Good morning, and welcome to Kymera Therapeutics, Inc.'s Immunology Innovation Day, our virtual event to introduce our next immunology program, IRAF5. I'm Justine Koenigsberg, Kymera Therapeutics, Inc.'s head of investor relations. Please note that we are hosting today's event in lieu of our regularly scheduled quarterly update call. However, we have reported our results and filed our 10-Q this morning. For additional details on our 2025Q1 results, please reference our press release issued this morning, which is available in the IR section of our site. During today's presentation, you'll hear from our team about our strategy, our pipeline advancements, and our next high-value immunology program. Joining me this morning are Nello Mainolfi, our founder, president, and CEO, Jared Gollob, our chief medical officer, and Veronica Campbell, our Senior Director of Immunology and Project Team Leader of our newly introduced program, IRAF5. Here's a snapshot of today's agenda. Nello will begin with an overview of our strategy and the opportunity with small molecule degraders. Then Jared will provide a high-level overview of our STAT6 program, and we will conclude our prepared remarks with a discussion of our newly introduced IRAF5 program before we open the call to questions. If you'd like to ask a question, please use the raise hand icon, which can be found at the bottom of your meeting window. To help us move efficiently through the Q&A discussion, we ask that you are ready to unmute your line and turn your camera on when called upon. A replay of today's event, including a copy of our corresponding presentation, will be available soon after the call concludes in the investor section of our site. But before we begin, I would like to remind you that today's presentation will include forward-looking statements about our future expectations, plans, and prospects. These statements are subject to risks and uncertainties that may cause actual results to differ materially from those projected. A description of these risks can be found in our most recent 10-Q filed with the SEC. Any forward-looking statements speak only as of today's date, and we assume no obligation to update any forward-looking statements made on today's call. With that, let's begin. Nello?

So thanks, Justine. Very exciting to be here today to share not only a pipeline update but also our new program, IRAF5, which Veronica will do in a few minutes. I thought I'd take a few minutes here to just give you an update on our strategy, where we're going, some important decisions we're making, and upcoming milestones. Just to remind you, Kymera Therapeutics, Inc. was founded about, actually, just very recently, nine years ago, with the goal of building an industry-leading pipeline of medicines using a novel modality called targeted protein degradation. We believe with this modality, we can give rise to a series of new programs and medicines that can overcome the challenges that the industry has faced for the past twenty years. In order to do so, we've built some unique capabilities. I will start with the fact that we have become a key leader in the space of targeted protein degradation. In doing so, we built some really unique capabilities of hit finding and optimization of oral degraders. We have always had and continue to refine a unique target selection strategy based on pursuing traditionally undrugged targets in highly qualified and validated pathways. And that has allowed us to build a portfolio that is poised to really disrupt treatment paradigms. We made a conscious choice a few years ago to focus on immunology. The main reason has been, as I'll explain in a few slides, that in that particular space, in this place and time, we've been able to combine really the right target with the disruptive potential of targeted protein degradation, delivering for the first time in the industry oral drugs with biologics-like efficacy. And this is really a unique opportunity for Kymera Therapeutics, Inc. and for patients. So Kymera Therapeutics, Inc. is founded and continues to thrive on three key pillars. One is a clear vision. We have always believed that with new technology, not only do you have an opportunity, but you have a responsibility to build a fully integrated company. So we are now building deep development capabilities to advance our programs into phase two and phase three studies with an eye on becoming a commercial-stage company. We've been fortunate to always be capitalized. We now have, as of the end of 2025Q1, $775 million with an extended runway into the first half of 2028. We have brought five new molecules into the clinic since 2020. We have dosed at this point way more than 300 between healthy volunteer patients across our pipeline. One thing that we're very proud of is our ability to continue to demonstrate impeccable translation from our preclinical studies into the clinic, achieving in all of our programs more than 90% degradation, with the desired efficacy and safety profile. The main feature of the technology is the ability to use small molecules to remove protein. So you have almost a genetic-like knockdown or knockout effect with the flexibility and convenience of oral small molecules. We can go after proteins that have not been drugged or drugged fully for the past decades with a simple oral drug that we're able to design, synthesize, and develop here at Kymera Therapeutics, Inc. So why immunology? Why is this such a unique opportunity for us, and I would say for patients? So we, with the team, did work in the past year or so looking at the most common immune inflammatory diseases. And those include allergies, asthma, COPD, you can see from the slide, HS, multiple sclerosis. Looking at the seven major markets, that's about 160 million patients impacted by these diseases. If you observe the number of patients accessing advanced systemic therapies, it's really around 5 million. We basically have a 3% penetration of advanced systemic therapy into this wide variety of immune inflammatory diseases, again, in the seven major markets. So we do not have a problem of innovation in immunology. There are plenty of great drugs in many disease areas. We have a problem of allowing patients to access these highly effective drugs. Of these, about two-thirds are accessing biologics. Only one-third access oral drugs, which often cannot deliver efficacy similar to biologics. We have an opportunity to expand access to highly innovative drugs with oral degraders that offer the efficacy of these advanced systemic therapies. When quantified, this market is hard to quantify. If you look at 3%, the 5 million threshold represents a $100 billion market or more. We're discussing a potential patient pool of over 90% who could benefit from our novel oral systemic therapies. Additionally, we can now provide a convenient, highly effective advanced therapy to the 90% currently untreated due to access, pricing, or convenience factors. The challenges come with biologics, which can be very expensive and complex to manufacture. They often have immunogenicity issues, cold storage requirements, and involve inconvenient routes of administration. In an industry survey conducted recently, several patients were asked if they would switch from a biologic to an oral drug with the same profile; 75% responded positively. Thus, there is not just a unique opportunity but a clear unmet need for oral therapies that would have a biologic-like profile. Traditional small molecule oral drugs cannot fully cater to this need due to their inherent pharmacokinetics and dynamics. They cannot block pathways continuously and show peak to trough pharmacodynamic effects. However, with a degrader, we can maintain a constant degradation state, mimicking biologics-like pathway blockade. I want to share two key features of Kymera Therapeutics, Inc. that contribute to our leadership in developing unique programs, especially in immunology. First is our capabilities. We excel in finding small molecule ligands for undrugged or hard-to-drug proteins. Our structural biology capabilities have produced significant publications, underscoring our understanding of ternary complex interactions between drugs and proteins. We demonstrate our deep understanding of PKPD interactions in patients and preclinical models, which mitigates risks when translating to human efficacy. And these capabilities have led to notable accomplishments; we have delivered over nine development candidates against undrugged transcription factors, proving our degraders are potent, specific, orally bioavailable, and show extensive tissue distribution. Another key feature of Kymera Therapeutics, Inc.'s strategy is our target selection process based on four established pillars. We prioritize targets that have not been drugged before, possess strong human genetics backing, and pathways validated by other agents typically upstream of our target. We ensure a clear clinical differentiation path early in our development strategy while focusing on programs with extensive clinical and commercial opportunities. Current targets reflect this approach, including STAT6 and IRAF5, known undrugged transcription factors. Kymera Therapeutics, Inc. has developed the first clinical candidate for STAT6, with preliminary data expected soon. The technology is missing for these targets, presenting first-in-class opportunities with strong validation. Our asset development is evident as we look across indications. Stat6 targets atopic diseases prevalent in dermatology and respiratory areas, reflecting efforts in multiple disease states. IRAF5 appears linked to traditional immunology and rheumatology indications, including RA and systemic lupus erythematosus. Combining these pathways presents strategic opportunities for synergy in achieving comprehensive solutions. The slide illustrates significant unmet needs across these diseases, with over 100 million patients needing advanced therapies in the major markets. The carryover effect on systemic therapy extends our expected reach and amplifies the necessity for innovative treatments. We're prepared for an extensive array of milestones in the pipeline, with anticipated milestones in the next eighteen months including the forthcoming data for STAT6 in June, phase 1b data later this year, and preparatory actions to commence two phase 2b studies as planned. Additionally, the IRAK4 program, outside of what we'll cover later, is progressing with studies slated to conclude in mid-2026. I will touch on a recent decision about the TIC2 program. We're steadfast in a volatile market, and we believe we're positioned well amidst these uncertainties. Our oral immunology pipeline caters well with anticipated catalysts. While we pursue opportunities to optimize resource allocations towards the highest return activities, we decided this strategic move allows us to pause TIC2 efforts and redirect resources effectively. This change allows us to allocate focus towards STAT6, a growing program with significant potential and IRAF5 funding. Our cash runway has now extended to the first half of 2028, allowing ample time to focus diligently on key program development points. I'm pleased with the decision to prioritize our strategy despite its inherent challenges. I look forward to addressing your queries during the Q&A session. Now I’ll pass it on to Jared to dive into the details of the STAT6 program.

