopic derm are the ones that are used for registration. So EASI-75, IGA 0/1. Obviously, our primary endpoint is still percent reduction in EASI. So we will definitely look at that. But I would say on itch for us, I mean, I think not for us, but patients tell us that itch is the most important -- has the most important influence on their quality of life, at least for most of them. So that's going to be an important also endpoint that we want to disclose in the top line.

Okay. Great. And maybe just thinking about other type 2 indications beyond atopic derm, right? Clearly, BroADen-2 can inform dosing for other dermatologic indications. But how much do the data for BroADen-2 derisk other type 2 indications? Is there a readthrough from BroADen-2 to your Phase IIb BREADTH study or other indications here?

Thanks. I think -- so the question is how much they derisk. I think the level of derisking is profound. I think given what we know -- given where the target sits in the pathway and what we know about the pathway assets that drug the pathway, indications in which they work and the doses required for optimal benefit risk in those indications, we can learn a ton from the first readout.

If you think about type 2 inflammation in maybe three disease area categories, derm, GI and rep, obviously, we're conducting robust Phase IIb studies in derm and atopic dermatitis and rest in moderate to severe asthma. Strategically, the way we're thinking about it at the minute is that the first readout would potentially ungate and unlock perhaps obviously, atopic dermatitis and potentially other dermatology indications, and Nello named some of those in his opening remarks.

But also, we think we'd learn enough to make intelligent decisions around the design of a registration program in the key GI indication, which would be eosinophilic esophagitis. Now -- at that point, obviously, we could make a lot of intelligent guesses about probability of success and dose in the respiratory indications, too. But we'll have a readout coming from our Phase IIb moderate to severe asthma study during 2027. So you can imagine that, that would be an ungating event that all being well, would unleash the suite of respiratory indications and Nello named some of those too.

Okay. Great. And I want to make sure we touch on KT-579, your oral IRF5 degrader. We're going to get some Phase I healthy data in the fourth quarter, so -- which I think will inform a lupus study after that. So can we maybe just talk about the opportunities in lupus and beyond for this asset?

Yes. I want to go back. I know we have limited time, but -- so why are we're working on IRF5. Again, another key node that has not been drugged, another really difficult -- really difficult to drug transcription factor. The pathway that influences are pathways that have been extensively validated in diseases like type 1 interferon, like myeloid-derived inflammatory cytokines like IL-23, 12, TNF and B-cells and all the impact that B-cell produce autoantibodies have.

So it's a very powerful mechanism, but what it has that is unique is that it's really only powerful when the pathway has been activated. So it's a very disease -- it's a disease-specific pathway activation. And how do we know that? Because we know that people with this target mutation or activation develop diseases like lupus, like IBD, like RA, like Sjogren's. So it's actually a very unique target if you look at the landscape of other targets in immunology.

We have prioritized lupus as the first patient indication given the strength of both genetics and preclinical data and the relevance of the biology. But we're well underway to potentially and hopefully add at least one other indication to execute somewhat in a parallel staggered fashion because obviously, in this day and age, time is of essence and the sequential paradigm is one of the past for any drug, especially small molecule drug. So more to be shared on this.

I think a couple of other things I want to add. So the data set on IRF5, 579 will be disclosed before the BroADen-2 data. So we'll have IRF5 data and then BroADen-2, again, all of them now, I think we're in Q4 or soon. So it will be in Q4 for both of them. And then again, I think what we want to see from the 579 data is the ability to safely degrade IRF5 and through some really sophisticated assays that the teams have built to measure and all this biology that I talked about, demonstrate that the biology replicate in humans.

Right. Okay. Excellent. In the last minute or so, we wanted to just tick off a few questions that we're asking all the management teams at the conference. Specifically on China's rise in biotech innovation, how are you thinking about whether it's competition or potential for business development in terms of Chinese biotech?

I think it's both, obviously. I think competition is good for patients, and we're all trying to improve human health. I'm a big believer that competition is there if the playing field is level. So maybe I might have some questions about that, but maybe we don't have time to get into it.

At the same time, yes, we're a growing company that has big ambitions. We are looking at developing the next generation of therapies for patients, including combination. So yes, is it possible that we could look at some assets in China? I think our bar is very high and not many companies -- it's hard to obviously meet that bar depending on the work that people do. But I guess the short answer is both.

Okay. And impacts of AI on your business, whether it's helping or...

I think it's tremendous. I mean I would like Kymera to be a completely AI-powered company. And I know it sounds kind of silly to say, but it's actually the impact -- the profound impact that -- and the efficiency that you can bring. And this is not all the hype stuff. I remove all of that out, but actually true impact on operating the company on efficiencies, on the right patients, on the right processes is like there are -- there is so much to gain from using it in the proper way that -- it is a train that we cannot miss, and we have to jump and actually drive and lead if we want to be a successful company in the next decade.

Okay. Excellent. And then lastly, just on the regulatory side, impacts from whether it's FDA, how you're thinking about pricing given MFN, tariffs, anything on the regulatory side we should be thinking about?

Well, I mean, that's a lot. So I think the only thing I'm going to say is that we've had great relationship with the regulatory agencies. We are a data-driven science-first company. We're a transparent company, and that has so far helped us to have really productive interactions. With regards to MFN pricing, we are actually deep in that work, but not ready to talk about it yet.

Okay. Excellent. All right. Well, thank you very much for being here. We appreciate it.

Thank you.

Thank you.

Back-to-school conference. So we're thrilled today to have Kymera Therapeutics. We have CEO, Nello Mainolfi, and we have Bruce Jacobs, CFO. So guys, welcome. Good to see you.

Yes. Thanks for having us. Back to school.

Yes, exactly. So give us -- for those that may not be as familiar with the story, just give us kind of the 2 minute. I know you're kind of long-winded, so we'll try to pause you there.

Okay. Good. Starting with Geoff. All right. So the long story is we started Kymera 10 years ago, so I'm going to go year by year now. And -- and the idea was high level, really simple. There is tons of targets that have not been drugged. There is tons of genetics information we have, but we have lacked the technology to go after these targets effectively, selectively and potently. And we thought that targeted protein degradation, which is a small molecule modality that can remove disease-causing protein was going to be that unlocking technology. And so we spent the past 10 years, we put actually, I think, by now, 7 molecules in the clinic. And we've shown that you can degrade specifically, potently, selectively and with patient impact, proteins that have historically been undrugged.

In the past, let's say, 5, 6 years, we have decided to focus almost completely in immunology for a couple of simple reasons. One of the biggest markets lots of -- dominated by biologics, tons of opportunities to change the treatment paradigm and impact millions of people around the world. And so we've developed, I think, one of the most exciting immunology pipeline in the industry with STAT6, which is obviously downstream of IL-4 receptor alpha. And we believe one of the most exciting drugs, if not the most exciting drug for type 2 inflammation, which is tens of millions of patients. We have an IRF5 program, which is targeting this incredible axis where several pathways signal through B-cell, type 1 interferon and downstream and other inflammatory cytokines. We have other programs that we haven't disclosed, and we have partnership with Sanofi and Gilead. So this is a big year. We have big readouts for both IRF5 and for STAT6. So I'll pause here, and we can go from there.

Well, let's talk about the -- so the data for STAT6 by the end of the year. Help frame kind of what -- how you think about this? I mean, obviously, the -- most people are thinking about this from a Dupixent context or from other standards of care. But at this point, though, is there -- does oral convenience sort of outweigh the is that -- obviously, you want efficacy, right? But does the oral anchor the differentiation piece or maybe help us with the profile?

Yes. So great question. So taking a step back, so there are 9 indications in which DUPIXENT has been approved. And if you look at worldwide, we're talking about more than 100 million patients. And so when you think about actually STAT6 and KT-621, we need to remember, this is one of the few mechanisms. The other one is IL-4 receptor alpha, which is DUPIXENT that has potential to address several comorbidities of patients with type 2 inflammation. And many patients, even north of 50%, in some cases, have comorbidities. So I will start there, just an important description of the opportunity.

Then if we just take one of those indications, let's say, AD, atopic dermatitis, let's -- if we do the math. So in the U.S., there is about -- depending on the literature you use, between 6 million and 9 million patients, actually 6.5 million and 9.5 million patients with moderate to severe AD, 12 million and up. So let's use 7 million as the number. There's only been about 400,000 patients that have been dosed with an advanced systemic therapy, and this is dupi, lebri, Rinvoq and others. So roughly about 5% penetration in the moderate to severe atopic dermatitis patients. So why such a small penetration? Because most patients -- and this is work that we've done. So this is not me speaking. This is market analysis that we've done. I'm still speaking, but it's coming from others.

Why such a small penetration? Because most patients and most prescribers feel that are not severe enough to be on an injectable biologic or on a drug that has black box warning. So what are they looking for? Safe, effective oral drug. It actually goes exactly to your question. Safe, effective oral will transform this space. It's not about dupi-like or not. It's about safety, efficacy. And we have millions of patients that are untreated or poorly treated with messy topical. So this is going to be -- has the potential to be the first-in-line drug for millions of patients that right now are undertreated or untreated.

And if you look at -- sorry, other comps, I'll actually get to your question eventually. If you look at other comps in the space, look at psoriasis, Icotyde, great launch. psoriasis, much more mature market, still one of the best launches in the space. Why? Because it's a safe and effective oral, not because it's actually the same efficacy of biologics, it hasn't. So if you ask me, though, scientifically, where do you expect KT-621 to land in terms of impact on signs and symptoms of AD, I will say that we will likely be in the dupilumab ballpark because that's what we've shown for the past 5 years. But I will say we don't need to, to have a successful drug.

Right. Yes. And let me just follow up on that. If you think about getting into maybe healthier, slightly less severe patients, what would you anticipate maybe a duration of therapy for a safe, effective oral to be? I mean, would it be 2x, 3x what we see with dupi? And the second part of that is that are there lessons to be learned for the patients that maybe dupi stops working? Or are they -- is it tolerability or whatever that you have a stoppage of therapy that you could -- that mechanistically maybe use TPD, use the mechanism a little bit more broadly?

Yes. So I mean, it's a lot in there. So let me start with the second one. So we know that people stop injecting themselves with DUPIXENT. That's a fact. I think that happens sometimes because you lose insurance coverage, and we've seen patients on our study that come on to our study because the insurance doesn't cover DUPIXENT anymore. People stop DUPIXENT because they don't want to inject themselves anymore. And then I think some people, although I actually don't know the exact number, might lose the level of efficacy that they were seeing early on. So what we allow in our clinical trials are the patients that have stopped taking DUPIXENT, not because they have stopped responding, but for other reasons. So we have nonrefractory patients on our study.

And it's important to have them because we believe it gives people also data to believe that they can stop those type of drug and come on to our drug. With regards to dupilumab refractory patients, I don't think it's well understood what the biology is. We know -- I believe there was a study that was run, I believe, by Eli Lilly with lebri that showed that 50% of refractory patients with dupilumab showed activity with lebri. So there's clearly maybe some level of biology that is maybe irrespective of the pathway and then there is some that is probably has to do with the pathway. But I wouldn't say that for a drug like ours, this is a first-line drug in the broader moderate to severe population, that's not really the problem we're trying to solve. We're trying to expand access to many more patients that right now are not on biologics.

Maybe talk about the BROADEN trial. How should investors kind of compare the BROADEN2 kind of population versus prior DUPIXENT kind of studies in terms of baseline and prior treatment population, just to see like what differences are this trial that could kind of determine the results for BROADEN2?

Yes. So one thing to remember, if you look at dupilumab trials from 10 years ago or so, that was actually the first systemic drug that was -- or the first targeted systemic drug that was developed in atopic dermatitis. So obviously, all naive patients with generally higher severity. In fact, the mean at baseline in those studies were high 20s, early low 30s. If you look at atopic dermatitis studies in the past few years, you see the mean EASI at baseline, it's more often than not in the mid-20s. And that's a natural evolution of the patient population. We go to all these clinical sites where patients have access to advanced systemic therapy, so the more severe patients are on advanced systemic therapies. That these are still moderate to severe patients. They're just generally milder.

So I think there is a school of thought that would say if you have less severe patients, actually your probability of showing a reduction of EASI is lower because you start from a lower base. I'm personally not a believer in that. I think that's an extremely weak argument. I think if you have a strong drug, you should work in severe patients and less severe patients. And we've shown it in the Phase Ib, although very small N, regardless of the severity, we saw the same EASI reduction. With regards to others, I mean, it's always to naive versus non-naive patients.

As I just said, we allow -- we allow respond -- biologics-experienced that were responders on our study. And so obviously, there is a population that was not studied back then in those days. But otherwise, I think moderate to severe patients, we should be able to assess in a robust manner, the safety and the activity of the drug. And again, I'm trying to stress that the focus should be less about how it compares to other drugs, but more on is it a safe and effective oral that can be the first in line, the post-topical drug in atopic dermatitis today because there are no drugs like this even in development.

You mentioned safety. One of the kind of safety issues with DUPIXENT is conjunctivitis. Maybe talk about high level, what kind of expectations you could have for this oral drug in terms of range of conjunctivitis you could expect? And what's the commercially kind of viable option in terms of the rates you could get for conjunctivitis?

Yes. So I think historically, what we've learned is that drugs that hit this pathway, whether they're actually IL-4 receptor alpha, which blocks IL-4 and 13, or IL-13 only, patients in atopic dermatitis studies and not in other indications, they develop -- there is an imbalance between placebo and treatment arm on conjunctivitis. I believe this is my personal view, that these rates of conjunctivitis have been generally consistent across studies. While the numbers may appear different, I think just the way that now conjunctivitis is diagnosed in these studies is probably higher than it used to be back in the dupilumab studies where it wasn't yet an AE of interest. So I will just say that I've said this for years now.

So it's hard for me to know actually, even if there -- if I look at all these studies, whether there is a dose response, the concentration response to conjunctivitis, it's not clear to me. So I'm naively thinking that I think it's kind of all the same. So now if you bring a new mechanism on the table, STAT6 degradation, same pathway, what do you expect? So in the Phase Ib, we did not see any cases. It was 22 patients for 28 days. Usually in 28 days, the rates are very low in the 4%, 5%. So it should have been one patient. So have we seen it, not seen it, it's not conclusive.

Generally, I said this again for a long time. I expect to see it because every drug in this pathway have seen this imbalance, but we'll see. I think the data will tell us. With regards to the impact on different rates, I guess it depends on what they are. I haven't had conjunctivitis, so I can't speak for patients. From what I've heard from dermatologists, it's not a reason for starting and stopping treatment of DUPIXENT. So I don't expect this to be a big data set in terms of impact of any potential conjunctivitis or adoption of these drugs. But I guess we'll see, again, for STAT6 what we see and then we'll go from there.

Now, give us the range of what you're thinking for Phase III as you look to the -- at least the AD kind of study. Is there a potential for maybe an interim trigger on that just to get to call it early? Is it multiple doses? Do you feel comfortable in just using one? I know obviously, it depends on the Phase II.

Yes. Yes. The Phase II, obviously, one of the goals -- so we had 2 equally important goals of this Phase IIb study. One was to establish safety and efficacy in a global population in a placebo-controlled, randomized manner and at the same time, selecting a Phase III dose. So ideally, I mean, I think it's not surprising if I say that ideally, we would like to take one dose to Phase III because it's easier, cheaper and faster. But many drugs actually in these pathways have taken more than one dose in Phase III and Regeneron and Sanofi did the same because they wanted to make sure that they would select the right commercial dose. So we'll see.

I think we're trying to figure out how we get this drug to market as quickly as possible, again, assuming success in the Phase II because patients want this -- a drug with this profile. And so we're thinking about creative ways to get to market as quickly as possible. That includes how we design same Phase III, how do we get to the right safety database to enable an NDA. And obviously, we have and we will continue to have regulatory interactions to ensure that we're holding hands in this process. It's too early for me to comment on specifics, but that's one of the -- obviously, the goal is to get to market as quickly as possible. Even if it's a month quicker, we'll do everything that we can to do that.

So atopic derm, then asthma, obviously, data dependent. For the range of other indications, is there a path to run sort of a basket? Do you have to do a formal Phase II? Can you go right to Phase III? I'm just trying to think of ways to kind of -- because there's tons of indications that you obviously have.

So there are a ton of indications. In reality, 4 or 5 indications are 90% plus of revenues of DUPIXENT. So there is a component of impacting patients, creating values and then there is a component of going as broadly as possible. So if we think about 4 or 5 indications, our goal now that has to be vetted with regulatory agencies is not to run any more Phase II studies and go directly into Phase III across these indications that we will disclose as we go into them. And we believe that the AD and asthma dose rangers will allow us to inform Phase III dose selection beyond those 2 indications.

Is there -- maybe if you tie it to the mechanism, is there would you need different -- are some of these diseases more severe? In other words, would you need a higher dose for, say, PN or for EoE or something like that? Yes, I'm trying to think of like linking that to the kind of STAT6.

This is a dangerous question because this could be a long-winded answer, just so you know. Because this is a great scientific question. So first, what we learned from dupilumab is actually they have approved the same once every 2-week dose in all indications besides EoE, where they're actually going every week and the every 2-week actually did not work. And so maybe starting there, why? I don't think it's ever been understood. Our hypothesis is that DUPIXENT is more sensitive to the local concentration of IL-4 and 13. We don't believe and we have data to show that our mechanism is not sensitive to local expression of IL-4 and 13.

So we might not actually see a dose discrepancy across indications. But what actually we will be able to see that other technologies cannot do is looking at systemic and when possible, local degradation of STAT6 and then what that correlates in terms of efficacy. So dose-ranging studies will be critical to establish that relationship. Once that relationship has been established, I think we can go confidently into these Phase III studies without repeating. So the ability to have this direct PD effect, we believe, gives us an opportunity to be a bit more aggressive with the late development design.

But you'd say atopic derm is pretty similar to asthma and COPD in terms of dose...

So the reason why we're doing dose ranging in AD and in asthma is because getting into the skin and getting into the lung is different. And we want to make sure that you really need the same dose and the same degradation profile. So I would say the AD is different from asthma and AD is different from COPD. Now maybe asthma is closer to COPD. So you can use asthma for COPD. I wouldn't use AD for COPD, for example.

In the Phase Ib data, you had AD patients, but you also had asthma data along with it. Is there a chance that we could see similar data in Phase II or the patient population is completely different.

No. No, yes. I think a large percentage of patients with AD will have comorbid asthma, will have comorbid allergic rhinitis. We had 4 patients that had comorbid asthma out of 22. That's about 20%, which is in the range of what's seen in the general population. It's actually usually a bit higher. I think it's 30%, I might be wrong. So we definitely will have comorbidity. And again, I say it again, the comorbidity story for this program is critical. So we will assess comorbidities. What we cannot do is do deep assessment of comorbidities because dermatologists are not going to do FeNO measurements in a big global studies. But there are other measurements that we will collect. And again, assuming success, we'll disclose them in the right meetings.

And then Phase II enrolled really fast. I mean you were able to push forward the kind of readout like by quite a few months. Is there a possibility to do something similar in Phase III where you'd expect like faster enrollment, faster kind of process there versus other trials historically in AD?

Well, obviously, we've set an internal bar. The team knows that expectations for Phase III will be that we enroll fast. I'm not going to say how long it's going to take us. But we have used the information to project Phase III. And obviously, again, I think we assume that in the presence of positive data, Phase III should enroll even relatively faster because now we have placebo-controlled, randomized safety and efficacy data.

Let me ask, I know that the focus has been maybe to the more mild to moderate AD. But if you look at the moderate to severe end of things, is a dupi refractory patient the same as a SKYRIZI refractory? If you look at the different mechanisms, do you think that.

So just to be clear, we are still looking at moderate to severe patients. Mild are not part of the equation. Again, the refractory to DUPIXENT, it's still a piece of biology that is not well understood. I think there are many companies, including us, that are doing studies to understand what happens. I think there are hypotheses -- if you look at the literature and you look at transcriptomic data of patients that have been on DUPIXENT for 16 weeks or longer, you see some upregulations of other pathways like IL-17, IL-22, in some cases, IL-18. So there is, in some patients, some skewing from type 2, Th2 to Th1, Th17. Is that the solution? We don't know yet. I think there are studies that are other companies are doing. There are combinations that we're doing in research to understand and explore whether we capture broader and deeper efficacy with combinations. So I think that story is yet to be told completely.

It's just odd that in I&I, you see sequential therapies for the most part, you don't see tons of combinations upfront like you do in oncology.

I think it's just that immunology is behind. I don't think it's the science. It's just oncology because you're dealing with patients dying, I think there has been obviously more energy to try combinations in immunology, not mostly -- in most cases, you're not dealing with it. So there is more sensitivity to the safety. But obviously, it's happening. There's tons of bispecifics and trispecifics. Some of those will answer some of these questions.

Just last one on -- maybe for AD, -- is there a read-through from this trial enrollment to asthma, you could expect that faster enrollment, faster process that we could kind of see a similar result with asthma, like being...

So I would say the reasons for the fast enrollment of AD has been patients, as I mentioned earlier, are really excited about an oral therapy. Investigators are excited about this pathway. They understand this pathway. We had exciting Phase I data. In asthma, we have the same thing. We have excited patients, excited investigators and interesting, exciting Phase I data. The difference is in AD, we are enrolling into the broader population. In asthma, we're selecting for the high type 2 patients, and we have some pretty stringent inclusion/exclusion criteria.

So actually, the funnel at the top is pretty -- if you look across studies, obviously, I'm not going to share the numbers. But actually, the rate of patients that are coming on to our studies between AD and asthma are quite similar at the funnel, the inclusion/exclusion criteria and the patients that drop off because of them is much higher in asthma versus AD. So we'll probably still enroll fast, but not as fast as AD.

Okay. All right. So 579. So HV data end of the year, maybe just give us some context for that.

Yes. So we'll have IRF5, 579 data, and then we will have BROADEN2 data. So we just put this out there for everybody to know. So do your homework on IRF5 first. So why are we excited about this target? As I tried to do earlier quickly, there are very, very few programs in immunology where you both have human genetics data and biological clinical validation. So the genetic says, if you have IRA5 activation, let's say, you're likely to develop lupus, RA, Sjogren's or IBD.

Also, once we learn the biology, what is the biology of IRF5? If you block IRF5 and the pathway is activated, you see blockade of type 1 interferon validated in lupus. You see blockade of inflammatory cytokines, TNF, IL-23, again, validated in IBD or you see blockade of B-cell autoantibody production validated in lupus and many other diseases. So you have the genetics kind of being the beacon and then you have the validated biology that confirms the genetics. So it's a very unique target. So what we want to show what we'd like to see in healthy volunteers, we can safely degrade IRF5 and that these 3 biological axes that we block in these preclinical models, can they be [ fed ] in humans in these assays that we're going to use. And we expect between 50% and 80% reduction of these different cytokines and transcripts based on the biology.

So similar to 621, just looking for target engagement and the effect.

Yes. Okay.

Yes. Okay. Given, I guess, the mechanism, the downstream mechanism of like a broader immune engagement for this, is that -- do you think that speaks to the difficulties of some of these diseases like lupus, Sjogren's, these are not -- have been a bit of a graveyard of development. Would you say IRF5 would be a more severe type of modality?

No, it's right. I mean, obviously, there have been challenging areas driven by heterogeneity of patient population, sometimes challenging in measuring endpoint, high placebo rate. But in reality, there are mechanisms that have been really powerful, B-cell mechanism has been really powerful. TLR7/8, which again signals through IRF5, have shown positive proof of concept, type 1 interferon drug from AstraZeneca, Saphnelo activity in lupus. So I think it's about the mechanism that capture the heterogeneity. So we have a mechanism that captures many of these proven mechanisms. So we expect that the power of IRF5 to, again, affect many of these proven mechanisms should be able to reduce the noise and increase the effect size in these patients. So we're actually quite bullish about the study, understanding and being humbled by failures that have happened as recently also as a few days ago.

Just multi-organ systems make it a lot more difficult, particularly for Sjogren's.

Yes. Yes.

For IRF5, I know you mentioned that you're going to present the biomarker data and you're going to pursue lupus as one of the indications. Maybe talk about like which kind of biomarkers, cytokine levels are more translatable to the lupus kind of studies. Are there any markers specifically that could help us determine kind of success rate in indication?

I mean I think if we're able to show that we can block type 1 interferon in these assays, if we're able to see that we can affect B cell production of autoantibodies, I think that should give us the confidence that this mechanism should translate into lupus. If we show impact on TNF, IL-23, should give us the confidence we can go into IBD. So that's how we're thinking about. Again, it's not only -- if we were just some ex vivo human volunteer assay, I don't think that's enough data, but it's obviously, the totality of this data with the genetics, with the preclinical data and this confirmatory data that gives us the confidence that we should move into the patient populations.

And is there anything that you could see in the data that would make you -- that would convince you to like pursue both lupus and IBD like simultaneously, like at certain point?

Yes. As I said, as long as we demonstrate the activity that we're looking for, again, I can't speak to timing of it. But yes, I don't think we're interested in sequential development. I think that thing of the past at this point.

And just along those lines, too, I mean, these are a lot of these are unmet needs, right? So I mean, a basket would make sense here as well. But there's less understood about the biology and it's a broader deployment, right, of the mechanism.

Yes. Obviously, Geoff loves basket trials. You said it already now.

Correct.

No, no, it's good. I mean, I think that they are interesting when you have like small population that are tied by similar biology. I think the concern we have with that, and I'm not saying it's not a good idea, is the signal to noise in these diseases is so small that we -- like we need to really think through how we make sure we have the right bar to hit across these diseases and whether it's easier to do individually versus together.

Are you comfortable with where FDA is on some of these like accepted endpoints? And because it's been a challenge, right? I mean there are just -- there's been so many failures.

Yes. And I think the regulatory environment is evolving, right? I think we're trying to use other composite endpoints, especially in CLE, right, we have seen recently with CLASI. Now I think there is innovation happening there where we can look more than the traditional endpoints, which have been difficult to hit for all sorts of reasons because these are complicated diseases with different biology. So I guess we'll see how things evolve.

And -- are there any learnings that you could carry forward from your KT-621 like healthy volunteer study to like Phase I, how you connect the AD study for this IRF5 program? Just trying to get like a high-level thought on like what you could take forward from that study into...

Yes. I mean I think high level, the strategy that we're trying to adopt for IRF5 is actually quite similar, healthy volunteer to confirm the molecule does what it's supposed to do, a smallish biomarker study to confirm that the biology is doing what it's supposed to do in patients and then a dose-ranging study to fully demonstrate that the molecule and the biology leads to the efficacy that you need. So in a way, we're trying to follow the same path, but obviously, different diseases and different endpoints.

Let's talk, I guess, more broadly about the kind of the discovery effort. The goals you guys have had as one new target on an annual basis. So how much of the effort really is in the preclinical discovery effort? Are there targets that are mechanistically and could be clinically distinct from what you have, but related to the same TPD?

Yes. I mean we have 100-plus people in our research group. So we're definitely putting a lot of effort into building -- continuing to build the pipeline. I mean, as you know, we -- our ambition is to become an independent commercial company -- and the only way that you can justify being a commercial company is if you have a real engine of innovation that continues to fill the clinical pipeline that you can use your commercial team synergies to commercialize. Otherwise, we're just reinventing the wheel here. And so we have tons of biology that we're investigating. Some is, as I mentioned earlier, what is the right potential down the road combo opportunities to broaden and deepen our responses in many areas we already are in and some are completely complementary areas that we're going with degrader technologies and beyond degrader technologies.

As you know, we are an oral immunology company and not defined by one modality. And as we continue to grow, obviously, we tap into what we believe our strengths are to deliver innovative medicines.

Is there a strategy to -- I know you guys have moved away from oncology, but there's a strategy to leverage the knowledge base at Kymera to maybe have others or out-license or -- I know you have the Gilead partnership, right?

Yes. Yes. No, it's a great question. I mean, yes, the technology is disease agnostic. And I am committed that once we demonstrate to all of you that we can do end-to-end in a disease area, let's say, immunology now, we can launch 621, then we earn the right to do more. Right now, I think it's distracting to play the game that we can do everything. I think that's how companies can do bad things. So we're preparing for what that other diseases could be. In the meanwhile, yes, we've -- when we have -- our creative scientists have unique insights sometimes. And if they're not right on strategy, then partnering could be an opportunity to maximize that value. That's what happened with CDK2. And I would say we have other programs that might lend themselves to that type of strategy, but it's not our focus.

Okay. Awesome. Guys, we're out of time. Thank you very much.

Thank you.

Good day, everyone. My name is Michelle, and I will be your conference operator today. At this time, I would like to welcome you to the Kymera Therapeutics Second Quarter 2026 Results Call. [Operator Instructions]

At this time, I would like to turn the call over to Justine Koenigsberg, Vice President, Investor Relations. Justin, please go ahead.

Good morning, and welcome to Kymera Therapeutics Quarterly Update Conference Call. Joining me today with prepared remarks are Nello Mainolfi, our Founder, President and CEO; and Bruce Jacobs, our Chief Financial Officer. We'll also have brief comments from Jared Gollob and Terence Rooney, our new Chief Medical Officer, who will also join us for Q&A.

Following our prepared remarks, we will open the call for questions from our covering analysts. To ensure we have time to hear from everyone, we will limit each analyst to question. Before we begin, I would like to remind you that today's discussion will include forward-looking statements subject to risks and uncertainties described in our most recent Form 10-Q filed with the SEC. Please note that any forward-looking statements speak only as of today's date, and we undertake no obligation to update them.

With that, I will now turn the call over to Nello.

Thank you, Justine, and good morning, everyone. Before we dive into the quarterly update, as we announced last week, I'd like to take a moment to recognize Jared as he prepares to retire and thank him for his many contributions over the past 8 years. Jared has been instrumental in helping build Kymera and has made a meaningful impact across virtually every aspect of the company. His leadership, dedication and partnership have helped shape where we are today, and we're incredibly grateful for everything he's done.

While we certainly miss him, he leaves the organization in a position of great strength. With Terence stepping into the role, I'm confident that we'll have a seamless transition and continue to build on the strong foundation Jared has helped create. You'll hear from Terence later in the call, but I'm very excited to have him join the team and believe that his long and deep experience across all phases of immunology development and commercialization, along with his insights and capabilities will be critical to helping advance our next phase of growth. On behalf of everybody at Kymera, thank you, Jared. We wish him nothing but the very best in this well-deserved next chapter.

Before we get started, we wanted to give him the opportunity to share a few words. Jared?

Thank you, Nello. While it's truly bittersweet to say goodbye, I have made the decision to retire after having spent 20 years in academic medicine, followed by 20 years in industry, including the last 8 years at Kymera. This is obviously an exciting time for Kymera, and I cannot be prouder not only of all that we have accomplished, but also of all that the company will accomplish in the future. I am happy to note that I'll be staying on as an adviser through year-end to help with the transition as needed.

But I'm ultimately excited for this next chapter and for the opportunity to spend more time with my family. But before I go, I want to say a heartfelt thank you to all of you. It has been an incredible privilege to be part of this organization and to work alongside such talented, dedicated and inspiring people. I have also enjoyed all the interactions I have had with all of the investors and analysts on the call today, which I will miss as well. Looking back, I'm filled with gratitude for everything we've accomplished. I have tremendous confidence in the future of Kymera and can't wait to see all that's still to come. It's been an absolute honor to be part of this journey. Thank you.

Thanks, Jared. Now with that, let's turn to our quarterly update. We entered today's call with strong momentum across the business, driven by progress in our lead programs, advancement of our broader pipeline and continued execution against our long-term strategy. At Kymera, our ambition is not only just to develop new medicines, but to redefine what is possible for patients by changing treatment paradigms. We believe we have the ability by leveraging not only targeted protein degradation, but also our broad small molecule capabilities to fundamentally reshape how diseases are treated. Our focus remains firmly on translating the science into transformative oral medicines that can create meaningful impact for patients.

Reflecting on our recent accomplishments, last quarter's highlights was undoubtedly the announcement that we completed enrollment in our Phase 2b AD trial, approximately 6 months ahead of schedule. As a result, we now expect to report top line data by year-end 2026 and to initiate Phase III development around mid-2027, both approximately 6 months earlier than previously planned. We view this rapid enrollment as a reflection of many factors, including the compelling preclinical and Phase 1b AD data generated to date.

Our appreciation and confidence from investigators and KOLs in a well-understood pathway, the incredible excitement from investigators and patients for the opportunity of a once-a-day oral therapy, as we have seen in other areas, outstanding execution by our clinical trial operations and medical teams. We completed this trial well ahead of expectations, as I mentioned earlier. I would add that we did that while maintaining our strict focus on quality, which included many measures that we put in place, some of which could be perceived as burdensome to patients and sites. And this approach remains consistent throughout enrollment.

In addition to the momentum around our STAT6 program, we continue to demonstrate that our platform can repeatedly generate differentiated investigational medicines against high-value targets, reinforcing our strategy of building a robust pipeline capable of driving high-impact patients and in doing so, delivering long-term value. Our second wholly owned program is also progressing in the clinic with the ongoing Phase I study of KT-579, our oral IRF5 degrader. We believe IRF5 represents a highly compelling target in immune -- in autoimmune diseases with the potential to address multiple high-value indications.

We expect to report Phase I healthy volunteer results in the fourth quarter of 2026 and to advance the program into its first proof-of-concept study in lupus patients soon thereafter. In addition, KT-485, our second-generation IRAK4 degrader partnered with Sanofi, recently entered Phase I development, resulting in a $20 million milestone payment to Kymera. The Phase I is designed to evaluate KT-485 in both healthy volunteers and patients with hidradenitis suppurativa, and we look forward to its advancement under Sanofi's leadership.

And last but not the least, we look forward to providing updates as our CDK2 molecular glue KT-200, partnered with Gilead, advanced towards an expected IND and clinical start next year. Taken together, our program -- our progress across all of these programs highlight both the power of our discovery and development capabilities and our ability to consistently translate into potentially transformative medicines for patients and meaningful value creation for shareholders.

Turning more specifically now to KT-621. As we prepare for the upcoming readout later this year, I wanted to quickly refresh you all on the details of the trial and then touch on how we view the opportunity for KT-621. As a reminder, the study is evaluating 3 doses of KT-621 compared to placebo. The primary endpoint is percent change from baseline in EASI score at week 16. Key secondary endpoints include EASI-50, EASI-75, vIGA-01 and pruritus NRS. When we report top line results later this year, these along with safety are among the key endpoints we expect to share.

As we think about the upcoming clinical readouts, our overarching goal is very clear. We are developing KT-621 to deliver what we hear patients want, an active, safe oral therapy in diseases like AD, asthma, EoE, COPD and others that lack such an option. This is not only true in these type 2 indications, but also more broadly. There is an overwhelming demand for oral pills that can help manage debilitating chronic diseases. It comes down to clear preference among patients and physicians for treatments that are better suited to fit their lives.

With respect to the market opportunity, we made this point in the past, but it bears repeating. Market data tell us that there are a significant number of patients that are not well served with existing treatments. In fact, there are an estimated 43 million adults in the U.S., EU5 and Japan with atopic dermatitis and only a small percentage of patients, single digits really, with moderate to severe diseases are on advanced systemic therapies. There is no doubt that this represents a significant, if not unprecedented opportunity for KT-621.

If we are successful and can deliver an oral therapy that is both clinically efficacious and well tolerated, we have the potential to meaningfully expand the use of systemic treatment and dramatically change the existing treatment landscape. Finally, on the opportunity, I think it's important to highlight that KT-621 has the potential to become not only the first oral therapy with a favorable safety profile for individual type 2 inflammatory diseases such as atopic dermatitis and asthma, but also the first and only oral therapy capable of addressing the full spectrum of type 2 diseases and their associated comorbidities. This would represent a powerful tool for physicians and position KT-621 as a potential first and best option for all patients with type 2 diseases, given more than 50% of the population presents with additional type 2 comorbidities.

Now with most of my comments focused on the AD trial, we're similarly excited about the progress we're making in asthma. We continue to hear strong enthusiasm for the potential of an effective oral therapy in type 2 asthma based on our discussions with KOLs, including most recently at the ATS conference. Importantly, we hear consistently from KOLs that a well-tolerated oral therapy delivering clinically meaningful benefit could address a significant unmet need and expand treatment options for a broader population of moderate to severe patients. Enrollment is underway in the BREADTH Phase 2b trial, and we remain on track to report top line data by late 2027.

As we continue to advance KT-621 in the Phase 2b trial, we're also focused on generating the long-term data that will be important both for regulatory purposes and ultimately for commercialization. We're pleased to share that we've initiated an open-label extension asthma study, which will allow patients who complete the BREADTH study to continue receiving KT-621 for up to an additional 52 weeks. Taken together, we believe our development strategies across both AD and asthma positions us once these 2 studies are completed to fully explore the broad potential of KT-621 across our dermatology and respiratory diseases in later stage trials.

Now turning to KT-579, oral IRF5 degrader. We remain on track to report top line data from ongoing healthy volunteer study in the fourth quarter of 2026. As a reminder, IRF5 is a genetically validated driver of innate immunity dysfunction and inflammation and is implicated across multiple autoimmune diseases such as lupus and IBP. KT-579 seeks to control a challenge that has been elusive among traditional drug development approaches in this space.

By selectively degrading IRF5, KT-579 is designed to modulate multiple disease-driving pathways with a single mechanism and therefore, has the potential to be the first novel mechanism with broad utility in diseases where patients are desperately seeing more efficacious and well-tolerated oral therapies. The Phase I healthy volunteer study is designed to evaluate single and multiple ascending doses of KT-579 with the objective of achieving more than 90% IRF5 degradation in blood at doses with a favorable safety profile.

We will also assess PD activity using ex vivo stimulation assays to understand the impact of IRF5 degradation on key inflammatory pathway biomarkers upregulated by TLR 7, 8 and 9 agonists, including type 1 interferons, pro-inflammatory cytokines and inflammatory pathway gene transcripts. We have guided that is our expectation that we should see between a 50% and 80% reduction in these biomarkers across the 3 TLR pathways assessed if we are engaging IRF5 effectively, which would suggest the potential for IRF5 degradation translating into clinical activity in subsequent patient study with KT-579.

Looking ahead, we plan to advance KT-579 into a study in lupus patients soon after the healthy volunteer study is complete. Despite recent scientific advances, most lupus patients continue to cycle through therapies without achieving sustained disease control, underscoring the need for differentiated treatment approaches.

