Good day, and welcome to the Kymera Therapeutics Third Quarter 2024 Results Conference Call. All participants will be in listen-only mode. After today's presentation, there will be an opportunity to ask questions. Please note this event is being recorded. I would like now to turn the conference over to Justine Koenigsberg, Head of Investor Relations. Please go ahead.

Thank you. Good morning, and welcome to Kymera's quarterly update call. Joining me this morning are Nello Mainolfi, Founder, President and CEO; Jared Gollob, our Chief Medical Officer; and Bruce Jacobs, our Chief Financial Officer. Please note that during Jared's remarks, we intend to reference data from slides in our corporate presentation, which is available within the IR section of our website at kymeratx.com. Following our prepared remarks, we will open the call to questions. We ask that you please limit your questions to one and a relevant follow-up to assure we have enough time to address everyone's questions. 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 will now turn the call over to Nello.

Thank you, Justine, and good morning, everybody. We have a lot of important updates today, so let's jump right in. First and foremost, we're extremely excited that we have started the Phase 1 study of KT-621, our first-in-class oral STAT6 degrader and the first STAT6 medicine to ever enter clinical development. It's important to highlight that we were able to accelerate the path to the clinic given our recent increased focus of resources and capital that we're directing towards our growing immunology pipeline. I believe this is also an important moment for the whole industry. We have shown in preclinical species that a STAT6 degrader like KT-621 can block IL-4 and 13 similarly or even more potently than upstream biologics like dupilumab in both cellular and in vivo models. We've also shown that KT-621 was well tolerated in all safety studies that we have run in a wide variety of preclinical species. In summary, we have an investigational drug that has the potential to have a dupilumab-like profile in a daily oral pill. Many of you know there are more than 150 million patients just in the U.S., Europe and Japan who suffer from diseases associated with Th2 inflammation. And according to market data, less than 1 million of those patients receive dupilumab. While one could focus on the roughly 1 million of patients currently on dupilumab, Kymera is focused on expanding access across the tens of millions of patients that are waiting for a convenient, safe, and effective oral pill, one that doesn't require needles, refrigeration, syringes and frequent trips to the doctor's office. We believe KT-621 is a medicine that has the potential to transform treatment paradigms in many diseases that affect millions of patients, such as atopic dermatitis, asthma, COPD, EoE, just to name a few. In addition, given that Th2 diseases are highly prevalent in children, we believe this has the potential to be a drug that will change the quality of life for many families in the future. Our next STAT6 update is expected to be upon completion of the healthy volunteer study in the first half of 2025, at which point we will share the full results. Following the completion of the Phase 1 study, our plan is to move quickly into patients. We have those plans well established, and we expect to provide guidance on the next stage of 621's clinical development next year. Jared will share more details around the ongoing Phase 1 study later in the call. I also wanted to briefly highlight another important update on KT-474, our first-in-class IRAK4 degrader. This is another program where Kymera was first to clinic and a success has influenced the industry with several companies following our lead with other IRAK4 directed assets. We're finally able to share more information on the expanded Phase 2 studies that are being run by our partner, Sanofi. The program is transitioning from proof-of-concept-like Phase 2 studies to fully powered Phase 2b studies with dose-ranging as a means of accelerating our path to registrational Phase 3 studies right at the conclusion of the ongoing studies. In terms of the specific trial changes, we have basically added one dose group to each study to have enough information to be able to select the dose for the subsequent registrational Phase 3 studies. We're thankful to our partner, Sanofi, for the increased confidence in and commitment to this important program. Turning to TYK2, we have exciting progress to report as well. At our R&D Day in January of this year, we introduced our TYK2 program and our lead molecule, KT-294. Similar to all of our programs, as KT-294 was being advanced through preclinical development, we had parallel work ongoing on other promising compounds. One of the compounds we were evaluating demonstrated an even more compelling profile than KT-294, highlighted by greater in vivo activity and with a similar selectivity and safety profile. As a result, we have decided to advance the new compound, KT-295, as our lead clinical candidate. Importantly, we believe we can do that without impacting our previously stated TYK2 development timelines, which assumed the Phase 1 trial start in the first half of '25. Finally, I just wanted to provide everyone with a broader strategic update and specifically as it pertains to our oncology programs. As many of you recall, it was around this time last year, we first shared that we had increased our focus in immunology. The rationale was driven by the profoundly impactful profiles we believe we could generate in immunology with oral degraders that could compete with injectable biologics in terms of efficacy and safety. As shown with KT-474 in the clinic and with our STAT6 and TYK2 efforts preclinically, we think we're positioned to develop the potential best-in-industry portfolio of oral immunology assets with opportunities to impact millions of patients. Even more today, with KT-474 in multiple Phase 2b trials, KT-621 in the clinic, and KT-295 close to the clinic, and other exciting immunology programs that we will be unveiling starting from next year, we believe that now is the time to focus even more of our resources into this space, where we believe we can create outsized value. As a result, while we made some encouraging progress with our clinical oncology pipeline, demonstrating promising clinical activity in a variety of tumor types, as we have completed Phase 1 enrollment, we have made the decision that we will only advance KT-333, our STAT3 degrader, and KT-253, our MDM2 degrader, beyond Phase 1 with a partner. You can expect that we'll share more on this if and when it makes sense to do so. While there are many considerations that contributed to this decision, ultimately, we believe our internal resources, both capital and people, are best focused on our expanding immunology pipeline. It should be noted that we did not take this decision lightly or make it without thinking about the potential impact on patients. We're, in fact, grateful to patients, families, and investigators and the Kymera team who supported our studies and these programs. In conclusion, as we approach year-end, it is quite exciting to see the trajectory that Kymera has had in 2024, especially within our immunology pipeline. We've advanced in the clinic KT-621 with what could become one of the biggest programs in our industry. We have supported Sanofi to advance KT-474 in expanding the Phase 2 studies. We've developed a TYK2 degrader with a compelling profile and are closer to the clinic. And we have raised a total of approximately $600 million in just 2024, which has enabled us to have cash into mid-2027 and through several inflection points across our pipeline. I will pause here and let Jared share more details on our programs, and Bruce will walk you through the third quarter financial results. I'm looking forward to the Q&A session at the end of our prepared remarks.

