Kymera Therapeutics, Inc.

Good morning and welcome to Chimera's Immunology Innovation Day, our virtual event to introduce our next immunology program, IREF5. I'm Justine Konigsberg, Chimera'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 10Q this morning. For additional details on our Q1 results, please reference our press release issued this morning, which is available in the IR section of our website. 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 Manolfi, our founder, president, and CEO, Jared Golub, 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'll conclude with our prepared remarks with a discussion of our newly introduced IRA5 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 website. 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 10Q 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, IRF5, 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. So just to remind you, Chimera 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 industry has faced for the past 20 years. In order to do so, we 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 heat finding and optimization of oral degraders. we've always had and continue to refine a unique target selection strategy based on pursuing traditionally untracked 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 have made a conscious choice a few years ago to focus in immunology. And 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 industry, oral drugs with biologics like efficacy. And this is really a unique opportunities for Chimera and for patients. So Chimera is founded and continues to thrive on three key pillars. One is a clear vision. So we have always believed that with the new technology, not only you have an opportunity, but you have a responsibility to building 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 of becoming a commercial stage company. We've been fortunate to always be well capitalized. We now have, as of the end of Q1, $775 million with now an extended runway into the first half of 28. We have brought five new molecules in the clinic since 2020, and we are on path to being able to deliver 10 molecules in the clinic by 2026. We have dosed at this point way more than 300 between healthy volunteer patients across our pipeline. And one thing that we're very proud of is our ability to continue to demonstrate impeccable translation from our preclinical studies into the clinic with achieving in all of our programs more than 90% degradation with the desired efficacy and safety profile. So just a quick summary about targeted protein degradation. So 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 the convenience of oral small molecules. So we're able to go after proteins that have not been drug or drugged fully for the past decades with a simple oral drug that we're able to design, synthesize and develop here at Chimera. So why immunology? Why is this such a unique opportunity for us? And I would say for patients. So the team did a work in the past year or so looking at the 10 most common immune inflammatory diseases. And those are AD, asthma, COPD, as you can see from the slide, HS, multiple sclerosis. And if you look at the seven major markets, that's about 160 million patients that are impacted by these diseases. And if you look at the number of patients that are right now are accessing advanced systemic therapies, it's really around 5 million. So we basically have a 3% penetration of advanced systemic therapy into these wide variety of immune inflammatory diseases, again, in the seven major markets. So I don't think we have a problem of innovation in immunology. There is plenty of great drugs in many disease areas. We have a problem of allowing patients to accessing these highly effective drugs. In fact, of these 5 million patients, two-thirds of these patients access biologics. So only one-third access oral drugs, and these oral drugs often are not able to deliver the type of efficacy that biologics can. So we have an opportunity to expand access and expand the reach of highly innovative drugs with oral degraders that have the efficacy of these advanced systemic therapies. And so when you try to put a number on the market, obviously, it's really hard to do. If you look at the five, three percent, the five million, it's a hundred billion dollar market. or more than $100 billion market. So we're talking about 90% plus of patients that we believe could be poised to receive our novel oral systemic therapies. And that's a very large number that obviously it's even hard for us to quantify. But our job here at Chimera is to develop, again, as I said, oral drugs that can not only displace biologics, because they ideally and hopefully will have a similar efficacy safety profile and the convenience of oral drugs. But more importantly, we can now offer a convenient, highly effective advanced therapy to the 90% of patients that right now are not treated, whether it's for access, whether it's for pricing, whether it's for convenience. And so here in this slide, it's really highlighting what are the challenges and the opportunities. So biologics, as we all know, have transformed treatment paradigms. They have transformed many diseases and how doctors treat diseases. But the challenge that come with them is obviously they can be very expensive. They can be complex and expensive to manufacture and as well as to prescribe and reimburse. They have often, not always, immunogenicity issue. They have cold storage issues. So if you're taking a biologics with you on a vacation, you have to think about cold storage. And obviously, they bring the inconvenience route of administration, often painful and, again, inconvenient. In an industry survey that was done, I think as recently as I believe a year and a half, a few hundred patients were asked, if you had an option to switch from a biologics to a neural drug with the same profile, would you make that switch? And 75% of patients said yes. So there is clearly not only an opportunity, but there is a clear unmet need. for patients to access oral therapies that will have a biologic-like profile. So the question would be, why wouldn't traditional small molecule oral drug capture that need? And the answer that we try to depict here is in the bottom of the slide. Traditional oral small molecules follow a traditional PKPD profile. So the efficacy is driven by the ability of the drug to block that pathway 24-7. And because the PK and the PD of a small molecule drug is really connected, you see a sigmoidal curve mostly that depicts that correlation. So you're not able to block the pathway constantly 24-7, but you have a pick-to-trough PD effect. And this is very evident when you look at targets, for