Before I wrap up my remarks, I'd like to briefly highlight a few additional leadership updates. We're pleased to announce that at our recent annual meeting, Felix Baker has assumed the role of Chairman, succeeding Bruce Booth. Felix has been a member of our Board since 2024, and we look forward to his continued leadership and partnership. We are also grateful for Bruce's many contributions since our founding, and we're pleased that he continues to serve on the Board as a Director.

We also recently welcomed Penny Carlson to lead our development operations and Liz Laws as global program lead for KT-621. Penny joined Kymera after a long and successful career leading global clinical development, most recently at Takeda. Liz joins us from Sanofi, where she was highly involved in the development of dupilumab. Both Penny and Liz bring extensive experience leading complex clinical development programs with direct relevance to Kymera. And their expertise will be invaluable as we advance our pipeline and continue building the capabilities needed to support a growing late-stage clinical portfolio.

And last but not at least, as mentioned earlier in the call and disclosed last week, I could not be more excited to introduce Terence as Kymera's new Chief Medical Officer. Terence joins Kymera with what can only be described as the ideal set of experiences, expertise and knowledge as we continue on this journey to transform the immunology market. He held senior leadership position at J&J, Eli Lilly, where he helped build and advance leading immunology franchises, including Icotyde, Stelara and TREMFYA. His extensive experience across clinical development and portfolio strategy is highly complementary to Kymera and will help guide the continued advancement of our pipeline.

I want to allow Terence to share a few thoughts with you, and we will also have him join the Q&A. Terence?

Thank you, Nello. I'm excited to be joining Kymera at such an important time in the company's evolution. With multiple programs advancing across the portfolio and significant opportunities ahead, it's a privilege to be part of the team as we enter this new chapter. By way of background, I've spent some 17 years in the biopharma industry, focused on the development of treatments for immune-mediated inflammatory disease.

Most recently, I served as the Head of Portfolio and Asset Management for Immunology at Johnson & Johnson, where I led strategy and asset development for a broad immunology portfolio. Prior to that, I've spent time throughout the pharma R&D value chain, including stints in early and late-stage clinical development, in business development and end-to-end R&D leadership. Before biopharma, I spent 12 years as a physician in academic clinical practice and research, specializing in rheumatology and internal medicine. So I've had the chance to work across academic medicine, translational research and global pharmaceutical R&D, all focused on advancing innovative therapies from concept through clinical development to approval and beyond.

What drew me to Kymera is the opportunity to help unlock the potential of targeted protein degradation to transform the treatment of disease. The science is highly compelling. The pipeline is strong, and I'm joining a great team that I'm convinced is well positioned to deliver meaningful innovation for patients. To wrap up then, I'll echo what Nello said earlier about KT-621. Kymera STAT6 program represents a truly transformational opportunity, not only for the company, but most importantly, of course, for human health. And I couldn't be more excited to be joining and to help Kymera fully realize the potential of this and our other assets.

Thank you, Terence. In conclusion, with KT-621 advancing through Phase 2b development and KT-579 expected to enter its first patient study shortly, we're sharply focused on building the team and capabilities needed to execute potentially more than 10 Phase III studies over the next 2 to 3 years. We have also begun building our commercial capabilities to deliver on our vision of becoming the global leader in innovative oral immunology medicines.

Importantly, we're doing all of this from a position of financial strength. With a robust balance sheet and cash runway extending into 2029, we're well capitalized to advance our pipeline. Looking back to the first half of the year, we've executed across our portfolio from accelerating the development of KT-621 to advancing KT-579 while also progressing our preclinical pipeline and partner programs. With multiple catalysts ahead, we remain enthusiastic about the opportunities in front of us and look forward to sharing additional data and updates in the months ahead.

With that, I will turn it over to Bruce to review the financial results before we open the call for questions. Bruce?

Thanks, Nello. As I walk through the second quarter results, please refer to the tables included in the press release, which was issued earlier this morning. Collaboration revenue for the second quarter of 2026 was $65 million, reflecting a $45 million option exercise fee related to the company's collaboration with Gilead Sciences and a $20 million milestone payment associated with Sanofi starting the Phase I study for KT-485. We have recognized all deferred revenue, so we do not expect additional revenue this year. Any future revenue will be tied to milestones achieved in either the Sanofi or Gilead collaborations in 2027 and/or beyond.

Turning quickly to operating expenses. R&D expenses for the quarter were $119.5 million, including approximately $10.4 million in noncash stock-based compensation. Excluding stock-based comp, adjusted cash R&D expense was $109.1 million, an increase of 22% compared to the first quarter of 2026, primarily reflecting continued investment across our advancing clinical portfolio. G&A expenses for the quarter were $21.1 million, including approximately $8.6 million in stock-based comp. Excluding stock-based compensation, adjusted cash G&A expense was $12.5 million, a decrease of 4% compared to the first quarter of 2026.

We ended June with cash, cash equivalents and investments of approximately $1.5 billion, providing runway into 2029 and positioning us to execute on a number of important value-driving milestones over the coming years. Our balance sheet supports the completion of the KT-621 Phase 2b trials in AD and asthma and the progression of KT-579 fully through our planned proof-of-concept study in lupus. Within our runway, we also expect to fund the beginning stages of the asthma Phase III study for KT-621 and most of the KT-621 Phase III study in AD.

At the same time, we will continue investing in our research pipeline and building the capabilities needed to support our transition into a later-stage development and commercial organization. Overall, we believe we are well positioned financially to execute on our strategic priorities while maintaining a disciplined approach to capital allocation.

With that, we'll pause briefly while we make our way to the conference room and assemble the question queue, at which point, we'll open the call for Q&A.

[Operator Instructions] Thank you. Our first question is from Thomas Smith from Leerink Partners.

Congrats on all the progress. And let me add my best wishes to Jared in his retirement. Given the really strong enrollment here in BROADEN-2, I just wanted to come back and ask if there's any color you could provide on sort of the baseline characteristics for these patients that were enrolled into the study. Anything that you can say relative to some of the other large contemporary Phase III biologic studies would be helpful. And then just thinking about the bar for success for BROADEN-2. I know you characterized this as clinically efficacious and well tolerated, but just wondering if you can provide a little bit more specifics with respect to the profile relative to [ Dupi ] and what some of the injectables have shown and what maybe some of your market research is pointing to in terms of a clinically meaningful profile.

Thanks, Tom. I love you had 2 questions in one. So let's start with the first one. So baseline characteristic. Obviously, one of our main goal of the study, and as I mentioned earlier, and we've done it in the past, was to actually prioritize quality of execution over speed. And in fact, our initial time lines were actually reflecting those expectations. We expected that some of the systems we have put in place would kind of direct the speed of execution towards those kind of expected time lines. And obviously, with that, we still saw a pretty fast enrollment, which, again, we can comment, as I commented earlier, driven, we believe, based on -- driven by the excitement around the program, the oral opportunity, the data that we generated, et cetera.

But going back to your first question, yes, the goal has been to ensure that we had the patient with the right severity on the study. As you know, when the first biologics in the space was developed, dupilumab at this point, I think Phase II was more than 10 years ago, there wasn't any approved systemic drug at that time for a broader population. So the severity of the baseline of those patients was probably higher than what we've seen in more recent studies.

I think, again, all the things that we put in place was to ensure that while we believe it's difficult, if not impossible, to replicate that type of severity at baseline that the patient in our study would follow at least what has been seen in the past few years. So I'm not going to comment on where we landed because I think it's unnecessary, but you'll see when we release the data. But we feel good about where we landed with the baseline characteristics right now.

On your second answer, the bar, I think there is maybe 2 ways to answer your question, and I'm sure this is a question from many others. So maybe I can be really good at answering it once. So the -- what we've learned, so when we started this program, obviously, we were very science focused, right? And we were showing for the first time ever that actually you can block STAT6 signaling through degradation of STAT6. And what we saw in our laboratories was basically a downstream blockade that mimic what we have seen with dupilumab.

And so our kind of narrative and science around this program has continued over the years to kind of continue to demonstrate the science behind STAT6 degradation and how effective it is how effective it is to block IL-4 and 13. So what we obviously learned along the way by interacting with the medical community, including patients, is the really strong need of an effective oral therapy. That's the feedback we've continued to hear. This is the feedback we've heard. I've been in every investigator meeting. I visited -- I've been in every medical meeting. I've talked to a lot of KOLs myself. And really, the main consistent feedback we've heard is the really, really important need of an effective oral drug. And that's what we want to deliver patients.

So we believe success, both clinically and commercially is to deliver what patients want, which is an effective, safe, well-tolerated oral option that right now doesn't exist. Not only it doesn't exist in AD, but actually does not exist across all these comorbidities. So that's, I think, maybe the North Star. Now when we go to the science of it, we've continued to see over the past 6-plus years that degrading STAT6 seems to be just as effective as blocking as I mentioned IL-4 and 13 as dupilumab.

And so the data has shown both preclinical and early clinical that we seem to be able to block the pathway and affect the downstream biomarker as well as initial clinical endpoint in a similar way as dupilumab. So our, let's say, data expectation is we will continue to be in this study to be in that ballpark of what dupilumab has shown at week 16 in the previous AD studies, understanding that, obviously, different studies, different populations.

Our next question is from Tazeen Ahmad from Bank of America.

I wanted to ask about 579. I think that's an exciting potential next big drug for you guys. I wanted to understand what you're hoping to learn from the healthy volunteer data that you're expected to show in the fourth quarter, especially since you've already picked lupus to move into Phase 1b there.

Yes. So thanks, Tazeen. So we're very excited about the IRF5. This is, again, we believe, unless we're mistaken, I don't think so. This is the first drug targeting IRF5 that has gone in the clinic. And so as we've done in the past, we feel the responsibility to actually demonstrate the power of this biology. So the underpinning excitement is around the human genetics that tell us that when you have this point mutation or activation of IRF5, you see many of these subjects develop diseases like lupus, RA, IBD, et cetera. But actually, I would say even more importantly, what we've shown, where is this biology coming from, right? And so what we've shown in preclinical species is that actually it comes from the fact that IRF5 is a central node for 3 key pathways. It's B-cell autoantibodies production, it's inflammatory cytokines like 12, 23 TNF, et cetera, and it's type 1 interferon.

And obviously, when this pathway is activated, and we believe in some of these diseases, it's extremely relevant, we see IRF5 being this master regulator of immunity. So in this Phase I healthy volunteer study, the kind of the necessary but not sufficient step is first to show that we can degrade IRF5 robustly, we're saying at least 90% or more and safely. And then I guess the next step will be to show that by blocking IRF5, we can modulate these 3 important key pathways. And we have -- the team has developed, we believe, some really good assays to actually measure all these pathways. And so we expect that while this is not a patient study, the fact that even in healthy volunteer, we can interrogate the relevance of these 3 pathways by blocking IRF5 signaling, I think, should give us the confidence to move into, as you say, lupus, but actually we're planning and discussing internally what other indications we could start as well in the relatively immediate future.

Our next question is from Andy Chen from Wolfe Research.

This is Jason taking for Andy. And I just wanted to ask if you guys have any plans around unveiling new degrader molecules maybe in the next year or 2? And how many molecules we should expect? And are they likely to continue to be in immunology indications or with like derisked mechanisms?

Yes. So obviously, we have a very productive research engine. And hopefully, this is also appreciated externally. We have a general goal/guidance of having at least one new molecule entering clinical development every year. And so we continue to be on track to have development candidates in 2026 that will be entering the clinic in 2027 and beyond. So for sure, we obviously want to be able to share more programs. Obviously, we have 2 important clinical readouts in the second half of the year in 4Q.

So we're figuring out whether the next clinical program to be disclosed will be either this year or early next, again, based on everything that we're doing, that decision still to be made. Likely, obviously will happen because we're on track with these programs, but we're still deciding exactly what the timing will be. And 80% of our effort preclinically is in immunology. So it's extremely likely, it's not almost 100% sure that at least the next program, next couple of programs will be immunology program with highly validated target without oral options.

Our next question is from David Dai from UBS.

So regarding the STAT6 degrader KT-621, given the high placebo response we're seeing in some of the AD studies, what assumptions were used around placebo response and effect size when powering for the BROADEN-2 Phase 2b study? And have the recent enrollment dynamics changed your confidence around those assumptions?

Yes. I mean -- thanks, David. That's a great question. We're not going to go into the details of your question, although it's a very good one. So we understand the STAT6 biology well. We powered the study within a range of expectation of what this biology can deliver clinically also with the Phase Ib data in hand. We obviously know that the placebo rates have increased and we've accounted for that. Obviously, there has been a couple of cases where at least one where we had some crazy high placebo rate in the 70s.

Obviously, no study can plan around such a high placebo rate. But otherwise, if you look at the recent studies that delivered, let's say, positive data in -- and we've seen many in the past few years actually. And we've seen increased placebo rates. Those have been accounted in the power of our study. The enrollment has not really changed. The speed of enrollment has not changed our assumptions. When you have a high enrolling study, you often end up enrolling slightly more than you plan just as the mechanics of the study will kind of force you to do. But we haven't done anything with regards to changing our power assumption.

Our next question is from Ellie Merle from Barclays.

Jasmine on for Ellie. Congratulations on all the progress. Can you give some more color on how enrollment is going in the Phase 2b asthma trial? So with the acceleration of the enrollment in AD, how should we think about whether we can see this in asthma as well? And what are, I guess, some of the different dynamics playing into the AD enrollment versus asthma that could attribute to why the time lines are shaping up to be different?

Thanks for the question. So I would say what is common between these 2 studies is the excitement around this mechanism. I think that, as I said earlier, one thing that might be appreciated or not is the fact that this pathway is really well understood by investigators all around the world, right? This is probably the most drug pathway in immunology, right? We have so many agents targeting IL-4, IL-13, both of them, et cetera. So I think that actually is a common theme of we understand the pathway. We as a team, I should say, have done, I think, an amazing job educating the public about our mechanisms and STAT6. So there is a level of confidence about where STAT6 fits in that pathway. And then you combine, let's say, the sense of, let's call it, comfort with our program and you combine it with, as I mentioned earlier, this really strong need of an oral option. I think what is common when we talk to both dermatology investigator and respiratory and allergist investigator, I think what's common is these kind of 2 aspects.

Now the 2 studies are quite different, right? For the AD study, obviously, there are more AD patients, let's start there. And also, we are enrolling all moderate to severe patients. For the asthma study, if you recall, we had some specific criteria with regards to FeNO and eosinophilia at baseline, which is looking at a subset of asthma patients. I like to call them, we call them type 2 patients. Some people call them eosinophilic asthma patients. Anyway, that's maybe for another day. And so that is a subset of the asthma population. So naturally, the denominator is smaller in this case. And because we have this, again, very specific entry criteria, generally, we would see a higher screen failure rate.

So while I think we have also in asthma an opportunity to move the program enrollment at a good fast speed, I don't think we can match what we've seen for atopic derm. But anyway, we are enrolling well. There's a lot of excitement. We're even in more regions than we were for the AD study. And so we're confident that we'll be able to deliver a fast but obviously, high-quality execution and within the time line that we set. In terms of changing time lines, as we've done for it, we're only going to do it if and when we complete or I should say, when we complete enrollment, but not before because these are highly variable parameters, and it's really difficult, high priority to start changing expectation time lines while you're [ in flight ] for these studies.

Our next question is from Brian Cheng from JP Morgan.

Just want to touch on the BROADEN2 OLE portion. Can you give us some color on the latest there? How is the rollover rate looking? And are patients allowed to dose adjust across the 3 doses in the OLE?

Yes. Thanks, Brian. Great question. So we're not going to comment on that. We might offer when we release the BROADEN2 data in the -- by the end of the year here in '26, we might maybe offer a bit of an insight on that. But right now, we feel it's too early to comment on how the percentage of patients rolling over into the OLE. So on the dose adjustment, I think we've said this publicly, patients are all going on to 1 dose. And I think I'll leave it at that for now.

Our next question is from Faisal Khurshid from Jefferies.

Congrats to Terence on joining a great team. I just wanted to ask your kind of latest and greatest thoughts on the competitive landscape. And I'm wondering both within the STAT6 class, like yesterday, we had Pfizer confirming that their STAT6 is active in Phase II and Nurix and Sanofi dosing their program. And then beyond that with bi and trispecific as well, we also heard some interesting comments on that yesterday as well. So yes, we would just love to hear your latest and greatest thoughts on that landscape.

Yes. So yes, I can share a few thoughts. So on the STAT6, I mean, as you know, this is a highly interesting targeted pursuit by I think probably at this point, majority of companies that are in immunology for all the reasons that we're all here today. So we -- our focus is obviously on execution and making sure that we execute with high quality and speed in order to maintain our -- the advantage that we've created in terms of time line. We know -- obviously, there is Pfizer in Phase II. We don't know much about their molecules. Obviously, there's been many flow of information from the study about starting and pausing enrollment and then restarting.

There are other pilot studies ongoing to study the molecule, the formulations and DDI studies. So really, obviously, Pfizer, from what I can see from macro where I sit is trying to understand more about this molecule, the performance and the behavior in humans. I think they're reporting to complete the study in early '28, which seems like a very long time. So again, I don't know what that means. I can only go by what's publicly disclosed. As you know, we don't believe small molecule inhibitors will be competitive with degraders, driven by our ability with the degrader to block the pathway completely at very low doses and low concentration over 24 hours, which we believe is needed to match this pathway blockade that you see with upstream agents.

Then yes, we've seen the Nurix, the Sanofi program starting. Again, I think we'll be in Phase III if everything goes well by the time some of this program might have some Phase I data. So we feel good about 621. I think so far, all I can say amazingly well-behaved molecule, well tolerated and we're focused really on ourselves, but being aware of the overall landscape. With regards to other mechanism, we're all -- we're really excited by our oral options. We're also excited about learning about new biology, right? I think the bispecific and trispecific is an opportunity for everybody to learn where some of these mechanisms can deliver enhanced activity in a still relatively heterogeneous population, which especially AD can be.

So we're obviously -- there was some early data from a small company recently with a bispecific. Obviously, Pfizer is going ahead with this trispecific doing a head-to-head study with Dupi, which makes sense. I mean our view is, again, as I said earlier, KT-621 position is, from our perspective, first-in-line drug for the millions of patients that have moderate to severe atopic derm that are not doing well with topical steroids, which is probably the majority of patients given how difficult it is actually to be responding well to topical steroids. It's not even how they work. It's just how complicated it is for patients to use them.

So if we think about 621 is the first-in-line drug, then I think many of these trial will probably be later lines once you don't respond to these, I think, single mechanism drug that address most patients, right, for in AD and other indications. So as we said also in the past, we're interested by novel mechanism. We're thinking about combination of STAT6 with other mechanisms. So we're obviously very curiously also observing these new mechanisms out there.

Our next question is from Brad Canino from Guggenheim.

Thanks to Jared for the collaboration over the past 5 years. I definitely learned a lot from our conversations. My question is about moving STAT6 to the late-stage development phase. How are you positioning the company to extend the benefit to pediatric AD patients? I know for Dupi, it took several years to expand the label from adults to different cohorts of pediatrics. Are you doing anything today with a goal to try to accelerate that?

Yes, Brad, thank you. So yes, we're heavily focused on how to accelerate pediatrics development. I mean the one thing that we've done, as you know, is incorporating adolescents in our study, right? We have 12 and up, which actually are pediatric patients. Now going younger in ages is obviously something we're not in full control of. This is a conversation with regulatory agencies. All I can tell you is that we're heavily focused on it, and we will update you all when we know more. For sure, we will know more after this Phase 2b data. You shouldn't expect any update between now and then.

Our next question is from Judah Frommer from Morgan Stanley.

Congrats to Terence and Jared as well on their moves. Just curious if you could help us with cash runway guidance remaining into 2029, given the acceleration in time lines for 621. Any changes to spend or trajectory over the next couple of years as you think about that?

Yes. No, thanks for the question, Judah. I think it's still intact. We had a runway into 2029. Even with the acceleration of timing, it's not enough to pull the runway in closer. So we're still into 2029 with that. So you can assume there has been a bit of cushion there as well. I think clearly, as we get to the end of the year and see the data and I guess, solidify all of our development plans, not only for the core indication, but some of the others that we're contemplating, we'll talk about whether there's an update warranted. But we're in good shape over kind of 10-plus quarters of cash even with the accelerated runway.

So we should be able to -- as we said in the past, we -- our runway will incorporate, obviously, all the Phase IIs that we're running -- the Phase II is running today, the full execution of the IRF program and then as well getting underway with both the Phase IIIs, and we should come pretty close to finishing the AD study within our runway if all goes well.

Our next question is from Geoffrey Meacham from Citi.

I just want to say congrats to Jared on the retirement and Terence, welcome to the team. So Nel, on 621, as you guys look to Phase III design in AD and asthma, I guess how important is the washout or prior therapy experience? I know there are multiple pathways that drive type 2 inflammation beyond STAT6, but are some sort of tilted pathways more heavily treated patients or maybe patients have gone for a longer duration or maybe those that have worse baseline. Just trying to think of like the entry criteria and kind of the probability of success as you look to a Phase III.

Yes. No, Geoff, that's a great question. It's actually a topic of discussion. I just want to separate the 2. So obviously, the washout is critical, right? No matter what the entry criteria are, how you parse out whether you're going to allow every previous biologic patients or not. Obviously, based on the half-life of the drug, you need to completely wash out patients to actually retain the integrity of the data of the study.

Then maybe the other question in your question was, do we allow a biologics experience patient in the study. And as you know, we've done that in our Phase 2b with a caveat of not aligning the nonresponders, previous nonresponders to this drug. But for Phase III, I think it's a topic that we're still discussing. Obviously, we need regulatory interactions as well. But we expect that in some shape, biologics experienced patients will be part of our Phase III study. There's just some nuance about what was their experience on biologics that we might have some kind of criteria around. But that's still something that we're discussing both internally and we'll have to align with regulatory agencies.

Our next question is from Derek Archilla from Wells Fargo.

Jared, good luck in the next chapter. Terence, welcome. So just actually following up on a prior question on the pediatric development. Are there any gating factors to a sprinkle formulation of 621? And I guess, how would you frame the pediatric opportunity relative to adolescents and adults?

Well, we actually had a 5-year-old child at Kymera a few weeks ago with their parents -- with his parents talking about the life of a child on an injectable biologic. I wouldn't say which one. It's not that difficult to guess. And I think he crystallized for us what it is that these kids have to go through and what is the -- not only the opportunity, but I would say the responsibility to deliver for children an easy to take, effective and hopefully, obviously well-tolerated drug. So we are doing, as I mentioned, all we can.

From a formulation perspective, we actually are in a very good place already. Again, I don't want to talk about specifics about what is it that we need to go into younger patients. And then it's really about when we will be allowed to do -- to run those studies. And as I mentioned earlier, obviously, having data from a global placebo-controlled randomized Phase II study, especially with regards to both efficacy and safety, we feel is the important data set to initiate those discussions with regulatory agencies. But all I can tell you is from Kymera perspective, we will be ready to go as soon as we have completed this study.

Our next question is from Alex Thompson from Stifel.

Congrats on all the progress. I appreciate you taking the question. Maybe another one. Nello, I'm not sure you will answer, but I just wanted to ask about -- you've had a lot more experience now dosing patients to 16 weeks plus across AD and asthma. Can you comment at all about blinded safety and your confidence in the continued clean profile of 621 heading into the data later this year?

Yes. No, thanks, Alex. It's a great question. I think you get it right. It's hard for us to comment on ongoing study blinded safety. So it's only actually a few months away where we can actually all look at the unblinded data and then share it with you. So just a little bit of patience. I feel the same way. I like to know everything, but we have to wait.

Our next question is from Jeff Jones from Oppenheimer.

Congrats, Jared, and welcome, Terence. Question on the IRF5 program with KT-579. As you look at those results coming late this year, is there anything that will guide you towards or away from particular indications beyond lupus?

Yes, great question. So we have this translational hypothesis around KT-579 around being this master regulator of 3 pathways when IRF5 is activated. So B-cell type 1 interferon and some of these inflammatory cytokines. I think if we don't see a profile that reflects our understanding of this biology, obviously, we will have to rethink what is our clinical strategy besides the translational one. I would be surprised if we are surprised by the data, but we'll see. I think we'll have to see what the biomarker data looks like.

Our next question is from Biren Amin from Piper Sandler.

It's interesting in your slide deck, you mentioned that the BROADEN2 trial data could support trials in GI indications. So now, I wanted to kind of understand that. What data from BROADEN2 could support development in GI? And also, is the interest in GI due to STAT6 activation in ulcerative colitis? And since I'm talking about GI, would you potentially look at IRF5 and IBD given the expression of IRF5 in IBD. And I think there's some proof-of-concept data with anti-TNF reducing IRF5 in IBD.

Biren wins. He asked 3 questions. So quickly, so what we mean -- so you caught an important point actually that requires a nuance on our slide. So first of all, when we talk about the GI, we talk about EoE, eosinophilic esophagitis, which actually should not even default the eosinophilic, but that's another point. So for that, the question is how is the Phase II study going to help us. So we believe the Phase III dose that we will get from the AD study should be applicable in all the other derm indications. Could be directly be applicable to EoE but maybe or maybe not. And actually, for EoE, we might have a slightly different plan, which we will be disclosing at some point after the Phase 2b data next year. So it will definitely be informed, but the development in EoE might not be the same as we might do for CSU and other derm indication. For IRF5, we're definitely interested in IBD. We have shown some really exciting preclinical data. So stay tuned as we share more information on that.

Our next question is from Brian Abrahams from RBC Capital Markets.

This is Kevin on for Brian. So maybe another one on 579. Just as you think more about lupus, the heterogeneity of the disease and just maybe some of the challenges prior agents have had and novel ones, which could be approved in the next few years. Just what are your latest thoughts on sort of what the addressable opportunity could be in lupus? And would the ambition here also be to have biologic-like efficacy? Or is this paradigm sort of a little bit more complicated or more nuanced than what we typically think about with 621 in atopic derm?

So maybe I'll start and given that Terence is a trained rheumatologist, maybe you can help me on this one. So the quick answer from me who I'm not a trained rheumatologist is that what we're seeing in lupus is what the patients need, which is our effective therapy that are acutely needed in this population. So I think we need different mechanisms. We need different options. The reality is there are no good right now oral options approved. There are some interesting ones in clinical development. So I think we believe that we can, again, continue to serve patients that want effective oral options.

Terence, is anything you want to add on this space in general?

Yes. Thanks, Nello, and thank you, Brian. I would just underscore that, yes, there remains tremendous unmet need in lupus, including for oral medicines with a favorable benefit risk profile. Brian, you flagged the challenges of lupus drug development. That's absolutely acknowledged. Key to that is going to be patient selection, site selection, careful trial design and careful oversight. So you can imagine that's exactly what we're working through at the moment.

Our next question is from Mark Frahm from TD Cowen.

Congrats, Jared, on a great career at Kymera and best wishes for the next step. This is mostly for Terence. The company kind of talked in broad strokes about being interested in combinations across the pipeline, but STAT6 and IRF5. But obviously, Terence at your prior job, that was a big push early on. So what do you think -- how do you view the optimal time to start those? What do you need to see from some of these earlier trials to really kind of start working on combinations?

Thanks, Mark, and thanks for the welcome. I think you're right. There's tremendous opportunity combining established mechanisms in particular, in pursuit of greater efficacy. Now I had some remarks earlier on about the field there, and we're learning as we go. In some instances, we have combinations that have altered. And in recent instances, we've seen some encouragement. I think the learning, therefore, for an oral drug developer is which combinations in the future might be rational for somebody like ourselves to developing an asset against one proven target. And I'll probably leave it there in terms of when to decide to combine STAT6 with another oral asset, but safe to say that it's a topic we're looking at carefully.

Does it need to be oral to be interesting? Or would you be interested in novel combinations that maybe aren't all oral?

Maybe I can help there. I mean I think it depends on what we're trying to do, right? I think there is a biological understanding of synergies or additivity and then there is like market positioning. We continue to believe that advancing oral options for patients is where the future needs to go towards. Would there be a case where we try to understand the mechanism with an injectable biologic? That might happen. But I'm not sure that's our North Star right now.

Next question is from Jeet Mukherjee from BTIG.

Just for the BROADEN data that's coming up by year-end, could you comment if there's a cap on the number of patients who are on prior biologics? And will you ultimately break out the data by patients who are on prior biologics versus those who are not?

No cap on prior biologics. With regards to how we break out the data, we'll have to analyze the data. So let's wait on that.

Our next question is from Mayank Mamtani from B. Riley Securities.

Best wishes to Jared and look forward to working -- getting to know Terence. So on the BROADEN2 program, if you could comment on what proportion of patients come from maybe ex U.S. or specifically Eastern Europe sites. And sorry if I missed the screen failure rate. I don't know if you commented on that, Nello, and how that's maybe similar or different than recent biologic trials? And if your expectation as an oral pill would be for discontinuation rates to be actually better than the biologics, if you could comment on that. And then just on timing, just clarifying last patient in was before the end of 2Q. So can the 4-month efficacy data drop maybe ahead of the IRF5 program? Or they're both tracking in parallel? Or how do you plan to have that disclosure?

Yes. Maybe I'll start with the last one. I think it's extremely likely that we'll have IRF5 data first, and then we'll have the BROADEN2 data. With regard to many of the other questions, I'm not going to -- all I can say our sites, as you know, you can look at it now on clinicaltrials.gov, there's a global presence. There is U.S., Canada, Australia, Japan, South Korea, Europe. So the majority of patients will obviously come from outside of the U.S. But we have a big -- obviously, expected big U.S. presence. I'm not going to be able to go into like a breakdown of patients at this point. I don't think we're not going to comment on screen failure rates. We might, when we release the data, be thoughtful to anybody, maybe our competitors. And then we'll talk about some of the other points you made about discontinuations, et cetera, when we release the data.

Could you comment -- sorry, for one follow-up, if I may. Could you comment on when you plan to have an end of Phase II discussion focused on AD? And would that need to wait until the asthma data?

No, we'll have an end of Phase II meeting with the FDA, obviously, as soon as we can after we have Phase 2b data in AD. So yes, no, we will not wait for the asthma data.

Our next question is from David Hoang from Deutsche Bank.

So I just want to ask, to what extent could we look at the ongoing launch of the oral IL-23, which is Icotyde in psoriasis as an analog for how commercialization of KT-621 in atopic derm might go. So what lessons can we learn there? And what reasons would that be or not be a good [ comp ] for KT-621?

Yes. Obviously, we have Terence here that was obviously involved in that program. So he probably will have a lot to say that he can even say. But what I will say is that I think what is in common is the fact that from where I sit, IL-23 peptide is a validated mechanism with a novel way of dragging in that particular target or pathway with a molecule that I believe has actually behaved quite well in terms of efficacy and safety and is showing that even in a saturated market. I guess the difference is the market, right? Psoriasis is a -- I think from a point of view, a much more mature market with several drugs that have been approved over the years, several biologics, several orals.

And even with all of that, you're seeing some really impressive adoption of that drug. I think in the first quarter, there are more than 100,000 patients on the drug, if I'm not wrong. So with KT-621, hopefully, right, I think that what we can match is the ability to drive efficacy and safety of an oral drug in a validated pathway. And I think what's different is that AD is a very early immature market with very low penetration overall. And I think our expectation is that we should be able to launch the drug and have even a superior success than Icotyde is seeing if we do a good job and if we obviously retain the profile that we want because there are so many patients that don't have any oral safe options, while for psoriasis, I think there are oral effective and safe drugs that maybe the Icotyde is slightly better, but still there are options there while in AD, there are no options.

There are no more questions at this time. I'd now like to turn the call over to Nello for closing remarks.

Well, I want to thank everybody for attending our call, all the analysts for attending and asking questions even in the -- we're in the middle of the summer. So we appreciate you taking time away from your vacation, if you are. And we continue to be super excited about where we're going. Please stay tuned. We're going to have some of the most interesting data set probably for the industry in the second half of the year, given these are both kind of first-in-class program in highly super relevant indications or population. So stay tuned and look forward to seeing many of you in our conference in September and then after that at our calls to disclose the data. Thank you.

[Audio Gap] chatting with Kymera Therapeutics. Up here on stage, we've got a couple of members from the management team. We've got Bruce Jacobs, who's, of course, is Chief Financial Officer; as well as Jared Gollob, who is the Chief Medical Officer. Gentlemen, thanks for making the trip over from Boston.

Thank you.

Thanks for having us.

So maybe we can just start off with a quick overview of the company. Maybe talk to us about atopic dermatitis is a very, very popular space to be looking at these days. That's just one of the many things that you've got going. Can you just talk in general about the platform and how you differentiate from others who might be pursuing similar indications, and then we can go into more specifics from there.

Sure. Thanks, Tazeen. Maybe I'll start, and Jared can chime in. So it's a good time for that question. Kymera actually last week celebrated our 10-year anniversary of the company's founding, May 4, 2016. So it's been a great opportunity for us to reflect on all that we've accomplished over that time, but also what we still have in front of us. But the company obviously was founded at the time on the promise of targeted protein degradation. And since that time, I think we've been incredibly productive as a discovery engine.

We've taken now 6 programs into the clinic. Over time, we've narrowed our focus really to immunology, where we think there's enormous opportunities. And I think have developed one of the better track records for targeting very unique, difficult-to-address targets with large opportunities, with clear biologic rationale and human genetics supporting them and puts us in a very good position with both the programs that we have in the clinic today, and I'm sure we'll talk about both STAT6 and IRF5 as well as those that will come in the future. And we still have an intention and goal to introduce at least one new program annually.

So excited about where we are as a company. This is -- obviously, every year is an important year for Kymera. This year is of particular importance as well because we've embarked on these Phase II studies for KT-621, one in atopic dermatitis and one in asthma. And I'd say the highest level of focus at the company right now is on executing on those trials. And we expect to complete the AD trial this year. I'm sure we'll get into that throughout the conversation. Asthma next year, and we'll have data we expect for both in 2027. So it's an exciting year for us in that regard.

Going back again to the overview, IRF5, which is our next program after STAT6, is in the midst of a healthy volunteer study. We'll be able to share data in that -- for that program in the second half of this year. And again, working to introduce one new program annually. At the same time, we have a couple of programs partnered, one with Gilead, one with Sanofi. Those continue apace as well. So really a lot of opportunity to progress all these molecules towards ultimately helping patients, which is the fundamental goal of the company.

Okay. So for STAT6, you guys are, I think, the most advanced in terms of data that's been shown so far in atopic derm, but you're not alone. There's quite a few companies pursuing this indication. So you can look at it that derisks it because a lot of companies are willing to spend time and money on this. But on the point of differentiation, do you think that these molecules are meaningfully different from each other?

Yes. I think in terms of, say, small molecule inhibitors, for example, of STAT6 versus degraders, we think that there is significant differentiation because the pharmacology of degraders allow us to degrade STAT6 completely and keep it down 24/7, which is really the sort of inhibition you need if you want to replicate what upstream injectable biologics do to the IL-4/13 pathway. So we're able to achieve that because of the catalytic mechanism of our degraders.

Small molecule inhibitors, and we looked at these as well preclinically, they're just not capable of that level of inhibition 24/7. Small molecule inhibitors because there's a stoichiometric sort of relationship, you get waxing and waning of exposure after a dose, and therefore, you get waxing and waning of pharmacology. So I think it will be very difficult for an inhibitor of STAT6 to hit the pathway completely and consistently and maintain that inhibition the way a degrader can. So I think that gives us a significant advantage pharmacologically over the inhibitors.

So yes, you talked about degraders versus inhibitors. In a clinically meaningful definition, what do you think that would manifest as?

Well, I think -- look, I think ultimately, it will have to come out on clinical efficacy, right? So the ultimate test will be in randomized placebo-controlled studies and looking at efficacy with standard AD endpoints, for example, or asthma endpoints depending on the study. So I think it will have to come out in the clinic ultimately. I think some of the early phase studies will be able to start to give a sense perhaps with inhibitors. There are several inhibitors in Phase I now that might start to give people a sense for what degree of inhibition are you seeing? What sort of effect are you having on biomarkers even in healthy volunteers like TARC and eotaxin-3, how do those compare to what we showed in Phase I.

You'll start to be able to make some comparisons. But ultimately, I think the true test is going to be when you're up against a placebo when you're in a dose range finding Phase II study. And again, I think just because we're able to maintain deep degradation over time without any letup, which is much more like what you see with biologics like dupi, whereas the inhibitors, we don't expect to have that same level of suppression, we think probably will compare favorably at least across studies once there are Phase II data out there.

Okay. If you think about how people describe 621 rightly or wrongly, they call it the oral dupi. So I wanted to get your thoughts. Do you like that term? Do you think that the main difference is the dosing? And how are you thinking about the overall efficacy profile over time as you compare it to DUPIXENT, especially as that goes at some point, biosimilar?

Well, I think, obviously, the history of that term is really rooted in the fact that we are -- STAT6 as a protein is downstream from IL-4/13, obviously, the target of dupilumab, and there's good reason to believe that if we can fully block that target as we expect to be able to do, that we have the opportunity to come close and hopefully actually replicate the -- both the efficacy and safety of dupi. So I think that's obviously the derivation of that. Obviously, it's up to us to show that. I can say that everything we've seen both preclinically all the way up through our smallish patient study, the Phase Ib 22-patient study has supported the fact that it does seem to look and act like dupi. We've seen efficacy levels that look comparable and the safety has been quite clean. But obviously, as I said, it will be up to us to replicate that in these randomized placebo-controlled trials, which we're in the midst of doing right now.

It's an exciting opportunity. You talked about AD. It's obviously a very prevalent disease. And as successful as dupilumab has been, the penetration is still quite low, and there is a large number depending on what source you evaluate, 40 million to 50 million people that have moderate to severe Th2 diseases that are effectively not on systemic therapies. And that might be for various reasons, aversion of needles. It might be insurance reasons. It might be just fear of having to admit that they have a serious disease. We think that's a great population for 621 should it achieve the TPP that we're hoping to see with the drug.

And so a lot gets made about how patient volumes will shift from injectables to orals, how many and so forth. I think the point we try to make is that there's a large number of patients out there available and frankly, excited about an oral mechanism, and that's where we'll mostly be focused.

And I think as Bruce said, while the term dupi-in-a-pill helps people to understand mechanistically what we're trying to do with 621, I think ultimately, we feel that KT-621 will stand on its own merits, essentially independent of dupi and maybe those comparisons down the line will start to go away.

So based on the data that you've presented so far, can you talk to us about what you'd expect to see at the next data update for AD?

