Good day, and welcome to the Kymera Therapeutics Second Quarter 2024 Results Call. Please note, this event is being recorded. I would now like to turn the conference over to Justine Koenigsberg, Head of Investor Relations. Please go ahead.

Good morning, and welcome to Kymera's quarterly update call. Joining me this morning are Nello Mainolfi, President and CEO; Jared Gollob, our Chief Medical Officer; and Bruce Jacobs, our Chief Financial Officer. Following our prepared remarks, we will open the call to questions. In order to have enough time to address everyone's questions, please limit your questions to one and a relevant follow-up. Before we begin, I would like to remind you that today's discussion will include forward-looking statements about our future expectations, plans, and prospects. These statements are subject to risks and uncertainties that may cause actual results to differ materially from those projected. A description of these risks can be found in 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, I'll now turn the call over to Nello.

Thank you, Justine, and good morning. Every day, we take important steps towards our goal of building a fully integrated global biotechnology company, demonstrating our ability to consistently deliver first and best-in-class programs that target validated pathways with the potential to address large underserved disease areas. The progress we've made over the past quarter highlights our novel approach to drug development that emphasizes innovative molecular design, fidelity of translation from preclinical settings to the clinic, data-driven development strategies, and the commitment to maximize the impact of our signed programs to improve patients' lives. Our unique approach has led to the development of a pipeline of exciting degrader medicines with the potential to change treatment paradigms for multiple diseases as evident in our recent updates and presentations at major medical congresses and publication in peer-reviewed journals over the past few months. Our STAT6 program, for example, was featured at both ATS and DDW, MDM2 at ASCO, and STAT3 at AACR and EHA. In addition, we published data from our noninterventional trial evaluating IRAK4 expression in patients with HS in the Journal of Investigative Dermatology. The findings we've shared across these forums highlight the differentiated profile of our programs. Before handing the call over to Jared for a more detailed overview, I wanted to highlight two important updates in our immunology pipeline. I will start with our IRAK4 program. As a reminder, KT-474, IRAK4 degrader partnered with Sanofi, is the first heterobifunctional molecule to have been dosed in healthy volunteers and then HS and AD patients. We have shown in our Phase I study TYK degradation of IRAK4 in blood and skin resulting in impact on biomarkers of inflammation, both systemically and in the skin of HS and AD patients. This robust pharmacodynamic profile has resulted in clinical benefits measured by EASI and pruritus scores in AD and HiSCR in pain in HS. KT-474 has likely been the most studied degrader in a Phase I setting. Last month, we announced after an interim review of safety and efficacy of the ongoing HS and AD Phase II trials that Sanofi intends to expand both of these trials with a goal to accelerate the path to registration of Phase III studies for both HS and AD. The impact of these expansions effectively allows us to transition seamlessly into more expansive dose-range finding Phase II studies. As a result, while the modified Phase II trials will be larger and extended, the expectation is that this will enable a direct transition into Phase III more quickly than anticipated. Staying with immunology, we've been talking about the concept of oral degraders with biologics-like activity, a unique value proposition for Kymera's platform in this attractive therapeutic area. Our STAT6 program best exemplifies this concept. Dupilumab is a drug that has transformed the lives of almost one million patients with TH2 diseases. And in doing so, it has become, with sales projected to reach $20 billion, a mega blockbuster and one of the largest drugs in this industry. At Kymera, we have developed an oral degrader by targeting STAT6, the selective transcription factor of the IL-4/13 pathway, which is able to block the pathway in a similar or superior way. In fact, we've shown in preclinical studies that our orally active picomolar STAT6 degrader, KT-621, is more potent than dupilumab at blocking TH2 signaling in cell systems and equal to or superior at blocking TH2 inflammation in preclinical disease models. Overall, the preclinical data generated to date demonstrates the opportunity for KT-621 with best impact potential given its dupilumab-like activity and the convenience of an oral pill. We believe that a paradigm-shifting oral drug with this profile has the potential to change how TH2 diseases, such as AD, asthma, COPD, and others can be treated. Our mission is not only to target the patients that are currently on biologics but the more than 100 million patients that are not currently on biologics. And by doing so, we have the potential to change millions of lives around the globe. We're excited to start our KT-621 Phase I trial soon. We usually don't comment on the status of our results of ongoing IND-enabling studies, but since one of the most frequently asked questions we receive is the current status of the program, I wanted to provide a brief update. Very happy to say that we have completed all of the IND-enabling studies with no safety findings of any kind. During our GLP toxicology studies at all doses tested, we did not see any adverse events. This is an important milestone for the program for Kymera and hopefully, for millions of patients in the future. With those activities behind us, the next update you should expect will be when we dose our first subject. And importantly, we look forward to sharing the Phase I results in the first half of 2025. I would like Jared to share more details on our programs, and then I'll be happy to take questions.

