KYMR

Good day, everyone. My name's 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. All lines have been placed on mute to prevent any background noise. After the speaker's remarks, there'll be a question and answer session. If you would like to ask a question during this time, and if you've joined via the webinar, please use the raise hand icon, which can be found at the bottom of your webinar application. If you've joined by phone, please dial star nine on your keypad to raise your hand. At this time, I'd like to turn the call over to Justine Koenigsberg, Vice President of Investor Relations.

Good morning, welcome to Kymera Therapeutics quarterly update conference call. Joining me today are Nello Mainolfi, our Founder, President, 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. Please use the raise hand icon to indicate you'd like to ask a question, and we kindly ask that you limit your question to one so we can accommodate everyone. 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 10th year anniversary of Kymera's founding. 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 drug-like, highly specific, and potent degraders. Importantly, key insights to deliver high fidelity of clinical translation. Finally, created early clinical studies to de-risk clinical development, late clinical development. We have continued to refine our target selection strategies, such as we believe we built one of the most compelling oral small molecule pipelines 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. 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. 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 result 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 two KT-621 phase II-B studies. In atopic dermatitis, we're on track to complete enrollment this year in the BROADEN II 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 IRF5, 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 pre-clinically.

IRF5 has been a target of particular interest across the industry for a very long time. Jared would spend more time on the opportunity, what's compelling here is that by selectively degrading IRF5, 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 one interferon, pro-inflammatory cytokines, all through one pathway. While individual drugs can address each specific pathway, we believe a single mechanism such as an IRF5 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. 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. 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 treatments. In fact, most patients are being treated with suboptimal therapies, such as topical creams, which can be massively ineffective, so 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.

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 as 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 treatments. 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 IRF5 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, proinflammatory 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 four-week GLP tox studies in non-human 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, TLR8, and TLR9 agonists, including type 1 interferons, proinflammatory cytokines, and inflammatory pathway gene transcripts. It's our expectation that we should see a 50%-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 plan 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 I-B 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 in BSA of 49% at four weeks across the two 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 four. These early data continue to highlight the potential of KT-621 in AD. We look forward to learning more in our randomized placebo-controlled phase II studies.

We are actively enrolling the KT-621 phase IIb BROADEN II 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. 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. With respect to operating expenses, R&D for the quarter was $98.2 million. Of that, approximately $8.6 million represented non-cash 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 non-cash stock-based comp.

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. With that said, we expect G&A growth to moderate in the coming quarters. 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.

Thank you. At this time, if you would like to ask a question, please click on the raise hand button, which can be found on the black bar at the bottom of your screen. If you've joined by phone, please dial star nine on your keypad to raise your hand. When it's your turn, you'll receive a message on your screen inviting you to join as a panelist. Please accept and wait until you're promoted to panelist. Please unmute your audio, turn on your camera, and ask your question. As a reminder, we are allowing analysts only one question today in order to accommodate everyone. We'll now pause a moment to assemble the queue. Our first question will come from Eliana Merle with Barclays. Please unmute your line and ask your question.

Hi, this is Jasmine Fels on for Eliana. Thank you so much for taking our question. I just wanted to ask a bit more about the IRF5 data in healthy use we expect later this year. In your remarks, I know you said you're looking for 50%-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?

Thank you. Maybe I'll start and then pass it to Jared to spend a bit more time on the details. Obviously, whenever we set out these expectations are always based, especially for the first human translation around or our preclinical data. Just remember, this is a critical node that actually intersects three key pathways. We see that when we block this node, 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.

Yeah, you know, we assess these pathways, in particular the TLR7, TLR8, TLR9 pathways, with ex vivo stimulation of whole blood. That's how we're planning to do it in phase I, using agonists to the TLR7, TLR8, and TLR9 receptors. Essentially, the way we came up with 50%-80% is that, you know, 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%-80% is approximate. You know, whether we end up seeing within that range or more than that remains to be seen.

That's an approximate level that we would expect to see of inhibition, in conjunction with at least 90% degradation of the target.