Well, I think, so for us, right now, all focus is on the Phase IIb BROADEN2 study, which is a dose range finding study. We have 3 different doses of KT-621 versus placebo. It's 16 weeks of dosing, daily dosing followed by a 52-week open-label extension. So this is the first placebo-controlled test for KT-621. So clearly, we want to see that the drug itself has superior activity over placebo. The primary endpoint is percent change from baseline in EASI at 16 weeks and a number of secondary endpoints that look at EASI and pruritus and a number of other relevant AD endpoints in all different ways.

And so I think really, what we want to see is that this is a drug that is superior to placebo. We want to see that it's safe and well tolerated. Of course, there will be cross-study comparisons in terms of what did we see versus what has been seen in prior dupi studies. But really, the aim of the Phase IIb is to pick the dose that we then bring into Phase III, not just Phase III in AD, but potentially Phase III across other type 2 indications, for example, other cutaneous type 2 indications that could include indications like CSU. Whereas with the asthma study, which is separate, which is the BREADTH study, which is ongoing, that's in Phase IIb study. We'll also have a Phase III dose come out of there. And that Phase III dose will be used not just in asthma, but also in potentially other respiratory indications like COPD, CRS with NP, et cetera.

We're obviously very encouraged by the Phase Ib data, but that was by its own right, limited in terms of number of patients was not placebo-controlled. So I think this will be a real opportunity to really see what this drug is capable of delivering. And we were asked many times for that study to put what's our bar of success, and we're asked that again. For IIb, I think the point is, as Jared mentioned, is really to be able to pick a single dose to move into Phase III, but everyone will be able to look up where dupi was at 16 weeks and make their comparisons, and then we'll see where it falls out.

Yes. On the point of the safety profile, mechanistically speaking, would you expect to see conjunctivitis show up at a certain point?

Yes. We get asked that question a lot. It's a really relevant question. What we've said is that because we are blocking the same pathway, IL-4/13, and we know that with dupi or drugs that block IL-4/13, one does see conjunctivitis predominantly in AD patients. Our expectation is that we should also see conjunctivitis. We may see conjunctivitis because we're also blocking that pathway.

Now with that being said, the mechanism for conjunctivitis in AD patients in response to IL-13, IL-4 targeted agents is unknown. So we don't really know what causes the conjunctivitis. So it's always possible there could be something unique to the antibodies that might be different from small molecules that might contribute. But our base case is that mechanistically, we would expect to see something similar. I think we'll learn a lot from the ongoing Phase IIb study to really know, are we seeing it? And if so, is the frequency similar or not to what's been seen previously with dupi?

And we didn't obviously see any cases in the Phase Ib, but it was 22 patients. And at that time point, 28 days, dupi only has about a 5% conjunctivitis rate. So you might have expected, right, one patient. So the fact that we had none, it's hard to make the call whether it was truly nothing or just small numbers. But obviously, we'll learn a lot from the Phase IIbs.

Yes. So based on our feedback from physicians, they don't, at this point, consider conjunctivitis to be rate limiting in use. It's certainly not for DUPIXENT. But do you think that, that bar has been set by dupi, I think it's 14% in the approved dose that you see conjunctivitis in general. The higher you go from there, does that kind of impact the way you think of the market opportunity for 621, if it's the case that it's higher?

Yes. I think probably we'd like not to see a significantly higher rate of conjunctivitis or greater severity. It's possible we could see the same, we could see less. And even though it is a sort of "nuisance adverse event" that usually doesn't lead to discontinuations or dose changes, it is something that patients and clinicians are aware of. So if we're going to see it, we'd like to be in that same ballpark. We don't want to see more of it necessarily. Now if we did see a little bit more, would it matter? I think if our efficacy is strong and we have an oral drug, I don't think that would be an issue.

Are there any other side effects to be looking out for here?

Well, I think with dupi, I mean, you see a very low incidence of viral infections over time, whether it be mostly herpes simplex. Sometimes you can see sort of facial eczema, facial rash and maybe 5% to 10% of patients who are getting dupi. Those are the main things that people have seen, maybe a little bit of arthralgia in a small percentage of patients. So those are some things that we'd be on the lookout for. The fact that we haven't seen any of this so far either in our preclinical work or in our Phase I means that these are not for us sort of "adverse events" of special interest. But I think we will be looking for those because those are things that have been seen with dupi.

I mean the data that we've been able to generate through all the preclinical work and then into the -- both the healthy volunteers and the Phase Ib has been as good as we could have expected from a safety standpoint. I think that speaks to, as we said earlier, what's known about the pathway, also the selectivity and potency of the drug being what it is. And so we went into the human exploration here having dosed at 30 to 40x the efficacious dose in preclinical studies without having seen any adverse events. So we come in feeling good, but obviously, that's the point of these studies as well.

And again, as we said earlier, the Phase IIb, it's a dose range finding study. So the aim is to look at safety and efficacy across the 3 doses and look at that in composite and then make a decision about what is the appropriate dose to bring into Phase III.

Do you just want to have one dose?

Yes, ideally, we'd like to have one dose in Phase III. And I think we should be able to achieve that given all we learned about sort of exposure response relationship in Phase I and what we'll learn hopefully from the 3 different dose levels that are in Phase IIb.

Okay. So next year is a big year for the company, right? You've got both the AD and the asthma Phase IIbs revealed. I think you've guided to midyear for AD and closer to year-end for asthma. When you do show the AD data, do you think that derisks the asthma study?

It's a good question. I mean I think we think of those studies as being separate. It's interesting that in the Phase Ib AD study, we did look at some respiratory endpoints. So in that study, we had some patients with comorbid asthma and allergic rhinitis, and we were able to see a nice impact of the drug on those comorbid illnesses as well as a nice impact on a lung biomarker called fractional exhaled nitric oxide. So even in the AD patients, that already give us confidence of what we think the drug can do in asthma, which we already knew preclinically, we had a very strong effect in the house dust mite asthma model.

And so I think, yes, I think the AD study can shed some light on potentially what we may end up seeing in BREADTH. But with that being said, the endpoints are different. They're different populations. And so I think we have to sort of view them separately, the AD readout first and see how we impact those AD endpoints. And then I think hopefully, the BREADTH study will stand on its own. The BREADTH study, just as a reminder, also 3 different dose levels versus placebo. It's a 12-week endpoint -- primary endpoint, which is change in FEV1 from baseline, and there are a number of other secondary endpoints as well for that study. So -- and it's also for patients with eosinophilic asthma, we call it high EOs, high FeNO.

So I think we expect, hopefully, to see encouraging results from both, but I think they'll both be sort of stand-alone studies and will tell us a lot about the Phase III dose to take into either AD or other skin indications or maybe even GI indications coming out of the AD study and then the asthma study, if it's a positive study, telling us what dose to take into asthma, COPD and other respiratory indications.

But I do think -- I think it's a fair statement, though, that if we indeed -- the AD will read out first, right? So we started just to level set on timing. We started that study last year. We expect to complete enrollment by the end of this year. And then that will -- once we announce that, that will start the clock for when you expect to see the data. I think positive results from that AD study will certainly make us feel more confident of the likely outcome in asthma, just given what's known about the mechanism, so that's...

Yes. And it does seem like other mechanisms of action for approved drugs, it seems like it's part of the natural progression from AD to asthma and other related indications.

Yes, exactly. If you look at dupi and its impact across all type 2 diseases, whether they be respiratory, cutaneous or GI, it's also worked across the board. And so we do have similar expectations there as well. I think for us, it's more a question of what is going to be the appropriate dose to take into Phase III on the respiratory side versus on the derm side.

And as you think about market opportunities for both of these, is there one that's meaningfully bigger as you sit here today for 621?

Bruce, go ahead.

Well, no, I think there's an enormous opportunity for both. We talked about the untreated -- when I say untreated, but the population that is not interested for a variety of reasons in advanced systemic therapies is significant. The other area that we haven't talked a lot about is the pediatric population. Obviously, many of these diseases afflict children. For right now, we're approved in the AD study, adolescents and up. But you can rest assured that the pediatric population is going to be a big focus of our time, attention and our investment going forward. So I think they're both significant opportunities.

Asthma, in particular, is interesting because they're so much known about what they call the atopic march and how patients worsen over time. So the sooner we can treat patients, I think the better for the prevalence of the disease. And if you talk to parents, and we have talked to many about the pain that both they feel and the children feel from having to give an injection, it's a real impediment and a traumatic experience for a lot of families. So we're excited about having the opportunity to intervene there with a small molecule oral approach.

Yes. And certainly, one of the reasons we chose to start with AD and asthma just because those populations are so large, 80% of dupi's revenues come from those 2 indications. And so it represents a very large opportunity for adults, adolescents and pediatric patients. Obviously, the other indications are very important as well, but starting with those, I think, made the most sense.

There's a question that's becoming more and more asked in my conversations, which is whenever DUPIXENT has a biosimilar in a world where there might be multiple different options for AD, does that, in your view, make it a little bit easier because you would be an oral option and for insurance companies that are always looking to kind of have patients step through therapies, would this be something easier that it would be able to get insurance to initially let you use earlier?

It's a good question. I think time will tell how the market unfolds. I think most people believe and expect that dupi -- that Regeneron and Sanofi will do their level best to extend the time line for generic entry. And we've heard anything from the early 2030s to 2033, '34 and beyond. We expect that we will likely be entering the market when -- before a generic dupi is on the market. So I think that's in our expectation, the most likely scenario. Obviously, a lot has to come to pass for that to be the case. But we -- again, going back to the patient population, I think we're focused intently on this large number of patients that are not on biologics today. Is it possible and perhaps even likely that some number of patients will likely want to switch? Certainly, but we would certainly like to be an early line of therapy for a big number of patients, which is what our goal is.

Okay. I did want to touch upon 579, IRF5, so mechanistically speaking, why does it make sense to pursue this for autoimmune disease?

So yes, there's been a lot of interest in IRF5 from both big pharma and biotech for years, in large part because of the very strong genetic association between mutations in IRF5 and susceptibility to lupus to IBD and to RA. The real problem has been just not being able to drug it. It's difficult to drug because there are multiple IRF family members. So you want to be specific for IRF5 if you want to have a drug with a good safety profile. And there are also multiple different isoforms of IRF5 itself. You have to be able to block all of the isoforms of IRF5. So that's been the main stumbling block.

But IRF5 has been of great interest because it's selectively expressed in certain immune cells like dendritic cells and monocytes and macrophages and B cells. And it's involved in controlling type 1 interferon response, controlling production of pro-inflammatory cytokines like IL-12, 23 and 6 and also involved in B-cell activation and autoantibody production. So you get all of that by targeting one protein.

So again, I think the limitation has been being able to target it. But now that we have a degrader that is highly selective for IRF5 that hits all of the isoforms of IRF5, we've been able to show preclinically that we can degrade IR5 completely and that it's safe and well tolerated. And we've also shown importantly in preclinical lupus models, several different models that we are even more active than either standard drugs that are approved or other active drugs that are in development. And we've also shown that recently in a model of [ IVD ] as well.

So I think we have a real profound opportunity here for targeting IRF5 to transform how diseases like lupus, inflammatory bowel disease and RA are treated with an oral drug that we think can be dosed safely to fully block IRF5, but by affecting multiple different pathways, not just single pathways, really have a transformative effect on the treatment of these diseases.

Okay. So as you think about the level of degradation that you think is going to be needed to produce clinically meaningful results, is that going to depend on the indication? Because I think this mechanism has been tried by others, and it's also been a little bit of a challenge to get good data. So you've talked about your view about differentiation of your platform, but how should we be thinking about level of degradation you're looking for?

Well, I think we've shown in our models of lupus and IBD that even 80%, 85% degradation is enough to give us very strong activity. I think our expectation in the clinic, just as we've had the expectation for other programs previously, is that we want to see at least 90-plus percent degradation of the target, and we feel we'll be able to achieve that based on our preclinical results. Do we need that level of degradation? I think we still don't know whether we need 95%, 98% degradation to impact these diseases, especially since our preclinical data suggests that 85-or-so percent might be sufficient.

But I think we want to understand in Phase I, can we get at least 90% degradation? Can we push the dose to get higher levels of degradation? Are those doses safe and well tolerated? And when we do see degradation, are we impacting the pathways that IRF5 is signaling through. So TLR7, 8 and 9 doing ex vivo stimulation assays as part of our Phase I study to really show how degradation in vivo in healthy volunteers translates then into impact or hopefully inhibition of those TLR7 pathways, which I think we were able to show at least 90% degradation and blockade across these 3 different TLR pathways that would hopefully translate into being able to see activity in a subsequent patient study.

Okay. So when is the next data update from that program?

So we're running the healthy volunteer study now, and the timing will be once we complete the MAD portion. Typically, we do a SAD and then partway through SAD, we start MAD. Once we finish the last MAD cohort and collect that data, then we'll share it with everyone. So we've guided to the second half of the year. We'll be able to give more specificity as we get closer. It just depends on how many cohorts we end up enrolling. So we'll hopefully have that data then, and we also plan at that time, if we haven't already done so, to share more data or more details around the plans for the next study, which, as we have said, is likely in lupus.

Okay. And then how many different indications do you think you'd want to pursue at the same time? Because I remember, this was in January, one of the questions that Nello was asked when we all met up in January was how many different programs do you think the company can support given the size of the company. So what's your thought because you're the Chief Medical Officer, how comfortable are you going to be?

We'll do everything. No, I think for IRF5, I think it's going to depend on first, let's see what we see in Phase I, if we get the levels of degradation and pathway inhibition that we want with doses that are safe and well tolerated. I think that will bring us into our first patient study, which, as Bruce said, will likely be a lupus study.

If we feel as though there's a pathway forward in lupus, then the question becomes as you're asking, okay, well, do we start to think about development in inflammatory bowel disease given the promising results we've seen in our preclinical models there? Or would we be interested in other type 1 interferonopathies like Sjogren's disease, where there's also strong genetic association or systemic sclerosis or even rheumatoid arthritis. So I think that remains to be seen. So maybe I'll punt it a little bit, but I think these are all potential opportunities for us. I think what we see in Phase I, what we see in the lupus proof of concept and how our preclinical animal model data continue to evolve will probably inform ultimately whether we parallel track or not other indications along with lupus.

The premise of your question is a good one, which is that the breadth of the opportunity in some of these targets is significant, right? Obviously, we've talked about AD and asthma with STAT6, but there's COPD, there's chronic rhinosinusitis, there's EoE and several others. Jared mentioned a couple with IRF5. I think we've -- obviously, we're a well-capitalized company, but there's also human resource constraints ultimately and broadly pursuing all of these indications. And so I think we'll continue to be rooted in the science, what indications are most supported by the preclinical work we do with obviously a commercial lens as well and then try to make the right resource allocation decisions as we advance both these programs through clinical development.

And I think Bruce maybe mentioned this upfront, but in terms of how we build our development group, we always try to be very proactive. And now even though we're in Phase IIb, we're already looking ahead to Phase III and building our development group to be able to manage multiple Phase IIIs. And then the same thing goes if 579 ends up being a productive successful program, then we want to be able to be staffed up to be able to support doing additional trials there across multiple indications.

Yes. And so on that point, what's your view going forward is probably for Bruce on business development, either partnering what you have, continuing to partner what you have with others? Or do you even think that there is a reason for you to bring in things that you don't have currently?

So as you might imagine, because of the opportunity in both of these programs, there's been plenty of companies who have kindly offered to lend assistance to our development efforts. Thus far, we've been focused on keeping these 2 programs internally run and wholly owned, and that's the plan for the foreseeable future. I think the opportunity that we might pursue would be one where we could, I'd say, capitalize on the breadth of the opportunity in a greater way than we could do ourselves. But heretofore, we have the team and the capabilities and importantly, we have the capital to execute in the case of STAT6 on these Phase IIb studies. So we'll see what happens beyond that, but that's our intention.

We have a business development effort as well that's looking at in-licensing opportunities, mostly in areas in immunology that would be synergistic to the programs we have today, but that also has to compete with a very productive internal discovery engine as well. And there's a lot happening on that side as well. So nothing to project and predict, but I just know that we're going to do what we think is the right -- take the right strategic option to really maximize very, very large opportunities in front of us.

Yes. On that last point...

Yes. So I think we've tried to stay focused on our core competencies, which is really on small molecule development. And so it would be difficult for us to venture into areas that were not kind of our core area of expertise. So most of the internal work we have, as you might imagine, is around protein degradation for small molecules more broadly. Could we in-license something a little bit afield from that? Certainly, if we thought there was an opportunity to perhaps combination therapy down the road is going to be an interesting area of development, that's one that we're exploring.

With that, we are just about out of time. So I want to say thank you again for making the trip over from Boston.

Thank you.

Thanks.

Good day, everyone. My name is Stefan, and I'll be your conference operator today. At this time, I'd like to welcome you to the Kymera Therapeutics First Quarter 2026 Results Call. [Operator Instructions] At this time, I'd like to turn the call over to Justine Koenigsberg, Vice President of Investor Relations.

Good morning, and welcome to Kymera Therapeutics Quarterly Update Conference Call. Joining me today are Nello Mainolfi, our Founder, President and Chief Executive Officer; Jared Gollob, our Chief Medical Officer; and Bruce Jacobs, our Chief Financial Officer. Following our prepared remarks, we will open the call for questions from our covering analysts.

[Operator Instructions] But before we begin, I would like to remind you that today's discussion will include forward-looking statements subject to risks and uncertainties described in our most recent Form 10-Q filed with the SEC. Please note, any forward-looking statements speak only as of today's date, and we undertake no obligation to update them.

With that, I will now turn the call over to Nello.

Thanks, Justine, and thanks, everyone, for joining us this morning. Next week marks the 10-year anniversary of Kymera's founding, and it represents more than just a milestone. We have stepped into a new chapter where we believe the strong foundation we've built over the past decades positions us to deliver transformative medicines for patients around the world.

In the past 10 years, we've built unique capabilities, including our hit finding approach to identify ligands to historically undrugged proteins, building on that, creating new rules on how we identify dry-like highly specific and potent degraders, importantly, key insights to deliver high fidelity of clinical translation and finally, creative early clinical studies to derisk clinical development -- late clinical development.

We have continued to refine our target selection strategies such as we believe we've built one of the most compelling oral small molecule pipeline in the industry. As we look to the next decades, our guiding principles remain unchanged. We'll continue to focus on both signs, demonstrate early proof-of-concept to support our investments and build medicines that we believe can change the standard of care for many diseases.

And we'll obviously be looking to make the final step becoming a fully integrated global commercial company that delivers groundbreaking medicines for patients around the world. And it's these principles that have shaped our innovative and increasingly differentiated pipeline.

We're laser-focused on our wholly-owned programs such as KT-621, KT-579, where we're applying targeted protein degradation to well-validated disease-relevant pathways in immunology. At the same time, we're extending our reach through partnership like our work with Gilead advancing KT-200, our first molecular glue program and Sanofi with IRAK4. What ties it all together is our commitment to pursuing high-value disease-driving targets with precision and to do it repeatedly across different therapeutic areas.

The sharp focus and the consistency of results we've delivered is what gives us confidence not just in individual programs, but in our ability to broaden and expand our pipeline. We've done a lot of groundwork over the past few years as we sit here today, we're well-positioned to execute on our strategy and deliver on the groundbreaking promises of our programs. Our immediate priority is execution of the 2 KT-621 Phase IIb studies.

In atopic dermatitis, we're on track to complete enrollment this year in the BROADEN2 study, and we expect data by mid-2027. We continue to be encouraged by the level of interest from both investigators and patients, and it's clear the enthusiasm for the trial is high. We're tracking with our internal expectations for asthma as well, where the BREADTH study readout is expected by the end of 2027.

As we advance these studies, we'll continue to assess a broader development strategy, including areas such as COPD, EoE, chronic rhinosinusitis and others to maximize the value of the program. Turning to IRAK5. We expect to report healthy volunteer data from the KT-579 Phase I study in the second half of 2026.

The overall goal is to demonstrate that we can safely degrade the target and the biology translates in humans in a way that's consistent with what we've seen preclinically. IRAK5 has been a target of particular interest across the industry for a very long time. Jared will spend more time on the opportunity, but what's compelling here is that by selectively degrading IRAK5, we have the potential to impact multiple key drivers of disease with a single mechanism.

If we think about lupus specifically, we're addressing autoantibodies, Type 1 interferon, pro-inflammatory cytokines, all through one pathway. While individual drugs can address specific -- each specific pathway, we believe a single mechanism such as an IRAK5 degrader has the potential to address all pathways and potentially have greater therapeutic potential.

We also have several opportunities emerging in our early research pipeline and expect to disclose the next target later this year when we reach development candidate. Before I move on, I wanted to touch briefly on our Gilead collaboration. We recently announced that Gilead has made the decision to advance KT-200, our CDK2 molecular glue, which could enter the clinic as early as next year.

This program is a great example of the power of Kymera's R&D capabilities. Our ability to reach a target like CDK2 with a highly selective molecular glue really speaks to the depth and reach of our capabilities. CCNE-amplified tumors need specific agents to address the underlying biology. CDK2 selective blockade has not been achieved by any investigational drugs, in my opinion. Mostly because of the homology and cross-reactivity with CDK1.

We designed an absolutely selective molecular glue degrader to achieve this target product profile. I'm thankful to Gilead for believing in this program early on and now for taking KT-200, Kymera Therapeutics discovered development candidate into development. Special thanks to our CDK2 team for delivering this molecule in record time.

So everything we're doing across all this program is to build long-term value. This isn't just about incremental progress. It's about our commitment to developing medicines that we believe can change treatment paradigms and expand access to important treatment options. KT-621 is the best example of our strategy in action.

Our continued engagement with KOLs reinforce the growing anticipation for a therapeutic that can potentially fundamentally change the treatment paradigm in Type 2 inflammatory diseases. As you all know, we have shared compelling data sets, including most recently AAD. With that as a backdrop, I thought it was worth stepping back and framing what makes this opportunity so compelling.

When it comes to treating these conditions, patients and physicians are often forced to make trade-offs. What they want most is simple, a safe, effective and convenient option. We believe KT-621 is well-positioned to meet that need with the potential to deliver the efficacy of biologics and the convenience of an oral pill. And that matters because patients' preference is clear.

Given the option, many would choose oral therapy over the burden of injections, especially for chronic diseases that require long-term treatment. In fact, most patients are being treated with suboptimal therapies such as topical creams, which can be massive ineffective or with inhaled medicines, often because they or their prescribers are not comfortable moving to advanced systemic injectable therapies.

KT-621 can change this dynamic completely, allow patients that are not well treated by these local therapies to access a simple, accessible, effective and trusted oral pill. So when you put it all together, the mechanism, the clinical profile and the simplicity of administration, we believe KT-621 can stand on its own has the potential to represent a true paradigm shift.

As a result, our focus is to expand the market and redefine what patients and physicians should expect from treatment. When you take a broader view, the scale of opportunity really comes into focus. This is a slide you've seen before, but it's worth revisiting because it highlights just how much untapped potential still exists in Type 2 inflammatory diseases, particularly for new entrants that can expand the market.

Importantly, nearly 50 million patients could benefit from better therapies. This opportunity is not just about taking share from existing treatments. It's about reaching the much larger population of patients who are untreated or undertreated today. We're already doing the work to better understand the patient population, market dynamics and access landscape, and these insights are guiding our development and ultimately, our commercial strategy.

If successful, KT-621 could become the preferred option and potentially shift treatment earlier in the disease course where earlier intervention can meaningfully reduce disease burden and progression. At AAD and through recent advisory board meeting, the feedback has been consistent. There is clear demand for a convenient effective oral option and strong excitement around this mechanism.

With that, I'll turn it over to Jared to discuss our clinical pipeline a bit more, including KT-579. Jared?

Thanks, Nello. Given the growing focus and attention on our IRAK5 program, I'd like to use most of my time this morning to highlight why we are enthusiastic about this program and target. There is a significant unmet need in autoimmune diseases like lupus, which are characterized by broad immune dysregulation rather than disruption of a single pathway.

While biologics have successfully validated individual targets such as Type 1 interferon, pro-inflammatory cytokines and B cells, these approaches act downstream and only narrowly address the underlying disease biology. As a result, many patients continue to experience inadequate responses.

This is where IRF5 becomes particularly compelling. It is a genetically and biologically validated transcription factor that functions as a master regulator and central amplifier of immune responses across multiple autoimmune diseases. When dysregulated, it drives coordinated activation of multiple inflammatory pathways, effectively locking the immune system into a persistent inflammatory state.

Importantly, human genetic data connect increased IRF5 activity to these pathways that are known drivers of autoimmune disease. This biology supports our confidence that modulating IRF5 has the potential to translate into meaningful clinical benefit. KT-579 is designed to selectively degrade IRF5 and thereby rebalance immune activity by simultaneously modulating multiple downstream disease-driving pathways.

Our goal is to rebalance the immune system more comprehensively and deliver a durable response compared to injectable biologics that target single pathways, while also offering the convenience of oral dosing. We continue to generate compelling preclinical data demonstrating activity across multiple disease-relevant models.

These results reinforce our confidence in IRF5 and support the potential for KT-579 to offer clinical benefit. We plan to present preclinical data, including new data in IBD models at DDW next month and Focus at EULAR in June. We have already generated a robust preclinical data package and have shown that we can effectively and selectively modulate this central node of inflammation.

As you'll see here in our lupus models, KT-579 demonstrated strong and durable activity associated with deep IRF5 degradation. Importantly, the level of activity observed compares favorably to both approved therapies and other clinically active agents evaluated in similar preclinical settings.

Taken together, these data further support the potential of IRF5 degradation to drive meaningful disease modification in autoimmune conditions like lupus and IBD. I should also note that from a safety perspective, IRF5 is not essential for host defense against infectious pathogens, which suggests there may be an opportunity to modulate the immune system through IRF5 targeting without the risk of bacterial or viral infections.

IRF5 knockout mice do not show any susceptibility to infections. And in our 4-week GLP tox studies in nonhuman primates and rodents, we did not observe any adverse findings. We've now advanced KT-579 into the clinic. The Phase I healthy volunteer study is designed to evaluate single and multiple ascending oral doses with a focus on achieving greater than 90% IRF5 degradation in blood and a favorable safety profile.

We will also assess pharmacodynamic activity using ex vivo stimulation assays to understand the impact of IRF5 degradation on key inflammatory pathway biomarkers upregulated by TLR7, 8 and 9 agonists, including Type 1 interferons, pro-inflammatory cytokines and inflammatory pathway gene transcripts.

It's our expectation that we should see a 50% to 80% reduction in these biomarkers across the 3 TLR pathways assessed if we're engaging IRF5 effectively, which would suggest the potential for IRF5 degradation translating into clinical activity in subsequent patient studies with KT-579. Looking ahead, we expect to report Phase I healthy volunteer data in the second half of 2026.

Following that, we are planning a proof-of-concept study likely in lupus where genetic and biological rationale for IRF5 targeting is particularly strong. We will share more details on the planned design later this year. Before I wrap up, I did want to touch briefly on our STAT6 program. There continues to be a lot of excitement around new mechanisms in AD and KT-621's profile continues to resonate well.

Last month, we had the privilege of presenting the KT-621 Phase Ib BROADEN data at AAD during a highly attended late-breaking trial results session. In addition to the presentation, we had a strong presence at our booth at AAD and meaningful engagement with the AD patient community, including patient support groups, which reinforced the real need for new treatment options and excitement over the potential of KT-621 to provide an effective and safe oral therapy for AD.

We also connected with a number of KOLs and investigators who shared their enthusiasm for KT-621 and viewed it as one of the most promising new approaches to treating AD. New in the AAD presentation was the first detailed look at impact on Body Surface Area or BSA, a measure of the extent of AD skin lesions. We saw an overall mean reduction of BSA of 49% at 4 weeks across the 2 dose groups, reflecting a substantial reduction in disease burden.

This, like other key clinical efficacy endpoints included EASI and pruritus was in line with published data for dupilumab at week 4. These early data continue to highlight the potential of KT-621 in AD, and we look forward to learning more in our randomized placebo-controlled Phase II studies.

We are actively enrolling the KT-621 Phase IIb BROADEN2 and BREADTH studies in AD and asthma and look forward to sharing data from these studies by mid-2027 and late 2027, respectively. Overall, we are highly encouraged by all the progress with both KT-621 and KT-579 and look forward to keeping you updated as these programs progress in the clinic.

With that, I'll pause here and turn the call over to Bruce.

Thanks, Jared. As I walk through the first quarter results, please refer to the tables found in today's press release, which was filed this morning. Collaboration revenue in the first quarter of 2026 of $34.4 million is attributable fully to our Gilead partnership. More broadly with respect to Gilead, we received an upfront payment of $40 million upon signing the licensing and option agreement last year, which now has been fully recognized in our revenue.

As Gilead has exercised its option on KT-200, we are due to receive $45 million investment from Gilead, which is expected to be recognized as revenue in the second quarter of 2026. And as a reminder, under this agreement, we are eligible for approximately an additional $700 million in total milestone payments. Also on the partnering front, we continue to expect Sanofi to advance KT-485 into Phase I testing this year, which will include the receipt of a milestone upon dosing the first healthy volunteer.

As a reminder, under the structure of the Sanofi agreement, we have the potential to realize nearly $1 billion in total milestones. Now with respect to operating expenses, R&D for the quarter was $98.2 million. Of that, approximately $8.6 million represented noncash stock-based comp. The adjusted cash R&D spend of $89.6 million, which excludes that stock-based comp, reflects an 18% increase from the comparable amount in the fourth quarter of 2025.

On the G&A side, our spending for the quarter was $20.4 million, of which $7.4 million was noncash stock-based comp and the adjusted cash G&A spend of $13 million, again, excluding that stock-based comp, reflects a 30% increase from the comparable amount in the fourth quarter of 2025. I should note that this quarter's G&A growth was elevated relative to our typical run rate, primarily driven by the timing of certain expenses.

And with that said, we expect G&A growth to moderate in the coming quarters. And finally, we ended March with a cash balance of $1.55 billion, providing a runway into 2029. This allows us to complete both the KT-621 Phase IIb trials in AD and asthma and to fund a large part of the first Phase III trial for KT-621 in AD.

The runway also allows us to advance KT-579 through initial proof-of-concept testing to progress our research pipeline and to grow our organization and build our capabilities as we prepare for later-stage development and ultimately commercialization. Overall, we remain well-positioned and well-capitalized to execute on our clinical programs and pipeline.

With that, we'll pause while we regroup in our conference room and assemble the queue for your questions. Thank you.

[Operator Instructions] Our first question will come from Ellie Merle with Barclays.

This is Jasmine on for Ellie. I just wanted to ask a bit more about the IRF5 data at healthy as we expect later this year. So in your remarks, I know you said you're looking for 50% to 80% modulation of the biomarker pathways in the ex vivo stimulation assays. Can you help us understand a little bit better how you get to that threshold and elaborate on what you would expect this to translate to clinically?

Yes. Thank you. Maybe I'll start and then pass it to Jared to spend a bit more time on the details. So obviously, whenever we set out these expectations are always based, especially for the first human translation or our preclinical data. Just remember, this is a critical node that actually intersects 3 key pathways. So we see that when we block this node, even not even -- we don't need to even get above 90% degradation, we're able to see modulation of a series of downstream biomarkers. Maybe, Jared, you can speak to how we come up with those numbers.

Yes. So the we assess these pathways, in particular, the TLR7/8/9 pathways with ex vivo stimulation of whole blood. That's how we're planning to do it in Phase I using agonist to the TLR7, 8 and 9 receptors. So essentially, the way we came up with 50% to 80% is that our expectation based on our preclinical in vitro data is that if we're able to degrade IRF5 by at least 90%, we should be able to see that range of blockade of these particular pathways.

Now that 50% to 80% is approximate-- whether we end up seeing within that range or more than that remains to be seen. But that's an approximate level that we would expect to see of inhibition in conjunction with at least 90% degradation of the target.

And maybe just to add, if this was a single pathway, like we've seen, for example, 621 with STAT6 and we have a downstream biomarker that is activated, obviously, we expect complete blockade of that one biomarker.

But given that these are multiple pathways and this pathway is also signaled through other receptor, this is why there is a range because it depends on what pathway, what stimuli, what biomarkers. That's how -- that's why there is a bit more nuance into this biology.

Okay. That's helpful. And then one quick follow-up. Should we expect enrollment completion for the 621 AD study as more of a near-term event or likely later in the year based on the trends that you're seeing?

Yes, great question. Look, I think we've said from the beginning of the study, we expect to complete enrollment by the end of the year. So we're going to stick with that guidance. I think the expectation will be that when we complete enrollment, we will communicate it.

Our next question will come from Brian Cheng with JPMorgan.

It's great that you have laid out the expectations for IRF5 degradations in healthy volunteers. But just kind of looking ahead into lupus patients, do you have a sense of the level of IRF5 degradations that we need to see in lupus patients where you start to see some clinical benefits?

And in other words, is there a minimum threshold of IRF5 degradation that you need to hit in patients? And for this mechanism, how translatable is it from healthy volunteers to patients in terms of IRF5 degradation?

Yes. No, thanks, Brian. So let's start with what we're trying to do here. So as we've done now, this is the sixth program, the human translation is focused on understanding key parameters, which is what is the exposure and dose needed to achieve a level of degradation X and then what level of degradation X translates in terms of clinical benefit as well as safety in patients.

So we always do this in multiple steps, as you know. So right now, what we're trying to figure out is what is the dose and exposure that gives us the level of degradation that we believe is therapeutically relevant. Based on preclinical data, and as you know well, if we -- if the preclinical model -- animal model data will always translate in humans, we would have cured all diseases.

So all this preclinical data has to be taken with a grain of salt. But what we've learned preclinically is that as low as, let's say, 80% degradation is sufficient to drive, let's say, efficacy benefit in this mouse model, benefits that actually are comparable, in many cases, superior to standard of care or drugs in development.

So with that in mind, our goal is always to being able to demonstrate more than 90% degradation because that gives us the flexibility to then titrate pack in a dose-ranging study and establish as we're doing for 621 now, what is the level of degradation needed to achieve maximal and minimal efficacy.

So that's the same we're going to do with 579. I think we want to establish, as Jared said, robust degradation. We want to see more than 90%, knowing that that might not be necessary. But for us, I think it's important to demonstrate that. And then translation of degradation between healthy and patients, which was the second part of your question, historically, we have never seen a difference of degradation between healthy volunteers and patients.

Remember, these are catalytic molecules that do not perform depending on expression of targets, but actually perform depending on exposure of drug and thresholds of exposure. So we expect that whatever we see in healthy volunteers will translate in patients. We've shown that with 621. We've shown it with IRAK4. We've shown it also in other programs in other disease areas.

Our next question will come from Faisal Khurshid with Jefferies.

This is [indiscernible] on for Faisal. Just wanted to ask about the initial enrollment in BROADEN2. Have the initial patients tracked with your expectations with respect to the baseline characteristics?

Thank you. Great question. So I think we're not going to comment on what -- where we are with baseline characteristics. I think it's a bit of a futile exercise until we complete the study and share the data. What I would say historically, we've said that if you look at the early dupilumab studies, the baseline entry criteria in terms of severity of disease have been historically higher, meaning more severe than more recent studies.

And that have been -- we said also historically that there are maybe 2 main reasons. One is that given that there are drugs on the market, more severe patients, especially in these highly advanced sophisticated clinical centers.

So more severe patients have access to these therapies. And also generally, the other main reason is because of the competitive landscape and the general, again, way that sites and investigators enroll in these studies, you've seen a bit more of a less severe population in studies.

And I'm not talking about our studies. I'm talking about studies in the past, I would say, 5 to 6 years. So we continue to have this expectation that a study that is run today, a global study has a mean baseline that is in the mid-20s based on what we've seen historically, what we've seen in the Ib. But I'm not going to comment about what we're seeing in the current study. We'll do so when we release the data.

Our next question will come from Brad Canino from Guggenheim. Brad is just asking this question, we'll just move on to Biren Amin with Piper Sandler.

Can you hear me now? Great. Okay. Maybe just to start [indiscernible]

Biren, it's not working. Maybe you can try again in a bit or I don't know if you're underground. Give it a shot in a couple of minutes, we'll circle back.

We'll move on to Brad Canino with Guggenheim.

Good developments with Gilead and the molecular glue for the CDK2. I'm wondering if you could just discuss what technology advances the Kymera scientists have been able to unlock for this technology and how to achieve the needed protein-protein interactions. And should we expect more named pipeline molecules to emerge as glues over the next few years?

Yes. Thanks, Brad. And you know -- I think you know Kymera well enough to know that we've always looked at the technology as a mean to unlock value for patients through going after difficult to drug or undrugged targets. And so we always look at what is the right technology for the right target. So CDK2 is a very interesting problem, right? We know that if you have CCNE amplified tumors, there is a mechanism of resistance to 4/6 that goes to CDK2.

If you can get to CDK2 either alone or probably more excitingly in combination, you can really have profound effect in breast cancer and other type of solid tumors that unfortunately affect lots of women. And so what has been the challenge with CDK2 has been that there is a high structural homology between CDK2 and CDK1. And CDK1 doesn't actually bring any benefit to efficacy and actually only brings safety issues.

And the comment I made earlier, which I'm really comfortable standing by, I don't believe there are absolutely selective CDK2 agents out there, at least in our hands. And so you're going to run into dose-limiting toxicity. I'm sorry if I'm going too long here. We're going to run into dose-limiting toxicity because CDK1 comes in play, and you actually do not exploit fully the power of CDK2, either mono or in combination.

So why we're using molecular glues for this target is because in the traditional binding site that people use for CDK2, which is the ATP binding pocket, there is just a high structural homology. We have published on an ATP binding site based heterobifunctional degrader and while we were able to have enough selectivity, it wasn't good enough for us.

So we moved on from that effort. And so we said, how do we get absolute CDK1 selectivity. We did it through a protein-protein interaction enabled molecular glue that is outside of the ATP binding pocket. So this is the kind of the premise to my answer, which is, yes, I mean, you should expect Kymera to have other programs from our pipeline that will use this concept because this is just a continuation of protein degradation.

It's just, again, solving a different problem with a slightly different solution. And yes, we expect to see more from there in any therapeutic areas. This is not just relegated, let's say, to oncology.

Our next question will come from Geoff Meacham with Citi.

This is Nishant on for Geoff. I want to go back to the data you presented at AAD. So in terms of the body surface area, you saw higher reduction at 100 milligram versus 200 milligram. So you didn't see much dose response. Is this simply like a small sample noise or is there like a pharmacological explanation such as like maximal degradation plateau effects?

Yes. Actually, I'll let Jared actually speak to the data. I just want to remind you and everybody that 100 milligrams and 200 milligrams gave the same degradation. Hence, we expect to see similar activity. But Jared, maybe you can speak to BSA, which I actually don't remember.

