Good day, everyone. My name is Sophie, and I will be your conference operator today. At this time, I would like to welcome you to the Kymera Therapeutics Third Quarter 2025 Results Call. I would like to turn the call over to Justine Koenigsberg, Vice President of Investor Relations.

Good morning, and welcome to Kymera's quarterly update. Joining me this morning are Nello Mainolfi, Founder, 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 from our publishing analysts. 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 would like to turn the call over to Nello.

Thank you, Justine, and thanks, everybody, for joining us this morning. Now in the final quarter of the year, as we reflect on 2025, I'm happy to say that our team has executed exceptionally well across all parts of our business, and we're very proud of all that we have accomplished this year. We're committed to building a global biopharmaceutical company and have established a strong foundation that will serve us well as we scale an organization and continue to advance our industry-leading oral immunology pipeline. As shown on this slide, I'd like to highlight a few of the key achievements this year that position us well for important future milestones. In less than 2 years since unveiling our STAT6 program, we have demonstrated exceptional progress in advancing our first-in-class STAT6 degrader, KT-621. To recap, we completed our healthy volunteer study ahead of schedule with impressive results. We enrolled and completed dosing in the Phase Ib trial in AD patients with data coming in December. We initiated our first of 2 Phase IIb trial, BROADEN2 in AD, and we're on track to start the BREADTH Phase IIb asthma trial in the first quarter of 2026. We were also featuring 2 recent late-breaking presentations, which have helped us maintain a high level of visibility with the medical and scientific communities where there continues to be strong interest in oral medicines with potential for biologics-like activity. Beyond STAT6, we unveiled our IRF5 program this spring and presented the robust preclinical data at the American College of Rheumatology Annual Meeting just recently. We've also completed the KT-579 IND-enabling studies and remain on track to initiate the first clinical trial in healthy volunteers early in 2026. In addition to IRF5, we continue to advance our earlier-stage undisclosed immunology pipeline, and our goal remains to address many of the major immunology indications with oral medicines. Importantly, we believe the synergies across our pipeline provide multiple development opportunities for broad patient populations. We also entered into a new partnership with Gilead outside of immunology. Gilead is an ideal partner to drive forward our CDK2 oncology molecular glue program, which we believe has broad potential in breast cancer and other solid tumors. In summary, it's been a very busy year and a successful one, and we look forward to finishing this year strong as we advance our pipeline towards more and more important milestones. More broadly, we built what I believe is one of the strongest oral immunology pipelines in the industry, where we're well positioned to deliver novel oral treatment options for patients with highly prevalent immune-inflammatory diseases. Several years ago, we made a deliberate strategic shift to focus our R&D efforts toward the significant opportunities in immunology. And the reason is quite simple. Within immunology, many pathways have been validated with upstream biologics. Traditional small molecule inhibitors are not able to block the signaling pathways as effectively as biologics, given the direct correlation between PK and PD and the need for high drug exposures. As a result, the power of protein degradation allows us to selectively remove disease-causing proteins through a catalytic mechanism and can block pathways completely, which we've consistently demonstrated across all of our programs. This allows us the potential for oral drugs with biologics-like activity for the first time in our industry, and our first-in-class pipeline is a testament to this strategy. If we look specifically at our STAT6 program, KT-621 exemplifies this approach. There is a tremendous opportunity for a convenient, safe and effective oral pill in highly prevalent Type 2 diseases like atopic dermatitis, asthma, COPD, EoE and others. Despite the large size of the patient population, the penetration of other systemic advanced therapies like injectable biologics is actually quite low. This creates a significant opportunity for safe and effective oral medicines, which we believe would have the potential to change the quality of life for many patients and families around the world. We have moved our STAT6 program at a rapid pace from preclinical to IND to initial clinical proof of concept and we're now embarked on our first global Phase IIb trials. In fact, we filed our IND in September 2024 and by the fourth quarter of 2025, we've already launched our first Phase IIb study. This progress is a strong testament to the speed, focus and executional excellence of our team in driving this program forward. Looking back at the KT-621 Phase I healthy volunteer study, we demonstrated that at very low doses, we can degrade STAT6 fully and block Th2 disease-relevant cytokines in healthy volunteers as effectively as upstream biologics and in a well-tolerated manner. We're moving quickly towards completion of the BroADen Phase Ib trial, which we initiated in