Thanks, Nello. Starting with KT-474. As mentioned, last month, we announced Sanofi's decision to expand the ongoing Phase II studies in HS and AD, following an interim analysis of KT-474 safety and efficacy by an independent data monitoring committee. This exciting development is a great outcome for Kymera and our IRAK4 program. Importantly, it not only reinforces Sanofi's strong commitment to the program, but also provides the potential to inform future registrational trials in a way that should accelerate overall timelines. But just to step back, the expansion effectively will allow a seamless transition into more expansive dose-range finding Phase II studies. The goal is really to structure the studies with the necessary regulatory perspective to enable dose selection for Phase III. While it will take longer to complete Phase II, these two expanded Phase II trials in HS and AD will support moving directly to Phase III. Therefore, the overall timelines to Phase III and ultimately, to registration should be meaningfully shorter. Since the update last month, Sanofi is undertaking activities to update the protocols. And once this work is complete, we expect the new details will be posted on clinicaltrials.gov. Once that happens, we will be able to discuss updated timing related to trial completion and data releases. As a result, we expect the Phase II results, which will be shared in their entirety following this expansion, will be beyond our prior guidance of the first half of 2025. As Nello mentioned, KT-621, our first-in-class STAT6 degrader, has the potential to be a once-daily oral medicine, capable of delivering dupilumab-like activity and safety in highly prevalent allergic diseases. We recently presented additional data at the ATS conference that demonstrated the activity of KT-621 comparable to a saturating dose of the IL-4 alpha antibody dupilumab in an asthma efficacy model, including robust inhibition of all the tested cytokines, chemokines, and cell infiltrates involved in TH2 inflammation in asthma. The data also demonstrated reduced disease severity in the lungs after low daily oral doses of KT-621 comparable to dupilumab. I should also note, as Nello mentioned, that KT-621 was well tolerated in our preclinical testing now in both non-GLP and GLP toxicology studies with no adverse events at any doses. We look forward to presenting additional KT-621 preclinical data in a poster session next month at EADV, the largest international meeting in Europe for dermatology. We remain on track to commence a Phase I single and multiple ascending dose clinical study of KT-621 in healthy subjects in the coming months with data expected in the first half of 2025. We plan to share more details around our development plans for Phase I and beyond when we provide additional updates on the program later this year. Founding out our immunology pipeline, we unveiled our first-in-class oral TYK2 degrader KT-294 at our R&D Day. We have shown that small molecule inhibitors do not block all the scaffolding functions of TYK2 and therefore, are not able to replicate the TYK2 loss of function profile. In addition, small molecule inhibitors cannot fully block the catalytic function at steady state. The opportunity for this program with depletion of TYK2 is not just to have a drug that is incrementally better than TYK2 small molecule inhibitors, but to bring to patients an oral biologic-like pathway blocker and thereby deliver a best-in-class agent for conditions like IBD, psoriasis, psoriatic arthritis, and lupus among others. For this program, we expect to initiate and complete Phase I testing in 2025. In summary, these timelines put us in a position to share Phase I data for our two new immunology programs, STAT6 and TYK2, in 2025, which is shaping up to be a very busy and exciting year for Kymera. Moving to oncology, this also has been a busy stretch for our two clinical programs, KT-253 and KT-333 targeting MDM2 and STAT3, respectively. We recently shared updates demonstrating the disease-modifying impact of these degraders at ASCO and EHA, highlighted by major responses in liquid and solid tumors. In addition to the clinical activity that has been demonstrated, we have been particularly encouraged by tolerability, which has exceeded our expectations in both cases. That has resulted in our ability