example, like TIK2, where the while you're blocking the I-23 pathway in principle well, you're not able to deliver the type of activity seen with an injectable I-23 antibody. And that's really because of small molecules' inability to block the pathway fully. With a degrader that we've shown extensively, both preclinically and clinically, we can block the pathway fully at steady state maintaining that degradation consistent. And that, as we've shown, can mimic biologics like pathway blockade. So in the next couple of slides, I just wanted to share with you two key features of Chimera that I believe has made us a leader in developing unique programs, especially now in immunology. One is really around the capabilities that we've built. I believe we're the best company today at finding small molecule ligands to undrug or difficult to drug protein. were some of the best structural biology capabilities. And we've published on these extensively in peer-reviewed journals on understanding ternary complex interactions of our drugs with the proteins and E3 ligases. And we've shown consistently our ability to translate in the clinic are a deep understanding of PKPD in different tissues in preclinical species and then in humans, which really de-risks the translation into patients and hopefully into a disease outcome. And all of these capabilities have resulted in some really important accomplishments in the past few years. We've delivered at this point, I believe, more than nine development candidates for, against, and drug transcription factors. We've shown now extensively that our degraders are very potent, very specific, orally bioavailable with a great and even distribution across tissues. We've shown over and over again, as I mentioned, our ability to translate these profiles effectively into the clinic. So another key feature, so we've talked about capabilities, another key feature of Chimera strategy is how we think about target selection. And we have these key four pillars that have been the same since day one. We go after targets that have not been drugged or drugged well before, where there is strong human genetics for the target. and importantly, where the pathway has been validated with other agents, usually upstream of our targets. We usually, if not always, have a clear path to show clinical differentiation early in our development strategy as well as now we're very, very keen on programs that have access to large clinical and commercial opportunities. So if you look at our targets today that we're actively pursuing, you know, STAT6 and IRF5, two undrugged transcription factors where Chimera has delivered the first development candidate or for STAT6 actually the first clinical entry, and soon the first clinical data. These have been, targets have been pursued for decades, and really the technology has been missing. And here we have first-in-class drug with targets with strong genetic validation. IREC4, the target that has been drugged, but not well with traditional small molecules. The beauty about our strategy is also that we're going after these pathways that have complementarity. So not only these are standalone important programs, after IL-4 and 13, type 1 interferon, cytokines, B cells, autoantibodies, IL-1, TLR pathways. But also you can imagine that eventually these pathways can be synergistic in how we think about further development in combination, et cetera. And this is probably even more appreciatable if you look at the slide 13 here, where we're looking at where we're developing these assets in which not only disease area, but also in which indications. So you see, for example, for STAT6, we have a big effort in atopic diseases, which are more often in dermatology and respiratory. And here you see seven or eight different diseases. For IRA5, which I would say it's more traditional immunology rheumatology, you see more in GI and rheumatology, RA, lupus, et cetera, while IRA4S places in each of these disease areas. So not only we can actually capture almost the totality of potential immune inflammatory indications, But then you can imagine when there is overlap, a potential strategy down the road could be combination of these assets. This is a slide that captures the concept that was made before about the unmet need in the space. And this actually puts number to the concept. We can use STAT6 and the concept can be applied to the other programs. Again, if you look at the seven major market, we have more than 100 million patients that are diagnosed with TH2 diseases. And you can see the most prevalent there, AD, asthma, COPD, chronic rhinositis, et cetera. The number of patients that have access to advanced systemic therapy right now dominated by dupilumab is really around a million patients. So we have almost 100 million patients, if not more, that I believe, we strongly believe, would benefit from a neural drug that has the efficacy and the safety of an injectable biologics. So a neural drug that can change how doctors prescribe medicines for patients with these diseases. And so that's really what we're trying to do, not only for STAT6, but also for IRF5 in diseases that are, as we said, complementary to the STAT6 diseases. This is really around SLE, RA, Crohn disease, UC, et cetera. And both Veronica and Jared will share more. And then IRF4 with, again, the more traditional IL-1 TLR-driven diseases. Hopefully this slide give you a sense of the opportunities we have in front of us with oral drugs. There are really best in pathway to combine the convenience of oral drug and the efficacy of a biology. So in this slide, we will actually go through the upcoming milestones soon. And so I don't want to spend too much time going through the details of the slide. I just want to say we have the next 18 months will be rich of milestones. We have STAT6 upcoming data in June, which we're very excited to finally get there. We have Phase 1b data at the end of the year. We have two Phase 2b studies to start. Veronica will tell you about IRF5. Maybe I'll give you an update on a couple of programs that will not be the subject of the later presentation. So first on IRAC4, as you know, Sanofi is progressing KT474 in two parallel phase 2b studies in both HS and AD. We continue to expect these studies to be completed in 2026, in first half, mid 2026, with data shortly thereafter. As you know, IRAC4 was our first immunology target and early success in that program has allowed us and has actually given us the impetus to invest even more in immunology and allowed us to build what we believe it to be one of the best, if not the best oral immunology pipeline in this industry. And so while Sanofi has been advancing 474, we've had additional ongoing effort at ChemAir