Thanks, Nello. As it relates to immunology, I'd like to first recognize our KT-621 team for the rapid progression to advance this first-in-class program through IND-enabling studies, culminating in the IND clearance and the initiation of the Phase 1 healthy volunteer study earlier this month. As we have not shared many details on the trial design, I wanted to take the opportunity now to provide a quick overview of the Phase 1 design. The SAD/MAD healthy volunteer trial includes single and multiple ascending dose cohorts evaluating KT-621 as compared to placebo. In the SAD component, each subject receives a single dose of either KT-621 or placebo. In the MAD component, each subject receives a daily dose of either KT-621 or placebo over 14 days. In terms of data we plan to share, the main objective of the trial is to demonstrate that we can robustly degrade STAT6 in blood and skin at doses that are safe and well tolerated. Based on our preclinical work, we are targeting STAT6 degradation of 90% or more, which is the level at which we saw strong biologics-like activity in our preclinical models. In fact, levels of pathway blockade, in this case measured by STAT6 levels, are the data that we have shown to be translatable to patient efficacy. As we have said, STAT6 degradation and safety and tolerability are the key readouts from this study. Additionally, as many of you know, we plan to measure certain Th2 biomarkers, specifically IgE and TARC in the healthy volunteers on our study. We fully expect KT-621 to have an impact on these biomarkers. However, we believe the impact is likely to be much more robust and relevant in patients, as was also true for dupilumab. With enrollment underway, we continue to expect to report the full SAD and MAD Phase 1 results for KT-621 in the first half of 2025. At or before that time, we will also share our plans for the next stage of KT-621's development. I'll now turn to our TYK2 program. As Nello mentioned, we made the decision to advance a new development candidate, KT-295 into the clinic, which we believe we can do without impacting our stated timelines over the first half of 2025 for the start of the Phase 1 study. I thought I would take a few minutes to share some details around KT-295, particularly a comparison to KT-294 that influenced our decision. You can also reference the TYK2 program slides in our corporate presentation, which is available on our website. On Slides 48 and 49 of our corporate deck, you can see that in preclinical testing, KT-295 demonstrated picomolar degradation potency and potent inhibition of the IL-23, IL-12 and type 1 interferon pathways, showing its potential to recapitulate the biology of human TYK2 loss of function mutations. Like KT-294, on Slide 50, KT-295 did not impact any of the other JAK proteins and spared IL-10 signaling, a feature important in the treatment of inflammatory bowel disease. Importantly, KT-295 had greater in vivo activity compared to KT-294, as shown back on Slide 48. With this profile, KT-295 has the potential to replicate the TYK2 loss of function profile and achieve biologics-like activity at lower doses than what was predicted for KT-294. To round out our I&I franchise, I will cover IRAK4. We are pleased that Sanofi has taken steps to accelerate the overall KT-474 development program. And as a reminder, the goal of the previously announced decision to expand the Phase 2 program was to structure the Hidradenitis Suppurativa and Atopic Dermatitis trials with the necessary regulatory perspective to enable dose selection and advancement directly to pivotal Phase 3 studies, ultimately with a meaningfully shorter timeline. To support this strategy, the size of the studies has increased with additional doses being evaluated in both trials. There are no changes to study endpoints. Specifically, the HS Phase 2 trial has been expanded from 99 to 156 patients and will evaluate two doses of KT-474 versus placebo, versus just one active dose previously. The AD Phase 2 trial has increased from 115 to 200 patients and will evaluate three doses of KT-474 compared to placebo versus just two active doses previously. These changes drive the primary completion dates to the first half of 2026 and mid-2026 for HS and AD, respectively. While that obviously extends the time before the complete Phase 2 data readout, we expect that it will meaningfully reduce overall development timelines for the KT-474 program by allowing a faster path to pivotal studies. We're energized by the progress and potential impact of our immunology programs, each representing pipeline and the product opportunity. And we believe that our oral degraders are uniquely positioned to have both the efficacy and safety of biologics with multiple development opportunities in large high unmet need indications. Finishing up on oncology, I will not add too much more to what Nello said earlier, but I did want to remind everyone that we will be sharing the totality of the Phase 1 data for our STAT3 degrader, KT-333 at ASH in December. As a reminder, our latest enrollment was focused on Hodgkin's lymphoma patients given the promising responses we observed in that population, and those results will be included in the poster presentation. I'll stop here and ask Bruce to review the third quarter financial results.