Yes. If you look at the error bars on those graphs, they're actually overlapping. And so the differences between 100 milligrams and 200 milligrams are really not significant differences, and it's probably a function of the small ends.

I think whether you look at BSA or EASI or the other clinical endpoints that we looked at through 4 weeks in that study, you don't always see complete overlap of the curves, but you do see overlap of the error bars. So I think that tells us that we're seeing comparable activity across doses across multiple different endpoints.

Got it. And then just a follow-up on that. In terms of EASI versus BSA, you see like a gapping magnitude, again, given like it's a small sample size. Is this expected given that EASI captures both extent and severity while BSA measures just extend alone. Does this suggest to you that there is deeper severity improvement with this molecule versus surface area clearance at 4 weeks?

Can I just jump into this, Jared? I'm not going to actually address the specific question. I just want to say that we've said -- I've said multiple times, let's try not to overinterpret the individual numbers in such a small study with, as Jared said, the confidence interval between the 2 doses were almost completely overlapping.

I think the important take home from the study is that all these measures showed a robust effect, consistent across all measures and consistent with upstream biologics. But Jared, if you want to add on the particular topic.

No, I think your point is the main one. I think BSA and EASI, there are overlapping but sort of distinct measures, right? As you said, BSA is looking more at the extent of disease. EASI is taking into account both the sort of severity of individual lesions as well as the extent of disease. So there's an overlap there. But the bottom line is that we're seeing a comparable robust effect on both of those endpoints with KT-621.

Our next question will come from Mayank Mamtani from B. Riley Securities.

Congrats on the progress. So on STAT6, there's a lot of activity in the inhibitor landscape, for example. So I was just curious what questions, Nello, you have for some of these highly potent claim to be selective approaches emerging. From the preclinical data, KT-621 does stand out based on whatever is available, but we'll probably get some clinical data next year from you and others.

So just curious, how do you expect the clinical data here to maintain your leadership? And then just quickly on the 621 physician excitement maybe between AD and asthma and recognize you are yet to present your data at ATS next month. Any thoughts on between the 2 indications, the importance of oral versus maybe less frequent injectable? Like if you've teased out what matters more to the different set of clinicians?

Okay. Well, those are 2 robust questions. So on the first one -- thank you. So on the first one, small molecules, degraders, we've touched on this also extensively in the past. So first of all, recognize that STAT6 has been seen as a key difficult undrug target by huge potential for more than a decade.

So it's actually quite exciting to see so many companies, large and small, pouring hundreds of millions of dollars into this mechanism, mostly, I would say, following the exciting data that we started to share as early as January of '24, but obviously, we've been working on these targets for multiple years. So I think it's great, first of all, that there is a lot of enthusiasm around this target.

The reason why we believe that degraders are going to be highly differentiated is because we are so fortunate that while obviously, technology requires a level of understanding that is not easily commoditized yet. So these molecules, though, with obviously, the challenge that it takes to make highly specific component degraders, the upside is that they are catalytic in nature and require exceptionally low exposures.

We're talking about nanomolar to picomolar to completely remove STAT6, which allows us to have complete degradation at very low doses and importantly, at very low exposures so that we can deliver a drug once a day. And actually, technically, you could probably deliver a drug less frequently than once a day. With a small molecule inhibitor, as you know, you're inhibiting stoichiometrically the target.

So one molecule blocks one protein. So for this type of protein, you require a large amount of molecules in the body, in all tissues for 24 hours. And this becomes a challenge with regards to PK exposure, safety, safety therapeutic index.

And so in our experience, and I think we've said this publicly, we've invested actually quite heavily in small molecule inhibitors to actually answer the question, do we need a degrader if an inhibitor is good enough? Our answer is, yes, you need a degrader because inhibitor can't quite reach the level of pathway blockade that a catalytic degrader can.

So I think the beautiful thing about drug development is at the end of the day, I can spend the next hour trying to convince you that I'm right. But the best thing is that we'll generate data soon enough. And I think that will be the final nail on the cockpit on this argument for us, I hope.

With regards to your second question, so we've had the fortune and hopefully, we did also something good about generating and importantly, presenting our data in many medical conferences. We were fortunate to be selected at the podium at [ EADP ], which I believe was probably the first time for healthy volunteer data, I might not be sure. And then we presented at AAD.

We presented [ ATS/T ] preclinical data we'll present later. So there is a very high appreciation from the medical community, both AD and asthma, about the potential of an oral drug in this space. I just want to remind you, whether it's AD or asthma, the majority of patients are not controlled well or not treated well with either local therapy like inhalers or topicals and not enough of them are on advanced systemic biologics.

So our goal is actually -- our goal is not to compete with less frequent dosing. That might come in place. It's just the market dynamics. But we're actually trying to mobilize the millions of patients that are sitting on the sidelines because they feel or their prescribers feel they're not ready for an injectable biologics, and we offer that biologics like oral pill that would change their lives.

And so I think what we're seeing in other disease areas, it's a complete different paradigm shift. And that's really what we're focused on. I think this obviously resonates with investigators and more importantly, resonates with patients based on our experience.

[Operator Instructions] Our next question will come from Judah Frommer with Morgan Stanley.

Maybe just building on the last one, I think it's fair to say you've established a sort of playbook for Phase I studies in AD. So just curious to get your take on that excitement for 621 on the oral aspect versus the mechanism aspect. There are others going after oral drugs, but maybe in more novel targets.

So the level of excitement for the oral nature of the drug, but also the fact that you're hitting IL-4/13, which is so well understood by docs. And then just within the landscape, curious specifically maybe on anything around IL-18 that you see as interesting within AD or more broadly and how that could apply to the IRAK4 program.

Yes. Thanks, Judah. I like your 90 years in your backdrop. You're 80 years older than Kymera at Morgan Stanley. So yes, to answer your question, I think you put it exactly right. The reason for the excitement for 621 is not just about the oral drug. I think it's the combination of oral, which is needed in this still early market, but combine it with the sense of understanding and comfort of a well-validated pathways like IL-4 and 13.

And I think that's really what's making this drug and this program very unique in the space. I mean, as you know well, there are several other potential oral mechanisms out there, which, to be honest, I hope that they have a path forward beyond early Phase I data. I think, obviously, what the burden approved for a mechanism in the IL-4 and 13 pathway, I assume, is a bit less than it is for completely new pathways with completely unproven efficacy and safety. So I don't know, Jared, if there was anything to add to the second part.

Yes. And the only thing I would add to the first part, too, is just around -- because you talked about mechanism, Judah. And I think there is an appreciation that the unique PPD mechanism, that catalytic mechanism of action that can lead to durable, maintained complete target suppression and pathway suppression that equals what you can get with upstream injectable biologics.

I think that's a big selling point here with regard to degraders versus small molecule inhibitors. You asked about IL-18. I mean, IL-18, some of those initial data coming out of [ autoimmune ] are interesting, right? And I think it sort of speaks to the fact that AD does not have this one flavor of inflammation, right?

Obviously, Th2 is one of the main drivers of the pathophysiology, but other types of inflammation, whether it be Th1, Th17 driven, probably have some contribution as well and seeing activity with the drug targeting IL-18 probably speaks to that.

Again, it was not as well validated a pathway here in AD. It's interesting to see the results coming out of that. And it makes one think of interesting possibilities down the road maybe for combination therapies by bringing on other drugs that are hitting other types of inflammation in addition to Type 2 inflammation.

Our next question will come from Biren Amin with Piper Sandler.

Can you hear me? All right. So on BROADEN2, I noticed in the press release that you're also including adolescents in addition to adults in the trial. But I think more recently, there was some inclusion criteria changes in the trial where you're now requiring, I think, adult patients needing at least 3 years of chronic disease, whereas with adolescent, it's a requirement of at least 1 year. Can you just maybe talk about the implications of that change?

Yes. So I mean, the addition is the inclusion of adolescents to the study. Again, this is part of our overall strategy to change treatment paradigm for adult and more importantly, I would say, for young children and adolescence is step one, right?

This is a disease of young children usually diagnosed in the first probably 6 years of life. And a drug like 621 could have a huge potential in children. So that's the main reason why we want to study this drug in younger population as early as possible. Jared, I don't know if you want to comment to the inclusion/exclusion criteria.

Yes. I think in terms of exclusion, the Hanifin and Rajka criteria, right, for AD, like you want to make sure that your patients have AD. So one element of that to make sure you're getting patients with that diagnosis is they need to have a diagnosis for a certain number of years.

So for adults, obviously, because they're older, the cutoff there is at least 3 years. With adolescents because they're younger, had the disease for a shorter period of time, there's a 1-year cutoff. And again, the reason for both of those is to give you increased certainty that these patients truly have a diagnosis of AD.

Got it. And then maybe just one question on IRF. There's clearly IR translocation in naive B cells, plasma blasts and monocytes in patients with lupus. I know translocation in healthy volunteers as well, but is there anything you could do ex vivo to evaluate the impact of IRF degradation on translocation?

Yes. It's unlikely that we're going to see activation or translocation of IRAK5 in healthy volunteers. So I don't think that's what we're going to be looking for. We're going to be, as Jared said, looking at ex vivo stimulation of the blood with or without translocation. Again, I think there's probably close to 0% chance we'll find that in healthy volunteers, but we'll interrogate the pathway regardless of that.

Our next question will come from Alex Thompson with Stifel.

Maybe again on the ongoing AD and asthma studies, can you talk a little bit about kind of more color on enrollment progress, site activation, your level of oversight of these sites? And then maybe could you tell us how many patients have been dosed at this point across both studies that would be helpful.

Yes. No, obviously, great question. As I said, we're trying not to comment on these things, not because we want to be secretive. I think it's only productive to do it at the end. I think what I can say is that the studies are on track, both in terms of site activations and patient enrollment.

And so the time lines that we put out are obviously still relevant. As I said, I think the best way to manage this particular question is as soon as we complete enrollment, we will communicate and then maybe then we can answer more specific questions about what we've seen and pace of enrollment, activation, et cetera.

Our next question will come from Marc Frahm with TD Cowen.

Maybe just back to prior comments about the attractiveness of oral options and the enthusiasm also for the mechanism. Maybe can you contrast 621 with the IL-23 space because we're seeing that launch just starting now in the psoriasis space.

And just how much should we view the success, hopefully, of that product as a proxy for 621 versus how different do you think these markets are in terms of their eagerness for an oral therapy?

Yes. Thanks, Marc. I don't want to hitch our wagon on to any other mechanism or drugs because we don't control those. But it is a fair point that I think we're seeing finally something we've been saying for a while, which is novel oral mechanisms that can deliver, in some cases, close to biologics like activity having a ton of enthusiasm.

Obviously, the psoriasis market is very mature. There are drugs that you can dose every 3 months or even less in some cases that are extremely effective. We're seeing even less frequent dosing. Obviously, you start to wonder what's the driver for that, but that's likely is not what we're working on.

And so the question is very mature market, can an oral drug with good efficacy and safety even impact the landscape? And it looks like it will. I mean I was at AAD and lots of -- not to advertise for J&J, our friend at J&J, but lots of dermatologists were super excited about that drug. So clearly, even in a well-established, super mature market where there are already multiple blockbuster drugs, a drug like that seems to be highly differentiated.

So we're talking in AD where there is no oral drug with good safety and efficacy. There is really only like 2 category of drugs approved, and IL-4, 13 and then all these other IL-13s that are not differentiated and JAK inhibitors. So this is where psoriasis was 10 years ago. So bringing to the market something that is so differentiated, so early in the treatment in the market evolution, I think will have a much bigger effect than what we might be seeing IL-23 in psoriasis.

So I think it validates, but more importantly, I think our opportunity is probably much more impactful given the -- again, the maturity of that market. One could point to the obesity space, but that's a whole different market dynamics. But you're seeing also there, these new orals are activating all new patients, mostly new patients, right? And that's really what our -- I think what many of these oral drugs are there to do is to really serve the millions of patients that are not on these advanced therapies.

Our next question will come from Joe Catanzaro with Mizuho.

A quick one for me on along the lines of 579's preclinical data at DDW and maybe also your comments on mechanism earlier. But there seems to be a growing effort towards developing combination therapies in IBD. So I wanted to ask about IRF5's mechanism and where you see it as most orthogonal or complementary with existing mechanisms in IBE like alpha-4 beta-7, IL-23, TL1A.

Yes. Fortunately, I'll let Jared answer this one. So Jared, I'll give you 30 seconds to come up with an answer why I say what I'm going to say. So fortunately, I think what we're trying to do here at Kymera is bringing a completely new mechanism to the IBD space, hopefully. Obviously, we haven't committed to developing in that space yet, but versus obviously combining existing mechanism or other things. But Jared, maybe you can speak to the science.

Yes. I mean I think one of the great aspects of IRF5 is that it really controls signaling through multiple different pathways. We talked about Type 1 interferon. We talked about B cells and autoantibodies, but also myeloid cells, monocytes, potentially neutrophils, also dendritic cells. And when it comes to inflammatory bowel disease, the myeloid component, in particular is very important in diseases like ulcerative colitis, for example, where you have cytokines like IL-12, TNF, IL-6 and others that are driving that inflammation.

And so I think being able to target IRF5 in IBD really helps get at that particular component of inflammation that's really important in ulcerative colitis and will lend itself to potentially combining with other mechanisms that go beyond those particular pro-inflammatory cytokines if you want to be able to tackle multiple different aspects of the pathophysiology of a disease like UC or Crohn's.

So I think that's the beauty of it. I think the other aspect is the potential safety profile of IRF5 and being able to knock IRF5 down hard and not really having to be risk of infectious complications that also will lend itself to combinations.

Our next question will come from Jeet Mukherjee with BTIG.

Maybe coming back to the market opportunity for KT-621. Nello, before you mentioned you're looking to mobilize patients on the sidelines because they aren't ready for an injectable. Could you maybe put some numbers or quantification around how big that population is on the sidelines due to needle aversion or phobias around that, particularly in atopic dermatitis?

Yes. Yes. I mean -- and to be clear, I don't think what's driving that is needle phobia. I mean there is a percentage of it. I think it's probably relatively a small percentage. I think most of it is, again, it's the barrier to an advanced systemic injectable therapy that both prescribers and patients have for just accepting or feeling like there is a need of having a protein injected in your body for a disease like atopic dermatitis.

I think that's really what's blocking people for transitioning from topicals into advanced systemic therapies. And the numbers are out there, we talk about -- there's probably 40 -- if you just talk about AD, there's probably 40 million patients with moderate to severe AD. But maybe it's easier to do -- we have the number of 50 million that includes also other Type 2 inflammatory diseases.

So only -- really only almost less than 2 million patients have received [indiscernible], Nivo, RINVOQ in these diseases. So some companies do the math differently, but those are the numbers. If you look at diagnosed moderate to severe patients, we're talking about tens of millions of patients. If you look about treated patients with this advanced systemic therapy, we're talking about less than 2 million. So that's the opportunity, and that's far greater than, for example, the opportunity in psoriasis these days.

So I think it's really hard actually to put the value on 6:1 right now. I think a lot of us are being quite conservative for a good reason. We're still relatively early in the development of the drug. But I believe strongly that post this Phase IIb data, we need to get much more, I think, aggressive with what we're really talking about. And I think maybe that would be a good time to talk about more discrete numbers.

Our next question will come from Sudan Loganathan with Stephens.

My question is on the 621 program for asthma and related downstream indications. As we get our first look at asthma data in the late 2027, does that outcome dictate read-through and investment in going forward with COPD and other related indications? And also, are there any other go/no-go decisions much like this coming in the next 12 months as we start seeing more data for 621?

Yes. No, I think as we said, thank you multiple times, it's really about dose selection. We hope to be able to take the Phase III dose that we'll use in asthma in other diseases. We have absolute confidence that this drug will work in all Type 2 diseases. So we're really waiting for the Phase III dose that will come out from the Phase IIb asthma study.

And our next question will come from Kripa Devarakonda with Truist.

This is Anna on for Kripa. Just one question on 621. I know you haven't disclosed the doses that you're going to be pursuing, but I was just wondering if you could give us a sense of the dose response range you're hoping to show with the 3 doses.

Yes. So I don't think we're going to get into it. I think we always think about the opportunity to explore a lower dose in which you'll see less activity for both kind of mechanistic and regulatory reasons. And then obviously, a dose that would be optimal to move forward within the 3 doses. And so that's how we're thinking about the dose selection.

Our next question will come from Brian Abrahams with RBC.

So on 579, as you think about optimizing its therapeutic window, you mentioned you'll be looking at degradation and some of the biomarkers. Anything specific that you're going to be looking out for on the side effect side there, just based on the mechanistic or preclinical data? Is it just over-suppression of the immune system or any other things that IRF5 or the other IRFs may be involved in metabolism, epithelial cells, et cetera? Thank you.

So based on preclinical data, we really haven't seen in animals at least adverse events of meaningful impact. And so -- or any actually. And so the question is always this theoretical infection risk. We know that all the IRFs are contributing to pathogen surveillance. And so we believe that removing only one should not have an impact on that. So I think that's -- we'll see, obviously, as things progress. But we don't expect any particular adverse event here with this drug of note.

Our next question will come from Tazeen Ahmad with Bank of America. My apologies. We now have Derek Archila from Wells Fargo.

This is [ Hal ] calling in for Derek, thank you for the question. So we were at AAD and we hear also KOL noting KT-621 as the most promising candidates in AD. A question on the efficacy. I think they wanted perfect safety.

On the efficacy side, I think we are hearing that even if it's less effective as to -- some of them point to 70% as effective, others using Otezla as an example, they will still be very excited. So I guess my question is like what you are hearing on what's enough to kind of really mobilizing those patients with not on biology, but be open to this oral option.

Yes. I mean you said it. I think I agree with you. And obviously, we've heard the same things. which is you don't need to have biologics like efficacy to mobilize millions of patients from topical therapy. Again, the only reason why we keep pointing to a dupi-like profile is because this is the data we've seen so far. But if we end up seeing less, I think this could still be a huge drug in the space.

Thank you. Well, that's all we have time for questions for now. So I'd now like to turn the call over to Nello Mainolfi for closing remarks.

Well, thanks, everybody. I'm sorry, we kind of ran out of time, and hopefully, we didn't leave anybody behind. But we're always available to take more questions offline. Thanks again for following us and for all the engaging questions, and see you soon on the next one.

Good morning, everyone. Thanks for joining us on the final day of the Barclays Global Healthcare Conference here in Miami. I'm Ellie Merle. Very excited to have Kymera Therapeutics here with us today. They have one of, I think, the most exciting platform technologies in biotech. Joining us from Kymera is Bruce Jacobs, Chief Financial Officer, for a fireside chat.

Bruce, thank you so much for making the time. Maybe just high level to start, can you give us an overview of Kymera as a company and your growing pipeline in I&I?

Sure. Ellie, so first of all, thanks for having us. I think this is the OG Miami March Conference. So we're happy to be ending our week here. So thank you. Yes. So it's a good time to ask that question. Kymera is actually coming up next month on our 10-year anniversary of the company's founding.

From the beginning, the company was founded to really capitalize on this exciting new modality, targeted protein degradation. And we approached it in a, I would say, a little bit of a unique way with a very disciplined, and I would argue, strategic approach to target selection, where we went into this company formation, this endeavor with a focus on targets that had not been addressed with conventional technologies, conventional small molecule technologies, where there were large markets of unmet need, but where there were proven and known biological pathways.

And we thought in doing so, we could really ultimately derisk the molecules that we were developing. And the company started with an approach that had both oncology and immunology in our sights. But a few years ago, several years ago, I should say, when we met with some success in our first immunology programs, we really narrowed our focus to these immunology targets.

And as a result, you see the pipeline that we have today. We built a team of upwards of 250 people with, I'd say, some incredible strength in lead discovery, in chemistry and really capabilities across what you would need as a biotech company to prosecute this pipeline. And we're excited about the programs that we're developing, those that you don't know about, but we will soon and really excited about the future.

Programs that we'll learn about soon. Any more color on timing?

No, I think we've said that historically that our goal is always to introduce one new program annually. So this year, hopefully, will be no exception. We've recently said that we would expect probably in the second half of this year to introduce our next program, likely in immunology, but we'll -- you'll have to wait for more than that.

Great. Well, we certainly look forward to that. There's a lot of companies in the targeted protein degradation space. Maybe I think its probably the leader in the space. Can you talk about why you think your approach is differentiated?

Sure. To say it's differentiated requires us to know everything others are doing, and that's sometimes from the outside hard to know. But I would say that probably from the beginning, the target selection approach that I just alluded to a moment ago is perhaps what made us unique.

Now others have followed us. So we're not alone in many of the targets we're pursuing today. But across our existing pipeline, I think what you see is really high-value targets that don't have good solutions. If you talk about -- we'll talk about, I'm sure about the STAT6 program.

We'll talk about IRF5, I would guess. Those are long targets of great interest for a long, long period of time across pharma. And because of the capabilities we've built, again, in lead discovery and also in all the work we do in lead optimization, our chemistry teams and others, I think, have unique capabilities to really prosecute those very, very difficult to address targets.

And I think that's where a great opportunity is to ultimately achieve our goal, which is to bring drugs to market that serve these patient populations that are large but with really significant unmet need.

So to me, that's where a lot of the unique aspects of Kymera come to the forefront. There's definitely a sense of urgency and intensity about how we have built the company and what we're trying to do because I think you need to have that intensity and that urgency with the size and scale and scope of some of these problems that we're trying to solve.

Absolutely. Well, it's a great place to talk about STAT6. Walk us through the data that was seen so far. And in particular, like atopic dermatitis is becoming an increasingly competitive space, not that there aren't a lot of patients, but sort of where do you see STAT6 fitting in this overall landscape?

Great. So last year, obviously, was a big year for Kymera and for our STAT6 program, both in June and in December, we had really, I think, important, and we would argue and believe derisking data releases first in healthy volunteers in June, where our principal goal was to show that we could degrade this target, which, again, the first to show that down to the levers -- lower limits of detection really and do it in a safe manner with really, I would argue, pristine safety in that healthy volunteer study.

And that helped us move then into a patient cohort, understandably small, 22-ish patients. But again, very, very compelling results, we believe, where the degradation again reached those lower limits, 94%, 95%, 98% range of degradation, almost to the point where it's very difficult to measure STAT6 in the blood and skin.

And for the first time, we were able to show an impact on some of these clinical endpoints, EASI scores, itch, quality of life measures that while it's very difficult to compare across different trials, I think gave us increased optimism that this pathway does indeed do what we expect it to do, that it has the same similar impact as blocking the IL-4/13 receptors, but doing it by eliminating STAT6 that is downstream from those receptors.

So very encouraging results, certainly in the intended patient population, which is atopic dermatitis. And we also had a chance, as you recall, to look at some patients with comorbid diseases, particularly asthma, which is the target for one of our Phase II studies that's currently underway, and we saw some encouraging signs there as well.

So everything that we saw in that patient cohort really supported what we've been able to build preclinically in terms of the overall package, which is that if you can block STAT6 fully, there's the potential to show activity that looks a lot like competitive biologics out on the market, obviously, Dupi being the most significant one.

And we do think there's a tremendous opportunity to bring an oral agent to this market. Dupi is an incredible drug, very efficacious, great safety track record. It does, though, obviously require injections, which is not ideal for all patients.

And there are a large number of patients in the -- if you look at the broader Th2 population that are untreated or at least treated with non-advanced systemic therapies treated with steroids and the like.

And that tells you that there's patients looking for better solutions. And if we can, as a company, deliver an oral alternative that has comparable efficacy and safety profile, which, again, we'll need to prove in the future studies, we think the market opportunity would be significant.

So we're excited about what we were able to share last year. This year is a big year for the STAT6 program in terms of execution. We started the atopic dermatitis trial late last year. We're well on our way with that and plan to complete enrollment before the end of this year, share data by mid-2027.

And the asthma trial also has started. That began a little bit later. We just spaced them out more for operational reasons, but that began earlier this year. and we'll enroll that trial through this year and into next year with a plan to have data by the end of 2027.

So we're focused intently on executing on those 2 studies. Obviously, we have some other programs we can talk about. But for STAT6 and KT-621, that's our primary focus this year.

Yes, absolutely. Those are certainly very, very important readouts next year that we're all eagerly anticipating. But I mean it's interesting, right, atopic derm, I mean, as an oral, you could show efficacy that's probably less than Dupi and have a large market. But here, in my view, you're showing signs that you could potentially be better than Dupi. So how are you thinking about that in terms of what's been seen in the preclinical models and the data so far? How you think you compare? And I know it's early, and we'll have to wait for more data.

So you know us well enough to know that we try not to put very specific bars and hurdles out there for -- particularly for clinical activity. The primary focus of our efforts with these Phase II studies is to, first of all, show that we can translate everything we've seen in the smaller patient studies in our healthy volunteer studies in animal models into a broader trial, randomized placebo-controlled trial in AD patients.

So we want to show that we can translate the level of degradation and ultimately, hopefully, we'll see the similar clinical activity. The other goal, if not probably, frankly, the primary goal is to allow us to select a single dose for a Phase III study.

So this will be 3 active doses. We haven't disclosed what they are, but 3 active doses and placebo. The objective would be for the AD side to move into a Phase III study with 1 single dose in AD, similarly for asthma to move into a Phase III study with one single dose.

When it comes to the efficacy profile, I think, obviously, we will see. Our view is that we would like to be in -- we use a very scientific term in the ballpark of what Dupi has been able to show. Whether it would be slightly better, slightly worse, comparable, I think that's what we'll learn from the data.

But I think if we can be in the ballpark, I think we'll have a very, very competitive drug given the size of the population out there that really is -- would be excited about an oral alternative to these injectable biologics.

And in terms of the Phase IIa data, I thought you have a late-breaker presentation coming up. What should we be looking to see there?

So we're very excited about that. Obviously, investors love data. So we don't always have the luxury as an earlier-stage biotech company to wait for these big scientific meetings to share our data. So we shared the healthy volunteer data in June. We were able then to do a late breaker for that data last fall at the AAD conference, which was great because it really gave us the opportunity to present the data to a broad universe of clinicians out there.

Similarly, for the patient cohort, which we shared with you all in December, we do have a late breaker at AAD later this month. And again, it's a great opportunity to share that data more broadly. The response out of the AAD was phenomenal. We had a standing room-only audience.

We're hoping and expecting a similarly large following when it gets -- when it comes to AAD. And one of the intentions of the Phase Ib is to build some excitement around the program, which we think will contribute to excitement around the enrollment for the Phase II studies.

And so having this data at the AAD conference, I think, will help build some more awareness of and appreciation for the data. You shouldn't expect there to be anything incremental. It's really a kind of a rehash of what you all have seen. But again, for some of these folks in the audience, it will be new.

Aside from that, we will expect to be active this year sharing data. Most of it is things you've seen, although we have a small Japanese study that was done in healthy volunteers that we haven't yet shared.

We said it's consistent with what you've seen in U.S. healthy volunteers. We'll share that. We're also working on a couple of publications this year that we hope will make it through. And so it will be an active year of getting the word out there about the STAT6 program, but less so on incremental data.

Okay. That's really helpful context. In terms of the data, I just want to -- we talked about atopic dermatitis, but I think what's so interesting about this target is the potential to work in so many different indications. Could you elaborate on what was seen in the atopic derm patients in the subset that had comorbid asthma?

Yes. So thanks for asking that question. So one of the exciting -- many exciting parts of the Phase Ib study were that we're able to look at some comorbid diseases and the impact that KT-621 had on those patients. And there was a small group of asthma patients with comorbid asthma, 4 patients in total. So understandably a small selection.

But we saw some impressive results there. So I would say, a meaningful reduction in [ FeNO >50. ] And I think that what that told us is that drug is getting into the lungs and has promise in that indication as well.

Obviously, we saw some nice easy reductions and itch reductions that gave us increased confidence that AD is going to be obviously a very meaningful potential indication for 621. But getting this additional data in asthma in a study that was really designed around 80 patients was a nice incremental piece of information. I think it was a surprise to investors.

We hadn't talked a lot about doing it. But we felt going in, frankly, that given what we know about the pathway that we had good reason to believe that 621 would be applicable and impactful in all the diseases where Dupi is approved.

And I think that asthma data just put one more piece of data behind that confidence that we have in that likelihood. So we're excited about that. Again, another piece of data that hopefully will help build excitement around the enrollment in the asthma trial, which is ongoing right now.

And so Dupi is approved in many more indications beyond just AD and asthma. So let's fast forward next year, this hypothesis plays out. We see positive data in AD and asthma, and you move forward into Phase III in both of those indications.

Then you're also sitting on the decision of how many more Phase IIIs do you start and how much do these costs. So walk us through the calculus, how you're thinking about that indication selection and sort of the phasing of all of these Phase III starts.

Sure. Great. Well, so if this drug is effective and safe as we believe it will be, I think our ultimate goal is to be approved everywhere Dupi is approved. And so the question really then becomes what is the timing and sequence of those pursuits.

It would require upwards of 20 Phase III studies to achieve approvals in all of the indications. That's an endeavor that if you try to do that concurrently, I don't think any company could do it let alone Kymera. But that having been said, I think we have a very deliberate strategy about expanding the indications we're going to be pursuing.

And it's predicated on a development strategy that has these 2 Phase II studies in AD and asthma, really effectively supporting subsequent work in both dermatology indications and in respiratory indications. And so the hope is that once we complete these Phase II studies, it will position the company to be able to start other Phase III studies even beyond AD and asthma.

And so we haven't shared a ton yet about the sequencing strategy. I would say that if you look at the current Dupi market, AD, asthma, EoE, COPD accounts for the lion's share of the market. So one can assume that those are probably likely to be prioritized by Kymera, I can tell you that much.

In terms of the exact timing, I think we'll share more as we move forward. The other really important part of our clinical development strategy will be finding a way as quickly as possible as we can into the pediatric population.

And historically, the protocol is that you complete a Phase III in adults and then subsequently move into Phase IIIs with pediatrics. We will do everything we can to get this drug ultimately into the hands of younger patients as quickly as possible, understanding that ultimately, the FDA will dictate how we get there.

But that's just a market of enormous unmet need. Again, Dupi is a wonderful drug, incredibly efficacious and safe, but it's not a pleasant injection. And if you're a parent injecting your 6-year-old, it's not a happy time. So I think if we can make this product ultimately accessible to that population, I think that's an area of enormous need.

So that's, I guess, how we're thinking about the development strategy. But you can assume that we appreciate that there's an enormous breadth of opportunity here, and we're going to take advantage of it.

We've capitalized the company in a way to allow us to do that. We have $1.6 billion on the balance sheet. That runway takes us into 2029 and really gives us the maximum opportunity to maximum optionality to pursue these broader list of indications.

Makes sense. That's a very helpful context. So in the second half of this year, you said that we'll get data in healthies and IRF5. Certainly, there's a lot of excitement when we saw data in healthies and STAT6.

But walk us through sort of the biology of IRF5, what we can expect to learn in healthies around the biology and target engagement.

Great. Yes. Thanks. So it's one of the kind of side benefits of having a year of execution on STAT6 has been that we've been able to get more focus and attention directed towards IRF5, which is an exciting target that probably didn't get its fair share of investor questions last year, but it's changed for sure this year.

IRF5 is a great target. It's been long pursued as well in pharma, but also has been on drug. It's a very, very difficult and challenging target to address. There's multiple IRFs that share some many similarities that make having a selective IRF5 target difficult to achieve. And also within IRF5, there's many different variants. And so you want to hit all of those as well.

So we've, I think, cracked the code there. We found a molecule that's like our others, is highly selective, and we think ought to demonstrate a really strong profile when it moves through healthy volunteers and ultimately into patients.

IRF5 is what we kind of call a master modulator of immunity. Importantly, it sits -- it's got -- first of all, it's got exceptional genetic support. It's very strongly linked with diseases like lupus, RA, IBD. And so that's obviously important and a critical part of our target selection strategy.

So it certainly checks that box. It sits downstream from many important pathways, Type I Interferon, pro-inflammatory cytokines, autoantibodies. And while there's drugs and diseases like lupus that impact each of these pathways individually, we think I5 could be one of the only ones that can impact all 3 of these pathways.

So if we fast forward to the healthy volunteer study, which has commenced, we announced last month that we had started dosing. As with all of our studies in healthy volunteers, the first goal will be to show that we can degrade the target fully and that we can do it safely.

From our clinical studies, from our preclinical work, we think we probably need 80% to 90% type degradation. So that's what we will hope to show. Obviously -- and that it's well tolerated.

The other important part of the study will be looking at biomarkers. So IRF5 is only activated in the disease setting. So we won't be able to show like we did for 621 reduction in those biomarkers because, again, it's not -- the target isn't activated -- the pathway is not activated in those healthy volunteers.

But we will be able to do some ex vivo stimulation studies to look at some of the pathways that I talked about, Type I Interferon, these pro-inflammatory cytokines, et cetera. And I think that will give us an indication if indeed degrading IRF5 is having an impact on those pathways.

So it will be an important and exciting study. We'll have that data before the end of the year. Our goal then is to move quickly thereafter into our first patient study. We said that would most likely be in lupus, but our plan would be to share more details around that as we move into the latter part of this year.

Great. That's really helpful. And so if you move directly into lupus, like what -- theoretically, if you could give a little bit more color on what that could look like? Would that be a Phase Ib? Would that be a Phase II?

Yes. I think we'll probably save the answer to that question for an update later in this year. We've built most of the development strategy for that program. We just haven't shared it all broadly.

I think we want to get a little further in the year until we shed more light on it other than just to say that the most likely first indication will be lupus, which has, again, a very, very strong genetic association with IRF5 and I didn't touch on this earlier, but we've done a lot of preclinical work that gives us excitement about the potential of targeting I5 in that lupus population.

Great. And yes, if you could also talk about some of the target biology in IBD and RA and some of the other potential areas that this could work.

Sure. So it's a tad bit premature other than to say what I noted earlier that there's very strong genetic association -- we have done -- as I said, most of our preclinical work is centered around lupus. We have some additional work we've done in RA. And then we have some work that is ongoing in IBD that we plan to share as we move through the year, but we'll save that for a later time.

Great. And just to wrap up on the portfolio more broadly, as you think about target selection from here, you obviously have this platform technology, but what are sort of the attributes of targets and indications that you think about as you advance more programs into the clinic?

Yes. Well, thanks. So we're really focused on having the strongest oral immunology pipeline in the industry. We think we're there, but we also have great opportunity to expand upon the existing portfolio with new targets and new molecules.

So as I said, we've got a few that we're working on today. I think everything that we're doing fits within the model that I discussed right at the outset, which is known biology. So we're not taking huge biology risk, big areas of unmet need.

Many of these markets are dominated by biologics. And so because of the appeal of an oral daily molecule, and I'm sure you've seen all these studies that say that 75% to upwards of 90% of patients that are on biologics would prefer an oral mechanism if it were equally safe and effective. Obviously, that's critical. So we think there's great opportunity.

So all of our targets meet those criteria. I'd say about 80% of our work is ongoing in immunology. And so it's most likely that you'll see some targets in that area, but we have some other things that are progressing through the pipeline as well.

But really, we're trying to build a pipeline with other targets that look like STAT6 and like IRF5 and that they have just really areas of big unmet need where an oral daily molecule would be a regimen that would be highly appealing to a group of patients who either are already on biologics and would love to find something maybe less invasive or frankly, and more importantly, is that really broad population like you see in AD of patients who are untreated because they're just not satisfied with the alternatives out therapy.

There might be orals that have safety baggage that they don't want to accept or again, they don't want to deal with the invasiveness of an injection. So we're excited about the pipeline. We've built a great team. And as I said earlier, incredible capabilities in hit finding and in chemistry that give me great optimism that we'll continue to stick to that one new entity per year goal that we've had for a long period of time.

Great. A question that I get from investors a lot is how to think about which assets you might want to keep wholly owned versus partner because obviously, you have a rich platform that can produce many assets. We've seen a lot of deals in the STAT6 space. How do you think about this strategically?

Yes. Well, we're building a company that we believe can and will be a fully integrated biotech company. We've capitalized the company. We built the team and the capabilities to do this ourselves. So partnership is not something that is a priority for us, certainly not with the STAT6 program. I think the question that -- where that becomes more pertinent down the road is when we have multiple Phase III studies going, we have multiple programs, how much can we, as one company do ourselves.

So I think if you see us partner in the future, it would be more likely because we've just reached the level of what we can progress through clinical development on our own. But it's really not central to our strategy.

And given we're capitalized to take these through trials ourselves, it's not something you should expect in the near term.

Great. That's helpful context. Well, awesome. Thank you so much for joining us today and sharing all your insights.

Thanks, Ellie. It's great to be here. Thanks, everyone.

Thank you.

Good day, everyone. My name is Kahai Illani, and I will be your conference operator today. At this time, I would like to welcome you to the Kymera Therapeutics Fourth Quarter 2025 Results Call. [Operator Instructions] At this time, I would like to turn the call over to Justine Koenigsberg, Vice President, Investor Relations.

Good morning, and welcome to Kymera Therapeutics Quarterly Update Conference Call. Joining me today are Nello Mainolfi, our Founder, President and Chief Executive Officer; Jared Gollob, our Chief Medical Officer; and Bruce Jacobs, our Chief Financial Officer. Following our prepared remarks, we will open the call for questions from our publishing analysts.

[Operator Instructions] Before we begin, I would like to remind you that today's discussion will include forward-looking statements subject to risks and uncertainties described in our most recent Form 10-K filed with the SEC. Please note that any forward-looking statements speak only as of today's date.

And with that, I will now turn the call over to Nello.

Thank you, Justine, and thank you, everybody, for joining us this morning. As this is our year-end 2025 call, I wanted to spend a few minutes recapping what was an incredible year for Kymera. Those of you that know us well appreciate the fact that we're always forward-looking, highly focused on what's in front of us. And the bulk of the call would feature just that.

But given how important our 2025 accomplishments were, I'm hoping that a quick reflection on the year will provide some context for the foundation we have set for 2026 and beyond. Before we start, I would like to mention that this year, we will celebrate our 10th year anniversary since Kymera's founding in May of 2016.

Over the past decade, we've executed on our strategy and have built the capabilities, the platform and the team to deliver on our goal to develop the next-generation breakthrough immunology medicines. We've accomplished so much in our short history, but arguably, 2025 was truly a breakout year. I'll start with the significant progress in our first and best-in-class STAT6 Degrader Program.