under the collaboration. We've said that in the past. As a result of these efforts, we're pleased to announce today that we have recently achieved at preclinical milestones resulting in $20 million payment that we expect to receive in the second quarter. So a validation of both the strategy and the work that both teams have been doing in the past few years. Secondly, I'd like to touch on the disclosure that we released this morning in the press release around our decision around TIK2. So first, I'll say that it's, I think, widely accepted that we're in a very volatile market period, not only biotechnology, but I would say the broader market. And with that, we believe that Chimera is exceptionally well positioned to navigate this uncertain environment. We have what we believe, as I just said, probably the best oral immunology pipeline in industry. We have multiple upcoming catalysts that we'll go through later in the presentation. We have an incredible research team that continues to deliver novel programs. You've seen IRF-5. You'll see more in the near future. in the near future. And we have a strong balance sheet of $775 million as of the end of Q1. But obviously, we can't just sit and be complacent. We continue to look for opportunities to ensure that our human as well as our capital resources are always prioritized towards the highest return activities. And in fact, it's with this philosophy that we've continued to optimize our resource allocation strategy. You've seen changes that we made in the past around our oncology investments. And so it's really with this spirit of prioritizing and funding the highest return activities that we're announcing today our strategic decision not to advance our tick-2-degrader, KT295, into clinical development. Now, I just want to take a moment to explain that well. First, I would like to say that we have completed IND enabling studies with this drug, and we have seen no adverse events in any of our studies, in any of our doses. So this was as a successful IND enabling campaign as you wished. And we continue, I'm a continue to be a strong believer in the differentiated case for a degrader in this highly validated pathway. At the same time, In this current environment, resource allocation is very important. And we believe resource allocation, and particularly our people, to programs with the highest probability of success is paramount. So at this point, we've decided to pause on our TIC2 efforts and redirect those resources. So this decision will allow us to address two important points. One, we're able now to dedicate more human capital as well as our finances to what I believe it to be one of the largest, potentially one of the largest programs in industry, our Stat6 programs and 621. I would say the Stat6 franchise and 621. that is really at the cusp of key inflection points. We also can use some of these both human and financial capital to fund IRF-5 and other efforts that we have in other areas. And then secondly, what this decision has allowed us to do is to extend our cash runway from mid-2027 to the first half of 2028. So this is very important because now our cash runway is well beyond important inflection points, especially, I would say, well beyond the phase 2b readouts for 6 to 1. So, I mean, you all know it's never easy when we make this resource allocation decision, but I hope I was able to convey our strategic thinking around this decision and then happy for myself and the team to take questions in the Q&A at the end. So I thought I'll pause here now and pass it on to Jared for him to go through our STAT6 program.

Thanks, Nello. This is a very exciting time for Chimera from a development perspective. 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 IRFI 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 IL-4, IL-13 pathway drives Th2 inflammation and is highly validated by dupilumab, an injectable biologic targeting IL-4 receptor alpha that inhibits IL-4 and IL-13 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 IL-413 pathway and is therefore the critical signaling node controlling Th2 inflammation. For this reason, blocking the function of STAT6 is expected to phenocopy IL-4 or IL-13 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 IL-4, IL-13-driven allergic diseases and suggest it can be safely knocked down. Only the unique pharmacology of STAT6 degradation has the potential to fully block IL-413 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 IO413 pathway to the same extent as biologics. We believe the only modality that can do this are degraders. Furthermore, if an oral stastic degrader can truly block the IL-413 pathway to the same extent as, say, dupilumab, this has the potential to transform the treatment paradigm for all of the different Th2 allergic indications that have already been de-risked by dupilumab. Dupilumab has transformed the lives of patients with dermatologic, respiratory, and gastrointestinal Th2 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 de-risked 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, and I'll walk you through this at a high level. Preclinically, KT621 was shown to be exquisitely selective for STAT6 and shows no 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 IL-4 and IL-13 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 stastic 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, and we did not observe any adverse safety findings in four-week GLP-TOC studies in non-human 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 1 studies in healthy volunteers and AD patients to quickly enable demonstration of clinical proof of concept and inform 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. That will enable dose selection for subsequent phase 3 registrational studies, not just in AD and asthma, but also across multiple other dermatologic, respiratory, and gastrointestinal indications de-risked by dupilumab. The Phase 1a Healthy Volunteer SADMAD Study has been completed and will be 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 de-risk 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 IL-413 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 1b trial, named BROADEN, is a single-arm open-label trial that will enroll about 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 Stas6 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 EZ and pruritus NRS. We expect to report the phase 1b 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 and 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 IRFI program. With her team she's done a terrific job advancing this exciting program to development candidate and into IND enabling studies, and we are excited to share the details with you now.