We are well-positioned to achieve multiple clinical data readouts that we believe will further validate our approach and strategy. Before we formally introduce our IRAF5 program, I'd like to give you a brief update on our ongoing and planned clinical trials for KT621, our first-in-class oral STAT6 degrader program, and the first STAT6 targeted medicine to enter clinical development. The IL4, IL13 pathway drives Th2 inflammation and is highly validated by dupilumab. An injectable biologic targeting IL4 receptor alpha that inhibits IL4 and IL13 signaling and is approved for the treatment of multiple different Th2 allergic diseases including atopic dermatitis and asthma. STAT6 is the obligate and specific transcription factor in the IL4 13 pathway, and is therefore the critical signaling node controlling Th2 inflammation. For this reason, blocking the function of STAT6 is expected to phenocopy IL4, IL13 targeting. There is also compelling genetic validation for the criticality of STAT6 in driving Th2 allergic diseases and the safety of reducing its expression. Including the following. First, the pathogenic role of STAT6 is supported by human genetics showing that gain of function mutations of STAT6 cause severe early onset allergic disease in humans. Second, a recent publication found that human heterozygous STAT6 loss of function mutations protected against severe Th2 asthma, showing for the first time how decreased STAT6 protein levels can be protective against Th2 diseases. Additionally, STAT6 knockout in mice is protective in multiple allergic disease models, and STAT6 knockout mice develop normally, are viable, and are fertile. So the human and mouse genetics tell us that STAT6 is a compelling target for treating IL4, IL13 driven allergic diseases and suggests it can be safely knocked down. Only the unique pharmacology of STAT6 degradation has the potential to fully block IL4 13 signaling with an oral daily drug and thereby phenocopy the activity and safety of an upstream biologic like dupilumab. Historically, the development challenge has been to design oral small molecules that can fully block STAT6 around the clock and thereby inhibit the IL4 13 pathway to the same extent as biologics. We believe the only modality that can do this are degraders. Furthermore, if an oral STAT6 degrader can truly block the IL4 13 pathway to the same extent as dupilumab, this has the potential to transform the treatment paradigm for all the different Th2 allergic indications that have already been derisked by dupilumab. Dupilumab has transformed the lives of patients with dermatologic, respiratory, and gastrointestinal tissue diseases and has become one of the largest drugs in this industry. We think we can change the treatment paradigm and reach an even broader patient population with an oral drug targeting STAT6 across all the indications derisked by dupilumab and perhaps open up new opportunities in additional allergic indications beyond these. We have a robust preclinical data set to support this program. I'll walk you through this at a high level. Preclinically, KT621 was shown to be exquisitely selective for STAT6, showing functional inhibition of other STATs. It degrades STAT6 at low picomolar concentrations across all disease-relevant human primary cell types evaluated, including lymphocytes, myeloid cells, epithelial cells, and smooth muscle cells, among others. We've shown preclinically that KT621 is more potent than dupilumab at blocking IL4 and IL13 pathway functions relevant to Th2 disease manifestations in cell systems and is equal or superior to dupilumab at blocking Th2 inflammation in preclinical disease models. This was demonstrated in the mouse house dust mite asthma model. At doses achieving 90% or greater STAT6 degradation. Overall, the preclinical data generated highlight the best in pathway potential of KT621 given its dupilumab-like activity and the convenience of an oral pill. In higher species, including dogs and monkeys, we have shown with oral daily dosing that we can fully degrade STAT6 at steady state in all relevant tissue types. We did not observe any adverse safety findings in four-week GLP tox studies in nonhuman primates and rodents. In light of the enormous potential for KT621 to transform the treatment paradigm for patients with Th2 allergic diseases, we have adopted an accelerated development strategy that begins with phase one studies in healthy volunteers and AD patients, to quickly enable demonstration of clinical proof of concept and informed dose selection for phase 2b dose range finding studies. Our plan is to run two sentinel phase 2b trials in AD and asthma, starting in Q4 2025 and Q1 2026, respectively. They will enable dose selection for subsequent phase three studies, not just in AD and asthma, but also across multiple other dermatologic, respiratory, and gastrointestinal indications derisked by dupilumab. The phase 1a healthy volunteer SAD/MAD study has been completed, and we're on track to report data next month. The primary objective is to show we can robustly degrade STAT6 in blood and skin, which we define as a reduction of 90% or more at doses that are safe and well tolerated. Given the extensive clinical pathway validation by dupilumab, all the human STAT6 genetics data, and the preclinical data we generated showing dupilumab-like activity with 90% STAT6 degradation in disease models of asthma and AD, we believe that if we can achieve this study objective, it will largely derisk the program and meaningfully increase the probability of success as we move into patient studies. We're also looking at how KT621 impacts several circulating Th2 biomarkers, including TARC and IgE. Our expectation entering the trial was that the effect would likely be comparable to what has been reported in healthy volunteers for dupilumab. Though as we have said, we believe the best opportunity to show a significant effect on Th2 biomarkers will come in patient studies, where baseline levels are greatly elevated due to IL4 13 pathway activation. Importantly, while completing the phase one healthy volunteer study, we were able to initiate the first KT621 trial in AD patients, well ahead of what we had initially planned. The ongoing Phase Ib trial, named 20 moderate to severe atopic dermatitis patients. Patients will be administered KT621 once daily for four weeks. The key study aim is to show that robust STAT6 degradation in blood and skin lesions by KT621 has a dupilumab-like effect on multiple Th2 biomarkers in the blood and on the transcriptome of active AD skin lesions. The study will also assess KT621's effect on clinical endpoints, such as EASI, and pruritus NRS. We expect to report the Phase Ib data in the fourth quarter. So in summary, we believe that targeting STAT6 for degradation with KT621 is the only oral small molecule approach with the potential to achieve a dupilumab-like profile with once-daily dosing. We are approaching KT621 development with a strong sense of urgency and focus on execution. This program has enormous potential to dramatically change the way we can treat patients with inflammatory diseases and expand their access to transformative drugs. We're excited by the progress we've made in completing our phase 1a healthy volunteer trial and initiating our phase 1b trial in AD patients, and look forward to sharing data next month for healthy volunteers and later this year for AD patients. And gearing up for the start of phase 2b trials in AD and asthma. I'd like to pause here and introduce Veronica Campbell, the research lead on the IRAF5 program. With her team, she's done a terrific job advancing this exciting program to development candidate and into IND enabling studies. We are excited to share the details with you now.