Thanks, Jared. As we have a lot to cover on this call, and I'm sure you all have many questions, I'm going to provide a quicker-than-normal overview of our financials and then refer you to the financial statements in the press release and our 10-Q, which we filed this morning. In the quarter, we recognized $3.7 million of revenue. That was all attributable to Sanofi and the collaboration. Combined spending of R&D and SG&A, excluding cash-based noncash stock-based compensation, was $61 million in the quarter, and that's down about 2% sequentially from the June quarter. And then finally, we ended the quarter with $911 million of cash on our balance sheet, providing a cash runway to mid-2027. I'll now turn the call back to Nello.

Thanks, Bruce and Jared. Before we open the call to questions, I just want to reiterate that we're more enthusiastic than ever about the opportunities in front of us. Advancing KT-621 in the clinic is a significant milestone for Kymera and the industry. And we're doing so with a very exciting drug profile based on our preclinical findings. We're executing on the rest of our immunology pipeline and look forward to sharing updates on TYK2 and providing more visibility on other pipeline programs, which we have yet to disclose likely next year. We're well-resourced to advance our best-in-industry pipeline of degrader therapeutics and look forward to keeping you updated with our progress. The next six months to 12 months will provide multiple value-creating catalysts, and we look forward to sharing these with you. Finally, I wanted to thank the Kymera team and our collaborators for continuing to deliver on very ambitious goals and first-in-industry endeavors. I'll pause here and ask the operator to open the call to questions.

Thank you. We will now begin the question-and-answer session. The first question comes from Marc Frahm of TD Cowen.

Hi. Thank you for taking my questions. Regarding the 621 healthy volunteer data, I appreciate the clarity on the target profile. However, when considering the Th2 biomarkers, it seems investors are trying to compare this to what was observed with dupilumab, as you mentioned. How reliable do you believe the percent changes in IgE and TARC from the healthy volunteer study conducted nearly a decade ago are, and how comparable do you think the results need to be?