to escalate to higher dose levels than expected. As a reminder, MDM2 is an oncogenic protein that modulates the most common tumor suppressor p53. While small molecule inhibitors have been developed to stabilize and upregulate p53 expression, they have been unable to show meaningful clinical benefits of p53 stabilization with acceptable safety margins. We believe this is likely due to their inability to overcome a feedback loop that increases MDM2 protein levels when p53 is upregulated. Due to its differentiated mechanism, KT-253 has shown the ability to overcome the MDM2 feedback loop and rapidly induce apoptosis with brief exposures in preclinical studies. This provides an opportunity for an improved efficacy and safety profile. We're encouraged by the data emerging from the KT-253 Phase I dose escalation trial. In our ASCO poster in June, we provided a clinical update from 24 patients as of April 9. That update included 16 patients in Arm A with solid tumors or lymphomas up to dose level 5, and 8 patients in Arm B with high-grade myeloid malignancies up to dose level 3. We demonstrated potent upregulation of p53 pathway biomarkers and signs of antitumor activity in multiple tumor types shown to be sensitive in preclinical models, including responses in one or two evaluable patients with Merkel cell carcinoma and two of two patients with post myeloproliferative neoplasm acute myeloid leukemia, at doses that were well tolerated without the traditional hematological toxicity seen with small molecule inhibitors. Dose escalation in the Phase III clinical trial is ongoing, and we expect to complete enrollment in the second half of 2024, and subsequently to share the Phase Ia data set and guidance on next steps. Separately, we expect to present our biomarker-based patient selection strategy for the next phase of KT-253 development at a medical meeting later this year. In June, we provided a clinical update on our STAT3 program at the European Hematology Association Annual Meeting. KT-333 is a potent, highly selective degrader of STAT3 and the first heterobifunctional degrader against a historically undrugged transcription factor to enter the clinic. The poster provided a clinical update as of June 3 from 47 patients enrolled through seven dose levels with a mean of 9.1 doses. We are encouraged by the data generated to date, showing strong target knockdown in blood and tumor, induction of interferon gamma response in blood and tumor, and signs of preliminary clinical efficacy in lymphomas at tolerated doses. Preclinically, we've seen robust single-agent activity in T and NK-cell lymphomas as well as a strong genetic rationale for why STAT3 targeting should be active in Hodgkin's lymphoma. This has translated well in the clinic in terms of the antitumor responses we have seen in Hodgkin's lymphoma, CTCL, and NK-cell lymphoma. We believe the emerging data in Hodgkin's lymphoma patients is particularly intriguing with complete responses in two of three heavily pretreated patients who had progressed after prior checkpoint inhibitor therapy and anti-CD30 ADC, enabling subsequent potential curative stem cell transplants. Because we do not see strong signals or preclinical activity as a single agent in solid tumors, it's not been surprising that we have observed only stable disease in a handful of solid tumor patients enrolled in the trial. However, we have seen activity in syngeneic mouse solid tumor models in combination with anti-PD-1 drugs. This is likely driven by STAT3's immunomodulatory mechanism, which we believe provides an opportunity for combination with anti-PD-1 in both solid tumor and Hodgkin's lymphoma patients. Given the activity we've observed in Hodgkin's lymphoma, which includes the two aforementioned complete responses, we are focused on the enrollment of additional Hodgkin's lymphoma patients to further explore the very encouraging activity we've seen there. We believe there is also an opportunity for future expansion into solid tumors in combination with anti-PD-1 and other targeted therapies. We expect to complete enrollment of this study and share data in the second half of 2024. We look forward to keeping you updated on all our preclinical and clinical programs. Before we take questions, I'll hand the discussion to Bruce to review our second quarter financial results.