Maybe just to add, if this was a single pathway like we've seen, for example, KT-621 with STAT6, and we have a downstream biomarker that is activated, obviously we expect complete blockade of that one biomarker. Given that these are multiple pathways, and these pathways also signal to other receptors, this is why there is a range because it depends on what pathway, what stimuli, what biomarkers. That's why there is a bit more nuance into this biology.

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

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

Okay. Thank you.

Our next question will come from Brian Cheng with JPMorgan. Please unmute yourself and go ahead.

Hey, guys. Thanks for taking our questions this morning. You know, it's great that you have laid out the expectations for IRF5 degradations in healthy volunteers. 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? You know, in other words, is there a minimum threshold of IRF5 degradation that you need to hit in patients? For this mechanism, how translatable is it from healthy volunteers to patients in terms of IRF5 degradations? Thanks for taking our questions.

Thanks, Brian. Let's start with what we're trying to do here. As we've done now, this is the 6th program. The human translation is focused on understanding key parameters, which is, what is the exposure in those needed to achieve a level of degradation X? What level of degradation X translates in terms of clinical benefit as well as safety in patients. We always do this in multiple steps, as you know. 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, as you know well, if the preclinical model animal model data would always translate in humans, we would have cured all diseases.

All this preclinical data have to be taken with a grain of salt. What we've learned preclinically is that, you know, as or 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. 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 back in a dose-ranging study and establish, as we're doing for KT-621 now, what is the level of degradation needed to achieve maximal and minimal efficacy. That's the same we're gonna do with KT-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. 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. We expect that whatever we see in healthy volunteers will translate in patients. We've shown that with KT-621. We've shown it with IRAK4. We've shown it also in other programs in other disease areas.

Great. Well, thanks, Nello.

Thank you. Thanks, Brian Cheng.

Our next question will come from Faisal Khurshid with Jefferies. Please unmute your line and go ahead.

Hi, guys. This is Anant Karandikar for Faisal. Just wanted to ask about the initial enrollment in BROADEN II. Have the initial patients tracked with your expectations with respect to the baseline characteristics? Thanks so much for taking our question.

Thank you. Great question. You know, I think we're not gonna comment on, you know, 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 will say, historically, we've said that if you look at the early dupilumab studies, the baseline entry criteria in terms of severity of disease, you have been historically higher, meaning more severe than more recent studies. That has been, we said also historically, that there are maybe two main reasons. One is that given that there are drugs on the market, more severe patients, especially in these, you know, highly advanced, sophisticated clinical centers, more severe patients have access to these therapies.

Generally, the other main reason is to build because of the competitive landscape and the general way that sites and investigators enroll in these studies. You've seen a bit more of a less severe population in studies. I'm not talking about our studies. I'm talking about studies in the past, I would say, five to six years. 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 phase Ib. I'm not going to comment about what we're seeing in the current study. We'll do so when we release the data.

Great. Thank you so much, guys.

Our next question will come from Bradley Canino from Guggenheim Securities. Please unmute your line and ask your question. Okay. Whilst Brad is just asking his question, we'll just move on to Biren Amin with Piper Sandler. Please unmute your line, turn on your camera, and ask your question.

Yeah. Hi, guys. Can you hear me?

A bit. Try again.

Can you hear me now?

Not great.

Okay. Maybe just to start on the BROADEN II trial. I think previously you noted that you're now also including

Wait. No, Biren, it's not working. Maybe you can try again in a bit or I don't know if you're underground or some kind of thing.

Okay.

Give it a shot in a couple of minutes. We'll circle back.

Thank you, Biren. I will move on to Bradley Canino with Guggenheim Securities. If you could unmute your line and ask your question. Thank you.

Hey, great good to see everyone. 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. Should we expect more named pipeline molecules to emerge as glues over the next few years? Thanks.

Yeah, thanks Brad 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 on drug targets. We always look at what is the right technology for the right target. CDK2 is a very interesting problem, right? We know that, you know, if you have CCNE-amplified tumors, you know, there is a mechanism of resistance to CDK4/6 that goes through CDK2, that 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.