I'm Veronica Campbell, Senior Director of Immunology at Kymera Therapeutics, Inc. I've worked at Kymera Therapeutics, Inc. for eight years, and I'm proud to be part of this pioneering team working to develop transformative treatments for chronic immunological diseases. As a project team lead, I'm very excited to share with you the story of our first-in-class IRAF5 degrader, KT579. Why we believe it has the potential to be the first IRAF5 targeted oral therapy to deliver transformative activity in several rheumatic autoimmune diseases, superior to standard of care drugs including several biologics. Today I will cover first how Kymera Therapeutics, Inc.'s TPD approach has a unique opportunity to provide a novel oral therapy against what has been historically undrugged transcription factors. From there, I will describe the well-established biological function of IRAF5 and the genetic and clinical pathway validation. Next, the clinical development and commercial opportunities IRAF5 presents. Then I'll describe the exciting preclinical data package for our development candidate KT579, and finally, the expected timelines and next steps for the program. I'd like to start by introducing our latest first-in-class oral development candidate, KT579. KT579 is a highly potent selective oral degrader of IRAF5, which is an essential signaling node in genetically and clinically validated immune pathways driving inflammation in multiple autoimmune diseases with significant unmet patient need. I'll share details in the coming slides on the robust activity of KT579 in primary cell systems including patient donor cells and preclinical efficacy models of RA and lupus. In addition, KT579 has a highly encouraging safety profile in preclinical tox studies where it was well tolerated at up to 200 fold above the predicted human efficacious dose. Our compelling preclinical characterization of KT579 is consistent with the innovative science we've shared across our immunology pipeline and positions this program well on the path of development. The program is currently in IND enabling studies, and we're on track to initiate phase one testing in early 2026. Consistent with Nello and Jared's discussion of our rigorous approach to target selection, IRAF5 meets all our criteria of what we think makes a compelling target for oral TPD approach. IRAF5 is an undrugged target with strong human genetic validation and supporting biological functional data within pathways that have been clinically validated. As seen in the pathway image on the right, IRAF5 is a central node activated downstream of pattern recognition receptors that can recognize foreign or self-antigens and is critical for mounting a pro-inflammatory response. For example, downstream of endosomal TLR7, TLR8, and TLR9 activation, IRAF5 regulates type one interferon responses, pro-inflammatory cytokines such as IL12, TNF, and IL6, and antibody production. Its expression is cell and activation specific, making IRAF5 an attractive target with potential to block immune while sparing normal cell function. IRAF5 is a highly validated target through human genetics and clinically pathway validation. IRAF5 functional risk variants that have been identified associate with increased susceptibility to lupus, Sjogren's, RA, IBD, and systemic sclerosis. For clinical validation, the IRAF5 regulated pathways have been validated by multiple cytokine biologics and B cell targeting agents, highlighting the importance of pro-inflammatory mediators like type one interferons, TNF alpha, IL12, and IL23 in autoimmune disease pathogenesis. I will expand on these two points in subsequent slides. IRAF5 has been challenging to drug to date likely due to its complex activation steps, splicing isoforms, and high degree of IRAF5 IRF family member homology. As previously reported, TPD is well suited to deplete undrugged transcription factor targets like IRAF5. Where a single and specific binding event drives molecule activity and can disrupt all IRAF5 signaling. Let's discuss IRAF5 more in the disease context and as a master regulator of innate and adaptive response. IRAF5 is selectively expressed in dendritic cells, monocytes, macrophages, and B cells. Pathway-specific IRAF5 dysregulation is cell and stimulant dependent. In autoimmunity, it is activated by pattern recognition receptors that can recognize nuclear self-antigens in the body to initiate and amplify both innate and adaptive immune responses. By increasing pro-inflammatory cytokines like TNF alpha, IL6, IL12, IL23, type one interferons, and pathogenic autoantibodies. This can lead to immune complex formation and propagate subsequent inflammation in autoimmune diseases such as lupus, systemic sclerosis, and dermatomyositis, among others. Therefore, targeting IRAF5 offers the potential for a transformative and multipronged approach to treat these complex and heterogeneous diseases. Now let's look further into the genetics associated with IRAF5. Literature shows the pathogenic role of IRAF5 is supported by human genetics where multiple genome-wide association studies identify IRAF5 as an autoimmune susceptibility gene. Specifically, if you look at the bottom left chart, meta-analysis of GWAS studies have shown IRAF5 to be a strong risk locus in lupus with risk haplotypes and functional variants in patients that associate with high serum interferon alpha levels, anti-double-stranded DNA autoantibodies, or anti-RNA binding protein antibodies. Beyond lupus, genetic associations and functional variants have also been identified in RA, IBD, systemic sclerosis, and multiple sclerosis. Looking at mouse knockout studies, IRAF5 knockout mice are viable and fertile with normal B cell development. In the bottom chart showing a mouse model of lupus, IRAF5 plays an essential role in lupus development and pathogenesis that is interestingly independent of type one interferon pathways, as shown in the survival curves below where Rites et al knocked out IRAF5 and showed increased protection versus the knockout of interferon A receptor, that results in modest protection against lupus. Additionally, knockout studies demonstrated attenuated disease in other mouse