Thank you, Jared. As I review our second quarter 2024 financial highlights, please reference the tables found in today's press release. Revenue in the second quarter of 2024 was $25.7 million. All of that was attributable to our Sanofi collaboration. With respect to operating expenses, R&D for the quarter was $59.2 million. Of that, approximately $7.3 million represented noncash stock-based compensation. The adjusted cash R&D spend of $51.9 million, which excludes that stock-based compensation, reflects a 22% increase from the comparable amount in the first quarter of 2024. On the G&A side, our spending for the quarter was $17.4 million, of which $7.1 million was noncash stock-based compensation. The adjusted cash G&A spend of $10.3 million, again, excluding stock-based compensation, reflects a 21% increase from the comparable amount in the prior sequential quarter. Finishing up, our cash balance at the end of the quarter was $702 million. Our cash balance is expected to provide a runway into the first half of 2027, and will enable us to execute on multiple data readouts, including oncology proof-of-concept results in 2024, KT-474 Phase II data, and several clinical inflection points for our STAT6 and TYK2 programs expected in 2025. This concludes our prepared remarks, and we would be happy to now address any questions you may have.

Our first question comes from Eric Joseph with JPMorgan.

Hi, good morning. Thank you for taking my question. Could you please provide more details on the type of data that you and Sanofi reviewed when deciding to expand the Phase II program? I’m curious if the decision was based solely on safety or if there were also considerations related to efficacy or any relevant surrogates. I understand there are various factors at play, but do you have a rough idea of when we might see data from the expanded Phase II trial and whether there will be any interim readouts?

Thank you for your question, Eric. There was an interim analysis conducted on both safety and efficacy, as we've mentioned. Both Sanofi and Kymera had access to the blinded data, and there was an independent data monitoring committee that had access to both blinded and unblinded data. I cannot discuss the specifics of the review or the questions that were posed. However, the main takeaway from our recent update, which we are emphasizing again, is that the data review supported further investment in the program. It's important to note that this is one of the few programs in the pipeline where Sanofi is conducting multiple phase studies simultaneously without a previous proof-of-concept study in a placebo-controlled setting. This underscores the enthusiasm we both have for the program. Regarding timelines, we anticipate an update on clinicaltrials.gov in the coming months, which will include expected completion dates. At that time, we should be able to provide more clarity on the timelines. As mentioned earlier, we expect it to extend beyond the first half of 2025, which was our initial guidance, but we cannot provide more precise guidance at this time.

Our next question comes from Jeff Jones with Oppenheimer.

Good morning, guys. And thanks for taking the question. Just a quick one on the R&D and G&A trends. Obviously, picked up significantly from the prior quarter with the extensive work you have going on. Just how should we think about the trends there? And then a follow-up as well on the jump in collaboration revenues from Sanofi. How should we think about that moving forward?

Yes, sure. This is Bruce. Jeff, thanks for the call. So in terms of the trends, there's nothing unusual there in terms of the growth quarter-over-quarter versus what we had expected. As the year progresses, obviously, we get closer to the start of the studies for STAT6, you'll see that come through in the R&D line. G&A is just modest growth either organization. We haven't guided towards annual burn, typically don't. But last as I looked at the street, they're generally in the right ballpark. But definitely for this year, a little more back-end loaded than front-end loaded. And that's typically how our care years have gone and represented what you'll see this year. In terms of the revenue, there was just a catch-up in revenue related to the Sanofi alliance, and all the revenue is a result of that. So that resulted in a higher level this quarter, but I think it will be a little unusually high vis-a-vis the rest of the year, and you can do some calculations based on the deferred revenue balances on our balance sheet for how you might look over the coming year or so. So hopefully, that helps a little bit happy to take more offline as well if you'd like.

Our next question comes from Kelly Shi with Jefferies.

Congrats on the progress. And thank you for taking the questions. Maybe I'll start on the STAT6 program based on the multiple preclinical studies you have presented findings please? With your comment on more specific plans for the Phase I? Would it be like a single indication or multiple indications to all that this area has been made on the discoveries from preclinical studies, which one to prioritize?

Yes, thanks. Maybe I'll let Jared comment on the Phase I plans. We haven't described the details of our plans before the healthy volunteers. I think maybe just to remind you that the update that we're giving today on the program is really on the fact that we were able actually to accelerate our path to Phase I, and we're able to conclude and complete our IND-enabling studies. And so we are on track, if not earlier, compared to what we have said to start the Phase I study. Maybe Jared, you can provide some high-level description of our healthy volunteer studies.

Yes. So the Phase I healthy volunteer study, being in healthy volunteers, we expect to be able to move through it quickly. It will be a traditional single ascending dose and multiple ascending dose Phase I study, the multiple ascending dose portion will consist of 14 daily doses. Within that study as we did for the IRAK4 Phase I, we'll have a number of different pharmacodynamic measures which will be critical to that study in addition to looking at safety. And those measures will include looking at STAT6 for example, in blood and skin. And also importantly, we'll have an opportunity to look at several different TH2 biomarkers in circulation, in particular, to be able to look at IgE and TARC, giving us an opportunity to show impact on the biology of the IL-13 pathway even in healthy volunteers.

Our next question comes from Vikram Purohit with Morgan Stanley.

Hi, good morning. Thank you for taking our question. We had two on the I&I pipeline. First on 474, just wanted to get your latest thoughts on when we can learn more from yourself and Sanofi on indication expansion beyond HS and AD and what might be flowing into those decisions? And then secondly, for the TYK2 program, just wanted to see how you're thinking about indication expansion or indication selection rather, I mean, how broad do you think the development program could be? And what will you be looking for in the initial Phase I data to help make those decisions?