What has been the challenge with CDK2 has been that there is a high structural homology between CDK2 and CDK1. CDK1 doesn't actually bring any benefit to efficacy. It actually only brings safety issues. 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. You're gonna run into those limiting toxicity. I'm sorry if I'm going too long here. We're gonna run into those limiting toxicity because CDK1 comes in play, and you'd actually do not exploit fully the power of CDK2, either alone or in combination. Why are we 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 high structural homology.

We have published on a ATP binding site-based bifunctional degrader. While we were able to have enough selectivity, it wasn't good enough for us. We moved on from that effort. 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. 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. Yes, we expect to see more from there in any therapeutic areas. This is not just relegated, let's say to oncology.

Thanks.

Our next question will come from Geoff Meacham with Citi. Please unmute your camera and your audio and ask your question.

Hey, guys this is Nishant Gandhi on for Geoff Meacham. Thanks for taking the question. I want to go back to the data you presented at AAD. In terms of the body surface area, you saw higher reduction at 100 mg versus 200 mg, 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?

Yeah. I actually let Jared actually speak to the data. I just wanna remind you and everybody that 100 mg and 200 mg gave the same degradation; hence we expect to see similar activity. Jared, maybe you can speak to BSA.

Sure

Which I actually don't remember the numbers.

Yeah. If you look at the error bars, you know, on those graphs, they're actually overlapping. Differences between 120 mg are really not significant differences, and it's probably, you know, 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 four weeks in that study, you know, you don't always see complete overlap of the curves, but you do see overlap of the, of the error bars. I think that tells us that, you know, we're seeing comparable activity across both doses, across multiple different endpoints.

Got it. Just to follow up on that, in terms of EASI versus BSA, you see like a gap in magnitude. Again, given, like, it's a small sample size, is this expected given that, you know, EASI captures both extent and severity while, you know, BSA measures just extent alone? Does this suggest to you that there is deeper severity improvement with this molecule versus surface area clearance at four weeks?

Can I just jump into this, Jared? I'm not gonna actually address the specific question. I just wanna 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 two doses were almost completely overlapping. I think the important take-home from the study is that all these measures show the robust effect, consistent across all measures and consistent with upstream biologics. Jared, if you wanna add on the particular topic.

I think, I think your point is the main one. I think, you know, BSA and EASI, they 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. There's an overlap there. The bottom line is that we're seeing a comparable robust effect on both of those endpoints with KT-621.

All right. Thank you.

Our next question will come from Mayank Mamtani from B. Riley Securities. Please unmute your line and ask your question.

Yes. Good morning, team. Thanks for taking our questions and congrats on the progress. On STAT6, you know, there's a lot of activity in the inhibitor landscape, for example. I was just curious what questions, Nello, you have, you know, for some of these highly potent, you know, claim to be selective approaches emerging. You know, from the preclinical data, KT-621 does stand out based on whatever's available. We'll probably get some clinical data next year from you and others. Just curious, how do you expect the clinical data here to, you know, maintain your leadership? Then just quickly on the KT-621, you know, physician excitement maybe between AD and asthma. Recognize you are yet to present your data at ATS next month.

Any thoughts on, you know, between the two indications, the importance of oral versus maybe less frequent injectable, like, you know, if you have teased out what matters more to the different set of clinicians?

Okay. Well, those are two robust questions. On the first one, thank you. On the first one, small molecules, degraders we've you know touched on these also extensively in the past. First of all, recognize that STAT6 has been seen as a key difficult and drug target, but huge potential for more than a decade. It's actually quite exciting to see so many companies, large and small, pouring, you know, 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 2024. Obviously, we've been working on these targets for multiple years. 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 gonna be highly differentiated is because we are so fortunate that while obviously technology requires a level of understanding that is not easily commoditized yet. These molecules, though, with the, 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. 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. One molecule blocks one protein.