models of lupus, RA, and IBD, showing biological functionality and supporting the therapeutic potential of IRAF5 degradation. As previously mentioned, IRAF5 is expressed in a limited number of cell types and is activated only by specific stimuli. This indicates that IRAF5 degradation has the potential to selectively block inflammation to restore immune regulation. Dendritic cells, monocytes, and macrophages, when activated by members of the TLR family or other pattern recognition receptors, mediate a pathogenic immune response via many pro-inflammatory cytokines including TNF alpha, IL6, and type one interferons. In addition, IRAF5 is activated by endosomal toll-like receptors in B cells, resulting in pathogenic autoantibody production. There are many agents approved in targeting some of these pro-inflammatory mediators, like anti-TNF alpha, anti-IL12/23, anti-interferon alpha, and others which directly target B cells, further validating the target. The multifaceted functions of IRAF5 which occur in specific cell contexts and upon specific stimuli point to superior efficacy and tolerability profiles compared to current agents for autoimmune diseases. The development opportunity for targeting IRAF5 is vast, and there are numerous potential indications across multiple immunological therapeutic areas, with a total potential patient impact of more than ten million patients. KT579, our oral IRAF5 degrader, is designed to block the source of multiple pro-inflammatory mechanisms and improve on effectiveness, durability, and tolerability over currently approved agents in diseases such as RA, lupus, Sjogren's, systemic sclerosis, and IBD, among others, listed on this slide. Our IRAF5 degrader will potentially serve as a transformative oral therapy superior to both oral and biologics standard of care across all potential indications. Now let's look at the exciting profile of KT579 and its impact across the biological mechanisms and pathways just discussed. We have an incredible opportunity with KT579 given its potential to have an enormous impact on treating autoimmune rheumatic diseases. As we walk through the preclinical characterization, we hope you will share enthusiasm for what we believe is another high-value target emerging in our pipeline. I will show you the potent selective activity of KT579 in normal human primary cells, donor cells from lupus patients, and in vivo disease models of lupus and RA. I'll start with KT579's effects in human primary cells from healthy donors. KT579 is an exquisitely selective degrader. We look at concentrations well above that achieving maximal degradation of our intended target. IRAF5 is the only protein degraded out of the 10,000 or so proteins detected by mass spectrometry. No other IRF family proteins were degraded to any extent, demonstrating KT579's selectivity. We also see that KT579 can degrade IRAF5 both in the cytoplasm and the nucleus. Additionally, KT579 has demonstrated potent inhibition of key pro-inflammatory cytokines and type one interferon production downstream of TLR4, TLR7, and TLR8 and 9 activation in primary cellular assays. For example, we show KT579 can block IL12 and interferon beta production in monocytes while blocking TNF alpha and IL23 production in PBMCs. These data illustrate KT579's broad and potent activity that is both cell and stimuli-dependent. Transcriptomics analysis also demonstrates that KT579 dampens the type one interferon response in select interferon-stimulated genes that are elevated in systemic autoimmune diseases such as lupus and Sjogren's. On the left, differential gene analysis demonstrates that KT579 can block the type one interferon at least as effectively as an anti-TLR7/8 inhibitor. On the right, we see that KT579 can achieve inhibition of select ISGs associated with increased disease activity in lupus. For lupus patient-derived PBMCs, KT579 effectively blocks TLR7 and 8 induced pro-inflammatory cytokines and interferon beta production, showing promise of an IRAF5-directed treatment to reduce the B cell-mediated inflammation in lupus patients. Finally, let's turn to the in vivo preclinical data. In one model, we evaluated KT579's activity in mouse acute TLR models that elicit a potent inflammatory cytokine response. This study showed that KT579 dosed orally once a day for four days achieved deep degradation of IRAF5 in spleen. However, we have also observed that the efficiency of degradation varies with population densities. KT579 demonstrated sustained and near-complete reduction of proteinuria in MRL LPR mice, achieving at least 85% degradation, which was better than approved agents like affameterin, dugravacitinib, cyclophosphamide, and anti-interferon A receptor mouse surrogate antibody. On NZBW1 lupus models, we administered an IRAF5 degrader for four months, resulting in sustained reduction of proteinuria and a near-complete reduction of circulating serum anti-double-stranded DNA autoantibodies. In the antigen-induced arthritis mouse model of RA, daily oral dosing with KT579 led to significant reduction in joint swelling, comparable to tofacitinib. We also observed a reduction in ankle swelling and circulating pro-inflammatory cytokines, as evidenced by infiltrating inflammatory pathogenic Th1 T cells. Our in vivo studies have confirmed that IRAF5 degradation leads to robust cytokine inhibition and demonstrates superior or comparable efficacy in lupus and RA models compared to approved drugs in this space. In summary, IRAF5 has the potential to be the first broad anti-inflammatory agent that effectively addresses immune dysregulation while sparing normal cell function. Both human and mouse genetics, alongside preclinical validation, indicate a best-in-class profile for IRAF5 in treating lupus, Sjogren's, RA, and other diseases. KT579 is a highly selective, potent oral IRAF5 degrader. Our studies demonstrate substantial degradation across multiple preclinical safety species and relevant tissues, maintaining a favorable safety profile. We expect to advance KT579 into the clinic in early 2026 as the first oral IRAF5 degrader. With that, I'd like to now turn the call back to Nello for his closing remarks.