We shared outstanding results from both our Phase I healthy volunteer study and our Phase Ib study in AD patients. In the healthy volunteer study, KT-621 demonstrated robust STAT6 degradation with excellent safety and tolerability. That was followed by a highly encouraging impact on efficacy endpoints in Phase Ib that supports our view that KT-621 has the potential to deliver robust efficacy in line with pathway biologics with the convenience of oral daily dosing.

On the strength of these 2 studies, we launched our first Phase IIb study in atopic dermatitis patients last fall and started the asthma Phase IIb early this year. Jared will talk more about our KT-621 clinical development plans, but both studies are benefiting from the awareness of and appreciation for the data we have recently shared as well as from clear enthusiasm from clinicians and patients around promising oral options.

We were busy advancing the rest of our pipeline as well. In May, we unveiled our first-in-class IRF5 program, supported by a compelling preclinical profile and validating human genetics. Last year, we completed IND-enabling studies, and we're excited to announce this morning that after IND clearance from the FDA, we recently initiated dosing in the Phase I healthy volunteer study with KT-579.

Finally, we're building on the success of our internal pipeline by advancing our existing collaborations with Sanofi around IRAK4 and by signing a new partnership last year with Gilead around our first-in-class CDK2 molecular glue program. Bruce will provide an update later in the call on the potential upcoming collaboration milestones, which would be incremental to our financial position.

Speaking of finances in 2025, we raised almost $1 billion, bringing our year-end cash balance to $1.6 billion. We believe that this amount of capital, which extends our runway into 2029, will enable us to execute on our broad development plans that are designed to realize the full potential of our wholly-owned programs while maintaining the productivity of our discovery engine, which we expect will expand our innovative pipeline.

Now with 2025 behind us, our focus is squarely on 2026 and beyond and the multiple milestones we plan to achieve. For KT-621, we expect to complete enrollment in the AD study this year and share data by mid-2027. The first patient was dosed in the asthma trial last month, and we expect to share that data in late 2027. In the meanwhile, we're planning to report scientific publication and presentation to continue to build awareness of this exciting program.

This is an important year for KT-579, our lead IRF5 degrader. We expect to complete the recently started Phase I healthy volunteer study and share the data later this year. And the next step will be to advance the program into a patient proof-of-concept study, which we expect to be in lupus soon after that. Our partner, Sanofi, is expected to start the healthy volunteer Phase I trial with KT-485 this year.

We also hope to be able to advance our CDK2 program in partnership with Gilead into further development. Finally, our goal continues to be to announce at least one new program annually, and we're targeting the second half of this year to share our new development candidate program.

We clearly have a busy 2026 plan, which makes me particularly happy to announce the most recent addition to Kymera's leadership team, Neil Graham, who joined us as Kymera's Chief Development Officer. Neil is a seasoned life sciences executive with more than 30 years' experience in global drug development in both early and late-stage clinical trials across a wide therapeutic spectrum, including dermatology, allergy, rheumatology, virology and pulmonology.

Neil has led several groundbreaking programs, including the development of dupilumab at Regeneron. We're thrilled to have him join our team as we enter the next phase of our growth and look forward to his contributions as we continue our efforts to build a fully integrated commercial company.

Now before I turn the call over to Jared, I wanted to spend the remainder of my remarks speaking in more details of the unprecedented market opportunity of our STAT6 program. I can't overstate the opportunity we have to significantly increase the number of patients who are treated effectively.

We hear overwhelmingly from both physicians and patients that current advanced therapies, including biologics, just aren't sufficient. There is a palpable excitement for the potential of a simple and convenient oral therapy for Type 2 diseases that doesn't compromise on safety or efficacy. We have cited these numbers in the past.

We believe there are about 140 million diagnosed Type 2 patients in the U.S., 5 major EU countries and Japan. Of this total, about 50 million patients are estimated to be in the moderate to severe category. Yet despite this significant need, only an estimated 2 million patients are treated with advanced systemic therapies, mostly biologics and overwhelmingly with dupilumab.

So the question is why are so many patients not treated with advanced systemic therapies? The gap is clearly not due to lack of need, but it reflects barriers built into the current treatment paradigm. There are many patients who rely on local therapies, most often topical or inhalers depending on the diseases.

However, most of these treatments do not address the underlying drivers of Type 2 diseases and as a result, do not deliver adequate treatment for many moderate to severe patients. There are existing oral systemic therapies in both asthma and AD, for example, but those can be limited by efficacy.

And certainly, for example, in the case of JAKs, safety concerns, including box warning and the requirements from blood monitoring and initiation and/or during treatment. Finally, injectable biologics have delivered important advances and now account for the majority of systemic therapy use, actually more than 75%.

However, they're associated with significant treatment burden, injection site pain, needle fatigue, burdensome loading regimens after often 4 to 5 injections in the first month, cold stain storage requirements and ultimately with high drop-off rates over time. So when we ask why so many moderate to severe patients remain untreated with advanced therapies, the answer lies in the limitation in efficacy for some, safety concerns for others and very real convenience and access hurdles built into the system.

The consequence is that millions of patients who would benefit from more effective therapies remain untreated, cycling through suboptimal options and living with inadequately controlled disease. This is the unmet need, and this is the opportunity in front of us. Going from patient numbers and unmet needs to market opportunities, the gap is even larger.

As previously mentioned, about 2 million patients are currently receiving advanced systemic therapies for Type 2 diseases. This segment represents an annual market value of about $20 billion with dupilumab serving as the predominant drug. Although this is already a significant figure, the broader market opportunity is much larger. given that there's tens of millions of patients that are not reached by current approved drugs.

In fact, I would characterize the current Type 2 market as very early in its development. Historically, the introduction of new products and mechanism has expanded immunology markets by enabling access to additional patient populations. In addition, an oral therapy that overcomes many limitations associated with existing treatments while maintaining safety and efficacy could, for the first time, provide a viable alternative for millions of patients across all age groups.

It is reasonable to assume, in my opinion, that the current market for Type 2 diseases is positioned for substantial expansion well beyond the current $20 billion. In fact, a comparable example can be found in the psoriasis market, which has experienced a fivefold growth over the past decade, mostly thanks to new drugs and oral therapies.

I think this all comes well together when we consider the limitation of existing therapies and what KT-621 has to offer, a drug that has the potential to deliver biologics-like efficacy and safety without requiring patients to compromise efficacy and safety for convenience, a drug that has the potential to change the way patients are treated around the world. How will it do so?

In two important ways: one, expand the existing treatment -- treated patient population, which for us is the #1 goal. Second, provide an easy and convenient alternative to patients currently on injectable biologics, many of whom, based on our market analysis and industry survey data are eagerly waiting to switch to an oral therapy. So then how might this paradigm shift look? And what will it mean for patients with Type 2 diseases.

Our goal and the cornerstone of our development plan is to position KT-621 as the product of choice for this large underserved or inadequately [ deserved ] patient population. In many inflammatory diseases, advanced systemic treatments are typically reserved for patients who fail conventional therapies, which in turn are typically biologics.

We believe having an effective safe oral medicine, we can fundamentally change the treatment paradigm, making it practical to intervene earlier in the disease course rather than waiting for significant progression or treatment failure.

If successful, we believe KT-621 has the potential to shift advanced therapy from being a last resort for a small subset of patients to a mainstream option for millions and improve standard of care. I hope that context around the market opportunity makes it clear why we believe that KT-621 has the potential to be one of the biggest programs in the biotechnology and pharma industry.

With that context, let's turn the call over to Jared and discuss clinical progress with KT-621 and KT-579, our IRF5 degrader. Jared?

Thanks, Nello. As you've heard, we're building significant momentum across our pipeline, driven by the strong scientific, clinical and operational foundation that we've established. This morning, I'll discuss our ongoing KT-621 Phase IIb trials in atopic dermatitis and asthma. I'll then provide additional context on our clinical development strategy for KT-579, our oral IRF5 degrader. I'll begin with KT-621, our oral STAT6 degrader.

In December, as many of you are aware, we released the BroADen Phase Ib results, providing the first look at KT-621's impact on patients with atopic dermatitis. The data demonstrated a dupilumab-like profile that strongly supports continued development of KT-621 in both AD and asthma. Across all of the study's objectives, we exceeded expectations.

We demonstrated strong fidelity of translation from healthy volunteers to patients with deep STAT6 degradation in blood and skin. We observed a significant reduction in Type 2 biomarkers across blood and skin lesions, including TARC and Eotaxin-3 and importantly, also in lungs as measured using fractional exhaled nitric oxide or FeNO testing.

The greatest impact on FeNO was observed in AD patients with comorbid asthma who had the highest baseline FeNO levels. We also achieved robust improvements across all key AD clinical endpoints, including EASI, Pruritus NRS, IGA, SCORAD and patient-reported outcomes or PROs, addressing disease severity and quality of life. For all of these endpoints, KT-621 data were in line with or numerically exceeded published data for dupilumab at 4 weeks, further highlighting the exciting potential patient impact.

In addition to these effects on AD, KT-621 had a clinically meaningful impact on patient-reported outcomes, measuring disease control in patients with comorbid asthma as well as on symptoms and quality of life in patients with comorbid allergic rhinitis. And importantly, KT-621 was well-tolerated with a favorable safety profile.

I should also note that we recently completed the 6- to 9-month GLP toxicology studies in rat and nonhuman primate and consistent with earlier KT-621 tox studies, we did not observe any adverse findings of any type across all doses and concentrations tested. We now have 2 parallel Phase IIb dose-ranging placebo-controlled trials underway in AD and asthma, supported by the positive biomarker and clinical endpoint results in both AD and comorbid asthma from BroADen.

The BROADEN2 trial in approximately 200 adult and adolescent patients with moderate to severe atopic dermatitis has a primary endpoint of percent change from baseline in EASI at 16 weeks. The study continues to progress as planned with completion of enrollment expected by the end of 2026 and announcement of top line results by mid-2027.

We will update you all on enrollment later in the year, but we can say now that we are confident in achieving this timeline based on the strong interest from patients and clinicians in a safe and effective oral therapy and given the high level of awareness of and appreciation for the KT-621 data we have generated.

Moving on to asthma. Just last month, we announced that we had dosed the first patient in our Phase IIb BREADTH trial in approximately 264 adult patients with moderate to severe eosinophilic asthma. The trial's primary endpoint is change from baseline in pre-bronchodilator FEV1 at 12 weeks.

Using pre-bronchodilator FEV1 will allow [indiscernible] effects across dose levels in a smaller, faster study and will inform dose selection and probability of success for subsequent Phase III trials. Data from this trial are expected in late 2027. Taken together, we expect to generate data in close to 500 patients next year from both KT-621 Phase IIb studies while also continuing to build our safety database with long-term treatment in AD patients rolling on to the 52-week open-label extension portion of BROADEN2.

Importantly, these trials are designed to support parallel Phase III development beyond atopic dermatitis in asthma and other Type 2 dermatologic, respiratory and gastrointestinal diseases as part of the overarching regulatory strategy for KT-621. Turning now to our novel IRF5 degrader program. We view IRF5 as an exciting new opportunity to address complex autoimmune diseases.

We continue to receive positive feedback from KOLs and investigators on the potential of KT-579 to offer an effective oral treatment for diseases such as lupus, IBD and RA. This past fall, we presented additional compelling KT-579 data in lupus and RA preclinical models at the American College of Rheumatology meeting in Chicago.

Chronic heterogeneous inflammatory conditions like lupus, RA, IBD and others are driven by broad immune dysregulation across multiple inflammatory pathways, including Type 1 interferons, pro-inflammatory cytokines and B cell-derived autoantibodies.

While biologics have clinically validated each of these pathways individually, the current treatment paradigm has been constrained by the reliance on injectable therapies optimized for narrow segments of disease biology and therefore, incapable of addressing the full complexity of the inflammation underlying the various disease manifestations. As a result, many patients experienced incomplete responses or loss of efficacy over time.

An oral medicine capable of modulating multiple disease-defining immune pathways simultaneously could enable more effective and durable disease control and potentially expand access to treatment across broader patient populations. IRF5 is a genetically validated transcription factor that functions as a central amplifier of immune responses.

In autoimmune diseases, where there is strong genetic association with IRF5, persistent IRF5-mediated immune activation drives skewed inflammatory signaling across Type 1 interferon, pro-inflammatory cytokine and autoantibody pathways.

KT-579 is designed to selectively degrade IRF5, enabling modulation of these interconnected inflammatory pathways through targeting of a single master regulator with a goal of rebalancing the immune system while avoiding the infectious adverse events caused by broad immunosuppression.

We are encouraged by the strong genetic rationale, our compelling preclinical efficacy and safety data and the potential to deliver a novel oral therapy across multiple serious autoimmune diseases with significant unmet medical need. With that said, we are now focused on advancing KT-579 in our ongoing Phase I healthy volunteer trial and reporting the first-in-human data in the second half of 2026.

In terms of the Phase I specifics, the study is designed to evaluate both single and multiple ascending doses of KT-579 administered orally once daily compared with placebo. The primary aim of the SAD/MAD study is to demonstrate robust degradation of IRF5 in blood, which we define as a reduction of approximately 90% or greater at dose levels that are safe and well-tolerated.

Because the IRF5 pathway is not activated in healthy volunteers, we plan to use full blood ex vivo stimulation assays to assess the functional impact of IRF5 degradation on the induction of Type 1 interferons, pro-inflammatory cytokines and inflammatory pathway gene transcripts by TLR7, 8 and 9 agonists.

It's our expectation that we should see a 50% to 80% reduction in these biomarkers across the 3 TLR pathways assessed if we're engaging IRF5 effectively, which would increase the probability of IRF5 degradation translating into clinical activity in subsequent patient studies with KT-579. As we did with our STAT6 program, we also expect to conduct a Phase Ib patient study and intend to share more details on the design and patient population later.

We have said, however, that we would expect to focus the study on lupus patients, which we believe is the right patient population for our first proof-of-concept study given the strong genetic association of IRF5 with lupus and the robust activity of KT-579 across multiple mouse models of lupus.

I'll now turn the call over to Bruce for a review of the fourth quarter results. Bruce?

Thanks, Jared. As I walk through the fourth quarter results, please reference the tables found in today's press release, which was filed this morning. Collaboration revenue in the fourth quarter of 2025 of $2.9 million is attributable to our Gilead partnership. More broadly, with respect to Gilead, we received an upfront payment of $40 million upon signing the licensing and option agreement last year.

Under this agreement, we're eligible for up to $750 million in total milestone payments, including $45 million payment payable if and when Gilead exercises its option on the CDK2 program at the declaration of a mutually agreed upon development candidate. In addition, Sanofi is advancing KT-485, our oral IRAK4 degrader, with plans to initiate Phase I testing this year.

We expect to share additional updates on this program in the coming months, including the receipt of a milestone upon dosing of the first healthy volunteer. As a reminder, under the structure of the Sanofi agreement, we have the potential to realize nearly $1 billion in total milestones.

While these 2 potential near-term milestones are not reflected in our current cash guidance and are not expected to materially impact our runway, they remain important validation points and support a continued advancement of these partnered programs and the downstream value we can realize.

We look forward to sharing further progress as these programs move forward. With respect to operating expenses, R&D for the quarter was $83.8 million. Of that, approximately $7.6 million represented noncash stock-based compensation. The adjusted cash R&D spend of $76.2 million which excludes that stock-based comp, reflects a 16% increase from the comparable amount in the third quarter of 2025.

On the G&A side, our spending for the quarter was $16.9 million, of which $6.9 million was noncash stock-based comp. The adjusted cash G&A spend of $10 million, again, excluding that stock-based comp, reflects a 1% increase from the comparable amount in the third quarter of 2025.

And finally, we are well-capitalized to execute on our goals. As Nello mentioned previously, we ended in December with a cash balance of $1.6 billion, providing a runway into 2029. This allows us to complete both KT-621 Phase IIb trials in AD and asthma and to fund a large part of the first Phase III trial for KT-621. The runway also will allow us to advance KT-579 through initial POC testing and to progress our research pipeline as we scale and grow Kymera.

With that, we'll pause while we regroup in our conference room and assemble the queue for your questions. Thank you.

Thank you. [Operator Instructions] Your first question comes from the line of Marc Frahm with TD Cowen.

Congrats on all the progress. Maybe a high-level one for Nello. Since your Phase I data came out with the STAT6, a handful of other kind of early mid-stage programs in AD have also read out data, and there were some data even ahead of yours. So over the past year, there's just a lot going on in AD.

What's your kind of vision for what the treatment of AD looks like and how these therapies all fit together when you roll the clock forward a few years? And then maybe if I can sneak a little bit in for Jared also. Just for IRF5, can you just remind us what really could be learned in the healthy volunteer portion of that trial beyond target engagement and safety or do we really need to learn more and have to wait for that lupus cohort to enroll?

Thanks, Marc. Great question. So I'll start with the first one. So just to remind you, as we shared today, hopefully, even more clearly than before, the AD, I would say the Type 2 diseases market is still very early. Again, there is -- if you look at moderate to severe patients, there is about 40 million to 50 million patients in the 7 major market and only about 2 have been dosed with advanced systemic therapy. So clearly, there is a need of more therapies.

And as we mentioned and others have done so, we mentioned if you parallel AD to psoriasis, psoriasis market in the past 10 years has grown fivefold. Maybe it is somewhere around where psoriasis was 5, 10 years ago or so. So we expect this market to increase dramatically. And you can only do that by bringing in new therapies to the market. So first, I want to start by saying that this is obviously a non zero-sum game, right?

I think there is a need of new therapies and new therapies would benefit patients first, but also actually companies that develop all the other therapies. I mean, for 2 simple reasons. We need -- especially from our viewpoint, patients need convenient oral options that can increase the probability of patients with moderate to severe disease to access effective therapies.

And so I think that that will transform how these diseases are treated. With our mechanism with STAT6, I think the main difference that I could point to without going company by company, which will take us half a day, is that we are targeting an intracellular target of the most validated pathway in Th2 inflammation, which is IL-4 and 13.

So we're going after well-validated efficacy and safety. We're going after a well-defined patient population. And so I think we have a level of derisking that I would point to being, I think, superior to many other agents that are still interesting and exciting that are out there.

So I think we need more therapy. I think it's great that there are more drugs. And obviously, we need to move into late-stage development to really assess for our drug and many others, what is the risk benefit that we can bring to patients. Jared, do you want to take the IRF5?

Sure. Yes, Marc. Regarding IRF5, as you mentioned, the primary clinical objective is safety and then our primary translational objective is to show 90% or greater IRF5 knockdown in blood.

And showing that knockdown is going to be important, we think, from a derisking standpoint for the subsequent patient studies because of the strong genetic association between IRF5 and lupus and the strong preclinical activity in multiple lupus models that we've seen with that degree of IRF5 knockdown.

Now with that being said, yes, it's true that unlike STAT6, where we had circulating biomarkers like TARC and Eotaxin-3 that were useful for us to assess that sort of translation in healthies, with regard to IL-4/IL-13 pathway. Here for IRF5, while we don't have those circulating biomarkers, as we mentioned, we have these ex vivo stimulation assays, which I think will provide very important functional information around IRF5 degradation.

These assays are looking at stimulation of toll-like receptor 7, 8 and 9, which are the 3 toll-like receptors driving hyper interferon, pro-inflammatory cytokine and B cell autoantibody production. And to be able to show an impact across those 3 pathways on ex vivo stim, we believe, significantly derisk our probability of success in subsequent patient studies, including the lupus studies.

And maybe just to add a quick thing on top of Jared, like if I think a bit more from my point of view, maybe higher, more simple level, which hopefully still scientifically sound, we know that the strength of this program is the genetic association, right?

There is very few programs in the history of drug development that have the strength and the depth of genetics that we have with IRF5. And that's why it's one of the most interesting programs in immunology, I think, in the next 5 to 10 years.

So -- but when you have genetic association, you try to figure out, okay, biologically, what does that mean? So we've shown preclinically that actually IRF5 activation leads to, as Jared said, activation of this pro-inflammatory cytokines, Type 1 interferon and B cell activation, autoantibody activation.

So even in healthy volunteers, we can prove even ex vivo that we can block these 3 axes of inflammation. I think it's going to tell us that you combine that with the genetics that it should work into patients.

Your next question comes from the line of Geoff Meacham with Citi.

Can you hear me? Okay. Awesome. So I just had a couple. Thanks for the question, first of all. So on 621, the BROADEN2 and BREADTH studies are probably mature next year. We're used to seeing you guys have Phase I biomarker data and kind of maybe -- a lot of data points along the way.

For these Phase IIbs, is it going to be -- let's just wait until the full and final? Are you guys planning on having any kind of biomarker or interim analysis or anything like that for these 2 studies? And then for the IRF5, interesting program for sure. The indications you guys have talked about include some that are very much unmet need, lupus, Sjogren's in particular and definitely not as crowded. Curious how that informs like your priorities when you think about kind of development for this program?

Thanks, Geoff. So on the first one, obviously, we'd love to get data along the way and understand what's going on in the Phase IIb studies. But obviously, these are important studies that are placebo-controlled. And to protect the integrity of the study, we're going to wait until the end of the study to unblind and obviously share the data.

For IRF5, yes, so I think I go back to the reasons to believe, and as I said, human genetics, lupus, Sjogren's, myositis, RA, IBD, those are areas that we believe this target is extremely relevant. And so we're letting that combined with the preclinical data guide us. So those -- the reason why we've talked often about some of those indications is because they match so well both the genetics, the preclinical data, the unmet need.

I mean if you look at the ones you mentioned, lupus, Sjogren's, these are diseases that don't have effective therapies that are approved or at least some that don't have, maybe I should say, at least oral effective therapies that are approved, which will serve a much broader population than what's being evaluated now in clinical development that I believe are really probably going to be positioned for really late-stage patients.

I think another important axis of our development plan will be outside of, let's call it, this interferon-related pathways or pathologies, which could be, again, IBD could potentially be [indiscernible] down the road. And I think we plan to share more data on IBD, which is increasingly becoming an area of focus for this program, at least preclinically, and we hope for it to be clinically as well in the not-so-distant future.

Your next question comes from Charles Ndiaye with Stifel.

Congrats on the quarter. One question from our side. I guess, as you think about starting Phase IIs for 621 outside of asthma or AD, what are sort of some of the gating factors?

Yes. So as we've outlined in the past, I believe it's still on our corporate deck. There is a new one today on our website. Our strategy is to use the ongoing dose-ranging Phase IIb study, the one in AD to support late development in all of the other derm indications, the one in asthma to support late development in the other respiratory indications. So we actually do not plan to start any new Phase II studies.

The new studies that you see us starting will be, we believe, all registrational studies. Now obviously, some of this still has to be vetted with the right authorities, but that's our current strategy. And we believe this is a strategy that has been proven to be successful with other drugs in this pathway. So it wouldn't be the first time that this is adopted.

The next question comes from Brad Canino.

A question from me on the trigger to start the KT-621 Phase IIIs. So to initiate, how far into the Phase IIs do you need to reach and what needs to be collected from those studies? And will this be one study start or multiple at once?

Yes. Thanks, Brad. So unlike what we may be getting everybody used to that we start a study while the previous one was still ongoing as we've done for the healthy and Phase Ib. For starting a Phase III study, we need to complete Phase II. We need to have an FDA meeting post Phase II, and then we can start Phase III.

I assure you that we will do our best as we always have, to do that as quickly as possible. But obviously, there are some things that we must do in order to move into Phase III. With regards to how many, as you know, at least the paradigm that companies have adopted in the past 10 years for, let's say, atopic dermatitis registration has been 3 Phase III studies, 2, there are 2 placebo-controlled, mostly placebo-controlled studies and then one on top of topical corticosteroid.

So we -- if that will continue to be the paradigm, which is something, obviously, we will explore given the recent news from FDA. But let's say, that continues to be the paradigm, you should expect us to start all studies as much in parallel as possible.

Great. The next question comes from Eli Merle with Barclays.

Congrats on all the progress. In terms of 621, if you could talk about both the clinical and preclinical data that you've seen, where do you see the most potential room for efficacy improvements over dupilumab? And can you talk about some of the respiratory preclinical model data and compare that to what's been seen preclinically in atopic dermatitis?

Yes. Thanks, Eli. You often asked the tricky question. So we want to make sure like we maintain kind of our credibility when we compare a drug that is -- have been so successful in millions of patients with the drug that has been so far in about a couple of hundred patients or subjects and up to 28 days. So I'm always very thoughtful about how we make comparisons.

What I can say is that in our preclinical models, if you look at the asthma models that we both published, KT-621 has performed always at least as well and in many cases, better than dupilumab. We don't know whether that is the result of the model or it's actually real biological differences or drug distribution differences.

And that's why we're really excited that we're in a Phase II study, so we can assess the full clinical activity of our drug in a large study with hundreds of patients. With regards to AD, the preclinical AD models are not very robust. We like to talk about the asthma model because it's a highly translatable model.

The AD preclinical models, you have this local activation with a pathway activator that is not really, in many cases, a Type 2 discrete pathway activator. So we also show really robust activity. But to be honest, as a scientist myself, I don't like to talk about preclinical AD models that are mostly useless.

But if we look at the clinical data, obviously, you've seen the data from last December, we have shown really robust activity. I start from biomarkers. I look at what we've shown even with biomarkers that were either not shown to change much with dupilumab like IL-31 or the ones that we showed comparable if not superior Eotaxin, even FeNO.

And then we look at all the clinical endpoints that we measured, we've been consistently at least as good as the injectable biologics. So again, it's hard for me to say it will be equal, slightly inferior, slightly better. But I think we delivered that ballpark scenario that we talked about for last year.

And so for us to really know how it looks, we need to wait for the Phase II studies. And to be honest, the only other thing to keep in mind is you can never compare drugs unless you run a head-to-head study.

But our goal, again, is to deliver an oral drug with biologics like activity with great safety and the convenience of being an oral pill that one can take once a day, stop and start whenever they want. I think that will transform the treatment paradigm for Type 2 diseases well beyond whether the drug is exactly like dupilumab, slightly less or slightly better. I don't think that will matter if we can deliver the type of drug with the profile that we speak about.

Your next question comes from [ Anna Lee ] from Truist.

This is Anna on for Kripa. One quick question on 621. I was just wondering if you could give us kind of an overview on how you're thinking about compliance you're seeing in the Phase IIb trials right now and how the durability of 621 kind of ties into that?

Cool. So that's a great question. So when you -- compliance, you mean patients taking the drug. That's what you mean? Yes. So I think that's obviously -- it's a very important point because when you're in a clinical trial or an injectable biologics, you can actually ensure 100% adherence, right, because patients often, in most cases, actually go on site to receive the injection.

When you -- the beauty of oral drugs is actually you give patients freedom, right? That's the beauty of oral drugs. And that obviously plays a role into clinical studies. So we have measures that probably go even beyond what has been done generally to make sure that we understand patients' adherence well.

So we are confident that the adherence of patients will be the one that will allow us to have a great integrity of our study. I will also add that the beauty about protein degraders, unlike small molecule inhibitors, if you miss a small molecule inhibitor dose, you actually lose all your activity.

If you miss one dose of KT-621, this is not an advertisement to not take the dose every day. But I will say, if you miss a dose of KT-621, if you miss one dose, you will not lose any of pathway degradation. So we have that additional layer of, let's call it, protection against any challenges that might come with humans forgetting one dose during a study or during normal life.

The next question comes from Judah Frommer with Morgan Stanley.

Congrats on the progress. Just on IRF5, I think we're clear on how you think about STAT6 degradation versus inhibition. Kind of same question for IRF5. I think we'll get a little bit of preclinical data from an inhibitor next month. And then just on the targeted nature of your degrader, any risk of kind of pan-IRF inhibition? I think IRF8 has been a question in degrading IRF5 previously.

Yes. Maybe I'll start and then I'll pass it to Jared to speak even maybe it's an opportunity to talk about how we think about the safety of IRF5. But maybe I'll talk more about the chemistry of it, even that I'm technically still a chemist. So the beauty about this target and the challenges with this target is that it's extremely hard to find a molecule that binds to IRF5 only without binding to all the other IRFs.

You mentioned a few. I think there is 11 or 12, sometimes I lose count, but there's more than 10 IRFs. So we need to bind only two IRF5. And there are different -- I like to call them splicing variants, people call them differently. There are different IRF5 splicing variants. They all need to be targeted. So you need to be consistent across the IRF5 family, but do not bind to any other IRF.

So we've been able to do that. Our selectivity is pristine because we've been able to find this molecule that is actually not functional. So it does not inhibit anything. It only binds to IRF5, all the IRF5s splicing variants, but not other IRFs. And this allows us to give the utmost selectivity. So we're not worried about any of those things. But Jared, do you want to speak about why we think 5 only is potentially really interesting.

Yes. I think IRF5, because it is one of multiple different IRFs, there is a certain redundancy there when it comes to the role of IRF in innate immunity. So even getting rid of IRF5 really does not impact overall innate or adaptive immunity.

It's also true that IRF5, its expression is very restricted, especially to certain immune cell subtypes like B cells and dendritic cells and monocytes and macrophages. So it's not ubiquitously expressed, which is another reason why one can knock it down and do so safely. And its activation is also very context specific.

So here, in the context of pathologic inflammation, that's where you're going to see activation, where you're going to see activation in restricted cell types. And that's the reason why you can really degrade IRF5 strongly and chronically and not get broad immunosuppression and not have infectious adverse events. And in fact, if you look at mouse knockouts for IRF5, you don't see any susceptibility to infections or any phenotype.

And in our preclinical animal tox studies, including our 4-week GLP tox studies in nonhuman primates as well as in rats, we don't see any adverse events -- adverse findings. We don't see any susceptibility to infection. So for all those reasons, we believe that this is a safe target for us to degrade deeply and chronically.

The next question comes from Joe Catanzaro with Mizuho.

Hope you guys can hear me okay. Maybe one on 579 and something kind of maybe related to something you just said, Jared. But I was looking at another healthy volunteer study for another anti-inflammatory drug, and they actually utilize a skin immune challenge model where they injected volunteers with actually a TLR agonist and then looked at cytokines.

Wondering if you guys are aware of that model, whether you considered this? And if you did consider why you didn't decide to use it? And then I guess related, what informs the 50% to 80% target reductions in biomarkers? Is that all preclinical or is there some genetic basis for that target reduction?

So maybe I'll take the first one and Jared takes the second one. So yes, we're obviously well aware of there are many type of skin challenge model, sometimes even systemic models, systemic challenge model, people have done LPS, inhaled LPS, local LPS. So there are many models that one could run preclinically for healthy volunteer studies.

We philosophically feel like the right context to ask these pathway questions are in patients. And what you do by activating the skin is you artificially activate a pathway and then you look at downstream regulation. You can do that just the same way by taking the blood and ex vivo activating the pathway.

So yes, you could do those things. We just don't believe that it's the complexity of it derisks any more or less what we would do with an ex vivo blood stimulation. If you have questions about does your drug reach particular tissues and especially with small molecule inhibitors where you actually cannot measure target engagement, that is a way to do it.

But we can measure target engagement directly. So we don't need a surrogate downstream biomarker to make sure our drug gets to the tissue. So that's at least our view. Jared, do you want to speak to the?

Yes. I mean we know in terms of the amount of knockdown that we think we need or the amount of functional inhibition that we would need for those pathways. One has to keep in mind that here, we're talking about not just one pathway that's controlled by IRF5, but multiple pathways.

Here, we're looking at 3 different TLR pathways, for example, 7, 8 and 9. And so whereas you're talking about one pathway and all your activity is dependent on one pathway, you might have a threshold that could be 80%, 90% or more to really have clinical impact.

Here, we know that if you're impacting multiple different pathways in parallel at the same time, you don't need necessarily 90-plus percent inhibition, 50% to 80% inhibition from our preclinical data across multiple different pathways can have a synergy that can give you significant activity in preclinical models.

So that's the reason why we say that, that's sort of a range, which is really just a range, if you're seeing it across multiple different TLR pathways with these ex vivo stim models would be very encouraging, and we would expect to translate into activity in subsequent patient studies in diseases like lupus.

The next question is from Derek Archila with Wells Fargo.

This is [ Hal ]. I'm calling in for Derek. So I guess our question is about the potential oral autoantibody delivery program. Just kind of the timing and what data, what events we can hear more from these assets?

Sorry, I didn't quite get the question. Say that again?

The internal oral antibody.

So do you mean the next oral immunology program that we were going to disclose? Yes. So as we said in, I believe it's in the press release and in our remarks earlier, we plan to disclose at least a novel program, most likely an immunology program this year and likely would be in the second half of the year.

The next question comes from Brian Cheng with JPMorgan.

Just on IRF5, as you mentioned, 50% to 80% reduction across the TLR7, 8, 9 pathways. Just thinking about IRF5 regulates many of the levers in the pathways. Are there any specific downstream cytokines that you can point to today that will be the most impacted, most reliable and perhaps the easiest to monitor from an ex vivo stimulation test setting to best assess the PD of the drug?

Yes, that's a great question. Jared, do you want to take that one?

Yes. Through the stimulation of these pathways, there are key cytokines that we can look at. So for example, Type 1 interferon psych interferon beta, we can look at interferon beta protein production in these ex vivo stim assays. We can also look at gene transcripts that are part of the type 1 interferon pathways, looking beyond just the interferon itself. You can look at various genes that are part of the type 1 interferon pathways.

We can also look for pro-inflammatory cytokines like IL-12 and tumor necrosis factor and even IL-6, which are stimulated by macrophages and dendritic cells. So these are a number of different pro-inflammatory cytokines that are coming off of these TLR pathways that can all be measured either the protein level or the gene transcript level that will be very helpful biomarkers for us.

The next question is from Brian Abrahams with RBC.

Can you hear me? This is [ Kevin ] on for Brian. Maybe just on IRF5. How are you guys thinking about degradation in -- I know you mentioned whole blood, but just in PBMCs and maybe potentially skin as well. I think that's something you're looking at in the MAD portion.

And I know you talked about IRF5 not being as activated in healthy volunteers. So just maybe curious what our expectations should be there for degradation in those tissues. And just kind of how much do we really know about sort of IRF5 expression in healthy volunteers and how that impacts your expectations for the study?

Yes. I mean in blood, we know that we can measure IRF5 well. And in fact, when we say blood, we obviously then practically need PBMCs because we isolate PBMCs as we measure it using mass spec.

The expression of IRF5 in healthy volunteers in the skin is extremely low. And so for that reason, we believe it's going to be -- it would be really hard to measure IRF5 in healthy volunteers.

This is something that as we go into patients and especially if we go into lupus with cutaneous manifestation or even CLE, eventually, that's maybe a context where we can look at IRF5 expression. I think in [indiscernible] expectation is to be extremely low, lowest than any other program that we've looked at even preclinically. So hard to measure.

[Operator Instructions] Your next question comes from Sudan Loganathan from Stephens.

I wanted to ask my question around 621's opportunity in asthma. Looking at the current FDA-approved treatment options for AD, not all of them have really panned out that well in asthma as maybe people have expected. STAT6 degradation is a new approach. So curious to hear what theoretical and preclinical data you may have that gives you some conviction here that it also has an opportunity in asthma.

Yes. I think IL-4 and 13, and just I remind everybody that there's only one drug that blocks IL-4 and 13, which is dupilumab. And so that has shown to have really, really robust activity in eosinophilic asthma and actually eosinophilic COPD, chronic rhinositis with nasal polyps.

So it's well established to really have huge impact on patients with Type 2 inflammation in respiratory tract. So STAT6 biology, again, we've shown it extensively preclinically and also in the early clinical development that we can mimic the same IL-4 and 13 blockade. And again, I refer you to the asthma studies that we've published preclinical study that we published, showing the robust activity we see both on biomarkers and efficacy endpoint.

The pheno reduction that we've seen in patients is actually even more robust than biologics in asthma patients. So we have all the ingredients to have reasons to believe that this drug actually is going to -- has the potential to be extremely effective in asthma.

Next question is from Jeet Mukherjee with BTIG.

As we just look ahead to the evolving competitive landscape in atopic dermatitis and specifically on the next-gen oral agents that might be coming around the corner, just your thoughts on ITK as a target and some of the recent data we've seen there and how that might compare and contrast to STAT6.

Yes, great question. As I said earlier, I think more mechanisms are great for patients first. I think, obviously, these are very different mechanisms. STAT6 is an IL-4 and 13 drug, as I said, the most validated pathway in the space, both in terms of safety and efficacy. We have shown preclinically that we can mimic biologics, both in terms of efficacy.

And I would actually argue in safety, we just shared today that we completed chronic tox, so 6- to 9-month tox in rodents and nonhuman primates, again, without any adverse event. Other targets, ITK is a target that we've looked extensively at Kymera.

We decided not to work on it because the human genetics show that because of challenges with clearing ETV, I think all patients end up developing some form of lymphoma. So this is the reason why we decided not to work on that target. That doesn't mean that it could not be a great target.

It's just something that we don't believe fulfills the risk-benefit profile of Kymera and how our target selection strategy has been evolved over the years. But again, I think more mechanisms, especially with complementary pathways, whether it's ITK or others, I think are going to be great for patients and expand in this market that we need to do so that more patients get access to more therapies.

Next question is from Faisal Khurshid with Jefferies.

I wanted to ask, as you guys get the sites up and running in the Phase IIb studies, do you expect to provide any kind of color or context around how enrollment is going in those studies?

No. I think what we -- obviously, if we feel we're not on track, obviously, we will share. But as long as we remain on track with the expectation, we don't plan to be providing ongoing updates on enrollment. I don't think it's necessary. But obviously, again, if we deviate from expectation, we will make sure to do so.

Next question is from Biren Amin with Piper Sandler.

Congrats on the quarter and all the progress. For the Phase IIb AD trial, what measures are you taking in the trial to mitigate against placebo response? For example, will you be requiring photographic evidence of AD at baseline to provide evidence of moderate to severe disease on screening? So I guess that's first question.

Second question on 579. I know you're enrolling healthy volunteers. However, there are healthy volunteers that may have positive antinuclear antibodies, but do not have autoimmune disease. Would you potentially screen for these types of healthy volunteers and that may potentially provide read-through into your Phase Ib lupus trial?

Great question, Biren. I'll take the second one quickly. Jared, do you mind taking the first one? Yes. So great idea. Sometimes simple is better than complicated. So we're going to actually enroll healthy volunteers that are healthy, move quickly through it, selected dose and go into patients. That doesn't mean your idea is not a good one. It's just not what we're planning to do. Jared, do you want to take that?