the spring. To remind you, the trial was designed to achieve 3 important goals: To confirm robust degradation in blood and skin and understand the translation from healthy volunteers to AD patients. To allow us to refine the Phase IIb doses based on that translation, and to demonstrate that robust STAT6 degradation in AD patients can impact biomarkers and clinical endpoints similarly to upstream biologics, specifically dupilumab. Given that the trial is fully enrolled and we plan to share the data next month, I wanted to use this call one last time to reiterate expectations we're setting into the study across the 4 dimensions we're evaluating KT-621 on, degradation, safety, biomarker and clinical activity. With respect to STAT6 degradation, the goal is to translate in AD patients, the robust degradation of STAT6 in blood and skin that we have seen in the Phase I healthy volunteer study. The safety profile is paramount, and we hope to continue to see a safety profile in line with what we've seen in both healthy volunteers as well as our preclinical studies. With respect to biomarkers, we plan to look in both blood and skin. In blood, we have highlighted TARC as the most relevant biomarker at the 4-week time point. After achieving up to a median reduction of 37% of TARC in healthy volunteers and given that atopic dermatitis patients generally have higher baseline TARC levels, our expectation is to show a meaningfully more robust TARC reduction. As a point of reference, in published dupilumab studies where baseline TARC levels were much higher than healthy volunteers, the reduction was in the range of 70% to 80% at 4 weeks, which is the bar we set for KT-621, assuming generally comparable baseline levels. In skin, we also plan to assess KT-621's impact on skin transcriptomics, which we have not assessed in the healthy volunteer studies. There, we anticipate changes in downstream genes that aligns with the expected biological effect of this pathway modulation. And finally, in terms of clinical endpoints, we went into the study with a robust body of evidence in all of our experiments demonstrating that KT-621 blocks IL-4 and 13 as well as dupilumab, and this has resulted in comparable downstream pathway effects in both in vitro and in vivo studies. As a result, we entered the BroADen study expecting clinical activity of KT-621 to be in the range that dupilumab delivered at 4 weeks in its published studies, including on both EASI score and itch with all the caveats of small sample sizes and the lack of a placebo arm. I hope that this is helpful as we approach the data readout next month. Given that we have quite a bit of investor activities planned this month, please understand we will refer back to these key objectives and reserve any additional commentary for the final data presentation in December. So before I hand the call back to Jared, I wanted to take a moment to welcome Brian Adams, our new Chief Legal Officer, to Kymera. He's a seasoned life science executive with deep industry experience, bringing more than 2 decades of experience across legal and compliance, corporate development, strategic planning and governance. We're thrilled to have him join our team as we enter this next phase of growth and look forward to his contributions as we continue our efforts to building a fully integrated commercial stage company. So to wrap up, as I said on the onset of the call, this has been a year of exceptionally strong execution, and we're well positioned to continue advancing all aspects of our pipeline as we head into 2026. I'm confident that through our expertise, scientific rigor and focused execution, we're building one of the most exciting immunology portfolios in this industry. Let me pause here and turn the discussion over to Jared, who will provide us an update on the pipeline, including additional color on our newly initiated atopic dermatitis study.

Thanks, Nello. We have made significant progress with KT-621, our STAT6 degrader, and I'm happy to share the advancements we are making in the clinic with you this morning. As Nello described, we see this as a transformative opportunity to develop an oral therapy that delivers biologics-like efficacy without the limitations of injectables. KT-621 is the first and, we believe, only STAT6-directed oral medicine in the clinic. It has the potential to positively impact the more than 130 million people around the world living with Type 2 diseases, considering all the indications where dupilumab is approved today. Our first development indication is atopic dermatitis, or AD, a common but complex dermatologic condition with a significant unmet medical need. This is a chronic inflammatory skin disorder, more commonly referred to as eczema, that manifests as inflamed, itchy, and often painful patches on the skin. These lesions can appear anywhere on the body and range widely in severity from mild irritation to debilitating full-body inflammation. One of the most burdensome aspects of this disease is the persistent itch. It's not just a nuisance; it's a hallmark symptom that can severely impact quality of life by disrupting sleep, daily activities, and overall well-being. While there are several treatments available today, they have limitations, forcing patients to make trade-offs. Antibody-based injected therapies like dupilumab have made a real difference for many patients, providing a well-tolerated and safe therapeutic option, but it's not a solution for everyone. For starters, access