Thank you, Veronica. It's always exciting to hear this even if I've heard that multiple times internally. I think when we do this, public disclosure, it's just an exciting time to put all our data out there and show how productive the team can be, and more importantly, the level of sophistication that the team applies when building these preclinical packages. So very excited to take this program into the clinic. I will now complete this presentation today by going through our pipeline and spending a bit more time on the upcoming milestones. We look forward to taking questions from the audience and the analysts. As we've stated multiple times, obviously, KT621 is moving very rapidly and much more rapidly than we anticipated. We've completed our study with healthy volunteers and are preparing to share the phase one data in June. An important date on your calendar. In April, we began our phase 1b AD study, and we're already recruiting patients. Data from this study is expected in the fourth quarter. The team is gearing up to initiate two large phase 2b studies; one in AD starting in the fourth quarter of 2025 and the other in asthma during the first part of 2026. Very busy with all these activities, thus crucial two data readouts: healthy volunteer in June, followed by AD patient data in the fourth quarter. Then we will embark on these larger studies that will take longer than the phase 1b study; additional timing and data readouts will be shared as we approach those milestones. For IRAF5, KT579, as Veronica mentioned, has provided an impressive preclinical package on both safety and efficacy; we expect to file an IND towards the end of the year, advancing into phase one testing early next year with data from phase one anticipated to be shared within our timeline. Our IRAK4 program results are expected in 2026 for HS and AD. Thank you all for joining our call today, especially on a Friday morning. Hopefully, you appreciate the level of detail we provided today, and we're happy to reconvene and take questions in a few minutes.