For this type of protein, you require a large amount of molecules in the body, in all tissues, for 24 hours. This becomes a challenge with regards to PK, exposure, safety, therapeutic index. 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. I think the beautiful thing about drug development is at the end of the day, I can spend the next, the next hour trying to convince you that I'm right.

The best thing is that we'll generate data soon enough, and I think that will be the final nail on the coffin on this argument for us, I hope. With regards to your second question, you know, we've had the fortune and hopefully with it also something good about generating and importantly presenting our data in many medical conferences. We were fortunate to be selected at the podium at EAACI, which I believe was probably the first time for healthy volunteer data. I might not be sure. We presented at AD, we presented at ATS last year, preclinical data we'll present later. 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 wanna 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. Our goal is not to compete with less frequent dosing. That might come in play as just the market dynamics. 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. We offer that biologic-like oral pill that will change their lives. I think we're seeing in other disease area, it's a complete different paradigm shift, and that's really what we're focused on.

I think this is obviously resonates with investigators, and more importantly, resonates with patients based on our experience.

Thank you, Nello.

Thank you.

Thank you. Just as a reminder, if we could just stick with one question just to accommodate everyone today. Our next question will come from Judah Frommer with Morgan Stanley. Please unmute your line and go ahead.

Yeah. Hey, guys, thanks for taking the question. You know, 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. Just curious to get your take on that excitement for KT-621 on the oral aspect versus the mechanism aspect. There are others going after oral drugs, but maybe in more novel targets. The level of excitement for the oral nature of the drug, but also the fact that you're hitting IL-4/IL-13, which is so well understood by docs. 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. Thanks.

Yeah. Thanks, Judah. I like your 90 years in your backdrop. You're 80 years older than Kymera at Morgan Stanley. Yes, to answer your question, I think you put it exactly right. The reason for the excitement for KT-621 is not just about the oral drug. I think it's the combination of oral, which is, you know, needed in this still early markets, but combine it with the sense of understanding and comfort of a well-validated pathways like IL-4 and IL-13. 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 of proof for a mechanism in the IL-4 and IL-13 pathway, I assume is a bit less than it is for completely new pathways with completely unproven efficacy and safety. I don't know, Jared, if there was anything to add to the second part.

Yeah, yeah, the only thing I would add, you know, to the first part too is just around, you know, cause you talked about mechanism, Judah, and I think there is an appreciation that the unique TPD mechanism, that catalytic mechanism of action that can lead to durable, maintained, complete target suppression or pathway suppression that equals what you can get with upstream injectable biologics. I think that's a big selling point here with regard to, you know, degraders versus small molecule inhibitors. You asked about IL-18. I mean, IL-18, you know, some of those initial data coming out of Ilumya, you know are interesting, right? I think it sort of speaks to the fact that AD you know, does not have just one flavor of inflammation, right?

Obviously, Th2 is one of the main drivers of the pathophysiology but, you know, other types of inflammation, whether it be, you know, Th1, Th17-driven, probably have some contribution as well. Seeing activity with a drug targeting IL-18, you know, probably speaks to that. Again, you know, it's not as well-validated a pathway here in AD. It's interesting to see the results coming out of that, and it, you know, makes one think of interesting possibilities down the road maybe for combination therapies, you know, by bringing on other drugs that are hitting other types of inflammation in addition to type 2 inflammation.

Thanks.

Our next question will come from Biren Amin with Piper Sandler. Please unmute your line and ask your question.

Yeah. Hi, guys. Can you hear me?

Yes.

Yeah, yeah. Yes.

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

Yeah. 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. Adolescents is step one, right? This is a disease of young children usually diagnosed in your first probably six years of life. A drug like KT-621 could have a huge potential in children. 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.

Yeah.

About the inclusion, exclusion criteria.