Yes, thanks, Vikram. So on the 474, as we said in the past, we believe this pathway has relevance in a broad variety of diseases. Our initial foray is in skin and dermatology. So with HS and AD again, based on pathway agents with existing proof of concept, we expect this pathway in this target to be relevant in respiratory conditions in both asthma and COPD, in gastrointestinal inflammation, IBD, as well as traditional, let's say, rheumatology, both RA and lupus. So the opportunities are vast. As we've communicated in the past, there is a process that has been ongoing within the collaboration to prioritize a series of indications that the team has done. And I cannot speak for Sanofi, who will have the final decision-making on this. But all I can say is that the recent update and what we have seen, I think, continues to support the enthusiasm around the program and the potential eventual expansion. I'll leave it to Sanofi to speak to the timing of that. But I will say that at least we're getting closer to, hopefully, that decision. With regards to TYK2, again, as Jared said earlier, this program is really for us an opportunity to provide an oral molecule with biologics-like profile and actually unique biologic-like profile. If you think about this pathway, it is involved in IL-23, IL-12, and Type 1 interferon and being able to block those three pathways fully with a single oral small molecule should provide a highly differentiated profile. So there's lots of potential diseases that one could go after. The ones that others have gone after include psoriasis and psoriatic arthritis, IBD, lupus obviously are among those. There are potentially others that could be interesting. I think our goal will be in the Phase I study to demonstrate that our mechanism of action is able to show blockade of these pathways unlike any other agents that have been tested so far, and then our plan would be to do a proof-of-concept in an indication that will actually demonstrate the differentiated profile. But we'll share more details about that once we're closer to the Phase I studies.

Our next question comes from Brad Canino with Stifel.

Thank you. And two for me. First, and Nello just talked about this a little bit. But given the recent external news, can you discuss the confidence of TYK2 as a tractable target for IBD? And then second, maybe a bit of a strategy question, but years ago before this named pipeline really evolved to the shape it is today. I mean you actually highlighted a lot of the discovery efforts at Kymera. And I just want to pull back and ask how would you characterize the degree of discovery efforts now? What are some of the areas of focus? And how do you maintain that while also asking a lot of questions individually and collectively across the clinical pipeline today?

Thank you. Jared, why don't you take the first question, I'll take the second one.

Sure. Yes. In terms of your question around our approach to targeting TYK2 and our expectations for activity in IBD. I mean, there have been some challenges with the TYK2 small molecule inhibitors to show activity in IBD. With deucrav for example, part of that might be due to the fact that while it's hitting, say, IL-12 and IL-23, it is also not selective just for TYK2, but also hitting JAK, and it's probably affecting IL-10 which can be a real problem in IBD because if you block IL-10, you're going to interfere with mucosal healing, which is going to be an important component of any therapeutic where you don't interfere with that. So we think one of the real advantages of our TYK2 degrader is that we can maximally block the key inflammatory pathways, IL-12, IL-23, and Type 1 interferon, while at the same time, completely sparing IL-10 signaling. And we think that this will be a distinct advantage for our approach in this disease, and that's why we anticipate being able to show activity in IBD as well as in the other indications that Nello was discussing earlier, including the dermatological indications like psoriasis and rheumatoid indications like lupus.

Yes. And just maybe to add a small statement on the recent data. I think it's important to look at the profile of the molecule tested and their activity, blocking the relevant pathways. And so it's difficult, as you know well, Brad, to compare or to use the other trials as a testament to the value of that biology in that particular disease without taking into account the context of the actual molecule profile.

With regards to the discovery efforts, I think one thing that we’ve been consistent with Kymera has been the focus on pathways that have a high degree of validation, and within those pathways, we're just going after targets that have not been well-drugged. I think if you look at the type of targets that we've gone after, what really rises to the top are two main classes, transcription factors, and we have STAT3 and STAT6 as examples, or scaffolding protein IRAK4 TYK2. And I believe that the general philosophy will continue to be the same. As we mentioned earlier in the year, we have increased substantially our efforts in immunology. Again, we’ve talked about STAT6 with an amazing profile so far, we’ve talked about TYK2 with great potential. We’ve talked about IRAK4 for years now. You'll hear about new programs, hopefully, as early as next year, again, in the context of difficult-to-drug or impossible-to-drug targets with other modalities within the same immunology landscape. I think our goal and our vision, and I have the highest degree of confidence where I sit today, is that we will have the best in industry oral immunology pipeline, if we don't already have that. And I think that's what the world should expect from us in the next few months and years.