Thank you. At this time, if you'd 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 9 on your keypad to raise your hand. When it is your turn, you will receive a message on your screen inviting you to join as a panelist. Please accept and wait until you are promoted to panelist. Please unmute your audio, turn on your camera, and ask your question. As a reminder, we are allowing analysts one question and one related follow-up today. We will now pause briefly to assemble the queue. Your first question comes from Derek Arquilla with Wells Fargo. Please unmute and ask your question.

Hey, we can't hear you. Can you unmute if you haven't?

Hi. Can you hear me?

Oh, yes. Yeah. This is Yifan for Derek. Thanks for taking our questions. Just a quick one from us. Can you talk a bit about your confidence in targeting STAT6 in AD and of showing an effect in the four-week study? Like, should we be expecting a relatively noisy dataset given it's such a short study? Thanks.

Yeah. Thanks for the question. The underpinning of this program is that IL4 and 13 signal through STAT6 to propagate the signal and impact downstream Th2 cytokines. The derisking and expectation that we've set on this program are driven by data shown in AD already by the IL4 and 13 agent, dupilumab, which is the only drug that blocks both IL4 and 13. From that drug, we know that even in four weeks, compelling datasets can be generated. The first observation being that significant changes in circulating and skin biomarkers of Th2 inflammation can be noted even with a four-week study. Clinical endpoints show robustness too. Given all preclinical data generated, we expect robust data in biomarker effects specifically, as that's our current study's focus, alongside robust clinical outcomes.

Got it. Thanks.

Your next question comes from the line of Jeet Mukherjee with BTIG. Please unmute and ask your question.

Hey. Good morning. Can you hear me?

Yeah. We can see you. Great. Yeah. Question.

Maybe just one question around the decision not to advance the TIC2 program. You obviously talked about the decision in the context of being capital conscious and the macro backdrop. But it appears you've swapped TIC2 for perhaps IRAF5. So is there anything there in terms of the molecule's profile or just the evolving competitive landscape that influenced your decision? Thanks.

No. Great question. I can personally say I remain confident in the TIC2 opportunity with a degrader. This decision revolves around our current resources—human and capital. We want to power up further the 621 program that has accelerated pace. I can't speak to the data specifically, but we have a lot of confidence going into these larger studies due to the evident risk-reward in this program. The IRAF5 program is quite distinct from TIC2. Most notably, the TIC2 space has significant competitive intensity, with 23 drugs actively being developed—one in particular being notably impressive. IRAF5 presents a unique opportunity within a less competitive pathway. We'll also see IRAF5 functions as a best-in-class drug for a wider range of diseases that we prefer to fully commit resources towards. The bar has certainly been raised in the TIC2 space, which has informed our decision to prioritize IRAF5. The risk-reward nature steered this allocation correctly and, potentially, with the largest program in the industry, outside GLP1 drugs. While redefining our resource allocation strategies, we believe it offers maximum output potential at this time.

Thanks for taking the question.

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

Thank you for taking my questions. Beyond the IRAF5 program that you disclosed today, just as you get into the clinic, what does that minimum target profile in terms of degradation look like? And, you know, as we get to clinical data, as you highlighted and you know, with your kind of intro Nello, the bar in some of these other diseases where you've started going after orals, things like psoriasis, like, is extremely high. There really isn't much room even there or some extent, AD to push efficacy higher. But, you know, some of these diseases you're talking about for IRAF5, there's certainly much more room for clinical efficacy improvement. How important is that to ultimately show versus just kind of matching available therapies but offering, you know, oral convenience?

I appreciate the question. First, looking at our preclinical data, it seems that achieving 80% degradation and above can deliver a strong best-in-class profile. We’re examining if even less degradation consistently shows adequate efficacy. Considering lupus, our exploratory studies indicate good effects with around 90% degradation, suggesting the highest impact. Currently, in approved therapies for lupus, we're aware that they generally do not perform very well, thus there remains considerable unmet need for improved efficacy. By delivering enhanced efficacy alongside the convenience of oral ingestion, our approach aims to surpass expectations for both existing and emerging therapies. Veronica has led efforts to ensure this molecule is well-behaved, promoting our confidence in its differentiation in the clinic.

I want to add that we've established our ability to achieve greater than 90% knockdown of IRAF5 across species, creating a safety profile that is reproducible. Terms on the question of how much knockdown we need, it’s worth noting that heterozygous IRAF5 knockout mice show protection against diseases like lupus. Thus, our target is to achieve higher knockdowns safely, ensuring the program's efficacy to meet those highest expectations.

Our expectation is again, that we would see superior efficacy due to multiple biological outputs that IRAF5 can impact, as elements discussed during the presentation highlight the route at which IRAF5 acts on pro-inflammatory mediators—allowing us to surpass existing drugs like anifrolumab, delivering highly effective treatments.

Thanks, Marc.

Your next question will come from the line of Ellie Mel with UBS Securities. Please unmute and ask your question.

Hey, guys. Just on IRAF5, just a quick search. There's obviously a lot of literature showing that this plays a critical role in a lot of diseases, but curious how you're thinking about balancing the safety here. It looks like there's some data showing that IRAF5 can act as a suppressor. I mean, obviously, we're new to this target, and it seems like it's involved in a lot of diseases. But just can you explain why you're comfortable with the safety here? And I know in the last question, you mentioned you can even get disease protection or modification perhaps with the 50% degradation just from a clinical development perspective, even if early on 90% degradation is safe, would you also explore moving forward with, say, 50% degradation, 90% with multiple dose levels and thinking about the long-term safety profile? Thanks.