Sure, I'll begin, and Jared, feel free to contribute. The primary aim of our Phase 1 study, particularly for us, is to show that we can predict pharmacokinetics and that the safety reflects the excellent tolerance we observed in preclinical tests. Using a degrader gives us a special chance to measure a direct biomarker. Many other companies rely on downstream biomarkers because they lack direct ones. However, we can directly measure STAT6 protein levels, which is the closest biomarker and allows us to demonstrate that we can fully block the IL-4/13 pathway, which is the study's primary objective. This is the only biomarker linked to disease impact—blocking the pathway correlates to disease benefits. Recently, a study identified a partial loss of function variant of STAT6 in humans that offered protection against Th2 asthma, marking a new correlation between protein function and Th2 protection. While many companies, including Regeneron in the past, have looked at downstream biomarkers due to the challenge of accessing direct ones, it is crucial to note there is variability among healthy individuals when measuring things like IgE and TARC. IgE data from dupilumab indicates it fluctuates between 10% and 30%, with subcutaneous doses showing up to 15% variability. TARC shows a range of 15% to 35%, consistent with findings from long-acting IL-13 biologics in Phase 1. This illustrates the variability in these measures, making it tough to predict reductions accurately. We remain focused on safety, pharmacokinetics, and STAT3 degradation levels, which signify our capacity to inhibit pathway signaling. We are confident that our biomarker changes will align with those observed from agents currently in clinical trials. I apologize for the lengthy response, Marc.

Long, but very helpful. Then maybe just more on the model with Bruce. Just can you talk through with the kind of continuing prioritization of the immunology side? Are there kind of any savings of that from the oncology or it's all going to be redeployed into immunology?

Yes. Thanks, Marc, for your question. So, I mean, there are savings, yes, in aggregate because of the fact that, obviously, some of the clinical development plans that we contemplated, we won't be undertaking on our own. However, we do imagine that a meaningful part of that, if not all, would be invested in our immunology pipeline, both the clinical development of the programs about and the ones that we haven't yet disclosed but will in the future. So while there might be a modest change in the ultimate cash runway, not enough to change the guidance, I think most of it, you should assume will be reinvested in our immunology programs.

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

Yeah. Hey, good morning and thanks for taking the question. Maybe just one on the STAT6 program here. I'm curious if you've made comparisons to dupilumab preclinically, if you've looked at the change in ear thickness in the atopic derm model, the MC930? And as a follow-up, I think the 32 milligrams per kilogram showed the most reductions in IgE. So I'm curious what that dose translates into humans? Thank you.

Thank you for your question, Kalpit. To address your second point, regarding the slides we've had up for almost a year, in mouse studies to achieve 90% degradation, we utilize a dose of approximately 30 to 32 mg per kg. However, in monkeys or dogs, the required dose is significantly lower, typically in the single-digit mg per kg range. This difference is attributed to the higher plasma protein binding in mice compared to dogs, monkeys, and humans. Therefore, for dose projections, it's more relevant to refer to the data from dogs and monkeys, as they provide more applicable insights than mice. While we don't focus heavily on dose projections, we have indicated previously that the doses investigated in the IRAK4 programs will likely be similar to those we explore in this program, which are relatively low. Turning to your first question, we concentrate on Th2 biomarkers and Th2-driven disease outcomes in our models. This is why we evaluate indicators such as IgE, TARC, and other measures of Th2 inflammation. For disease outcomes, we primarily examine the asthma model, allowing us to assess both lung conditions and the infiltration of cells within the lungs, alongside other Th2 biomarkers. It's worth noting that this model encompasses more than just Th2 factors, and we do not monitor ear thickness for either dupilumab or our degrader since it represents a broader outcome not exclusive to Th2.

Okay. Got it. Thanks for taking the question.

Operator, next question.

Our next question comes from Kripa Devarakonda from Truist Securities.

Hi. This is Alexei Siniakov on for Kripa. A question on the TYK2 asset. We've had some conversations with investors about what they would describe as a slow launch for TYK2, citing some efficacy, good efficacy in indications like psoriasis and maybe some challenges in others like IBD. Do you think that a degrader could address these issues and provide additional benefit? And when you think about future enrollments for the studies, would you consider enrolling TYK2 inhibitor experienced patients in the trial as an expanded opportunity? Thanks.