Our next question comes from Marc Frahm with TD Cowen.

Hi, thanks for taking my question. Maybe one quick one on oncology. Just the 253 update. Can you clarify, is the data presentation this year just the biomarker approach? Or should we also expect the kind of full clinical update this year to happen this year? Or is that going to be a next year event? And then maybe a broader question on the I&I portfolio and just Kymera's approach. Do you guys view the oral convenience of your molecule as so important that it's acceptable to develop molecules that end up having clinical profiles that are maybe not quite as good as the leading injectables? Or is it the idea here that you really have to show every bit as much efficacy, if not more, than kind of anything that's out there?

Regarding your first question, we have been discussing our commitment to present a biomarker-based strategy for future recruitment related to 253 and MDM2, focusing on sensitivity biomarkers. We are optimistic about sharing this data at a medical meeting this year. Concerning our clinical data, we plan to complete the total escalation this year, which is contingent upon the safety profile of our drug and the necessary doses to reach the maximum tolerated dose (MTD). For STAT3, we escalated more than expected due to a better safety profile than anticipated from preclinical data. For MDM2, our intention is to present the complete escalation data once we finish it, which we aim to do by the end of the year, depending again on the safety profile and the timing to reach MTD. The trial is progressing rapidly in terms of patient recruitment, which is not the main concern; rather, it is the profile of the drug that is critical. In terms of the immunology pipeline, we have selected targets that excel in blocking pathways compared to upstream biologics. This is evident with IRAK4, which is expected to be more effective than individual upstream IL-1 biologics. The same applies to STAT6 and dupilumab, where we have demonstrated similar pathway blocking capabilities. We anticipate being able to show equivalent results in our TYK2 program in clinical settings. Our ambition, which we believe is unprecedented in immunology development, is to create an oral drug that does not compromise efficacy in comparison to on-pathway biologics. We believe our drug can block the pathway as effectively as dupilumab, the IRAK4 receptor alpha blocker, resulting in a clinical profile and activity at least on par with dupilumab. Historically, oral drugs have required compromises on efficacy, but we are striving to change that narrative. When we mention a paradigm shift, it refers to a significant change in how we perceive treatment options for patients with these diseases. We believe our programs have the potential to transform that paradigm.

Our next question comes from Kalpit Patel with B. Riley.

Yes, hey, good morning. Thanks for taking the question. You mentioned the expansion of the IRAK4 trials also includes testing of additional doses. Maybe help us understand the decision-making for that specifically and why more doses need to be tested now. And as a follow-up, if you can share, can you give us any additional color if the new doses are outside of the 50 to 200-milligram daily dose range?

Great question, Kalpit. To initiate a Phase III registrational study, a sponsor is expected to conduct dose-ranging to establish the relationship between efficacy and safety. The existing Phase II study has only one dose and one placebo. Transitioning from such a study to a Phase III registrational study without exploring multiple doses would have been extremely challenging, if not impossible. This need for additional doses is driving our acceleration into the Phase III study after this one. Regarding the specific doses, we are not able to provide details at this time. However, in Europe, the doses are made known much earlier than they are in the U.S. With some investigative work, it shouldn't be too difficult to determine what the existing dose and the new doses will be. I will say that the doses will fall within the range you mentioned, but I cannot provide further details on their exact levels.

Our next question comes from Michael Schmidt with Guggenheim.

Hi, thanks for taking our question. This is Paul on for Michael. Just following up on a prior question on STAT6. Can you talk about how we should interpret that early biomarker data coming out of the healthy volunteers next year? For instance, is there a certain threshold of serum IgE or TARC reduction that you're hoping to see? Or are there any directional and dose-dependent reductions sufficient to give you confidence in that program? And then just as a follow-up, is the goal here just to establish proof of concept? Or could the pharmacodynamic data actually guide your thinking on target indication prioritization?