I'll let Veronica address this, but at a high level, the beauty of IRAF5 is its expression in specific cells. Its activation depends largely on context within active systems, meaning we could provide significant anti-inflammatory benefits while preserving immune functions.

Exactly, thanks for the question. It was part of our extensive due diligence initially. We examined the target, including the literature you mentioned. Our examinations of TCGA aggregate studies revealed little conviction that IRAF5 suppression leads to cancer. Instead, gain of function was more commonly related specifically. Notably, we lacked robust follow-up supporting any adverse effects. With our broader analysis, we anticipate that loss of IRAF5 will not present a significant risk.

Your next question comes from the line of Sudan Loganathan with Stephens. Please unmute and ask your question.

Hi. Good morning. Thank you for the detailed presentation and taking my questions. My first question is on the IRAF5 program. In your preclinical work or any of the literature out there, did the degradation of IRAF5 trigger any feedback mechanisms that may have activated IRAK4? MyD88, not one two, or any other IRFs that could cause a means of relapse in a disease state, whenever treated in humans? Going forward.

This is something we pay a lot of attention to. We haven't seen any feedback mechanisms in our studies. Even in our longer studies, such as the four-month study with lupus models, we did not observe any inflammatory flares or rebounds in these pathways. The key takeaway is that these pathways involved do not express excess components when the signal through IRAF5 has been blocked. The expectation is not convergence into a damaging reactive state, and we do not feel that we will experience unexpected increases in protein expression. Thus far, we have not observed this phenomenon in any of our studies.

Great. I appreciate that. If I can squeeze in a follow-up, just regarding the STAT6 and degradation. I think you've mentioned previously about achieving a high level of STAT6 degradation, hopefully, in the human population as well in your trial. You know, between the different indications you're pursuing with STAT6 degradation, does the level of that degradation need to exceed 90% for all the indications or is it different between each type to achieve a specified clinical benefit? For instance, with AD concerning the skin and blood, are there specific targets between the two tissue types when looking at the STAT6 degradation necessary for clinical benefits?

That’s a great question, providing two parts. Ideally, our phase 1 study aims for more than 90% in both blood and skin. This approach ensures consistency and allows us to ascertain whether high levels of degradation achieve effective results across different conditions. The second aspect examines the varying degradation levels required for different diseases and interested patients. Therefore, our phase 2b dose-ranging studies provide valuable insights, correlating degradation profiles with clinical outcomes to select appropriate doses for phase three studies.

Great. I appreciate the details here, and thanks for the detailed presentation.

Thank you. Your next question comes from the line of Vikram Purohit with Morgan Stanley. Please unmute and ask your question.

Great. Good morning. Can you hear me?

Yeah. Hi, Vikram.

Thanks for taking the questions. I just wanted to follow up on IRAF5. You've alluded to how challenging this target has been through your prepared remarks and responses to the last few questions. Can you provide more detail on prior attempts at therapies targeting IRAF5, where they might have faltered and how KT579 has been specifically engineered to correct such prior mistakes in the field?

Absolutely, great question. The main challenge with IRAF5 is that identifying a highly specific binder or inhibitor is remarkably challenging. The high sequence homology complicates matters. Our team has been fortunate to discover a molecule that selectively targets IRAF5 with 100% specificity, without binding to other IRFs. Furthermore, the complex nature of IRAF5's activation can involve various biology elements in signaling. Our drug is designed to bind effectively to all IRAF5 variants, enabling transformative solutions for targeting this difficult agent pragmatically. The difficulty in targeting IRAF5 is perhaps underappreciated, as we aim to bring first-time efficacy to market with a highly focused approach to this target.

Great. As a follow-up, how broad will the initial development plan for KT579 be? Is it reasonable to expect an approach similar to that with 621, where you start with two indications before expanding, and given that you mentioned a runway to mid-2028, how advanced into development can we expect you to be with KT579 during that period?

At this point, it's a bit premature to delve into the full scope of the development plan, but we see a plethora of opportunities that could help numerous patients with rheumatological and immune inflammatory diseases. Therefore, we anticipate a broad development program for multiple indications. We plan to start phase one testing early next year but will complete phase one within that year, leading to some clinical data within the runway you mentioned.

Your next question will come from Eric Joseph with JPMorgan. Please unmute and ask your question.

Thanks for the questions. Just on IRAF5, can you talk about the relative infection risk given the broader or more pan pro-inflammatory cytokine suppression profile here? To what extent are you able to model that preclinically, perhaps? And then, given that lupus or SLE is one of the focal indications for this approach, have you examined the comparative efficacy of KT579 against B-cell-depleting or modulating approaches, particularly in mouse models?

Great question. I'll let Veronica address the infection risk first; after that, Jared, you may want to provide insights on comparative efficacy.

Of course. We do not expect IRAF5 to behave like broad immunosuppressants as its expression focuses on key immune cells; its activation is stimulus-dependent in inflammatory contexts, allowing for significant anti-inflammatory benefits without eliciting widespread immune suppression.

Regarding your second question about comparative efficacy, while our preclinical comparisons haven't been made directly to B-cell depleters, we have at least observational studies demonstrating KT579's performance versus comparative standards like dupilumab and TYK2 inhibition. The efficacy data suggests that our degradation capacity across various disease components exceeds that observed in exclusive B-cell targeting approaches.