I'll address the first part, and then I'll let Jared talk about recruitment. You've highlighted the current commercial success of TYK2 inhibitors. I’ll respond from a slightly different angle while still addressing your concern. In the industry, we currently have a genetically validated target, TYK2, which has been explored by multiple companies, with one drug already approved by BMS, and at least two or three others in various stages of development. At Kymera, we strongly believe, and I think others familiar with TYK2 biology would likely concur, that differentiating between these inhibitors will be challenging because they only partially address TYK2's functions. TYK2 plays a significant role in receptor signaling, particularly for IL-23, IL-12, and type 1 interferon. By completely eliminating the protein, we can fully block TYK2 signaling and nearly completely inhibit three of these pathways. Therefore, if our degrader's profile resembles that of the inhibitors, it would indicate a failure on our part, which is not what we aim for. We are striving for a profile that can compete with biologics in many indications. I truly believe that if we can translate our preclinical success, we will have an even more effective molecule with 295, as achieving complete target degradation is crucial in this program. I think we are working towards a highly transformative drug. Currently, there may be some fatigue in the TYK2 space, which has led to it being overlooked. Jared, could you provide any insights on recruitment?

Yeah. I think for the initial proof-of-concept study in patients, we would likely not put on patients who had been on prior TYK2 and had progressed, whereas we might include patients who have been on a prior TYK2 inhibitor but have come off due to tolerability issues. Further down the road, once we've gone through initial proof of concept, we might be interested in understanding the activity of our drug even in those patients who have progressed after prior TYK2 inhibitors, but we probably wouldn't do that in the first study.

Next question, operator?

Our next question comes from Brad Canino of Stifel. Please go ahead.

Hi. Good morning. I know you stated in the prepared remarks that the next steps for STAT6 will be shared after the SAD/MAD results and hitting that 90% plus degradation safely. But dupilumab replication in Th2 patients is the major question. Is there a particular type of Th2 disease where this test is best to conduct? I guess, how much duration of testing is likely needed? And do you need hard clinical endpoints or will biomarkers in patients be sufficient to accelerate mid- to late-stage development? Thank you.

Yeah, Brad. Great question. So I would kind of say it this way. I think the goal of the Phase 1 study is to demonstrate that you can reach STAT6 degradation levels that we believe are therapeutically relevant, which, as you said, actually anywhere between 70% and 90%, we've shown that is therapeutically relevant, but 90% is where we see maximal activity in a safe manner. I believe that Regeneron and Sanofi have done an excellent job actually doing studies of what does dupilumab do in the blood and skin, especially of AD patients with regards to biomarker signature. And I think there is a really well-established dupilumab signature, especially in the skin of AD patients. And I think that one could actually very briefly get into that type of context and demonstrate that you're able to have a relevant biomarker signature that shows that STAT6 degradation blocks the pathway at least as well as an IL-4 receptor antagonist. So you could imagine a biomarker study in patients to be exceptionally telling of the profile of the drug. And that will probably allow you to move into large studies in all the important relevant populations. So I think that could be an interesting sequence of events. I think we're not quite ready to share what our plans are, but those are important opportunities to validate this mechanism.

Our next question comes from Vikram Purohit from Morgan Stanley. Please go ahead.

Good morning, everyone. This is Gospel on for Vikram. We have one question on KT-253 and KT-333. What would an ideal partnership look like? And are discussions with potential partners currently underway? And should a partnership be something we expect in the near term? Thank you.

Thank you for the question. We won't discuss any ongoing or potential conversations, as those are part of the company’s regular operations. However, I can say that our oncology pipeline has demonstrated strong translation of our pharmacokinetics, pharmacodynamics, and safety data into clinical outcomes across various programs. We've observed promising early clinical activity in different indications. As Jared mentioned, we will have an ASH poster on 333 that I encourage everyone to check out. The activity we’ve shown has primarily involved hematologic indications. To maximize value in those patient populations, it would be beneficial to partner with a company that has a strong clinical and commercial presence in those areas, as that would enhance value creation. Ultimately, our goal is to support patients effectively, and this focus will guide our decision-making, especially as we concentrate on our internal resources in immunology.