Yes, that's a great question, Paul. To start, we've developed a comprehensive preclinical package. In vitro studies demonstrate that we can completely degrade this target at picomolar concentrations across all relevant human cell types associated with TH2 diseases, including respiratory, dermatological, and gastrointestinal conditions. In terms of pathway inhibition related to IL-4/13 biology downstream of the receptor, our drug has proven to be more effective than dupilumab. In vivo studies, including an atopic dermatitis model and a more translational asthma model, reveal that we can achieve 90% degradation of STAT6, blocking a variety of TH2 biomarkers and disease endpoints as effectively or better than DUPIXENT. Our preclinical pharmacology indicates that this drug operates as a very robust, likely best-in-class pathway inhibitor. Additionally, we have observed a pristine safety profile, with no adverse events reported in our non-GLP toxicology studies. Our recent updates indicate that even in GLP toxicology tests, we have not encountered any adverse events at any tested doses, making the safety profile quite compelling. The aim of the Phase I study is to validate that our preclinical results will largely be mirrored in humans, particularly focusing on pharmacokinetics that result in a dose-dependent and significant degradation in blood and skin. We will also monitor biomarkers influenced by DUPIXENT to confirm, as expected, that blocking STAT6 will lead to corresponding changes in biomarkers, which we have documented extensively in various preclinical models. Based on the data presented, I encourage everyone to review it to align on expectations. We've demonstrated a reduction in TARC and IgE over 28 days, with reductions ranging from 20% to 40%, depending on the biomarker, suggesting pathway obstruction even in healthy volunteers without ongoing inflammation. This serves as confirmation of target engagement. However, I don’t anticipate using this data to make decisions about indications since these are qualitative biomarkers from a healthy volunteer population. Our aim is to move into patient studies soon to establish a stronger proof of mechanism and proof of concept.

Our next question comes from Ellie Merle with UBS.

Hi, this is Jasmine on for Ellie. Thanks very much for taking our question. We have two in oncology. So for STAT3, could you give a little more color and talk about your view on the potential opportunity in Hodgkin's lymphoma? And then secondly, on your MDM2 strategy, specifically in solid tumors, are we going to hear an update on this when you give your biomarker patient selection update this year? And just based on the mechanism of action, what can you say about what you see as the most applicable set of solid tumors?

Yes, maybe starting with your question on STAT3 and Hodgkin's. We've reported that we've seen complete responses in Hodgkin's lymphoma in patients who have gone on to hopefully curative transplant. So that very encouraging data and Hodgkin's is consistent with what is known about the genetics of Hodgkin's disease, where there's amplification of PD-L1 as well as JAK amplification, both of which would render those tumors potentially responsive to STAT3 targeting. So as we've guided previously, with the Phase I study, we have now completed dose escalation, and enrollment now is really focused on enrolling additional Hodgkin's patients. We see there being several different development opportunities for the drug. If we continue to see the sort of activity that we've seen to date. Those include opportunities for the drug as a monotherapy in third line and beyond. So for patients who have had prior anti-PD-1 drugs or prior anti-CD30 ADC, and also a potential opportunity in second line in combination with anti-PD-1. So I think it would be very interesting in terms of what we see for the remainder of the study this year; we plan on reporting data later this year once we've completed the enrollment of those additional Hodgkin's patients that can provide both efficacy and safety update at that time. With regard to MDM2 and patient selection, I think Nello referred to this earlier, we have had an ongoing extensive effort preclinically to identify different solid tumor types that are specifically sensitive to the degrader mechanism of action. And we've been in the process of developing a biomarker signature of sensitivity using various solid tumor models. Our plan is to present later this year at a medical meeting, an update so that people can see sort of what those preclinical data are showing and how those are potentially guiding how we plan to further enrich for certain solid tumor types for the MDM2 degrader program. So stay tuned for that presentation, hopefully later this year, where we can provide more details on what that biomarker strategy is going to look like.

Our next question comes from Andy Chen with Wolfe Research.

This is Brandon filling in for Andy. Congratulations on the progress made so far. Could you discuss some of the challenges encountered while developing the STAT6 degrader? What were the initial hurdles? If another larger company focused on this, how quickly might they move from discovery to IND, and how challenging would that process be?

Great question. So first, I would say that STAT6 has been a target that has been on the priority list of the biopharma industry that I can at least remember for the past 10 years since the early proof of concept of dupilumab and this pathway relevant to TH2 inflammation. And I believe that most pharma companies have had an effort in this space. But we have spent years working on this program. We're not going to talk about details. But at some point, we will. The depth and breadth of work that we've done in STAT6 and our ambition to own this target completely from all points of view of pharmacological blockade of STAT6, I think it's what's fundamentally driving all the effort that we've had so far. This is one of the best molecules we've made at Kymera in the past eight years. And I think it's going to be difficult to compete both in timing and quality with Kymera, given everything that we've shown so far, but I can speak to what it will take others. I don't know the capabilities that other companies have. I know that there is no company that is at a clinical stage or almost clinical stages as we are. And I haven't seen any data from any other company. So it's hard for me to comment on the competition.