Yeah. I think in terms of exclusion, you know, the Hanifin and Rajka criteria, right, for AD, like you wanna make sure that your patients have AD. 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. For adults, obviously, cause they're older, you know, the cutoff there is at least three years. With adolescents, because they're younger, have had the disease for a shorter period of time, there's a one-year cutoff. Again, the reason for both of those is to give you, like, increased certainty that these patients truly have a diagnosis of AD.

Got it. Then maybe just one question on IRF. There's clearly, you know, IRF translocation in Naïve B cells, plasmablasts and monocytes in patients with lupus. I know you know, translocation healthy volunteers is low, but is there anything you could do ex vivo to evaluate the impact of IRF degradation on translocation?

Yeah. It's unlikely that we're gonna see activation or translocation IRF5 in healthy volunteers. I don't think that's what we're gonna be looking for. We're gonna 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. All right, next one.

Our next question will come from Alex Thompson with Stifel. Please unmute your line and go ahead.

Great. Good morning, thanks for taking our question. You know, maybe again on the ongoing, you know, AD and asthma studies. Could you talk a little about kind of, you know, more color on enrollment progress, site activation, your level of oversight of these sites? Maybe, could you know, tell us how many patients have been dosed at this point across both studies? That'd be helpful. Thanks.

Yeah. No, obviously, great question. As I said, we're trying not to comment on these things, not because we're, you know, wanna 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 in both in terms of set activations and patient enrollment. The timelines that we've that we put out are obviously still relevant. As I said, I think the best way to manage this particular question is, you know, as soon as we complete enrollment, we will communicate, and then maybe then we can, you know, answer more specific questions about, you know, what we've seen and pace of enrollment, activation, et cetera.

All right, thanks.

Our next question will come from Marc Frahm with TD Cowen. Please unmute your line and ask your question. Marc, please unmute your line and ask your question.

Great. Thanks for taking my questions. Maybe just back to prior comments about, you know, the attractiveness of oral options and the, you know, the enthusiasm also for the mechanism. I mean, can you contrast KT-621 with the IL-23 space? We're seeing that launch you know, just starting now in the psoriasis space, and just how much should we view the success hopefully of that product as a proxy for KT-621 versus how different do you think these markets are in terms of their you know, eagerness for an oral therapy?

Yeah. Thanks, Marc. I don't want to hitch our wagon onto any other mechanism or drugs because we don't control those. It is a fair point that I think we're seeing finally something we've been saying for a while, which is, you know, 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 three months or even less in some cases that are extremely effective. We're seeing even less frequent dosing. Obviously, you start to wonder you know, what's the driver for that, but that's likely it's not what we're working on. You know, the question is very mature market.

Can an oral drug with good efficacy and safety even impact the landscape? It looks like it will. I mean, I was at AAD and lots of, not to advertise for Johnson & Johnson, our friend at Johnson & Johnson but lots of dermatologists were super excited by that drug. 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. We're talking in AD, where there is no oral drug with good safety and efficacy. There is really only, like, two categories of drugs approved, an IL-4, IL-13, and then all the other IL-13's that are not differentiated and JAK inhibitors. This is where psoriasis was 10 years ago.

Bringing to the market something that is so differentiated so early in the treatment, in the, in the market evolution, I think will have a much bigger effect than what we might be seeing with IL-23 in psoriasis. I think it validates, but more importantly, I think our opportunity is probably much more impactful given the, again, the maturity of that market. You know, one could point to the obesity space, but that's a whole different market dynamics. You're seeing also there, these new orals are activating whole new 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.

Thank you. Our next question will come from Joseph Catanzaro with Mizuho.

Hey, great thanks guys. Appreciate you taking the questions. quick one from me on along the lines of KT-579's preclinical data at DDW and maybe also your comments on mechanism earlier. There seems to be a growing effort towards developing combination therapies in IBD, so wanted to ask about IRF5's mechanism and where you see it as most orthogonal or complementary with existing mechanisms in IBD like alpha-4 beta-7, IL-23, TL1A. Thanks.

Fortunately, I'll let Jared answer this one. Jared, I give you 30 seconds to come up with the answer while I say what I'm gonna say. 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 you know, combining existing mechanism or other things. Jared, maybe you can speak to the science of it.