The next question comes from Kelly Shi of Jefferies. Please go ahead.

Congrats on the progress and thank you for taking my questions. I would appreciate your insights on what are the major differentiations of targeting STAT6 compared to targeting interleukin 4/13 or like OX40 from a biology perspective? For example, STAT6 is also now involved in innate immunity besides IL-4/13 signaling. So what do you see the breadth of indications that the STAT6 program could pursue based on its MOA? Thank you.

Yeah. Jared, I'll take a bit of this, but maybe you can help me. So yeah, great question. So what we've shown in our studies preclinically is that the activity we see of STAT6 in immune cells is really almost all, if not all, driven from IL-4 receptor signaling, so IL-4 and 13. And we've shown that if you block IL-4/13, as others have shown, you reduce phospho-STAT6 levels. If you reduce STAT6, you reduce IL-4 receptor level. Again, I don't want to keep quoting this recent paper, but if you read this recent paper on the partial loss of function variant of STAT6, it actually shows the same that there is a reduction of IL-4 receptor signaling. If you look at gain of function in humans, so again, I'm talking about human people, sorry. Also there, the STAT6 gain of functions have severe allergic diseases, Th2 biology. So we kind of expect it to be Th2 biology that were the mechanism we were eliciting. So biologically, we feel like it's really on pathway to IL-4 receptor. Jared, anything you want to add? Okay?

No. I think that covers it. I mean we expect STAT6 degradation to phenocopy what's been seen with drugs like dupilumab that are resulting in full blockade of IL-4 and IL-13. And we've seen that impact both in our in vivo models where we see efficacy that's comparable to dupilumab in the asthma and the AD models. And we've seen it in multiple cell types, even in our recent EADV presentation where we looked at STAT6 degradation in human sensory neurons, we saw that it was able to block IL-13 induced upregulation of transcripts involved in itch and pain, which are key symptoms in AD. So we think STAT6 targeting really has an advantage in addition to the unique pharmacology of being able to degrade STAT6 by over 90%, sort of 24/7 could give us pharmacology that may be unique and differentiated from what can be achieved with the upstream monoclonal antibody biologics.

Our next question comes from Jeff Jones of Oppenheimer. Please go ahead.

Good morning, guys and thanks for taking the question. I guess we'll stay on 621 and STAT6. Clearly, you guys aren't the only ones targeting STAT6 and your IRAK4 partner, Sanofi, is working with both Recludix and Nurix. Could you comment on the differentiation between a degrader approach here for STAT6 versus the small molecule approach? And maybe any differentiation between your degrader platform and Nurix's? Thank you.

Great question. First, I want to emphasize that we are the only company that has produced substantial data comparing the degradation of STAT6 to approved therapies. Although our data is primarily from preclinical studies, which comes with its own limitations, we have demonstrated that STAT6 degradation can replicate the effects of dupilumab in various models, displaying both depth and breadth of activity. Some might even say we have observed greater activity than dupilumab in certain cases. That said, we believe that the only pharmacological method to completely inhibit this pathway is through degrading STAT6, comparable to using a full-dose IL-4 receptor alpha antibody. While small molecule inhibitors can block STAT6, they face challenges related to the correlation between pharmacokinetics and pharmacodynamics, which we do not face with our degrader approach. Our compound is both highly potent and catalytic, allowing for a more significant blockade of the pathway without needing that correlation. I encourage you to be patient; we will share more information on this topic soon. Regarding our position among other companies, it's tough to provide a direct comparison, but to our knowledge, no other company has presented any data or has compounds that have moved beyond the development candidate stage. The two companies you mentioned are just a couple among many that are still working on preclinical research related to STAT6. Since we released our data, I have noticed several other companies attempting to replicate our work. Please keep following our progress; we will have more updates regarding our efforts in STAT6 beyond just 621 as we advance this program.

Appreciate the update, guys. Thank you.

Thanks.

The next question comes from Eric Joseph of JPMorgan. Please go ahead.

Hi. Good morning. I would like to know more about the Phase 1 trial with 621. Could you provide information on the number of dose cohorts and patient numbers being evaluated in the SAD/MAD? Will the readout in the first half include both SAD and MAD components, or a partial readout? Also, how relevant is the previous Phase 1 with IRAK4 as a guideline for this?