Yes. I think in the Phase IIb, I mean, your question about avoiding high placebo rates is an important one. And while I can't get into all the details at a high level, I can tell you that we're paying a lot of attention to this, both with regards to our eligibility criteria, how we're providing oversight with every patient that comes on and is screened in terms of looking to make sure that patients are truly meeting eligibility criteria, not just in terms of actually having AD, but also having moderate to severe disease.

And we've carefully trained the investigators and selected investigators who are more certified dermatologists to make sure that they're fully capable of doing all of the clinical endpoint measurements across the study and that they're doing it consistently from baseline all the way through to the end of the study. And we also have global site selection.

So we're not just in the U.S., we're also ex U.S. And in fact, the majority of our sites are ex U.S., whether that be in Europe or in Asia and Australia. And I think that's also important because access to drugs like dupilumab are diminished ex U.S.

And so those are patients who are more apt to come in maybe more on the severe end of the spectrum of disease, and that can also be very helpful in helping to mitigate placebo effect, which you tend to see in milder patients compared to more severe patients. So I think all of those steps are being taken, and we're really very actively staying on top of all of that to try to mitigate a high placebo rate on study.

I mean we're doing -- I'm sorry, we're way out of time. But we're doing lots of things, probably more things than anybody has done before to ensure that we do that. Obviously, we can't guarantee the lowest placebo rate, but we're trying our best.

Your final question comes from [ Paurav Desai ] with B. Riley.

I'm on for Mayank. On asthma trial, if you could kindly confirm the dose levels are the same as BROADEN2? And how might you be enriching for pheno in your target patient population? And is there a chance your 12-week FEV1 endpoint data could come around the same time as your 16-week BroADen Phase II study? And also it would be helpful to learn competitive trial enrollment dynamics in atopic dermatitis versus asthma.

Yes. Thank you. These are 4 questions in one. But let's see if you guys have to help me remembering. So the first one, the dose levels, yes, they are the same across AD and asthma. So the inclusion criteria for the asthma study is high [ EOS ] more than 300, high pheno more than 25.

So that's how we're going to select that patient population. In terms of timing, we said that we expect the Phase IIb AD study data by middle of next year, while the asthma data by the end of next year. So I guess that answers the question. Things would always change one way or the other.

And as I said earlier, if they change materially, we will share. And then competitive dynamics, all I can say that we have seen a ton of enthusiasm for our study in both actually, I would say, AD and asthma. And that's for 2 main -- actually, I would say 3 reasons. One, sites and hopefully also patients appreciate the really, really interesting and innovative science of our program.

They appreciate that this -- while this is a novel target within a well-established biology and clinical experimentation. It's an oral drug and has some compelling early data. When you put all of that together, we have seen a ton of enthusiasm. So we really hope that this enthusiasm will translate into good enrollment. And that's what we're seeing so far, but we're still a long way to the finish line.

There are no more questions at this time. Yes. There are no more questions at this time and I'd now like to turn the call over to Nello Mainolfi for closing remarks.

Yes. So first, let me apologize. This call has taken the longest that we've ever done. I'm not really sure why. But I want to thank everybody for attending the call. All great questions, so I don't blame our analysts. And you know where to find us. We're very excited about where we are. This is a pivotal time for the company. And so we're excited to engage beyond the call if there are questions, and enjoy the rest of the day.

Good morning, everyone. Thanks for joining us for another session at the 44th JPMorgan Healthcare Conference. I'm Brian Cheng, one of the senior biotech analysts here at the firm. On stage, we have the CEO from Kymera Therapeutics, Nello Mainolfi. I'll now pass the mic to their CEO for a short presentation, followed by a live audience Q&A.

Nello, the stage is yours.

Thanks, Brian. Thanks, everybody, for joining us. Hopefully, the sound is good. Always great to be at JPMorgan in a new room this year. So in the next 20 to 30 minutes, I want to take the opportunity to tell you a little bit about Kymera, where we're going in 2026 and probably more importantly, where we're going in the next 3 to 5 years.

So if you look back -- so actually, this year, in May will be the tenth year anniversary since we founded Kymera and we spent the past 10 years building strategy capabilities and team to deliver a whole new generation of medicines. What we're trying to build is something that has actually never been done before: oral drugs with biologics-like activity. And what we've done in the past 10 years, and we'll take a quick look at last year is taking us a step and a step closer to our vision and our goal.

So if we just look for a minute on what we've accomplished, 2025 was really a pivotal year for the company. About 2 years ago, around this conference, we presented, for the first time, our STAT6 program. We showed with preclinical studies that if you degrade STAT6, you can deliver activity, the blockade of IL-4 and 13 in cells and in vivo models that can mimic if not being numerically superior to what has been seen with a mega blockbuster drug like dupilumab.

So last year, in -- actually in two portions in June and December, we have been able to complete the early clinical translation of KT-621 and demonstrate that actually if you degrade STAT6 in humans either in healthy volunteers and later in patients, you can actually deliver full pathway blockade of IL-4 and 13, and impact both biomarkers and clinical endpoints, at least as effectively as upstream biologics. So we'll talk about that, but there was a really exciting important part of our 2025. We've initiated a Phase 2b study. We'll talk about a new study that we started recently.

We also presented a new program, our IRF5 degrade or KT-579, another transcription factor in highly validated pathways where there are effective biologics, but not effective oral convenient drug. And that's where 579 was delivered. And last year, we've not only presented the program, but also completed our IND-enabling work to being able to go into the clinic soon this year.

We also had a lot of important corporate updates. We continue to collaborate with Sanofi on our IRAK4 degrader and decided to advance the second-generation degrader in the clinic this year. We entered the collaboration with Gilead on this novel first-in-class CDK2 molecular glue for oncology. And we were able to raise almost $1 billion last year, which gives us about now $1.6 billion that will fund the company through at least into 2029. And importantly, allows us to take several of our programs through proof-of-concept Phase II studies and for KT-621 in several Phase III studies.

So this is a snapshot of this 2025 is the foundational pivotal year for what Kymera trying to do. And we can only do this, thanks to both the team, the strategy and the capabilities that we built, as I mentioned, a few days -- a few minutes ago. And maybe it's worth highlighting just a few of the things that I think make Kymera really unique in biotech.

One, our target selection strategy. Our target selection strategy was defined about 10 years ago and actually has not changed. We go after untracked targets that have never been drugged before either fully or at all in pathways that have been validated by usually injectable biologics, where we know our oral intracellular degraders can deliver a completely differentiated profile. Again, the concept of oral drugs with biologics-like activity. We have decided about 5 years ago to focus almost solely in immunology, we believe this is the time to advance a whole new generation of oral therapies in immunology. Obviously, we're not the only ones, but we believe we're leading the transformation of how patients with immune inflammatory diseases will be treated in the next decade.

We can only do this thanks to the team and the capabilities that we've built. We understand the specificity of our degraders at the molecular level, at the atom level, we know how to make them behave like pharmaceutical agent, selective specific, safe and well tolerated. And importantly, we're rediscovering, redefining these new rules of discovery and development.

What does it mean to develop oral drugs that match the activity of biologics? They're whole new concept that we're pioneering at Kymera. And we can only do it thanks to the team in our translational development organization that have been able to build very creative early clinical studies that not only derisks but also validate our mechanisms and allows us to accelerate late development. And you'll see the work that we're doing with STAT6, how it speaks to this particular point.

So this is the problem statement. And this is the problem statement that we're very passionate about at Kymera. We're just going to talk about order of magnitude and not individual accurate numbers. But if you look at the 10 most common immuno-inflammatory diseases, they are written very small in the slide, but you can imagine, go from AD, asthma , RA, SLE, et cetera. There are about, let's say, more than 100 million patients in the 7 major markets. The patients that access advanced systemic therapy are about 5 million patients.

So we have lots of effective therapies, but we have two problems: how the system prescribes advanced systemic therapy, so treatment paradigms. And again, how patients can access advanced systemic therapy. And we believe strongly that if we develop drugs that have the activity, the safety, the efficacy of these advanced biologics but the convenience of oral drugs and the access that we can deliver for patients, we can transform how patients are treated. This is not about the convenience over a biologic. It's about where patients are going to be accessing our drugs. And our vision here is to be our drugs, the first option for all patients with immune inflammatory diseases.

So how can we accomplish that? So this is probably the only technical slide of today, so bear with me. But at least on the, let's say, chemistry discovery part. So we know, obviously, how biologics work. You inject the drug that generally a long half-life, and you can cover the target for an extended period of time. And this allows you to have an extended saturating effect on the target and obviously, an extended effect on the clinical manifestation of that disease.

Traditional small molecules, let's say, in the past 50, 30, 20 years have tried to get close or replicate that type of pathway blockade. The problem is that for every copy of protein, you can see on the left of the slide, you need one molecule. So you have a stoichiometric inhibition of your target that requires for targets that are expressed usually in the micro -- nanomoral to micromoral levels, you need a large amount of drug for a long period of time, usually for 24 hours. And that's generally extremely difficult to accomplish, if not impossible with a once-a-day oral drug. In fact, I don't remember of a small molecule inhibitor traditional small molecule inhibitor that covers the target more than 95% for 24 hours.

So what -- the reason why degraders can accomplish this is because one molecule of our degrader can degrade hundreds, if not thousands of cabrio protein. We can only fit 5 on this slide. But believe me, we can do more than that. And so this allows us to have a catalytic mechanism. So a small amount of drug for a short amount of time, can degrade the protein completely and fully.

So when we dose once a day, we can accomplish sustained complete pathway inhibition. I would say, in some cases, if you take a drug every day, you will probably accomplish more pathway inhibition than a saturating dose of an injectable biologic.

So just -- we are landing here on our pipeline, just to give you a quick sense of where we are and where we're going. So I think it's fair to say that KT-621 and STAT6 program is probably in the top 3, I would say, the first or the most compelling program in biopharma, but let's say, in the top 3. Given the breadth of opportunity, the validation that is behind it, and also the stage of development. So we've just started Phase 2b study, we started the AD Phase 2b study late last year, actually, we dosed our first patient in, I believe, late October. And then recently, we said we were going to start the asthma Phase 2b study in Q1, we actually ended up starting in week 1 of the year. And both of these studies will have data in 2027. So we'll have about 500 patients worth of data for KT-621 in 2027. We'll talk more about this study soon.

Exciting year for KT-579, we are shortly initiating our Phase 1 study, and we'll have Phase 1 data in the second half of the year. We're also planning to start the patient study, hopefully also this year after the healthy volunteer study.

We also have, as you know, two programs in collaboration, one with Sanofi, we're on track to initiate our Phase 1 study with the second-generation IRAK4 degrader KT-485. And then we have the exciting partnership with Gilead on this really unique CDK2 molecular glue, which I don't have any time to go into the details of, but hopefully, we'll be able to share more data this year and in the future.

So I thought it makes sense to use KT-621, our strategy, our discovery, our data and our development strategy to exemplify how we think about both the drug discovery and development principles at Kymera, our strategy, and more importantly, how we believe we're going to change how patients are treated with our drug.

So this -- the introduction slide has been used by myself multiple times. Nonetheless, I think for being comprehensive, it's worth highlighting two key pieces of information here. One, IL-4 and 13 is the most validated biology in Type 2 inflammation. Type 2 inflammation or one could say, allergic inflammation is the most common type of inflammation in the western world with more than 150 million patients suffering from a series of diseases, 8 diseases in which dupilumab has been approved, but there is actually more. There are food allergies and other diseases that have not yet been treated with a Type 2 drug.

So the drug that is most successful at blocking IL-4 and 13 biologists, dupilumab. This is a monoclonal antibody that blocks IL-4 receptor alpha and in doing so, blocks the signaling of IL-4 and 13. We have found that if you degrade STAT6, the selective and obligated transcription factor for IL-4 and 13 signaling, you're able to block the pathway as well as in upstream biologic like dupilumab and this is not only our work, but also if you look at human genetics data, it points to the fact that static is the key transcription factor for allergic diseases. There are many drugs in this pathway, but there is no oral drug that target this pathway intracellularly. And that's really what we're trying to transform.

So this slide contains a lot of information. I just want to guide you through like the two important ones. So you can see the diseases on the right, these are indications in which dupilumab has been approved. We're talking about more than 100 million patients the penetration of upstream biologics into this patient population is in the single-digit percentage.

So you would ask yourself how is this possible? Well, the challenge is, again, as I said earlier, some diseases are treated, not thinking about the underlying inflammation in the proper way. And actually, they're just treating the symptoms. And then lots of patients and prescribers think twice before prescribing an injectable biologics. So when we talk about the Type 2 drugs, dupilumab and others being $20 billion to, soon, $30 billion drug. While this is obviously an important statement, and it's actually a fact, what we're trying to do is not necessarily competing with these agents in that $20 billion market. We're trying to expand by multiple of that market, the number of patients that we can access. So that's the opportunity that is in front of us.

So maybe to spend a couple of minutes of what's stopping the penetration of many of these medicines to even just moderate to severe patients. So obviously, here, we're using asthma and AD. About 60% of patients do not have adequate control of their disease. We have topical drugs that -- or inhaled drug only target mild patients. Current oral therapy is either not active enough or have safety challenges. Biologics, again, they're associated with high treatment burden. So patients go through a needle fear fatigue often and you need to go through several injections before you reach steady state, a complex treatment initiation from some drugs, we need blood testing.

So we've done a market analysis. Many companies have done this market analysis. I think the data is absolutely consistent. What patients want is, first, rapid onset of relief of their symptoms, convenience of a neural pill, no treatment initiation requirements, so no blood tests and obviously, a good safety and tolerability profile. So the data that we've generated so far on KT-621 fulfills exactly what patients want. And so this is a drug for all patients. We believe if you have a Type 2 disease, moderate to severe disease initially, KT-621 should be the first option for these patients. And this is why we believe we can expand this $20 billion market to a multiple of that number.

So let's go through some exciting data. This is my favorite slide because it was my idea, but we'll see if it works out with the audience. So this was a way to try and summarize everything that we learned on KT-621 in a single slide.

So on the left, we have the preclinical data, obviously, highlights extremely potent degrader that blocks IL-4 and 13 in vitro and in vivo completely and at least as well as dupilumab, in many cases, even better. In terms of safety, all the studies that we've run, 4 weeks, 4 months, we're actually about to complete 6 to 9-month talks. We even have completed embryo-fetal development studies in all species, and we have seen no findings, no adverse events. So the most compelling safety profile that I've seen in my career. In humans, we've learned a lot, some of it summarized. Deep -- a complete degradation in blood and skin of STAT6, impact on lesions of AD patients and skin, impact on each of AD patients, impact on FeNO as well as relief of asthma symptoms in comorbid asthma impact on allergic rhinitis. So in -- with 200 humans between healthy volunteers and patients, we have basically derisked the biology of STAT6 and KT-621. And now I'm going to take you through some data.

So in this Phase 1b study that we reported last year in December, these were 22 patients with moderate to severe AD we looked at a series of biomarkers in blood, in skin and actually in lungs. And we saw a really robust reduction, all these Type 2 cytokines. TARC, about 74% in patients that had elevated target baseline at least as well as what has been seen with upstream biologics. Eotaxin which is the cytokine [ right ] downstream of IL-4 and 13, we've seen really robust reduction into the 70%, superior to even what has been seen with biologics in this pathway. Ig that requires much longer time to see an effect for biology reasons, we still saw a measurable effect even at 4 weeks. IL-31, which is the most important pruritogenic cytokine, Kymera was the first company to demonstrate you can actually see a reduction -- a robust reduction even after 28 days in the blood of AD patients. And then, again, another creative idea from the team, not for me, was actually looking at FeNO in -- so this is Fractional Exhaled Nitric Oxide, is a biomarker of lung inflammation. So we actually learned that even AD patients have a tone of inflammation in their lungs, we're able to reduce the Th2 tone in lungs of AD patients for the first time. So again, just looking at biomarkers effect of KT-621 shows that we have an extremely compelling profile to treat patients with Type 2 inflammation in blood and skin and in lungs.

So let's look at some of the efficacy data. So one thing maybe I'll start by saying, obviously, we don't have time today to go through all the data, but the important thing about KT-621 that these two doses that 100 mg and 200 mg that had the same degradation profile gave the same effect on both biomarker or similar effect on biomarkers and clinical endpoints. KT-621 had the same effect whether you had very severe disease or if you had less severe disease. So if you had high easy at baseline or low easy at baseline, a high target baseline, or low target baseline, we had exactly the same type of impact on disease end point. And this is why it goes back to the point I made earlier, a drug for everybody. This is why this drug is so compelling because of the fact that it works just as well regardless of your disease at baseline.

And also works just as well, whether you were previously on a pathway biologics like dupilumab or you were naive to a pathway biologics. So that's very important because we want to be able to offer for people that are on injectable biologics and oral auction.

So here, we're looking at changes of lesions, whether you measure by EASI or SCORAD, 60% and about 50%. This is, again, in line, if not numerically superior to what has been seen with injectable biologics at day 28. We also had robust effect on categorical endpoints like EASI 50, EASI 75, each, which is the critical effect that the critical symptoms that patients have to deal with every day. We had a really robust effect. Whether you measure it with peak pruritus, NRS or you measure through SCORAD itch, we're able to see between 40% and 45% reduction. You can see in both EASI and itch, very quick impact on symptoms already a date. And importantly, in both cases, I'm actually going back here. And fourth, we see no apparent plateauing of this response. So this leads us to believe that there is much more efficacy to be seen as we continue to dose this drug.

Another -- so what we're trying to treat, obviously, we're trying to treat the manifestation of the disease. But importantly, we're trying to make patients' lives better. And so this slide, together with each slide, is actually the most important slide. If you look at the left, this is the measure of sleeplessness, how many times do you wake up at night for scratching. And that is what changes people's lives. If you cannot sleep at night, you can't work, you cannot function. And this -- I believe there isn't a lot of data with other agents with this particular endpoint, but I believe we outperformed many other drugs from this point of view, even at day 8, we have really robust reduction of sleep business and at day 28 to 29, almost 80%. Also other quality of life like DLQI and POEM, really robust responders rates.

So this has enabled us to accelerate the development of KT-621 and we initiated this BROADEN2 study. So Phase 2b, this is moderate to severe patients, the criteria on the left, 200 patients, 16 weeks of dosing, 52 weeks of open-label extension, three doses of KT-621, one placebo, 1 to 1 to 1 to 1, primary endpoint and secondary endpoint that are traditionally used for AD. Importantly, we have recently started to also enroll adolescence on this study. Again, it goes back to the drug for everybody. This is a disease of children, so we want to try and bring children into our development and into our label as quickly as possible. So we expect data for this program by middle of next year.

So we weren't happy with, obviously, measuring AD in AD patients, we look beyond that. And we're able to validate the effect of KT-621 also in lower and upper respiratory inflammation. So we had 4 patients, small number. We have 4 patients that had comorbid asthma and we looked at FeNO, again, fractional exhaled nitric oxide. If you remember, when we look at all patients, we had about 33% reduction. Now we have uncontrolled mild asthma. So the baseline of FeNO was around 50%. So it was actually quite elevated. And we were able to reduce it between 50% and 60%, very rapidly, at day 8 already we're close to actually above 50%. So this is really telling you that our drug distributes to the lung effectively and has an effect that is as robust, if not superior, to upstream biologics.

Not only we measured FeNO, which is a biomarker, we actually measured, at 4 weeks again, also impact on a clinical measure of asthma, which is this ACQ-5 questionnaire. And here, we saw all patients have a reduction of ACQ-5, that was superior than a minimum clinically important difference, which led to 100% responder rate, meaning all patients had a response to our drug. So beyond Asthma so -- lungs, we also looked at allergic rhinitis. This is a very common comorbidity for patients with atopic dermatitis. Here, we had between 6 and 7 patients that were invaluable for this particular comorbidity and also here, we had high responder rate, again, in line with what has been seen with upstream biologics.

So this has, again, emboldened us and give us the confidence and the excitement to initiate our Phase 2b study today, actually, we're describing for the first time the design of the study. So -- and we've started the study, as I mentioned, about a week ago. So this is a moderate to severe eosinophilic asthma. So we're looking at patients with high eos, 300 and high FeNO, 25. This is because we know, based on the development of other drugs in this pathway like dupilumab. This is the patient population where we expect to see the biggest treatment effect. This is a dose-ranging study, about 264 patients for 12 weeks, again, 3 doses of KT-621, the same 3 doses that we're using for the AD study and one placebo and we're looking at FEV1 as the primary end point. This allows us to actually differentiate doses versus placebo in a short amount of time to allow us to move into a registrational Phase 3 study as quickly as possible. Also for this study, we expect to have data next year.

So this concludes , as I said earlier, really the early translation of clinical translation of KT-621 and STAT6 targeting in patients -- in humans, I should say. So we have so much data, starting with human genetics saying that if you target STAT6, you should block type 2 inflammation and potentially deliver this dupilumab in appeal kind of profile that we like to use for simplicity's sake. We've shown in preclinical data, our ability to robustly block the pathway again completely. In healthy volunteers, we were able to show that we can degrade the target exceptionally well and have impact on biomarkers and type 2 biomarkers even in healthy volunteer with an absolutely pristine safety profile. And then now in AD patients, again, we've shown that we can degrade the target in blood, in skin, in lungs, obviously, given the effect of this biomarker. We have impacts on these biomarkers broadly. We have impact on clinical endpoints in both AD asthma and allergic rhinitis. That we have pristine safety, no treatment-related adverse events in this study. And all the numbers that you've seen today really are in line, if not, in some cases, numerically superior to biologics in this pathway is just telling you that we can block IL-4 and 13 exceptionally well. And so we're excited about obviously these Phase 2b studies and what we can do for patients with these diseases.

So here's where we are today. And I think the important aspect that I want to kind of highlight is that from these Phase 2b studies, let's start with the one on top, our AD study. The goal is out of these three doses to select one that will go into Phase 3 campaigns. We expect to initiate multiple Phase 3 campaigns in parallel. And hopefully, we can use the same dose without repeating Phase 2b studies for multiple other skin indications using the Phase 3 dose that we select in the AD study. Similarly, for asthma, we hopefully will select the dose to go into Phase 3 with asthma and the same dose we can potentially use for asthma, CRS and other respiratory indications. So in order for us to being able to go into Phase 3 studies directly, in parallel, in multiple indications. And that's really our strategy that we obviously continue to bet and validate as we get closer to initiation of our first Phase 3 study, which is actually quite soon relatively quite soon.

So Kymera is obviously not just about KT-621 and STAT6. I like this slide because it gives us an opportunity to look at the programs and the impact. At the end of the day, that's what we're trying to do. And we divide it across, let's say, disease areas. So KT-621, I think, is the best type 2 drug so that treats all these indications you see in the left part of the slide. IRF5, which is a program, again, will generate data this year, is really in the rheumatology space. So IBD, RA, SLE, Sjogren's, et cetera. We have a partnership with Sanofi and IRAK4, this is more Th1, Th17. And here, we're just giving a preview of a couple of programs that are close to disclosure time, hopefully, at least one of them will be able to disclose.

So just to give you a sense of the areas that we're going to be looking into developing these drugs, I would say one is more focused on Type 1 inflammation and one is let's say, more focused, if you look on the right side of the slide on autoantibody-driven diseases. Again, these are all oral drugs against targets that have never been drugged with oral molecules.

So this is, I believe, my last slide. So 2026, a busy year. The goal is to complete enrollment of the AD study with KT-621, continue to enroll the asthma study to generate data by '27, initiate and complete and release the data for the Phase 1 study of KT-579. As I just mentioned earlier, we hopefully will be in the position to disclose a new program in immunology that will be going into IND-enabling studies later this year. And then, again, continue to advance our partner program to important inflection points.

So I wouldn't be able to do anything that I've shown you today without the amazing team that is in Watertown, Massachusetts. So I want to thank them for everything that they've done. The team here for inviting me and all of you for taking the time out of your busy schedule to listen to this presentation.

Thanks, Nello.

I took too long.

No, no, not all. Let's start the Q&A. [Operator Instructions] I'll just start off with more of a broader picture question. Can you put 621's data last -- from last month into a bit of context. I think as we think about your portfolio overall, is there -- do you see a read-through to your next work and so on? And overall, how does that derisk the underlying technology to roll out the next degrader?

Yes, a great question, Brian. I think this, I believe -- I should know this, I believe this is our sixth program that goes into the clinic. And in all the programs that we've advanced in the clinic, we've shown an absolute amazing fidelity of translation between the data we have generated preclinically and how we've seen safety, target engagement early clinical impact. And so I think, obviously, we've also learned a ton in the past 10 years. I always say that KT-621, KT-579, 485 and others that you'll see. These are -- I like to call them second generation degraders, meaning it's -- they're benefiting from years of learnings that we've had with the first programs that we discovered and then advance into a clinic. And I think the data, the 621 data, which I think for many ways that you look at it is as good as you could ever hope for just speaks to the fact that we have really absolute control on how we design these degraders and how they behave clinically.

So yes, the short enter is, I think it validates the work that we're doing for 579 with second-generation IRAK4 degrader and all the future programs that we're bringing forth because all programs are following this type of strategy of high specificity, high potency and good physical chemical properties and the right targets.

And we'll take a question from the audience.

I actually have two questions. The first one is you explained the logic of like choosing PROTAC compared to the inhibitor very well. But I want to ask like what is the clinical consequence of PROTAC? Is it leading to like stronger efficacy or is leading to a less frequent dosing? That's the first question.

And then second question is like we all know that DUPIXENT is doing very well with AD and asthma. So did we try to compare the maybe the efficacy on the animal test or whatever like compared to DUPIXENT?

So the first question is what can degraders offer? So many things. First, as I said, there are no small molecules that can block a target completely 24/7 because the PK and the PD relationship is one to one. And extremely difficult to have enough drug on board 24/7 to block the target. So it allows you to actually have maximal target inhibition, which should lead to blockade, which should lead to superior clinical benefits.

I would also say that in many cases, not in all cases, proteins have more than one function. So when you remove the protein, you can actually benefit from removing all functions of the protein and not the catalytic function that the small molecule is able to block.

And then your second question is about -- so we've done plenty of preclinical studies comparing KT-621 to dupilumab. I'm always very careful to claim superiority because dupilumab is such an exceptionally effective and successful drug. And I cannot use a few preclinical studies to claim that we're a better drug. All I can say is that in these preclinical studies, when we degrade the target 90% or more, we see an effect that is at least as good as what you see with the saturating dose of dupilumab in these models. But we're still close to generating robust placebo-controlled clinical data. And so I would love to use that data to delve more into these comparisons.

I like it. We have audience. I never get audience questions in this day and age. So thank you.

Thank you for your presentation. So I have two questions. The first one is we noticed that you have a QD but I also noticed that you're empathizing the lasting effect, especially for asthma [indiscernible] efficacy. So do you have a plan to do QW dosing?

So a great question. Actually, you also asked a similar question. I forgot to answer. So the question is, yes, the -- sorry, I'm not used to repeat questions. I apologize. You guys have all heard the question. So QD is what we believe to be the most commercially viable dosing paradigm that we believe, based on analysis, will allow for maximum compliance. We know if you look at our data in Phase 1, we know that actually one dose of KT-621 is able to retain maximal degradation for multiple days. So it is possible that you could dose less frequently. It's not something we're exploring clinically today, but it's something that could be explored at some point.

So second point is just my curiosity because degrader and the PROTAC and the molecular glue noticed that's the first one that's [indiscernible] as PROTAC and CDK2 is molecular glue. So what's your basic criteria some technology to which one you would choose for which target [indiscernible]?

Yes. Excellent question. very simple answer. It's really, really driven by the problem we're trying to solve. If we want to degrade a target that we can find a small molecule binder for selectively. There is no better technology that heterobifunctional integrators, you have complete control of specificity and of the mechanism. If we cannot find a specific binder to the protein X or, for example, for CDK2, we cannot find the specific binder that is specific for CDK2. As you know, there is high homology between CDK2 and CDK1 so we choose this protein-protein interaction enabling technology, which many call molecular groups. So that's how we separate the two.

Well, thank you so much for your time, and that's all the time we have. Thanks for coming.

Thank you, everybody.

Thank you.

Good morning, and thank you for joining us to review the KT-621 BroADen Phase Ib results in patients with atopic dermatitis. I'm Justine Koenigsberg, Head of Investor Relations. Joining me this morning with prepared remarks are Nello Mainolfi, our Founder, President and CEO; and Jared Gollob, our Chief Medical Officer. For today's discussion, Nello will start with an overview of our strategy, how we're advancing oral small molecule degraders in immunology and the exciting opportunity to see our first-in-class STAT6 degrader or KT-621. Then Jared will take you through the BroADen Phase Ib trial design and results. After our prepared remarks, we will open the call to questions, and we'll also be joined by Bruce Jacobs, our Chief Financial Officer. [Operator Instructions] We plan to wrap up the call by 9:30.

We will make the presentation slides available as soon as we complete our prepared remarks this morning in the Investors section of our website, and a replay of today's call will also be available shortly after in the same location. The team will also be available after the call for any follow-up questions. Please note that during today's presentation, you will see references to data from prior dupilumab studies. It is important to note that no head-to-head studies have been conducted comparing KT-621 to dupilumab. As a result, the KT-621 data presented may not be directly comparable to dupilumab clinical data due to differences in study designs, endpoints and patient populations, and these data are provided for reference only. Before we begin, I would like to remind you that today's discussion will include forward-looking statements about our future expectations, plans and prospects.

These statements are subject to risks and uncertainties that may cause actual results to differ materially from those projected. A description of these risks can be found in the most recent 10-Q filed with the SEC. Any forward-looking statements speak only as of today's date, and we assume no obligation to update any forward-looking statements made on today's call.

With that, I'd now like to turn the call over to Nello.

Good morning, and thank you, everybody, for joining us today. This is a truly special moment for Kymera, for the immunology community and more importantly, we believe, for all the patients who one day may be treated with our innovative medicines. For the first time ever, we're sharing today the profound impact of a STAT6 degrader KT-621, on patients with type 2 inflammation. I believe this is a watershed moment and marks the beginning of a new class of transformative medicines, targeting STAT6 for more than 100 million patients around the world suffering from type 2 diseases that have no effective, safe and convenient oral options. 2025 has been an incredible year of accomplishments for Kymera, and we think of no better way to conclude this year than with these compelling results, which bring KT-621, another important step closer to the promise that is foundational to our drug development strategy to bring in safe and effective oral medicines with biologics-like activity to areas with significant unmet needs. I'm eager as you to get to the data. But before I turn the call to Jared, for a full review of the results, I wanted to take a few minutes to provide an overview of our strategy of how we're working to fulfill our mission to revolutionize the way in which inflammatory diseases are treated.

Kymera has established itself as a leader in targeted protein degradation, redefining what's possible in the treatment of immune inflammatory diseases. From the beginning, we focused our efforts on solving the industry's most difficult problems, challenging ourselves not with what could be done, but with what needed to be done. As a result, our target selection has been focused on going after previously undrugged targets or difficult-to-drug targets, which we believe we could leverage our best-in-industry capabilities in hit finding and optimization of oral degraders into innovative solutions to diseases with significant unmet need. As we've said often, no program is more emblematic of our strategy and capabilities than STAT6. But it's important to note that beyond STAT6, we're advancing a broad pipeline of additional targets. Through this work, we're building one of the most novel and impactful pipelines in immunology that we hope will lead to an entire portfolio of first and best-in-class immunology oral treatments. We're intentional in our focus in immunology, and we believe we can disrupt a category that needs new innovation by advancing this exciting new modality. We're just scratching the surface of the mass market opportunity.

Currently, global sales for advanced therapies are in excess of $100 billion annually; however, while there are approximately 160 million patients diagnosed with 10 of the most common immunological diseases across U.S., Europe and Japan, it is estimated that only about 3% are treated with advanced systemic therapies, which are largely made up of biologics. So we have a $100 billion market for only 3% of the patients, mostly dominated by biologics because traditional small molecules have failed to provide comparable efficacy and safety. So here is the real opportunity. Biologics have transformed the treatment of most immuno-inflammatory diseases, but they come with many challenges. These include inconvenience associated with injection or in some cases, injection site reactions or pain, stringent storage requirements, the potential risk of immunogenicity, often complex reimbursement or adoption may be hindered by administrative burden and high costs, which are often not adequately covered by insurance. Additionally, physicians have noted that the top patient concern with injectable drugs is that patients don't like needles and many patients are not comfortable with self-injecting.

As a result, in a recent patient survey, more than 90% of patients on injectable biologics confirmed that they will be willing to switch to a safe and equally effective oral treatment. Clearly, converting many of these patients is undoubtedly a great opportunity for Kymera. At the same time, even more exciting is that KT-621, an oral drug with potential for biologics like safety and efficacy, could, in fact, expand the market to the tens of millions of patients that are not on any advanced systemic therapy. The appeal of oral small molecule solutions is clear, but the path to developing compelling small molecule alternative to biologics has been a challenge, at least we believe until now. Historically, oral small molecule approaches have focused on inhibition. The key challenges of small molecule inhibitors is driven by their PK/PD profile, which does not allow for full and importantly, continuous pathway blockade. Degraders as opposed to small molecule inhibitors can provide continuous pathway suppression.

This is due to the catalytic mechanism of degraders that allows for repeated elimination of disease-causing proteins to enable deep, durable target knockdown with once-a-day oral dosing with low doses and low exposures. As a result, degraders have the potential to deliver biologics-like efficacy with oral treatment. We believe that this will unlock the opportunity to treat a broad range of immunological conditions. With that description of the power of targeted protein degradation and our strategy as background, let's turn to the focus of today's call, KT-621, the first drug targeting STAT6, a transcription factor in the IL-4 and IL-13 pathway. The pathway has been validated clinically by dupilumab across multiple allergic and atopic diseases from AD to asthma, COPD and many other where dupilumab is approved today. STAT6 is the obligate and specific transcription factor in the pathway and is therefore, the critical signaling node controlling type 2 inflammation. By blocking the function of STAT6, we expect to phenocopy IL-4 and 13 targeting. There is also compelling genetics and clinical validation, which supports why STAT6 degradation should lead to dupilumab-like efficacy in type 2 diseases with a favorable safety profile.

This includes human gain-of-function mutations, heterozygous partial loss of function and knockout mice, all of which support the clinical and genetic validation of STAT6. The opportunity for STAT6 degradation is enormous with more than 140 million potential patients across type 2 diseases like AD, asthma, COPD, EoE and others. Yet less than 2 million patients today receive systemic advanced therapies. As I said earlier, an oral option could unlock access for tens of millions of patients transforming the treatment of type 2 diseases. Today's data puts KT-621 one step closer to making this a reality. I wanted to remind everybody that we moved KT-621 into the clinic with confidence given the compelling preclinical package we have generated. Preclinically, KT-621 demonstrated an exceptional profile. As we've said in the past, dupilumab-like, in many cases, numerically better than dupilumab in many preclinical studies. Importantly, this profile has translated extremely well into humans. To step back briefly, in preclinical testing, KT-621 has demonstrated several key attributes. It's exquisitely selective and highly potent. In addition, we've shown complete IL-4 and IL-13 pathway inhibition that was comparable or superior to dupilumab. From a safety perspective, it was well tolerated even at concentrations up to 40x above the efficacious dose.

And finally, in efficacy models, we see a clear reversal of disease shown here in the goblet cell metaplasia model with effects that were comparable or superior to dupilumab arm, highlighting the broad therapeutic potential across type 2 diseases. Building on this compelling preclinical foundation, we've also generated a strong data set in healthy volunteers. KT-621 demonstrated robust degradation potency, a safety profile undifferentiated from placebo and impressive initial effect on type 2 related biomarkers that were in line or numerically exceeded published data for dupilumab in healthy volunteers at 2 weeks. This data validated our thesis and built even more confidence in KT-621's potential as a differentiated treatment option for type 2 diseases as we advance the program into patient studies. Our clinical plan for KT-621 is designed to be both broad and very efficient. We successfully completed our Phase I studies in healthy volunteers, showing robust PK/PD results and favorable safety profile. And today, we'll discuss the exciting results in atopic dermatitis patients. Before we get to those results, I wanted to remind everybody that we've already progressed the program into the first Phase IIb trial for moderate to severe AD.

We've initiated that trial in October and just recently announced that we dosed our first patient. Additionally, we're preparing to start our Phase IIb asthma study next quarter, which remains on track. I should mention briefly that our enthusiasm around asthma is further supported now by some really exciting data that you'll see today in comorbid asthma patients in the Phase Ib study. Taken together, we believe these dose-ranging studies, which we refer to as BROADEN2 and BREADTH will enable rapid progression into Phase III registrational trials across multiple type 2-driven indications, including dermatology, respiratory and GI. Jared will share with you the full trial results next, but I wanted to highlight why we're so excited about the data that we've generated as they demonstrate for the first time ever in patients a dupilumab-like profile that strongly supports continued development of KT-621. Across all study objectives, we have exceeded our expectations. We've shown strong fidelity of translations from healthy volunteers to patients with deep STAT6 degradation in blood and skin. We've observed significant reduction in type 2 biomarkers across blood and skin lesions as well as in lungs using FeNO, which was the primary goal of the study. And these results are comparable to, and in some cases, numerically exceed results reported in dupilumab studies at week 4.

We also achieved robust improvements on all key clinical endpoints, including EASI pruritus NRS, IGA in AD patients and clinically meaningful impact on patients with comorbid asthma and allergic rhinitis. For all of these endpoints, KT-621 data were in line or numerically exceeded published data for dupilumab at week 4, further highlighting the exciting potential patient impact. And importantly, KT-621 was well tolerated with a favorable safety profile that was similar to the exciting and encouraging healthy volunteer data that we have previously shared. Altogether, these data provide a powerful validation of the enormous opportunity that is in front of us with KT-621 as we advance the program in Phase II development in both AD and asthma.

With that preview, I'll turn it over to Jared to review these positive results in more details. Jared?

Thanks, Nello. It's a privilege to be able to present these exciting results from the BroADen Phase Ib trial in AD on behalf of the exceptional KT-621 team and Kymera. I'll begin with a brief overview of atopic dermatitis and the Phase Ib trial design and then dive into the results, starting with demographics and baseline disease characteristics and then covering STAT6 degradation, impact on type 2 inflammation biomarkers, clinical activity and safety. Atopic dermatitis is a highly prevalent chronic inflammatory skin disease that most often starts in childhood and then stays with patients throughout their adulthood. Skin lesions in AD are disfiguring, intensely pruritic and painful, impacting quality of life through incessant scratching, sleep loss, depression, missed work or school and disruption of social activities. Common type 2 comorbidities include asthma and allergic rhinitis. Many treatment options address symptoms, but not the underlying type 2 inflammation. Biologics like dupilumab represent a significant advance in the treatment of AD, but only a very small fraction of moderate to severe patients are on dupilumab, and there remains a high unmet need for effective therapies that can reach a much larger segment of the AD population.