Your next question comes from Faisal Khurshid with Leerink. Please unmute and ask your question.

Hey, guys. Good to see you. Thanks for taking the question. I saw there is one other disclosed development program for IRAF5 that details allosteric modulation. Can you talk about how you see the potential benefits here of a degrader approach over an allosteric modulator?

Absolutely. There are developmental obstacles targeting IRAF5 since achieving selective inhibition via an allosteric modulator remains complex due to multiple homology traits. In our perspective, developing a degrader allows targeting multiple aspects of IRAF5, removing all types of IRAF5 signaling effectively. This aspect will enable continuous blockade. Anyone pursuing an allosteric approach faces difficulties maintaining therapeutic levels throughout the day without compromising efficacy.

Got it. Great. Thank you for taking the question.

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

Hey folks, this is Nishad on for Geoff. Thanks for the questions and informative presentation. My first question relates to IRAF5; there have been genetic links between certain IRAF isoforms and lupus susceptibility, so are there any concerns that KT579 could exacerbate disease in a subset of patients? Whether you have designed this degrader to focus specific isoforms to avoid this effect?

I'd like Veronica to discuss how the various isoforms are approached in relation to our degrader strategy.

Targeting specific isoforms can be particularly challenging due to how they may have limited expression. Our inclination is toward targeting all IRAF5 isoforms since they play a role in driving pathogenicity within relevant inflammatory contexts. Historical precedents show that inhibiting IRAF5-driven activation pathways may outperform treatments aimed solely at specific isoforms.

Your next question comes from Michael Schmidt with Guggenheim. Please unmute and ask your question.

Hey, guys. Good morning. I just wanted to return to KT621 and STAT6, especially with the June update approaching. How will you interpret the PD marker analysis from the phase one healthy volunteer study, given that your healthy volunteer baseline is much lower and variability surrounds TARC with some dupilumab investigations? How meaningful could PD marker interpretations be in the June dataset? For your upcoming phase 1b study in patients, what specific mechanisms or outcomes are you looking to assess before the randomized phase two trial?

In short, our expectations remain that STAT6 degradation should respond comparably to dupilumab across studies. Primary and secondary data points will reassure robustness and support strong effects observed with lack of control, albeit assessments will emphasize predicting outcomes and biomarkers. Treated healthy volunteers could demonstrate early usage of serum and other relevant cellular readouts down the line, escalating into the patient studies where clinical endpoints truly matter.

Got it. Thanks, Nello. Appreciate your time.

Your next question will come from Yifan Zhu with Jefferies. Please unmute and ask your question.

Hi. This is Yifan from Jefferies for Kelly. Thank you for taking my question. Can you provide additional color on the dose level used in the phase 1b trial as it is a single-arm trial? How does it compare to the highest dose tested in the healthy volunteer studies? What is its relationship to the potential dosing you will see in the phase 2b trials?

We can't really comment on the specifics of the dose quite yet. We've established a target degradation benchmark of above 90%, and we will evaluate the insights gathered from healthy volunteer data integration while sharing relevant findings during the 1b rollout. I can infer that findings from both studies should solidify our strategy moving forward in dose selection.

Okay. Thank you.

Your next question comes from Andy Chen with Wolfe Research. Please unmute and ask your question.

Hey. Thank you for taking the question. On IRAF5, do you see this concept as equivalent to a combo therapy including belimumab and anifrolumab and perhaps also Humira? Is this like a dual or triple biologic? In terms of in vivo studies, can the agents be combined in mouse models to observe efficacy enhancements?

I appreciate the query. The advantage of IRAF5 involves its unique capacity to combinatorically address multiple inflammatory pathways within a single agent in context-specific manners. If working effectively and safely, we can have standalone therapeutic equivalence to dual combinations, reducing inflammatory markers without incurring harms via classic biologics. Jared, would you like to add?

The assumption that IRAF5 would exhibit broader effects makes it plausible to design additional combinations seamlessly, as we assess pathways of interest across our pipeline in addition to existing agents. The efficacy data we've generated thus far supports a powerful single agent's profile but does keep open the possibility of synergistic explorations.

Your next question will come from Kalpit Patel with B Riley. Please unmute and ask your question.

Yeah. Hey. Good morning. Thanks for squeezing me in here. Nello, I just had one question on the degradation kinetics you may show here with the STAT6 degrader in patients by the year-end. For the IRAK4 program, there was a rebound of the protein between day 14 to day 28, which you attributed to variability in method approaches for testing. What steps are you taking to ensure the kinetics will reflect accurate target knockdown as you progress?

To clarify, IRAK4 studies demonstrated robust degradation using mass spec in healthy studies. Yet larger-scale studies introduce complexities where mass spec becomes less feasible. Thus, we will incorporate improved sampling measures and analysis protocols during the trials. Our intent for both 621 and future trials will involve multiple methods ensuring accuracy in measuring protein levels, particularly vital for efficacy determination.

Thank you very much for taking our question.

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

Thank you. First, I wanted to thank everyone for attending our call. I want to thank the team at Kymera Therapeutics, Inc. for putting together a great story today. Obviously, we have a lot more opportunities ahead of us to engage further on some exciting milestones that we're reaching soon. In the meanwhile, if you have further questions, you know where to find us. We want to make sure that the richness of the data we share today can be appreciated to the fullest. So again, thank you, everybody, for attending. The slides are on our website. So you can review them in your own time. And we'll see you soon.