On the good side, you didn't miss anything, Eric. So Jared can tell you more about at least what we can at this point about your question.

Yeah. I mean we can't provide a whole lot of color around the actual number of dose cohorts. But I think your comparison to the IRAK4 Phase 1 SAD/MAD probably is the ballpark in terms of how we plan to interrogate both the SAD and MAD portions. And just as a reminder, these are placebo-controlled cohorts of healthy volunteers with the MAD being 14 days of dosing and the SAD obviously being single doses. So I think they'll generate a very robust data set going across the full range of doses in both SAD and MAD, and we plan on doing that efficiently with healthy volunteers. And as we mentioned, the data readout in the first half of next year will include both the SAD and MAD portion. So it will be the full data set from the healthy volunteer SAD/MAD that we revealed in the first half of next year.

I just want to add that this will be available on clinicaltrials.gov soon, and we expect the total number of patients in the single ascending dose and multiple ascending dose studies to be around 120. That's the additional information we can provide today. Do you have a follow-up question?

Yes, thank you for that information. We were expecting the trial entry, but I couldn't locate it. Nonetheless, I appreciate it. As a follow-up, regarding the focus going forward in I&I, should we expect any additional targets or programs in that area over the next year?

We have dedicated over three years to our research and development in immunology. We are working on numerous programs and will be nominating several development candidates in the coming months. We will share updates when we are nearing clinical trials, as we have in the past. However, we have learned from prior experiences that it may be prudent to wait a bit longer before revealing our targets and data due to competitive reasons. Therefore, we plan to share information closer to the clinical stage than we have previously. You can expect at least one disclosure next year.

The next question comes from Eli Merle of UBS. Please go ahead.

Hi. It's Sam here for Eli. I guess can you just touch on a little bit your level of confidence for IRAK4's efficacy in HS versus atopic derm heading into those Phase 2 readouts in '26? And then second, on STAT6, how quickly do you expect to move into patients following the SAD/MAD portion? And any expectations for timing on that? Thanks.

I'll address the second question and then let Jared respond to the first. As we mentioned earlier, we anticipate starting patient trials shortly after the Phase 1. To be candid, due to competitive reasons, we are not yet disclosing those plans. We have had these plans in place for several months, if not years. However, we will provide details as we get closer to the studies regarding both our short-term and long-term development strategies. Jared, could you comment on IRAK4?

Yes. I think in terms of your question around our level of confidence in being active in HS versus AD, I think we have, and Sanofi as well have a high level of confidence in potentially being active in both of these indications. I mean mechanistically, for example, HS, we know is driven by IL-36, IL-1, toll-like receptor activation. AD, we know there's an important component of IL-1, IL-33 and toll-like receptors. And so I think there's a mechanistic basis for believing that IRAK4 targeting should be effective there. And I think also if you look at our Phase 1 study where we did have experience with both HS and AD patients, we did see impact both on skin lesions and importantly, on symptoms in both of those diseases impacting pain significantly in HS and pruritus and AD, these being the number one symptoms that affect quality of life in these patients. And so I think in addition, in that Phase 1 study, we showed modulation of pro-inflammatory pathways and skin biopsies from both of those patients. So I think we have confidence in both and look forward ultimately to the clinical readouts from the Phase 2b trials, which will ultimately answer that question.

The next question comes from Michael Schmidt from Guggenheim. Please go ahead.

Hey, good morning. Thanks for taking my question. Another one on 621, Nello. So degraders as a modality have obviously been very safe so far. But based on the mechanism and perhaps preclinical data, what are potential on-target or perhaps off-target AEs that one might expect to see in the study at high 621 doses in the clinic? And what are learnings from STAT6 knockout animal models?

Thank you, Mike. Regarding what we know, STAT6 degradation has shown no adverse events in preclinical species, even at levels 40 times higher than those needed for complete STAT6 degradation. Our molecule, 621, is highly selective based on our proteomics and other biological tests. Therefore, we do not anticipate any off-target activity. I can't specify what safety signals we might expect, but thus far, we have not observed anything, and we hope that continues in the clinical setting. From our genetic studies, we find that knockout mice are both normal and fertile. We also know that gain of function of STAT6 is linked to severe atopic diseases in people, indicating that STAT6 primarily signals through the IL-4 receptor alpha pathway. Additionally, I’ve noted that humans with partial loss of function do not exhibit any phenotype. Overall, considering all our data, we believe we have an ideal target, and we are optimistic about our findings.