BroADen is a single-arm open-label Phase Ib trial in patients with moderate to severe atopic dermatitis. The study allowed treatment with prior biologics after washout if the patient had responded, but concurrent medications for AD, including topical therapies were not permitted. Patients received an oral once-daily dose of KT-621 for 28 days with an additional 14 days of follow-up after completion of dosing. Doses of 100 and 200 milligrams were selected based on the results from the Phase I healthy volunteer trial and were enrolled sequentially as separate dose groups, 10 patients on to the 100 milligram and 12 patients onto the 200-milligram dose groups. Endpoints included safety, PK STAT6 degradation in blood and skin, type 2 inflammation biomarkers in blood, skin and lung and clinical activity using endpoints commonly assessed in AD trials. While the dose groups were enrolled sequentially and therefore, patients were not prospectively stratified by baseline demographics or characteristics, the 2 arms were generally well balanced for gender, age and race. Overall, 54.5% were black or African-American and 22.7% were Hispanic or Latino. The dose groups were also generally balanced for measures of disease severity, including vIGA-AD, EASI and peak pruritus NRS. In the 100-milligram dose groups, 60% were moderate and 40% were severe with mean baseline EASI and peak pruritus NRS scores of 23.5 and 7.4, respectively. In the 200-milligram dose group, 50% were moderate and 50% were severe with mean baseline EASI and peak pruritus NRS scores of 26.1 and 7.6.

Overall, 54.5% had moderate disease and 45.5% had severe disease with overall mean baseline EASI and peak pruritus NRS scores of 24.9 and 7.5. Approximately 46% of patients had comorbid asthma or allergic rhinitis and approximately 23% had prior biologics treatment, including 4 with prior dupilumab, one of whom also had tralokinumab and with prior tralokinumab only. The 200-milligram group had a higher proportion of patients with comorbid asthma or allergic rhinitis as well as more patients with prior biologics treatment. Turning now to the STAT6 degradation results. We measured changes in STAT6 protein levels in blood using flow cytometry. As shown here, deep degradation of 98% was achieved in both KT-621 dose groups by day 8, which was the first time point measured after the start of dosing and reflected steady-state degradation that was maintained through end of dosing with recovery apparent at the next time point 2 weeks later. The plasma PK profile at 100 and 200 milligrams was similar to what we observed in the Phase I healthy volunteer trial. These results demonstrate high fidelity of PD and PK translation from healthy volunteers to AD patients.

In AD skin lesions, STAT6 levels were approximately twofold higher compared to healthy volunteer skin. Using mass spectrometry to measure changes in STAT6 protein levels in skin, 94% degradation was achieved in both KT-621 dose groups after 4 weeks of treatment, with multiple patients showing reduction below the LLOQ. We also observed up to 95% to 98% reduction in STAT6 staining by immunohistochemistry in the epidermis and dermis. This confirmed the strong correlation between STAT6 degradation in blood and skin that was observed in healthy volunteers and was consistent with the systemic effect of KT-621 on STAT6 levels. As we will be reviewing the effects of STAT6 degradation across multiple biomarkers and clinical endpoints, it is important to note that degradation in blood and skin were essentially the same in the 100- and the 200-milligram dose groups. In order to demonstrate that the STAT6 degradation observed in blood and skin lesions was associated with systemic inhibition of the IL-4/13 pathway, we measured the effect of KT-621 on 5 different disease-relevant biomarkers of type 2 inflammation. You are all familiar with the blood biomarkers, TARC, eotaxin-3 and IgE, which we studied in our Phase I healthy volunteer trial. In healthy volunteers, baseline levels of all 3 were low, but we were still able to show a dupilumab-like effect on TARC following 14 days of KT-621 dosing as well as an even more robust effect on eotaxin-3.

As with dupilumab, we saw a little effect on IgE in healthy volunteers, consistent with the requirement for higher baseline levels and longer treatment duration to see an impact on that biomarker. Our expectation going into BroADen was that these biomarkers would be significantly elevated in moderate to severe AD patients at baseline, thereby facilitating our ability to show a greater effect with KT-621 dosing in patients compared to healthy volunteers. With today's data set, we are sharing 2 additional and important biomarkers that were not measured in our healthy volunteer trial. IL-31 is a key cytokine driving itch that is elevated in the blood of AD patients. Notably, a small study of dupilumab in AD patients did not show any impact on blood IL-31 levels. Fractional exhaled nitric oxide known as FeNO is produced by airway epithelial cells in response to type 2 inflammation. In asthma, FeNO is a point-of-care biomarker used to detect type 2 airway inflammation that has utility in diagnosis and in monitoring response to therapy with biologics like dupilumab targeting the IL-4/13 pathway. Higher levels have been associated with lower lung function and increased risk for future asthma exacerbations.

While FeNO has not been studied in AD patients, we included it in BroADen so we could assess the baseline levels and response to KT-621 in all AD patients and also assess KT-621's effect on any AD patients enrolled who had comorbid asthma. Starting with TARC, I thought I would provide some important context before I share the KT-621 results. As shown here, the published data with dupilumab in AD, eosinophilic esophagitis, asthma and CRS with NP clearly show that the magnitude of TARC reduction is a function of baseline levels with higher baselines leading to greater percent reduction in response to dupilumab. In earlier AD trials, where median baseline levels were in the 2,000 to 4,000 picogram per ml range, median TARC reductions at 4 to 52 weeks were in excess of 70%. It's important to note that the CHRONOS study was a combination of dupilumab plus topical corticosteroids. In contrast, median baseline TARC levels were only approximately 300 picograms per ml in the EoE, asthma and CRS with NP trials and median TARC reduction at 12 to 52 weeks was only 25% to 39%. In BroADen, median baseline TARC in the KT-621 dose groups was 868 picogram per ml at 100 milligrams and 800 picograms per ml at 200 milligrams, with median TARC reductions at 4 weeks of 48% and 55%, respectively, consistent with the relationship between baseline TARC and percent TARC reduction established with dupilumab in type 2 diseases, including AD.

In those BroADen patients with baseline TARC in line with earlier dupilumab AD studies, defined as greater than or equal to 1,600 picograms per ml, which is the lower bound of the 95% confidence interval for the median TARC baselines from the dupilumab SOLO-1 and SOLO-2 AD studies, the median TARC reduction at 4 weeks was 74%, comparable to the dupilumab effect of 4 weeks in the single-agent Phase III studies. Similarly, in the subset of KT-621 patients with lower baseline TARC, defined as less than 1,600, we also observed TARC reduction. In this case, 38% that was comparable to the dupilumab results in studies with similar lower baseline TARC levels. Here, we summarize our results with KT-621 by showing the time course for TARC reduction stratified by KT-621 dose cohorts on the left, where KT-621 achieves similar levels of TARC reduction across both doses by day 29. As shown in the previous slide, when we stratified for dupilumab AD studies like baseline levels, including TARC greater than or equal to 1,600 versus less than 1,600, KT-621 achieved dupilumab-like inhibition of 74% in the high TARC cohort. We also show the results stratified by median TARC baseline from BroADen, where the median reduction of 71% in patients with baseline TARC greater than or equal to 800 is comparable to the effect of dupilumab. For Eotaxin-3, KT-621 achieved strong reduction by day 8 with median reductions of 62% and 73% at day 29 in the 100 and 200-milligram dose groups, respectively, followed by recovery towards baseline 2 weeks after the end of dosing. These results at 4 weeks exceeded the effect of dupilumab on Eotaxin-3 at 52 weeks in patients with asthma and CRS with NP.

While we did not expect to see much of a response in IgE with a relatively short 4-week treatment duration in light of the modest effect reported with dupilumab at 4 weeks, we did observe a 5% to 14% reduction across the 2 dose groups at day 29 that was in line with the dupilumab results at week 4. Strong IL-31 median reduction of 54% to 56% was observed across both dose groups at day 29 with recovery to baseline occurring 2 weeks later. To our knowledge, this is the first demonstration of IL-31 reduction in the blood by a drug targeting the IL-4/13 pathway. This is an important data point as IL-31 is believed to be the most important biomarker of its response and is known to be downstream of the IL-4/13 pathway. FeNO, which was noted earlier as an important biomarker of type 2 airway inflammation was elevated at baseline in AD patients, including those without comorbid asthma with median levels of 13 to 20 ppb across both dose groups. Reduction in FeNO was observed as early as day 8 with median reductions at day 29 of 25% and 33% at 100 and 200 milligrams, respectively, followed by recovery back to baseline 2 weeks after end of dosing. To our knowledge, this is the first demonstration of FeNO reduction in AD patients and provides initial proof of concept for IL-4/13 pathway inhibition in the lungs resulting from systemic STAT6 targeting with KT-621.

Dupilumab has been shown to down-regulate type 2 inflammation and other AD disease-relevant genes in the skin lesions of AD patients as early as 4 weeks into treatment. We used paired skin punch biopsies from the same lesion obtained from patients at baseline and on day 29. Given the similar levels of STAT6 degradation and pathway impact across the 2 doses, we pooled the available samples from all patients to generate a more robust data set. Using a core type 2 inflammation gene set, KT-621 showed significant reduction at day 29. Specifically, downregulated genes included Eotaxin-3, TARC, PARC and MCP-4. Results were comparable to dupilumab data at 4 weeks. Using an AD disease-relevant gene set that includes not just type 2 cytokines, but also Keratin 16, Periostin, TSLP and genes involved in Th17 and Th2 response, among others, KT-621 also achieved significant dupilumab-like reduction at day 29. Taken together, these results demonstrate how deep degradation of STAT6 in AD skin lesions leads to disease-relevant transcriptomic changes reflective of IL-4/13 pathway inhibition.

Moving on to clinical endpoints. We saw strong and generally comparable results across both dose groups and in patients with or without prior biologics treatment. As shown here, KT-621 achieved 62% and 63% mean reductions in EASI by day 29 in the 100 and 200-milligram dose groups, respectively, and overall 63% mean reduction with robust impact as early as day 8. The time course shows continuous improvement through day 29 without reaching an apparent plateau, suggesting the potential for further improvement with dosing beyond 4 weeks. The improvements on EASI as well as on all the other upcoming additional endpoints were in line with or numerically exceeded published data for dupilumab at week 4 in AD trials. An analysis of EASI in patients stratified by baseline TARC or EASI showed that the effect of KT-621 on EASI was comparable in patients with low and high baseline TARC or EASI. This demonstrated that KT-621 benefited patients with moderate to severe AD to the same extent regardless of disease severity. The substantial improvement in EASI at 4 weeks translated to EASI-50 scores of 67% and 83% in the 100 and 200-milligram cohorts, respectively, and 76% overall. EASI-75 scores were 33% and 25% in the 100- and 200-milligram cohorts, respectively, and 29% overall. And vIGA-AD 0/1 was 22% and 17% in the 100- and 200-milligram cohorts, respectively, and 19% overall.

While categorical endpoints are highly sensitive to and impacted by small ends, we were encouraged to see robust activity in these measurements. SCORAD is a validated composite measure of AD severity, integrating extent, intensity and patient-reported impact. KT-621 achieved 52% and 46% mean reductions in SCORAD by day 29 in the 100 and 200-milligram dose groups, respectively, and overall 48% mean reduction with robust impact as early as day 8. Pruritus or itch is a major clinical manifestation of AD severely impacting quality of life. KT-621 achieved a rapid and strong impact on 2 independent measures of itch, including peak pruritus NRS and SCORAD itch, a component of SCORAD. As shown here, KT-621 achieved 47% and 35% mean reductions in peak pruritus NRS by day 29 in the 100 and 200-milligram dose groups, respectively, and overall 40% reduction. KT-621 also demonstrated 40% and 47% mean reductions in SCORAD itch in the 100 and 200-milligram dose groups, respectively, and overall 44% reduction with impact as early as day 8.

The time courses show continuous improvement through day 29 without reaching an apparent plateau, suggesting the potential for further improvement with dosing beyond 4 weeks. This impact of KT-621 on patient-reported measures of itch is consistent with our observed effect of KT-621 on blood levels of the pruritogenic cytokine, IL-31. Just as was demonstrated for EASI reductions, an analysis of peak pruritus NRS in patients stratified by baseline TARC or EASI showed that the effect of KT-621 on pruritus was comparable in patients with low and high baseline TARC or EASI. This again demonstrated that KT-621 benefited patients with moderate to severe AD to the same extent regardless of disease severity. The next 3 measures were used to capture the effect of KT-621 on various dimensions of patient quality of life in order to further assess the clinical meaningfulness of reducing disease burden and symptoms. SCORAD sleeplessness is a validated measure of AD severity, capturing quality of life impact. KT-621 achieved 72% and 78% mean reduction in SCORAD sleeplessness by day 29 in the 100- and 200-milligram dose groups, respectively, an overall 76% mean reduction with mean 45% reduction as early as day 8.

This is a compelling outcome measure as impact on sleep is one of the most burdensome sequelae of moderate to severe AD. The patient-oriented eczema measure, or POEM, is a measure evaluating patient experience and impact on quality of life. KT-621 achieved 7-point and 11-point mean reductions in POEM by day 29 in the 100- and 200-milligram dose groups, respectively, and overall 9-point mean reduction, which is greater than the minimum clinically important difference of 4 points. This translated to an overall 73% POEM responder rate. The Dermatology Life Quality Index, or DLQI, is a quality of life measure validated in AD. KT-621 achieved 6-point and 9-point mean reductions in DLQI by day 29 in the 100- and 200-milligram dose groups, respectively, and overall 8-point mean reduction, which is greater than the minimum clinically important difference of 4 points. This translated to an overall 61% DLQI responder rate. Here, we show an example of response to KT-621. This patient has severe AD with baseline EASI of approximately 37. She had a history of prior response to dupilumab but came off treatment in 2017 due to lack of insurance. She was treated with KT-621 100 milligrams once daily on BroADen and demonstrated a rapid response on EASI and itch with 84% EASI reduction and 56% and 63% reductions in peak pruritus NRS and SCORAD itch, respectively, by day 29.

This clinical response was associated with 95% STAT6 degradation in blood and 94% degradation in a biopsied skin lesion, which showed deep reduction of STAT6 nuclear and cytoplasmic staining in epidermis and dermis. The patient also had robust biomarker reductions at day 29, including 78% decrease in TARC, 92% to 96% decreases in skin and blood Eotaxin-3 and 93% decrease in skin keratin 16. This exemplifies the internal consistency between STAT6 degradation, biomarker response and clinical activity in patients treated with KT-621 on BroADen. The reported frequency of asthma and allergic rhinitis comorbidities in AD patients is approximately 25% and 40%, respectively. The enrollment on to BroADen of 4 patients with comorbid asthma and 9 patients with comorbid allergic rhinitis provided us with an opportunity to look beyond AD and perform a focused assessment of biomarker and/or clinical activity relevant to these other 2 type 2 allergic diseases. The 4 patients with asthma had higher baseline levels of FeNO compared to other AD patients with a mean baseline of 49 ppb compared to 17 ppb in those without asthma. KT-621 achieved a median FeNO reduction of 56% at day 29 in patients with comorbid asthma compared to 25% in those without asthma.

This substantial reduction in FeNO, which exceeded the 31% reduction observed with dupilumab at 4 weeks in asthma was associated with a mean 1.2 point reduction in asthma control questionnaire 5 or ACQ-5 and 100% ACQ-5 responder rate that represents a clinically meaningful improvement in asthma control. This represents a first demonstration of the potential impact of KT-621 in asthma and is a meaningful result as we approach the initiation of our Phase IIb asthma study next quarter. In those patients with allergic rhinitis who were evaluable for symptoms and quality of life, KT-621 achieved a mean 0.9 point reduction in total nasal symptom score, or TNSS and a mean 0.8 point reduction in Rhinoconjunctivitis Quality of Life Questionnaire or RQLQ, at day 29. These clinically meaningful reductions in TNSS and RQLQ were associated with responder rates of 57% and 33%, respectively. Overall, these results in AD patients with asthma and allergic rhinitis comorbidities highlight the potential for KT-621 in these type 2 respiratory diseases in addition to AD.

This table summarizes the results for AD clinical endpoints by dose group and for all patients. Remarkably, KT-621 treatment led to improvement in all endpoints covering disease burden, symptoms and quality of life. The robust treatment effect with KT-621 across these endpoints exceeded the upper end of the 95% confidence intervals for historic placebo rates in moderate to severe AD. Importantly, none of the patients on BroADen required rescue therapy during the 4 weeks of KT-621 treatment, underscoring the clinical benefit of treatment. This clinical activity was internally consistent with the deep degradation of STAT6 in blood and skin lesions and the strong effect on disease-relevant biomarkers in blood and skin by KT-621. It is also notable that the clinical improvements on disease endpoints with KT-621 were either in line with or numerically exceeded published data for dupilumab at week 4 derived from the SOLO-1 and SOLO-2 AD trials added here as reference.

KT-621 was well tolerated with a favorable safety profile across the 100 and 200-milligram dose groups, consistent with the Phase Ia healthy volunteer trial results. There were no SAEs, no severe AEs, no dose-dependent pattern in the TEAEs, no related TEAEs or TEAEs leading to discontinuation, no AEs of conjunctivitis, herpes infections or arthralgias and no clinically relevant changes in vital signs, laboratory tests or electrocardiograms. In summary, BroADen Phase Ib achieved all of its objectives, demonstrating deep degradation in blood and skin with strong translation from the Phase Ia healthy volunteer study, profound effect on disease-relevant type 2 inflammation biomarkers in blood, skin and lungs, reflecting systemic IL-4/13 pathway inhibition. Robust clinical activity in AD with dupilumab-like effect on all measured endpoints as well as early evidence of activity in comorbid asthma and allergic rhinitis based on improvements in biomarkers and/or patient-reported outcomes and excellent tolerability with safety profile similar to what was observed in the Phase Ia trial. These results underscore the significant potential of KT-621 in AD and other type 2 allergic diseases and support advancement of the program into Phase IIb trials in AD and asthma.

I'll now turn the presentation back over to Nello for his concluding remarks.

Thank you, Jared. What a presentation. Like we did earlier this year for the healthy volunteer data, I think we have again demonstrated a compelling clinical translation of STAT6 degradation with KT-621. And again, I think we've exceeded our best expectations. As you just heard, we believe these results collectively reinforce the potential for KT-621 to deliver biologics-like profile in patients. And as you've heard me say before, the next few years will be very exciting with what I believe is once-in-a-generation drug development opportunity. As you all know, we take a lot of pride into careful assessment of human genetics and preclinical biology. We built comprehensive data set to inform our investment thesis and increase the POS of positive clinical translation for our programs. We started the STAT6 program several years ago with the idea that once-a-day oral STAT6 degrader had the potential to be the first biologics-like oral agent in immunology. And I believe this data set in AD patients complete successfully our initial clinical translation.

We started with strong genetics data, compelling preclinical data, a healthy volunteer translation that demonstrated well-tolerated deep degradation that led to dupilumab-like biomarker impact and finally, the true translation, the one in patients. And here, we have again demonstrated the impeccable translation of the human genetics, the preclinical data that point us to an oral STAT6 degrader to have the potential to transform the treatment of inflammatory diseases with a dupilumab in appeal profile. And I'm sure you'd agree with me that the data we've shared today show that we're well on our way to delivering on this important goal and more. It is worth taking a moment to reflect on what has been an exceptionally encouraging safety profile as we progress KT-621 through preclinical and early clinical testing. Throughout all of our preclinical testing up to and including 4-month tox studies, we have not observed any safety findings at any dose. And in testing in what has now been over 200 combined healthy volunteers and patients, there have been no reported safety issues of any significance. While this is a small Phase Ib study, it seems clear that KT-621 is blocking this pathway as well as an upstream biologic. It's reducing several disease-relevant type 2 cytokines in blood, skin and lung and in many -- as well and in many cases, numerically exceeding published dupilumab data.

These have resulted in improvements in objective and patient-reported clinical endpoints in AD, comorbid asthma and comorbid allergic rhinitis. The coherence of all data is, I believe, compelling. And in my view, strongly suggests that we have a potentially transformative drug. Now it's on us to focus on the execution of these critical Phase IIb studies in AD and asthma and then build our late-stage capabilities to build a global commercial stage company that will deliver life-changing oral medicines. I want to thank, first of all, the Kymera team for the exceptional work and dedication in driving the KT-621 program forward. And everyone at Kymera should be so proud of what we've delivered today. I also want to extend our sincere gratitude to the investigators, study site teams, our collaborators and CROs and most importantly, the patients who participated in the BroADen study. Their partnership and trust has made this progress possible.

With that, we look forward to the Q&A discussion.

[Operator Instructions] Your first question will come from Judah Frommer with Morgan Stanley.

Congrats on the update here. I guess, first, one of the questions we've been getting over time is just can you help us with dose selection in the Phase Ib, which dose came first? I guess, given the STAT6 degradation you were seeing in TARC reductions, why they need to add the second dose? What do you think you learned from it? And then second, I would just say on itch reduction, that seems to be a real differentiator here. I guess, how does that make you feel about market opportunity in itch prevalent conditions outside of AD and also that rapidity of itch reduction. What does that do in terms of the potential in AD specifically?

Well, thanks, Judah, for both questions. So let's take it one at a time. So the first one, so I don't think at this point, it's important that we figure out what dose came first. I think what's important is we wanted to understand really well the translation from healthy volunteer to patients to enable a refinement of our Phase IIb doses. So we decided to pick doses that were actually quite similar, I would say, almost equal in healthy volunteers and see whether we would see the same profile in patients. Obviously, if you do that, you should probably pick in the higher range of the dose because you want to translate a robust degradation profile into patients. So that's where the 100 and 200 came from. Obviously, you've seen that what we saw in healthy volunteers we saw in patients, almost equal degradation in blood and skin, and I would say almost equal or comparable downstream effect across the 2 doses. So much so that will allow -- it actually allowed us to look at the overall patient profile of the 2 doses, as we've shown at the end in the summary, one can look at the overall patient to kind of get a more powered number of patients in the study.

With regards to the second question, which is a great one, as we know, I'll let Jared actually answer more specifically. My first reaction is the most -- I think one of the most impactful deliverables of this study has been the impact on patient-reported outcome. Not that is superior to others, but because that's what we're treating, right? We're treating patients that have itch, that have trouble sleeping at night, and the fact that we can deliver a drug that has a robust impact on all of these just shows you that this is the type of drug that patients we hope will be looking for. But maybe, Jared, more technically on the other diseases.

Yes. I mean I think we're very gratified to see impact on itch across 2 different measures, the peak pruritus NRS as well as the SCORAD itch. So that concordance, I think, was really important as well as seeing the relationship between that and the effect we saw on IL-31, which is one of those key pruritogenic cytokines. So fascinating to us and very encouraging to see the impact on that cytokine. And I think all that together, I think, does potentially lend itself to thinking about treatment of diseases even outside of AD. Obviously, very important to treat itch and to see rapid kinetics of improvement in itch, which is what we saw. But to be able to treat other diseases like CSU and prurigo nodularis, right? These are other Th2 allergic diseases where itch is a big component. I think it gives us encouragement that we should have activity there as well.

Your next question will come from Derek Archila with Wells Fargo.

Congrats on the data here. So just first question for me. I'm not sure if I missed this, but I just wanted to understand maybe the level of efficacy you might be seeing in the Dupi and trial experienced patients. That would be interesting. And just as a follow-up, I guess these FeNO changes that you guys highlight today, they not only look competitive relative to Dupi, but some of the other biologics in development or on the market. So I guess, how do you think oral STAT6 could kind of reshape the kind of emerging treatment landscape in asthma?

Thanks, Derek. Great questions, both of them. So the first one on -- so Jared mentioned in his conclusion slides that the activity we saw in biologics-naive patients and biologics-experienced patients was similar, if not the same. I can say that in the 4 Dupi patients, we had 100% EASI-50. Now I don't want to make a big deal out of it. I think it just tells you that our drug works well and obviously should work well in patients that respond to this pathway drugs. On the second part, again, I'll let Jared maybe comment more on the specifics, but we've been telling everybody for the past 2.5 years that STAT6 degradation is going to transform treatment paradigm along -- across all the type 2 diseases. And I have to thank the team. I take no credit for it for actually thinking about FeNO even in AD and obviously, in comorbid asthma. And it just shows you the drug distributes well to all tissues, including lungs, degrades the target well. And it tells you if you have a small molecule drug that is very potent, I think we're going to outshine a lot of drugs that are out there. But maybe, Jared, taking us back to Earth with...

Yes. No, I think you addressed it very well. I mean I think we were, again, very excited to see this effect on FeNO, both in patients without asthma, which tells us that even in patients with AD without over asthma, there is some TH2 inflammation probably in the lung, leading to upregulation of FeNO and then to see an impact on there, I think, was very gratifying in addition to this profound impact on FeNO in asthma patients. And so I think the fact that the STAT6 degrader is able to clearly reach the lung, impact Th2 inflammation there, impact lung biomarkers of Th2 inflammation does have important implications for asthma for our ability to use a once-daily oral drug in asthma and really be as effective as we could be across other Th2 allergic diseases like AD. So I think it just speaks to the enormity of the opportunity for this drug across multiple Th2 allergic diseases where Dupi has shown an impact.

Your next question will come from Tazeen Ahmad with BofA Securities.

Congrats on the positive update. I have a couple of quick questions. You didn't see any instances of conjunctivitis. It's a small line of patients, but I think that could be a positive indicator of further differentiation from Dupi. Can you talk about what your expectations might be for Phase IIb on side effects specific to conjunctivitis? And then does this data, albeit early, indicate that there could be other indications beyond which you've already discussed wanting to go into as potentially available to explore?

Thanks, Tazeen. Great question. So just -- we've been saying this for months. So it looks just empirically that if you target IL-4 and 13 in patients with atopic dermatitis, you will see rates of conjunctivitis. In -- if you look at all drugs in this pathway, you've seen usually rates that are in the 10%, 12%, 15% at week 16. If you look at the data across all those studies, at week 4, you see about 5% rates of conjunctivitis. So in a study like ours, we're talking about one patient roughly. So I think the data tell us that at least we don't have worse rates of conjunctivitis than there are other drugs in this pathway. Whether we'll have similar or less, I would ask to wait for the Phase IIb studies that are ongoing, at least the AD studies ongoing. Jared, do you want to maybe address the second one?

Yes. In terms of indications outside, say, AD and asthma, I mean, I think, again, we feel that all Th2 allergic indications where Dupi is approved and/or shown activity are really fair game, I think, for KT-621. Again, the key here is, are we showing systemic inhibition of IL-4, IL-13 pathway signaling and functional effect. And I think the data, the biomarker data as well as the clinical data coming out of Ib tells us clearly, yes. And so I think that then allows us to think about multiple indications that go beyond AD and asthma, whether that's also COPD on the respiratory side, CRS with NP, some of the various other pruritic disorders that we talked about earlier, CSU, PN, et cetera. I think those are all open.

Maybe I just want to add a quick thing. I know we have many more questions. But I think that what we love about our data is the consistency across all the measurements. So while obviously, it's a very small data set, so we should be careful with over interpreting them. The fact that we have impact on skin, we have impact on lower airways, we have impact on upper airways. Obviously, we haven't talked much yet about allergic rhinitis. It just bodes well for all these indications that dupilumab has shown activity when it's chronic rhinosinusitis with nasal polyps, asthma, COPD, AD, pruritus and all the other indications. So again, small data set, but it speaks so broadly to the potential of this drug, and that's really what we're excited about.

Your next question will come from Alex Thompson with Stifel.

Congrats on the data again. It was interesting to see the data split out by TARC, but I was wondering if you could talk about whether there was any correlation on a patient level between STAT6 degradation and either biomarker or clinical efficacy. I guess, for instance, did patients that got to a lower limit of quantification on STAT6 degradation do better generally? Anything you could say there would be helpful.

Yes. Great question, Alex. I think that the data set is too small. I mean we also have very, very tight data across degradation. So it's really difficult to try and tease out these correlations. I'm sure as we build larger data sets, for example, in this Phase IIb study, we'll attempt to look into that, but this was too small for that kind of analysis.

And then maybe as a follow-up, will you include both 100 and 200? Are those both doses in the Phase IIb?

As promised, we're not going to disclose our Phase IIb doses. So we'll know that in 2027, but thanks for asking.

Your next question will come from Brian Cheng with JPMorgan.

Just to touch on the trend in improvement across multiple measures over time. Can you speak to the response out to day 43 once patients are off drug at day 28? How does that line up with your understanding of the PK/PD and also target engagement? And then for the second question, as we think through the BroADen 2 setup for atopic derm, that will look into efficacy out to 16 weeks. How should we think about the step-up in efficacy over time?

Great question. So let's start with the first. Maybe just high level, just if you look at our -- the degradation in blood, you see that at day 43, obviously, the target recovers, and that's expected to be after 2 weeks that you stop dosing. Obviously, we know that the target doesn't recover one day when we stop dosing. It actually takes a few days, if you remember in the healthy volunteer studies. And so I think what's important is that when we stop dosing in the following 2 weeks, there is a recovery of target. There is a recovery of biomarkers. In the clinical endpoint, I think it's more obvious once you affect this disease morphology in the skin or you affect sensory, things like itch, we expect and see that the recovery is lower, right, because it just takes a while for the disease to come back. So I don't think it's surprising what we see.

And I'll let Jared comment maybe just quickly on the second, and Jared, maybe you can comment on both. On the second question, I think the most compelling data that we're seeing, and Jared highlighted it, if you look at, for example, if you go to a slide where we have the EASI, we see really robust reduction of EASI right already at day 8. And that kind of slope of curve continues to be steep through day 29. So in a way, this tells us that -- I believe we don't know, but I believe that tells us that we're nowhere near the maximal efficacy of our drug. And the exciting part of this ongoing study is to actually figure out where we plateau.

Yes. And just to follow up on what Nello was saying, I think we do expect to see a step-up in efficacy with continued dosing. If you look at dupilumab, what they saw with EASI, for example, they saw 50% -- roughly 50% reduction at 4 weeks and then 70% reduction out of 16 weeks. And for pruritus, they saw a 30% reduction approximately at 4 weeks and then 50% reduction out of 16 weeks. And so our results at 4 weeks, as we show, numerically exceeded what Dupi showed at 4 weeks. And I think we're excited at the possibility and expectation that we would see further step up with 16 weeks of dosing.

Our next question will come from Kripa Devarakonda with Truist.

Apologies. My Internet is a little bit slow in the hotel here, but congrats on the data, fantastic data. So a couple of questions. One on TARC reduction. Just can you remind me, I might have missed the data, but if the data that you showed was from all patients or if you took a cut of the patients? And also, if you can comment on the dose effect, I know small numbers, but dose effect on EASI-75, what could be the reason that you saw dose dependence in EASI-50, but not in EASI-75?

Yes. So on the TARC, we show all data. So if you look at -- I don't think we have to pull up the slide, but I just suggest you look at Slide 29 of our deck, you see all patients data stratified by dose by TARC at 1,600 by TARC at 800 baseline. So you'll see that. With regards to a dose response, so I want to take kind of a step back. So 100 milligrams, 200 milligrams, as we expected, showed exactly the same degradation profile in blood and skin. As expected, this degradation profile leads to impact on biomarkers and clinical endpoints that are comparable. So I'm not sure we should look into any numerical differences between the 100 mg and the 200 mg look, it's possible that if you run this study longer, you might see differences. I think at 4-week, it's a bit hard to say there are differences. Then we go to the next step of -- we've said for many months not to focus on these categorical endpoints.

They're impacted by one -- a fraction of a patient, right, we're talking about. What you're seeing the difference between the 2 is the fact that the 200 milligrams at 12 patients, the 100 milligrams is at 10 patients. So we really can use the category endpoints to even compare. And if you look at the continuous variable endpoints, you look at EASI especially, they're basically the same. So I think the take-home message for us, the 2 doses behaved similarly, and that was what we expected. And in a way, that's what we wanted to see, especially with regards to degradation for us to make the right Phase IIb dose selection.

Your next question will come from Brad Canino with Guggenheim.

Okay. Perfect. Well, let me add my congratulations as well. And I guess I have a follow-up on one of the previous questions around the deepening of effect. And the question is really, why might you expect EASI change from baseline to deepen further when you've already hit a range of what antibodies deliver at week 16. And I'm also thinking about this in the context of JAK inhibitors, where you really see that effect within the first 4 weeks play out and then plateau from there.

Yes. I think, Brad, the answer is we don't know, obviously. Our expectation is that generally, atopic dermatitis is a disease, especially with regards to skin impact, takes a while to see maximal effect because you're waiting, obviously, for skin cells to regenerate, et cetera. We also believe that unlike JAK inhibitors, our biology is very much an IL-4 and 13 biology, as you know well. And we know that we expect our biology to be coherent with the general kinetics of what has been seen with other drugs in this pathway. So whether we're slightly faster and better than Dupi, I'm not going to say that. I promise I wouldn't say that. I would say we're in the ballpark. We talk about numerically, maybe slightly better. Let me not get into this diatribe. But what I would say is this is a different modality, right? It's a small molecule. It is possible that you're able to engage the pathway a bit faster, but that doesn't mean that you plateau faster. I agree with what Jared said earlier. I don't have data for it, but I agree with this instinct that I think our effect will deepen with more dosing.

Your next question will come from Brian Abrahams with RBC.

Congratulations on the data. Should we expect the BroADen patients to be representative of the types of patients that you're planning to and expecting to enroll in the Phase IIb? And how might any differences -- or how much might any of the differences there impact either the rapidity of response or efficacy over longer dosing?

Yes. Thanks for the question. The eligibility criteria for the Phase IIb are going to be very similar to the Phase Ib criteria for defining what is moderate to severe. So we expect there to be a very similar population. If you look at our population and our baseline characteristics, we have about close to 45%, 50% of patients on Phase Ib had severe disease. the baseline NRS pruritus scores, baseline SCORAD, et cetera, were very similar to what we're seeing with Dupi. So we are -- we did manage to enroll a broad range of moderate to severe patients on Phase Ib with those eligibility criteria, and we expect to do the same in Phase IIb.

Maybe just to add a small comment. If you look at the early dupilumab studies, our baseline EASI was in the, let's say, low 30, 31, 32. The AD trials in the past 5 years, the mean baseline EASI was around 25. Obviously, we have taken a different approach with the IIb in a way that we're very, very focused on obviously delivering on these large studies. So this is a global study. We've said that a majority of our sites would be outside of the U.S. We're very focused on quality of patients, quality of sites. And keeping the expected placebo rates in the smaller range possible. So again, I think patients are what they are at this day and age, but we are being very proactive on making sure that the patient population delivers -- allows us to deliver impeccable data for this drug that has obviously huge potential.

Your next question will come from Andrea Newkirk with Goldman Sachs.

Congratulations on the data this morning. Jared, just thinking ahead, I know we're a little ways off from this. But as you think about a potential Phase III trial, would you expect to need a head-to-head trial versus Dupi, either in order to support approval or physician adoption? And then just one for Nello, Bruce. You've referenced now the potential utility for 621 or STAT6 degradation across a range of type 2 diseases. But how are you thinking strategically about internal versus external development for those programs and prioritization of resources?

Okay. Yes. Thanks for the question, Andrea. So I'll start with your first one, which is do we need to do a head-to-head Phase III with Dupi. I think the short answer is no. If you look at the precedents for registration and approval, whether it's in the U.S. or Europe, in these diseases like AD and asthma, it's not going up against an active comparator. It's going up against placebo. So our anticipation is that we will have a placebo-controlled study for Phase III for initial approval. Now whether there might be opportunities down the road for doing a head-to-head comparison in order just to see what our activity is like relative to Dupi or to support reimbursement in some of the European markets, that's always a possibility. But I think our base case is a placebo-controlled Phase III for registration and approval.

Thanks, Jared. On the second question, just high level, we are building the company to take 621 all the way. In our current plans, obviously, we have these Phase IIb studies. Bruce can tell you more about our runway and cash we have today. But -- and we believe that as we continue to derisk the program and as our cost of capital decreases, we should be able to continue to fund the program. Now if we go after 7 indications in Phase III in parallel, we're talking about 28, 29 Phase III studies. I don't think any company in the world can actually do that, not just afford but execute. So for us, it's really the priority indications. We have 4 or 5 that are the majority of the patients in type 2 inflammation that we're getting ready to support as a stand-alone independent and wholly owned company and program. Obviously, post Phase II study, we always are going to be open to discuss potential different win-win opportunities. in terms of partnerships, but that's not our base case right now. Maybe, Bruce, you want to.

Yes. I wouldn't add too much, Andrea, other than, as Nello said, we're acutely focused on executing on the Phase IIbs right now. We're capitalized to take the company into the second half of 2028, which is at least a year beyond the first readout of those Phase IIb studies. So that's where our internal focus is.

Your next question will come from Tom Smith with Leerink.

Congrats on the data. Just in the patients who had prior biologic exposure, I appreciate the color on the one patient who responded after prior response to Dupi. I was just wondering if you could expand on the background and maybe the narrative for the other 4 biologic experienced patients. Were there any nonresponders or suboptimal responders that subsequently responded to 621? Or were these patients all prior responders? And then maybe as a follow-up, you talked about the slope of the EASI pruritus curves here suggesting we could see some greater benefit of longer dosing. Also appears to be some durability and response on some of these measures out to that 2-week follow-up period. Just curious how you're thinking about the potential durability of effect. And for patients that seem to have more of an extended response, are there any common features among those patients?

Jared, do you want to take the first one?

Yes. In terms of prior biologic, in order to come on to the study, if patients had prior biologics, they had to have responded to those biologics. If they came off of them, it had to be not because of nonresponse, but because of maybe they didn't tolerate it or their insurance didn't covered or they didn't want to take injections anymore. So all of the patients with prior biologics, whether it was Dupi or Tralo had an actual good response prior -- in the past. And then they had an adequate washout period prior to coming on to the study.

And obviously, we saw that they responded well to 621. On your second question, it's hard for us. We don't really have enough [indiscernible] to dissect patients that respond slightly longer than not longer. So those are things we'll continue to keep an eye on. I would say that if you look at the clinical benefits and the clinical effect of drugs in this pathway, obviously, we expect that as you stop dosing, you will eventually have less response. I think what's important that maybe it's underappreciated that if you're able to dose drugs from this pathway, dupilumab, hopefully 621 one day in the early life of patients with type 2 inflammation, you can actually change their life forever, right? If you're able to stop the atopic march, you actually are able to provide even cures to some of these patients. So that's why for us, pediatric development, it's not maybe a topic for today. It's an area that we're very focused on as we continue to advance this program.