Our next question comes from Kripa Devarakonda with Truist.

Thank you for taking my question. I want to follow up on the earlier discussion about the STAT6 degrader. I understand that one of your peers is working on a STAT6 degrader in collaboration with Sanofi, though it’s not close to the clinic yet. They seem to be casting a broad net with this approach. Can you explain how this collaboration with Sanofi might influence your own work on the IRAK4 degrader? Do you see any potential overlap? Additionally, regarding the KT-474 dose expansion you announced—you're increasing the patient count and expanding the doses—there seems to be a push towards the Phase III study. Can you clarify if you've already discussed this with the FDA?

Thank you for the question. Kymera and Sanofi have different goals and strategies, but we collaborate on IRAK4. Beyond that, we operate independently. We recognize Sanofi's strong interest in STAT6, and they are our only competitor in that area as they have licensed STAT6 agents available, while ours is not. From my perspective, although some validation of this target's importance could be beneficial, we already see its value for any company since Sanofi has two collaborations for this target with a small molecule inhibitor and an integrated approach. We have a strong relationship and an excellent team working on 474. We do not believe that competition regarding STAT6 will impact 474. Regarding your question about doses, the goal for the expansion is to accelerate entry into a registrational study. However, I can't comment on specifics with the FDA. There is a process in place for protocol amendments, and since Sanofi is the official sponsor, they manage that path.

Our next question comes from Chris Shibutani with Goldman Sachs.

Right. Thank you very much. Many questions have been asked. Perhaps two on the bigger picture side; one, thinking about additional immunology indications from your R&D day started the year, you had a slide that included. The end market opportunities being very vast in some of the traditional indications like MS and rheumatoid arthritis; it would seem that there's a lot of existing therapies, combinations tend to be the playbook and the industry is also looking to figure out how to better identify patients, patient selection strategies. And my questions are twofold. One, how are you feeling about the potential to expand into CNS-type indications, noting that degraders are small molecules, but larger? And number two, how are you starting to thread in patient selection strategies in terms of thinking about how you can enhance probabilities of success? I know that Sanofi is in control of the advanced clinical development, but is there any scientific work, biomarker data that is helping inform what you think might be a way to select a better patient population to study to enhance your success there?

Thank you, Chris. This is a key focus for us at Kymera. Our work with STAT6 and the ability to identify patients with TH2 inflammation represents one of the few examples of targeted therapy in immunology. The case of DUPIXENT in eosinophilic asthma and COPD illustrates how we can effectively select patients for this treatment group. I will mention one more point before giving Jared a chance to discuss our patient selection efforts. Regarding the CNS aspect, we have shown, along with others, that degraders can effectively penetrate the CNS compartment, as evidenced by several internal preclinical examples. Therefore, our decision to pursue CNS indications will depend on the mechanism, opportunity, unmet needs, and the capabilities of our technology. Jared, would you like to share your thoughts on targeting?

Maybe in terms of the patient selection sort of question, is applied to IRAK4 and STAT6 and I think the TYK2 as well. I think it's a very important question, but I think it's also important to emphasize that our expectations regarding the activity of these oral degraders is that we should not have to narrow the patient population upfront in order to be competitive. If we are as active as upstream biologics, we believe that these drugs could be approved and used upfront for very broad populations of patients across these very large indications for STAT6 and IRAK4 and TYK2. With that being said, we are building in our studies. We did this with IRAK4 and certainly, we're doing this with STAT6 and TYK2 to extensive pharmacodynamic assays in Phase I and Phase II that include proteomics and transcriptomics on blood and also, for example, on skin lesions for patients with skin diseases when they come onto our study, whether it be AD for STAT6 or psoriasis, potentially for TYK2. That will allow us to retrospectively look at these various proteomic and transcriptomic profiles because that helps us understand whether there are patient subsets that might be benefiting even to a greater extent than the broader population, and that might be important in helping us differentiate from other therapeutics.

Thank you. I just want to thank everybody. Actually, we made it almost to 9:30. So maybe just to highlight the key news of today, one which we had shared a few weeks ago on the expansion of the 474 Phase II programs in both HS and AD. We're very excited and thankful to Sanofi for their increased investment and confidence in the program. And then more recently, the news of today was that we're really, really close to initiating our Phase I study with KT-621 and especially, showing that we've completed all the IND-enabling studies with a great safety profile. So we're really excited about updating you all next time on our progress towards our first in-human dose that should happen soon. So thanks again. We're available for any follow-up today.

The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.