Right. And just a quick follow-up. So in terms of subsequent studies, how do you think about prioritizing potential indications? Would you move into AD first, perhaps? I know there's a lot of work on STAT6 out there in lung inflammation. So asthma, is that top of the list? How do you plan on prioritizing potential opportunities?

Yes, as I mentioned earlier, we won't disclose our clinical development plan at this time because we believe it's too early. However, I can tell you that we think this is a Th2 drug, not specifically for atopic dermatitis or asthma. This drug has the potential to be effective in all the conditions where dupilumab has been successful, which includes seven or eight different indications based on the latest data. Our strategy will focus on the larger indications for clear reasons, meaning atopic dermatitis, asthma, and COPD will likely be our primary targets. Still, we are dedicated to supporting patients of all ages and with varying degrees of disease severity. This commitment represents our mission and vision for this program and our franchise as a whole. Therefore, we will do everything possible to assist as many people as we can, in contrast to the biologics currently available or soon to launch in the market.

The next question comes from Faisal Khurshid from Leerink Partners. Please go ahead.

Hey, guys. Thanks for taking the question. I realize this might be premature, but I wanted to ask anyways. So how are you thinking about partnership opportunities on KT-621? And when do you think the best time for that would be?

One answer will be that we are not currently considering that. However, to address your question, it's a valid one. It's not too early to discuss this. We believe we are well-positioned to develop KT-621 and our franchise as we approach the next pivotal moment. Personally, I feel it would be particularly early to have these discussions in the near term. We have a solid development plan that should guide us through some compelling, hopefully successful, Phase 2b studies. As we draw closer to commercialization and Phase 3, the questions will revolve around our capital costs, our pipeline, and the best methods to create value and impact patient care. One approach could be to fully commit and establish ourselves as a leading company that commercializes this product on a global scale. Alternatively, we could seek a partner to help us commercialize this drug in specific regions. However, partnering on STAT6 will set a very high bar for us, and we've been approached about this many times, which is likely an understatement.

The next question comes from Andy Chen from Wolfe Research.

Hey, everyone. It's [indiscernible] here for Andy. Thanks for the clarification on the changes to the IRAK4 trial design. Sanofi is planning to add an additional dose for both HS and AD. Are they making this change because they believe the previous doses are too safe or too unsafe? Our assumption is that the earlier doses are quite safe. So, can we assume that these new higher doses in both trials are safe? Can you all hear me?

Yes, I think you may have stopped at some point. Did you have anything else to add?

Okay. Thanks. Sorry. Yeah. It sounded like it cut off for a second. So is it safe for us to assume that the new doses are higher in both trials because the efficacy can go higher? Or are we thinking of this wrong?

That's a great question. Let's take a moment to recap. We may not have covered this in detail today, but it's important to remember how we arrived at this stage. Sanofi chose to conduct an early safety and efficacy interim analysis earlier this year to evaluate the drug's profile up to that point. They decided to use that data set to inform their investment decision. Initial data on both safety and efficacy supported an increased investment to speed up the development timeline. While we haven't disclosed whether the new doses are higher or lower, you can certainly speculate. However, what we've stated publicly is that the addition of another dose was prompted by regulatory requirements to perform dose-ranging studies before finalizing a dose for Phase 3. Therefore, it seems that neither of your assumptions completely captures the reason for adding another dose. The goal was to ensure compliance with regulatory requirements as we advanced into late-stage development for Phase 3 studies, rather than suggesting any safety concerns. The compelling data we reviewed was focused on accelerating the study.

Got you. Makes sense. Thank you.

So I think this was the last question. I wanted to thank everybody for joining our call. As you all know, we're easily reachable if there are any follow-up questions from our stakeholders externally. I want to thank our team again because they continue to do some amazing work. And looking forward to an exciting year-end and early next year. We've probably never been busier at Kymera. And so, I think everybody says busy is good. So looking forward to the next update.

This concludes today's presentation. You may now disconnect.