Your next question will come from Geoff Meacham with Citi.

Okay. Good. Awesome. Congrats on the data, guys. I wanted to ask you about the speed of onset. The release mentions a pretty rapid onset by day 8 in EASI and pruritus. Just curious if you could tie clinical responses to the mechanism and biomarkers more specifically. That's the first question. And the second one is just another one on FeNO, really impressive data there, obviously, just a few patients, but maybe does the baseline in this study in comorbid patients with asthma look like what you want to explore in Phase Ib and future studies. Just wanted to put maybe that in context.

Yes. That's great question, Geoff, actually, I like it. So the first one is if you look at degradation of STAT6 at day 8, you see, obviously, we crash it already. If you look at biomarkers at day 8 in most of them, the ones that we were measuring, we see a really robust effect at day 8. So it's not surprising that we're starting to see this initial impact on disease already at day 8. I mean we're probably impacting all of these biomarkers as well as STAT6 already on day 1. So again, we reached steady state at 4 hours in our study. So I think what we have seen is not surprising that this pharmacology happens quickly. On the second question, which I thought was really cool, maybe, Jared, you can speak to the baseline of FeNO.

Yes. I think those baseline FeNOs that we saw that were sort of in the 50 range in those patients with comorbid asthma, that's very similar to the levels you're going to see in moderate to severe asthma. Now these patients on our study didn't have moderate to severe asthma. They were having control issues with their asthma, and that's why their ACQ-5s were actually elevated, indicating that they had poor control. So the fact that we were able to see in these patients who had FeNO levels that were at least as high as what you'll see in your standard moderate to severe asthma and see such a profound impact on FeNO and also a real impact on improving asthma control by that 100% ACQ-5 responder rate, does give us encouragement, even though this is a small end, clearly, it does give us encouragement that in a Phase IIb asthma study that we should be active and potentially as active as Dupi, but that remains to be shown in that study.

Your next question will come from Joe Catanzaro with Mizuho.

Actually, I think, a good follow-up, maybe just to the last question in terms of asthma in those 4 patients, given their comorbid with AD, is it fair to assume that they had high baseline levels of eosinophils, so eosinophilic asthma and then I guess, relatedly, thinking about 621 and its mechanism and utility in asthma, how should we think about it relative to phenotype eosinophilic versus non-eosinophilic, whether it will behave like Dupi or not?

Yes. I mean, based on our data, we -- based on what we understand about this pathway, this is a type 2 drug. So we expect that -- and in fact, our patient population will be eosinophilic asthma. Many of our patients had elevated EOS. That's both a feature of AD, especially given that it's the more Th2 skewed of the type 2 diseases. And obviously, the ones that had -- I don't remember exactly, but the ones that had high FeNO likely had also elevated [ EOS ] at baseline. So again, in terms of placing this drug, we expect it to be an eosinophilic drug. And I think the important thing about 621 in asthma is that I think the opportunity we will have after obviously, Phase III and being approved is to really work with the community here to change how patients are treated with asthma. Right now, patients are treated with steroids for too long without addressing the actual inflammation. I think this drug can change that paradigm. And that's why we're very passionate about asthma, AD and the pediatric population for both.

Your next question will come from Mayank Mamtani with B. Riley.

Congrats on the fantastic results. If I could ask one more asthma question. If you could clarify the treatment duration that you might be looking to explore in the Phase IIb. Dupi had a bunch of different trial designs initially that were conducted. So if you're able to give any information what you've learned by FeNO and the eosinophil comment you had earlier. And then on the sort of the safety AE table, I'm sure we'll get at a future medical conference, combining exposure across healthy volunteer. Now I think of 150 subjects. Could you just confirm if you've established the safe minimally effective dose threshold? Or is that going to be a key Phase IIb objective? I was just curious about the details there.

Yes. So on the duration, we're not going to disclose the design of the study yet. So I think it will be early next year when we start the study for custom. On the safety of our drug, I mean, we have placebo-like safety in the healthy volunteers. We didn't have placebo here, but you could say that it was very similar to that the safety we saw there. There, we pushed the dose all the way up to 800. So we actually haven't seen any dose-limiting toxicity or any actually toxicity that are relevant of any type. So this is as good of a safety profile as one could hope.

Any AEs that were dose dependent you can comment on, Nello?

Jared?

No. There were no dose-dependent AEs, either in patients or in the healthy volunteers.

Your next question will come from Andy Chen with Wolfe Research.

You broke up Andy.

It appears we have lost Andy.

Okay. Maybe we'll try back -- the next one.

Sure. We'll take our next question from Jeet Mukherjee with BTIG.

Great. Pretty momentous day for you folks as a company. So I wanted to extend my congratulations as well. One thing I'm just still quite fascinated by is some of these differences that you're seeing versus DUPIXENT, such as on IL-31 and on FeNO. So just from a biologic and perhaps pharmacologic basis, is there anything you could point to that perhaps might be driving this difference?

Well, it's a great question. I would be kind of careful at this stage to claim that we are superior to DUPIXENT. I don't think the message that we want to send today is that. I think the message that we want to send is all the data we've accumulated to date in the past multiple years has shown us that we've embarked the pathway as well as an IL-4 and 13 biologics. I think we can safely say that with this data. We will require larger studies and more analysis to actually get to the specifics of differences. Again, one thing I would say that as we've seen also in preclinical studies, the small molecule is extremely fast at degrading and it's extremely good at getting into tissues, so it's obviously telling us that we have robust effects in the right tissues. And that might be something that with more studies, we'll be able to show more and more data that might share and give rise to some level of differentiation. But again, I would be unscientific to say that we have robust data right now to say we're different. I think we're at least as good as what has been shown with upstream biologics. So let's put it at that...

Fair enough.

Your question is very good. I'm not dismissing it. You know what I'm trying to do.

Absolutely. Maybe just as a quick follow-up, obviously, focusing -- or focus now turning to your Phase II studies. Can you just remind us what steps you're taking to mitigate that placebo response?

Yes. So Jared, maybe you can speak to this.

Yes. I think for the Phase IIb AD study, for example, I think it's very important that we have eligibility criteria and train seasoned physicians to make sure that, number one, they're putting on AD patients because sometimes patients who don't have AD are put on to these studies. And number two, to make sure that the patients, if we have an EASI cutoff of 16, for example, from moderate to severe, that they're not putting on patients with lower EASIs actually really have mild disease, not moderate. This does happen.

And so it's very important for us as we've selected sites, selected investigators and we ourselves as a sponsor will be providing a lot of close oversight in terms of the screening of patients to make sure the right patients with the right eligibility criteria are enrolled on to the study. That's going to be critical, also making sure that we have dermatologists doing the clinical measures and the same person doing the measure at baseline. And then afterwards, that's going to be really important. And again, making sure that we as a sponsor are providing close oversight. It's also very important to have an array of sites in these global studies. We have both North American sites in U.S. and Canada as well as sites ex U.S. in Europe and in Asia. In fact, our AD study will have a majority of sites outside of North America, although there will still be a substantial number of North American sites.

For our next question, we'll return to Andy Chen with Wolfe Research.

Just one question from my side. Curious if your Phase Ib here has generated additional confirmatory evidence that degraders are better than inhibitors. And I'm hoping that you can help us quantify how much better a degrader is compared to an inhibitor. Or in other words, if a STAT6 inhibitor were to produce TARC or IgE data, where do you think they will land?

Yes. No, it's a great question. And we've said it for a very long time that for this particular pathway in order to achieve biologics-like activity, you have to get really robust blockade. We've said in the past, 90% plus. Some would argue maybe even more than that. And obviously, I think we've shown that in both healthy volunteers and now in patients. We believe, given how much target is expressed, we believe it's almost impossible with an inhibitor to cover the target 24/7 at this level of inhibition, again, given the PK/PD reliance of traditional small molecules. With regards to your question, look, IgE is extremely noisy in the first few weeks.

So it's really hard to put a number on IgE that one could actually make a comparison with. And on TARC, again, you've seen that it's very dependent on baseline. But assuming you have comparable levels of baseline, I actually don't think that blood biomarkers are the story of differentiation. Even if you look at preclinical models, you can actually change biomarkers even with suboptimal target engagement. When I say suboptimal, I say even 80%, 85% you've seen our preclinical data. But it's the clinical endpoints and the efficacy endpoints preclinically is where you need the robust deep pathway blockade.

Our next question will come from Sudan Loganathan with Stephens.

Kymera team, I really appreciate the update here, and I want to convey my congrats again also on the data that you presented for 621. So my question, given that BroADen enrolled a substantially higher proportion of African-American patients than dupilumab's earlier AD studies, I think it was about 50% in your study versus Dupi was closer to 70%, 80% of actually white Caucasian patients. And considering the known challenges in scoring erythema or skin redness in darker skin, how are you thinking about interpreting the observed EASI-50 or 75 responses in that context? And then did you incorporate any scoring standardization or digital tools to mitigate skin tone-related variability? And will there be any focus on that in the Phase IIb in this population or going forward?

I want to just high-level answer, Jared, you can be ready to answer the more technical part. I don't believe that this is going to be trend that you've seen in all the other studies. Just to remember, this was a U.S.-only study, 28 days, 2 required biopsy, the third option of biopsies. So this was really a difficult study to enroll, which also the site selection was based on, we believe, patients that we would have access to that would have less access to systemic biologics. Again, I can't predict what the Phase IIb study will look like, but I would be surprised if the percentages will continue to stay the same. But Jared, what do you want to add to the technical...

Yes. I think from a technical standpoint, I think all the clinicians and dermatologists that were used in our Phase Ib study were all well trained to be able to assess lesions in both dark skin individuals as well as lighter skin individuals. Also important to note that in our African-American patients, we saw concordance across all endpoints. So it wasn't just EASI, it was also pruritus, SCORAD, biomarkers, sleeplessness, all these other endpoints all sort of came together.

So in addition to the investigators being well trained to assess extent and severity of skin lesions in a measure like EASI, the fact that all the other measures also came together, just as you saw in that one example that we gave in the presentation, which was a dark skin patient, that really isn't an issue. And I think if we have those patients in our Phase IIb study, again, we'll be using sites with experienced dermatologists who will be well versed on how to do these measurements across the board.

I think this was the last question here. So I wanted to thank everybody for tuning in. This is a momentous day for the company, and we're happy to spend more time with any of you today in the next few days. And again, I wanted to thank the team here at Kymera for doing an amazing job in the past few years and especially in the past few months. And thanks again, everybody, for joining us today.

All right. So welcome to the second day of the Citi Global Healthcare Conference. So I'm Geoff Meacham, I'm the senior biopharma analyst, and my team is here in front, too. So we're thrilled today to have Kymera Therapeutics. We have Bruce Jacobs, the CFO. We have Jared Gollob. So welcome, guys. Good to have you.

We got some questions here, but maybe you want to give sort of just a real quick like kind of a couple of minute overview, and then we can get into some of the detail.

Sure, Geoff. Thanks so much for having us. It's always great to be at your conferences. So it's been a busy and active year for Kymera. As I think most of you hopefully know by this point, we're one of the leaders in the targeted protein degradation field. We're actually coming up upon the 10-year anniversary of Kymera's founding, which will be next May. And I think it's amazing from where I sit to look at how the company has evolved in terms of our capabilities and then obviously, in terms of how that's manifested itself in our pipeline.

But we've taken that focus on protein degradation. We've, over time, narrowed our focus to the immunology space, where we think there's a tremendous opportunity to develop drugs that using this really powerful modality have, we think, the ability to deliver, as you've heard us say many times, biologic-like efficacy with a similar safety profile of some of these biologic drugs, which are incredibly powerful in their efficacy, but have some drawbacks, which we think make oral options a compelling alternative.

So at this point, we've developed a pipeline that we think is quite exciting. I'm sure we'll talk about our 2 wholly owned programs, our STAT6 program, which is on the cusp of some data, as you all know, and I'm sure we'll talk about that as well. And our IRF5 program, which we introduced earlier this year and is poised to enter the clinic next year as well as share some -- we'll have some data next year on that program also.

And we've got a couple of partnered programs as well if we have time to talk about them. We partnered with Sanofi on our IRAK4 program. They've focused on our next-generation IRAK4 degrader and we'll be entering the clinic next year in 2026. And also just recently, actually, it was June now, but feels recent, we announced a collaboration with Gilead around a CDK2 molecular glue, and we'll hopefully have news on that molecule's progression next year. So it's been an exciting time for Kymera, and we've got a lot to discuss, I'm sure.

So I'll turn it back to you for some specific questions.

Awesome. Yes. Thanks, Bruce. Yes. So let's talk about pipeline first, so we can get into strategy and kind of the longer-term outlook. So the 621 data, atopic derm coming up, there's obviously a category where there's a lot of innovation. There's a lot of competition, but you guys have a really unique platform technology and the potential to have really a very exquisite potency. So talk a little bit about the what maybe a win looks like there in terms of differentiation, how you're thinking about this data set as you look to mid- to late-stage trials?

Great. Thank you. Maybe I'll start. Essentially, the 621 program has been through Phase Ia healthy volunteers, right? We showed we think, impressive data there in terms of safety, knockdown and biomarker effect. And now we have this readout coming this month for Phase Ib. I think we've been very clear upfront from the very beginning of the study that for us, a win was to meet multiple objectives with that particular Phase Ib study in AD patients.

One of the main objectives was to show translation of safety, PK and PD from healthy volunteers to patients. Another important objective for us was to show or to allow us actually to confirm the doses that we had already really selected for Phase IIb based on our Phase Ia healthy volunteer data, but with translation, hopefully, between healthy volunteers and patients to be able to confirm those doses for Phase IIb.

We've talked about biomarkers being an important objective. We wanted to show a dupi-like effect on various Th2 biomarkers, probably TARC in blood being one of the main biomarkers that many focus on in AD because it's so elevated, but other biomarkers as well in blood and in skin and to be able to show a dupi-like effect at 28 days. And then finally, being able to look at a variety of different AD clinical endpoints.

Again, if you look at 28 days and what dupi showed across their Phase III studies at 28 days on various endpoints, that provides you with a ballpark for where we'd like to be with 6:1 with regard to those endpoints in our Phase Ib study. So for us, that would be a success being able to sort of hit those various objectives. And for us, I think we see ourselves right now as being obviously sort of furthest along in the space with regard to certainly degraders.

And even with inhibitors, even though Pfizer recently announced that they are moving into a Phase IIb, they haven't shown any Phase I data. We feel as though we're quite ahead of the pack with regard to either any degraders that might be out there of STAT6 or any inhibitors by at least a year or 2, now having very quickly over the last year or so moved through healthy volunteers patients in Ib and even just recently initiated our Phase IIb AD study dosing our first patient just over the past couple of weeks and plans to start our Phase IIb asthma study in the first quarter of next year.

That's super helpful, Jared. Yes, when you think about the 28 days for dupi, I guess, the comps, how would you think about further differentiation? Is it sort of depth of response? Is it speed of response? Or what are the opportunities, I think, to really separate from this study for 621?

I mean I think we've said it all along that based on our mechanism of action, blocking the IL-4/-13 pathway through a different mechanism, but to the same extent as what dupi can do and what we've seen in our preclinical models is that we expect in the best case scenario to be similar to dupi with regard to both efficacy and safety. So when we look at 28-day results, for example, we've been a little more granular around TARC in the blood just because this is not a placebo-controlled study, but biomarkers don't tend to change much in placebo. So if you look at the dupi data at 28 days and you see a 70% to 80% reduction in TARC, that's sort of the ballpark we'd like to be in, if you want to say that we're dupi-like on biomarkers at 28 days.

We've been a bit more reluctant to sort of land on a specific number for clinical endpoints in the absence of a placebo control. But I think, again, if you look at those like the SOLO 1, SOLO 2 Phase III data and you draw a line at 28 days and you look at what they saw for EASI, pruritus and other endpoints, you'll get a sense for that's the ballpark that we'd like to be in with regard to 621.

From a kinetic standpoint, I think we're going to sort of learn about our kinetics for the first time in Phase Ib. Again, remembering that this is a 4-week study. So we're not looking over the entire 16 weeks where the Phase II and registration Phase III studies are usually run that also usually include even a longer extension period of 1 year beyond that. So I think we'll get our first sense of kinetics with this 4-week study, but it won't be the final word.

Okay. And then looking broader at biomarkers, you mentioned the TARC Jared, but also the eotataxin. Maybe talk about predictive biomarkers that maybe aren't as FDA or regulatory validated, but are a very good indicator of your mechanism and deployment. What are the potential learnings from that as you look to Phase IIb?

I mean I think from the Phase Ia healthy volunteer study, we looked at TARC, but we also looked at eotaxin, which had not been looked at by dupi in healthy volunteers and sort of a very robust effect on both. So I think in Phase Ib in patients, we expect these biomarkers to be elevated to a greater extent, obviously, compared to healthy volunteers. And actually, with regard to TARC, it's known if you look at the published data with dupi that the sort of percent change that you see in TARC is a function of the baseline level of TARC.

So if you look at some dupi studies outside of AD where TARC levels are lower to begin with, you see less of a percent reduction, even though it's hitting the pathway hard. And then if you look at the -- some of the AD studies where 10 years ago, TARC levels were very high, you see much greater percent reduction in TARC. So TARC changes are a function of where you start.

But in addition to TARC, which we're obviously looking at is important, you mentioned eotataxin in the blood. There are other Th2 biomarkers there, but also in the skin. So we have the opportunity here to biopsy skin lesions in AD patients and look at the Th2 transcriptome and other AD sort of disease-relevant genes. These have been published on by Sanofi previously. So we know what the benchmarks are for seeing effects at even 4 weeks on the skin transcriptome. So I think the totality of those biomarker data, I think, hopefully will give us a sense of whether we're in that sort of dupi ballpark even after 4 weeks.

Yes. And I guess the one question is if you look at the -- you have a lot of dupi prior data that can kind of give you a sense for the transcriptomics, the profile. But when you look to larger studies, are there -- is there less evidence when dupi -- refractory dupi patients are nonresponsive? Or how do these biomarkers trend? And would you guys be looking to study that in the larger studies, more mature clinical trials like some of the more special populations in atopic derm.

It's an interesting question. I'll answer first and if you has more information, he can answer as well. I think there hasn't been a lot of work done on understanding mechanisms in patients who don't respond as well to dupi. It turns out that many patients do have a good response to dupi. So there aren't really many dupi refractory patients in either AD or asthma. But it's a very important question around are there certain features, biomarker features in either blood or skin that might predict for better or worse responses to a drug like dupi and therefore, could those by extension also potentially predict responses to our drug targeting STAT6.

Those sorts of things might be out there, and that might be something that we look at in the future. I think right now, it's important that we're really focusing on looking at activity of our drug, not in dupi refractory patients. That's not where we're going with the drug.

We want to go to patients who are dupi naive because only a very small percentage of AD and asthma patients are even getting dupi. So that's where we intend to go with our drug. Even on our Phase Ib study, we do allow prior dupi, but only in patients who have responded previously to dupi and then had a washout, and that will also be the case in our Phase IIb.

I don't know, Bruce, if you want to add to that?

No, I would just add, and Jared alluded to this, if you look at the AD population today in the developed markets, it's over 40 million-some-odd patients diagnosed and the number of patients treated with dupi are on the order of 1 million or less. And so I guess the way we have looked at this opportunity set is that there's clearly various reasons why that penetration isn't higher despite the fact that it's a $20-ish billion run rate drug. There are some drawbacks from biologics. There are some people who have issues accessing them, paying for them.

So I think when you think about the opportunity set for 621 or you think about even the long-acting agents, I think there's a big pie here, if you will, that is, frankly, just underserved. I mean dupi is a fantastic drug, but it doesn't reach nearly as broad of a population as as we think it's possible that an effective and comparably effective and safe oral drug could reach. And that's really the opportunity set.

So as Jared mentioned, we will -- if we have any dupi experienced patients, we'll be able to share that when we have data. But clearly, you would expect there will probably be some on the Phase IIb for sure, where we'll have larger numbers overall to really do some of that analysis by different patient types.

Yes. I guess, Bruce, as a follow-up to that or Jared as well, but when you look at the investments you're making in 621 in just atopic derm, how are you thinking about maximizing the commercial opportunity? Is it really to have more of a commercial partner, perhaps like in Europe? Is it to grow eventually the indication base that you're studying from atopic derm to respiratory IBD? How do you see this playing out from a maybe a mechanism, but also from a commercial.

Yes, that's a great question, Geoff. I'll maybe start and Jared can add in. one of the aspects that I think makes this opportunity so unique for Kymera, for STAT6 targeting agents is the playbook is out there, right? We know where dupi is approved and where it's been effective, safe and effective. And so we have in front of us, if you will, a menu of potential indications that we could pursue that if our thesis is right, that a STAT6 agent will act on the pathway similarly to dupilumab, we ought to be able to show similar results in a multitude of indications.

So the question then becomes from a company standpoint, how does that drive our regulatory strategy and ultimately, our commercial strategy. The approach we've taken to this point is to initially focus for our Phase IIb studies on the 2 largest markets, AD and asthma. Those are, as I said, obviously, they represent the lion's share of dupi sales, I think, somewhere upwards of maybe as much as 80% of revenue. But they also can become what we think of almost as like sentinel type Phase IIb studies for us, one in dermatology with AD and one in respiratory with asthma.

So the AD trial Phase IIb is underway. We've initiated the sites, and we've dosed the first patient. Asthma will be off and running in the first quarter. And I think over time, as we develop this data, we'll be able to refine and share more about our development strategy and frankly, our partnering strategy for the drug as well.

To this point, anyway, we've made the very clear strategic decision that we're not interested in partnering the program despite, as you might imagine, some pretty strong interest that has come our way. We have the team and we have also the capital to fully execute on these Phase IIb studies. We don't see any scenario where any partnership could improve upon how effective we are in operating these studies and also the timeliness of how quickly we run them.

So I think the question about our development strategy becomes obviously much more pressing and real when we get to the Phase IIb data, which we expect the first of that would be by the middle of 2027. And at that point, I think we can start to really contemplate whether there's a scenario where working together with a partner could expedite our the trajectory of this path to multiple indications and how we would prioritize them.

The scale and scope of pursuing everything where dupi is today is -- would be almost unprecedented in biotech. There would be on the order of 20 Phase III studies just to target the 8 or 9 indications that are the first group of dupi indications. So I think even with a partner, there would have to be some level of prioritization. But I think those are some of the discussions that we'll have when we get to that point, if it makes sense.

I should say we're building this company to take this through ourselves, and that's our anticipation and expectation. The bar to partnering for this program for us is exceptionally high because we would have to -- it would have to be proven to us that we could develop this faster, more effectively and most importantly, more broadly with a partner than we could on our own. And right now, we have a very clear pathway to some very, very large markets.

We have 2 Phase II studies that will be incredibly informative, I think, in our opportunity set there. And we're building right now. We've frankly already built the development capabilities. We're already now focusing on the Phase III studies and the commercial side of the organization, which we need to build as well.

So -- but I think talk to us maybe 1 year, 1.5 years, we'll have more to report. But right now, it's all systems go and getting through the -- getting these Phase IIb studies rolling.

And just a follow-up to that, Bruce. So I think one of the capital with respect to growing the indications that are in development is probably pretty reasonable that you guys have access to that. But when you think about the down the road commercial investments on a global basis, geographic basis, don't get the impression that's a big priority now, but maybe we'll have to see based on data, right? Is that right?

No, I think that's fair. I mean I think clearly, the size and scale of this opportunity is commensurate with the investment that will be required on our part to capitalize on that. Right now, the company is very fortunate to have had a very committed, engaged, strategically aligned group of investors who have supported us along the way. We have $980 million of cash. We have a runway into the second half of 2028. That runway pays for both of the Phase IIb studies. It gets us started on at least the first Phase III study for STAT6 and then also pays for IRA5 and everything else we have in our pipeline.

I think we have multiple inflection points along the way to look to how we might capitalize the company to, again, further advance the program. I think the question of commercialization is a very good one, irrespective of what we do from a development standpoint. There will also be a time at which we ask the question, are we the right company solely to take this into the market? Or are the dynamics? And you know as much as well as anyone about the competitive dynamics, rebate environment, et cetera, what's the right model for that? And that's something that we're already thinking about today, but we've got a little time before we have to make some of the most important decisions there.

Yes. And Jared, you're right. We said that -- I mean, the penetration rate of dupi in the atopic derm is very, very low. But from a mechanism standpoint, when you guys run the analysis of all the biomarkers and maybe outside of atopic derm, is there an indication that maybe stands out that you feel like you could really separate versus dupi on some of the more like a respiratory biomarker or a biomarker that's more prevalent in IBD? I'm just trying to think of like maybe a nonintuitive kind of next step in terms of indication?

Yes, that's a good question. I mean I think at this point, we still view sort of all the places where dupi has gone and been approved or sort of be active really is the landscape where we should also be able to go with 621. In terms of how we prioritize, if there's a reason to prioritize above and beyond what Bruce was referring to in terms of market size, so yes, prioritizing AD and asthma because that's 80% of the dupi market. Eventually, COPD is also going to become more and more a market. Eosinophilic esophagitis is going to be important in others. I think those are all places that we think it will be important for us to go.

I should also mention that diseases like AD, asthma and EoE, there are substantial pediatric populations there as well, and those represent a sizable part of not just the market opportunity, but also the urgency of really providing drugs for these young patients, right, who are not accessing them now. You can imagine that giving injections to young children as young as 6 months of age is very difficult, both for parents and for children.

So to be able to have oral drugs that can now access pediatric patients within these big indications. I think that's also going to be an important imperative for the company in terms of if we see this, which we do as a transformative medication now for Th2 allergic diseases and now it can be given orally, you can imagine being able to access and provide unmet need for these pediatric patient populations as well as for adults and adolescents.

I mean I'm sure there's -- everybody's got their own market studies and there's many of them out there, but most that we have seen clearly indicate that there's a strong preference when given a choice between an effective and safe oral medication and an injection. And particularly, as Jared mentioned, when you get to the pediatric population, some of these injections can be very painful.

There's a large volume of drug. Oftentimes, there's induction regimens. I think particularly for parents who have to inject their own children, you can imagine that this would be a very compelling alternative. So we think about the opportunity set, not just across different indications, but also these different populations, it becomes a very interesting value proposition.

Yes. No, that makes sense. So looking to the Phase IIb study, you guys have talked about a super pharmacologic dose based on all your PK/PD analysis. Just give us the background and the context for that and why that gives you kind of confidence.

Sure. Yes. So I think for a Phase IIb dose range finding study, what FDA is going to want to see, right, is that you're looking across a range of doses that are giving you different degrees of pharmacology, potentially different degrees of efficacy. and also allows you to look at safety across these different doses where you can now sort of connect safety to what you're seeing with regard to pharmacodynamics. So I think a classic dose range finding study, you want to be able to look across a range of doses that's going to accomplish that.

And I think fortunately, for us, because from a degradation standpoint, our target is STAT6 and we can measure the impact of the drug on STAT6 and have done that, for example, in our Phase I healthy volunteer study, we know sort of what range of doses are going to give us sort of super maximal degradation versus sort of maybe clinically optimal maximal degradation versus submaximal degradation, and that's the dose range that we want to be at in a Phase IIb study in order to do that properly. We're probably not going to end up revealing what those doses are for the Phase IIb study, just given the competitive landscape.

We will obviously reveal the doses for Phase Ib when we present those data this month. But I think for Phase IIb, I think we're going to be keeping it at a high level and thinking of it in those 3 different sort of buckets, but not actually providing what the doses are other than to say that the doses selected for Phase IIb are among the doses that we did look at in our Phase Ia healthy volunteer study.

That's helpful. Yes. So we had -- yesterday, we had a chat with Marty Makary who was talking about novel technologies, novel approaches and the opportunity for certain diseases to be fast tracked or certain drugs.

Did you get us a voucher?

I was working it. So talk about the -- your accelerated development plan. Is there an opportunity in your view to maybe help speed up even more? I know you move pretty quickly, right, from Phase Ia to Phase IIb, but there's a further opportunity to kind of put this on a bit of a faster.

Yes. No, that's a great point. And I think aspirationally, that is what we want to do. It's important for us. And one of the reasons we want to maintain control of development is to be able to do just that, to accelerate development so we can get this drug to patients as quickly as possible.

Our strategy right now is to have only 2 Phase IIb studies. I think Bruce mentioned this earlier, 2 sentinel Phase IIbs that would then allow us to drive the Phase III doses for multiple Phase III indications. So you could go from 2 sentinel Phase IIbs in AD and asthma right into multiple Phase IIIs across multiple cutaneous GI and respiratory indications. So I think that's one way that we'd like to accelerate. Of course, that's going to require a discussion with FDA, for example, and European regulators once we have Phase IIb data to get buy-in, but we think there's a good chance that, that could happen.

Likewise, we talked earlier about getting into pediatric patients. If there are innovative ways of getting the drug to pediatric patients faster, given our novel mechanism of action and given what's already been derisked in terms of dupi across IL-4, IL-13 in both pediatric patients, adolescents and adults, that's something that we're also going to want to be able to explore, again, in the spirit of if we have a transformative drug that hopefully is not just convenient, but also potentially as safe and effective as dupi, we want to make sure we're getting that drug to the right patients as quickly as possible.

I was just going to add a couple of small points. I mean, those who know Kymera know that we move very quickly, and we've only gotten faster in how we develop drugs and move through the clinic. And that's always our aspiration, always will be. The one point I wanted to make is with respect to at least the IIb studies, patient quality is absolutely critical. And obviously, there's been plenty of examples, unfortunately, of trials that have not achieved objectives because of the patients that were admitted to those trials.

And so we're going to be moving as quickly as possible, but I will also say that for these IIb trials, we will certainly be over-indexing to getting the right patients on the study, and that's going to be our central focus. We believe we can do both. We can move quickly and get the right patients, but that will be a key focus of us for these IIb studies.

And maybe also, Geoff, just to add one last thing is we don't want there to be much white space, right, between finishing Phase I and going to Phase II, finishing Phase II going into Phase III. So we're constantly looking at the next phase of development, making sure we're building out our development group and capabilities and being prepared to start that next phase of development as soon as we complete the prior phase. And that's another part of the, I think, overall philosophy of being efficient here and accelerating our development program.

That's one thing that Marty kept on bringing up is idle time, right, trying to minimize that from a review perspective. But when you look at the body of data from a pure safety tolerability to do the 2 Phase IIbs, is there is there an end or an exposure or maybe even preclinically, is there something that the FDA wanted to have a sort of a foundational safety -- sorry, safety, tolerability kind of like database that before you can pursue multiple Phase IIbs?

Yes. I think that's also an important question. It may not be so much the size of the safety database just as much as a conviction that whatever doses you've chosen for, say, AD and asthma can be applicable across other indications that might be related, but not the same. So that's probably more of the issue. I think hopefully, we will have a robust safety data set coming out of these Phase IIb studies with 200-plus patients in each of these studies that will support moving on to Phase III.

And then, of course, the sort of safety database that one needs to get initial approvals in these indications, I'm not sure there's a whole lot of flexibility there. the need for multiple Phase IIIs. But again, it's about being able to execute on those Phase IIIs, not to have a lot of white space between your Phase IIs and your Phase IIIs and to be prepared to execute on those Phase IIIs by building up your development group and having the right sites working with us. I think that's going to be what's most important.

And I think you know this, but for the Phase IIbs in addition to the 4 months of treatment, patients will be eligible to move on to a 12-month OLE. So that's both an important attraction to those entering the study, but also is a big part of helping us build that safety database as we move forward towards registration.

Yes. To what degree are you guys using AI or using any sort of language model to maybe help with the -- accelerate the database or maybe translate your biomarkers to checking the box more profoundly on the safety tolerability...

Yes. No, I think it's an important question. I'll let Bruce answer as well. I think we're starting to think about AI with regard to clinical operations, right? And with regard to trying to maximize efficiency within our clinical trials, right, to make sure we're getting the right patients on to our trials to make sure that sites are performing the way they need to perform as we closely monitor and supervise those sites. So I think AI does have a role there, and we've been exploring sort of how we can incorporate it there. I'm sure there are other places where we can also use AI to increase efficiency.

I think as a company, we're still looking into that. We're already using AI and have been using AI on the research side, on the chemistry side. And so I think that continues to help us with our hit finding and all the evolution of our platform that's really allowed us to go after targets like STAT6 and other -- IRF5 and other high-priority targets. But Bruce, do you want to add?

No, I think you covered most of it. I think certainly, another part of AI will be in the data analysis side of the world. So obviously, for a 20-ish patient study, that's less relevant than a 200-patient Phase II study, but you can envision there is an area where we have some investments as well as we start to generate more data to help us understand that.

And I think down the road, there are some arguments that the way pharmaceuticals are sold could well be impacted by these AI agents, if you will. And so that's -- those are all areas where we're focused right now.

No, it was just such a big part of the conversation yesterday, right, with Marty about using more technology and early in development.

No. And I think it's really important that we're aware of what's out there and that we're looking into how we would use it as a company. And I think you're right. I mean the future is there, and we're starting to use it in select areas within the company, but I think it's going to be important to continue to maximize so that we are as efficient as we can be in our clinical development and how we go about that.

Yes. Yes. So let's switch gears to the IRAK4 IRF5 program. So this could be maybe even broader beyond just I&I into maybe more autoimmune. Give us kind of the framing of the -- how you guys position this. And obviously, it's a high priority. But what would you say is the kind of first bit of kind of derisking that we'll see that gives you confidence to to grow this indication base pretty broadly.

This is for IRF5. Yes, this is for the IRF5 program. So this is another program that we're really very excited about, another one of our solely owned immunology programs in our pipeline. This has been a target that's been in the sights of many different pharma companies for years. Nobody has been able to drug it. There are many different IRFs. There are many different isoforms of IRF5. So being able to only hit IRF5 and hit all the isoforms of IRF5 has been very challenging. We're fortunate to now have a degrader that is very selective for IRF5, gets all the isoforms of IRF5. We have a very potent selective oral drug that can be used at relatively low doses. So we're very excited.

IRF5, the reason why it's so interesting is because it sits at the crossroads of essentially signaling from all the toll-like receptors as well as other innate immune receptors. And it's really critical for activation of B cells, B-cell autoantibody production, activation of myeloid cells like plasmocytic dendritic cells that are producing pro-inflammatory cytokines and also for the type 1 interferon response. So by hitting one target, you can hit all those different pathways that are important across diseases like lupus and other interferonopathies, across IBD, rheumatoid arthritis. So there's a plethora of diseases that can be treated that you can really hit all those pathways with one target.

And I think it's also important that IRF5 is not ubiquitously expressed. Its expression is restricted to B cells, certain myeloid cell types, and it's only activated really predominantly in the disease context. So you can hit IRF5 hard as we've shown in knockout models, for example, and not have infectious complications. So very attractive from that standpoint. And we presented very strong preclinical data at AACR just last month in multiple models of lupus where our IRF5 degrader is more active than any of the other drugs out there, either approved or active in lupus. We've shown very profound activity in RA. We're currently doing models in IBD and other interferonopathies.

So I think this drug really has the potential to be transformative in these types of diseases where there are very limited therapeutic options. And so our plan, we've completed IND-enabling studies now for IRF5. We're planning on moving into Phase I early next year. So there will be a Phase I readout from healthy volunteers next year. And then the plan would then be to right on the heels of that, move into patients.

And on the patient side, we're thinking about different possibilities, but certainly lupus is high up on the list because I forgot to mention that IRF5, there's a very strong genetic association with IRF5 polymorphisms in lupus. In particular, that's number one, also RA and IBD, but that's another reason in addition to our preclinical data, why lupus has been sort of rising to the top for us.

Are there lessons from 621 sort of early development and kind of derisking going into an IND that you could deploy for IRF5? Or is it -- you just look at them as separate platforms within the TBD kind of...

I mean they are separate platforms. I think all the learnings that went into developing 621, all the chemistry learnings certainly went into IRF5 and certainly helped us be successful in developing an amazing drug for IRF5.

I think from -- in terms of IND-enabling studies and moving into Phase I, I think we always have learnings from our prior programs that hopefully help us be even more efficient and better with our next program. I think our 621 development so far, and this is kudos to our Kymera-621 team has been amazingly efficient in terms of how we've gone through Phase I healthy volunteers, Phase Ib AD patients and now into Phase IIb already. So if we can be as efficient as that with IRF5, and hopefully, we will be, that would be great.

Yes. I think when you look at the, say, atopic derm, the probability in the known mechanism, probability of success and the market is there, there's not really a track record. There's a pretty successful track record of assets that have moved from Phase I to II to III. But in lupus, obviously, it's been a bit of a scour earth kind of approach. So how do you consider, I guess, risk in terms of the indications that you could pick for IRF?

Yes, that's a really great point. again, lupus, whether it's scorch or third rail or something like whatever your metaphor is going to be. I think what's important in deciding where to go with the drug, look, for 621 and STAT6, there's much more of a linear relationship, right? You can look at derisking of IL-4, IL-13 by dupilumab and that provides amazing clinical derisking in addition to genetic derisking for that program.

We don't have that degree of sort of clinical derisking for IRF5. There's the genetic derisking that I just mentioned. The clinical derisking is more indirect. You have to look at drugs that are targeting the type 1 interferon pathway like Saphnelo, drugs that are targeting B cells like the BAFF inhibitors or other drugs that are targeting pro-inflammatory cytokines like IL-12, 23. Those provide, I guess, indirect clinical validation for IRF5, which is important in all of those pathways. But because there's not a drug that blocks IRF5 right now, specifically, there's probably a little more biologic risk there.

So I think what's important for us is to think very carefully about the genetics, about our preclinical data and to be very strategic in how we go about what indications we're going to prosecute first. And what we're going to learn from those initial studies in patients about the pathways we're affecting in addition to the clinical activity that will then help to inform exactly where we go with the drug.

I mean it's not terribly surprising that STAT6 gets the lion's share of the attention right now, particularly given upcoming data and the status of the program. But IRF5 is a very exciting program. And if you talk to your pharma coverage, you'll probably find that, that target is on their top 10, if not top 5 list in immunology across many of the companies. So we're really excited about it.

Next year will be a big year for that program entering the clinic and then sharing data as well, and we'll be able to also give you more details around the development strategy for IRF5. And we didn't get to it yet, maybe it was on your list, but we have a goal of one program introduction per year. So we've got a couple of few that are vying to take center stage in 2026. So hopefully, we'll be able to talk about a new program next year as well, which is the plan.