Yeah. 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, you know, monocytes, potentially neutrophils, also dendritic cells. 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.

I think being able to target IRF5, you know, in IBD really helps get at that particular component of inflammation that's really important in ulcerative colitis and will lend itself, you know, to potentially combining with other mechanisms that go beyond those particular proinflammatory cytokines if you wanna, you know, be able to tackle multiple different aspects of the pathophysiology of a disease like UC or Crohn's. I think that's the beauty of it. I think the other aspect is the potential safety profile of IRF5, you know, and being able to knock IRF5 down hard and not really having there be risk of infectious complications. That also will lend itself to combinations.

Great. Thank you.

Thank you. Our next question will come from Jeet Mukherjee with BTIG. Please unmute your line and go ahead.

Great. Thanks for taking the question. 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? Thanks.

Yeah. Yeah. 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 you know, 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 from transitioning from topicals into advanced systemic therapies. The numbers are out there. You know, we talk about. You know, if you just talk about AD, there's probably 40 million patients, with moderate to severe AD.

Maybe it's easier to do. You know, we have the number of 50 million that includes also other type 2 inflammatory diseases. Really only almost less than 2 million patients have received dupilumab, Adbry, Rinvoq in these, in these, in these diseases. You know, 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. That's the opportunity, and that's far greater than, for example, the opportunity in psoriasis these days. I think it's really hard actually to put the value on KT-621 right now.

I think, you know, a lot of us are being quite conservative for, you know, a good reason. We're still relatively early in the development of the drug. I believe strongly that post this phase II-B data, we need to get much more, I think, aggressive with what we're really talking about. I think maybe that would be a good time to talk about more discrete numbers.

Okay. Thanks folks.

Thank you. Our next question will come from Sudan Loganathan with Stephens. Please unmute your line and go ahead.

Thank you. Good morning, Bruce, Nello and Jared. My question is on the KT-621 program for asthma and related downstream indications. You know, 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? 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 KT-621? Thanks.

Yeah, 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 the drug will work in all type 2 diseases. We're really waiting for the phase III dose that will come out from the phase II-B asthma study.

Thanks.

Thank you. Our next question will come from Kripa. Just one moment please. Sorry. Yep. Our next question will come from Srikripa Devarakonda with Truist. Please unmute your line, turn on your video and ask your question.

You may proceed, yes.

Hi, guys. This is Anna on from Truist. Thanks for taking our question. Just one question on KT-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 three doses.

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

Thanks so much.

Thank you. Our next question will come from.

Sorry. Let me turn it off quickly.

Evan Szakos with RBC Capital Markets.

All right. Thank you.

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

Thank you. Based on pre-clinical data, we really haven't seen, in animals at least, adverse event of meaningful impact or any actually. 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. I think that's what we'll see obviously as things progress, but we don't expect any particular adverse event here with this drug of note.

Thank you.

Our next question will come from Tazeen Ahmad with Bank of America. My apologies, we now have Derek Archila from Wells Fargo. Please unmute your line and go ahead.

Good morning, this is Hal calling in for Derek, thank you for the question. We were at AAD that we hear also KOLs noting KT-621's, you know, the most promising candidates in AD. A question on, you know, the efficacy. I think they wanted, you know, perfect safety. On the efficacy side, I think we are hearing that even if it's less effective as Dupixent, some of them point to, you know, 70% as effective, others using, you know, or Adbry as example, you know, they will still be very excited. I guess my question is like what you are hearing on what's enough to kind of really mobilizing those patients, you know, with not on biology, but be open to this oral option?

Yeah, I mean, you've 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 a topical therapy. The only reason why we keep pointing to a Dupi-like profile is because this is the data we've seen so far. If we end up seeing less, I think this could still be a huge drug in the space.

Awesome. Thank you so much.

Thank you. Well, that is all we have time for questions for now. I would now like to turn the call over to Mainolfi for closing remarks.

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

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.