can be very limited and is a challenge for many patients. For those who are prescribed these drugs, it can be inconvenient or a painful route of administration, with compliance impacted by a lack of tolerance for injection site reactions or a phobia of needles. There are also issues with cold storage requirements and immunogenicity risk. In fact, in an industry survey, 75% of patients taking biologics said that they would switch to oral options with an equivalent profile. There are some oral options such as JAK inhibitors that offer an effective oral alternative. However, they come with significant safety concerns, including box warnings that limit their use, especially in long-term disease management. Given this important unmet need, coupled with the strong preclinical and clinical profile of KT-621 in healthy volunteers, we have developed an accelerated clinical development strategy, including conducting a small Phase Ib biomarker-focused trial in moderate to severe atopic dermatitis patients that we initiated earlier this year. The key aim of the 28-day BroADen study is to show that robust STAT6 degradation in blood and skin lesions by KT-621 has a dupilumab-like effect on multiple Th2 biomarkers in the blood and skin. We will also assess KT-621's effect on clinical endpoints such as EASI and Pruritus NRS. The team has worked very hard to advance this program. And in line with expectations, we completed enrollment in the study last month and dosing is now complete. The final patients are completing follow-up, and we will collect and evaluate the rest of the data and report results in December. As we have said, this Phase Ib study was not gating to the start of the parallel Phase IIb dose range finding trials in AD and asthma, which in turn are designed to enable subsequent Phase III registrational studies across multiple indications. This quarter, we initiated BROADEN2, our Phase IIb AD study, a global randomized, double-blind, placebo-controlled trial to evaluate KT-621 in approximately 200 patients with moderate to severe atopic dermatitis. This study is designed to evaluate 3 different doses of KT-621 over a 16-week treatment period compared to placebo. Patients from the study have the opportunity to participate in a 52-week open-label extension period after completion of the trial, which will contribute to building the long-term safety database we'll need to support eventual regulatory filings and is also an additional incentive for patient recruitment to the trial. Eligibility criteria to ensure we're recruiting patients with moderate to severe AD include an EASI score of at least 16, at least 10% of body surface area affected, and an average weekly Pruritus NRS score of at least 4. While prior use of biologics is permitted if treatment was not discontinued for lack of response and following a study-defined washout period, we expect to enroll a substantial number of systemic treatment-naive patients given the attractiveness of the ease and convenience of a once-daily oral treatment option. The primary endpoint is the percent change from baseline in EASI score at week 16. Secondary endpoints will evaluate a range of additional safety and efficacy measures, including but not limited to, the proportion of patients achieving EASI-50, EASI-75, a validated Investigator Global Assessment score of 0 to 1 and at least a 4-point improvement in Peak Pruritus NRS. We expect top-line results from the Phase IIb study will be available by mid-2027. In addition to atopic dermatitis, we plan to initiate the BREADTH Phase IIb study in asthma in the first quarter of 2026. We'll share more information on the trial design next year when we get closer to initiation. Beyond the STAT6 program, we have completed IND-enabling studies with KT-579, our IRF5 degrader, which we plan to advance into a Phase I healthy volunteer study early next year with data expected in 2026 as well. Last month, we shared incremental updates in 2 posters at the ACR meeting in Chicago. In several preclinical efficacy models of lupus and RA, KT-579 was generally more efficacious than clinically active or marketed small molecule inhibitors and injectable biologics, phenocopying IRF5 knockout studies. The compelling preclinical data we have generated showcase that targeting IRF5 can lead to correction of immune dysregulation across multiple disease pathologies while generally sparing normal cells. We continue to be excited about this opportunity and look forward to moving it into the clinic soon. I'll pause here and turn the discussion to Bruce to review our third-quarter financial results.

Thanks, Jared. As I walk through the third-quarter results, please reference the tables found in today's press release and 10-Q, which was filed this morning. Revenue in the third quarter of 2025 was $2.8 million, all of which was attributable to our collaboration with Gilead. With respect to operating expenses, R&D for the quarter was $74.1 million. Of that, approximately $8.4 million represented noncash stock-based compensation. The adjusted cash R&D spend of $65.7 million, which excludes that stock-based compensation, reflects a 7% decrease from the comparable amount in the second quarter of 2025. On the G&A side, our spending for the quarter was $17.3 million, of which $7.4 million was noncash stock-based compensation. The adjusted cash G&A spend of $9.9 million, again, excluding that stock-based compensation, reflects a 3% decrease from the comparable amount in the second quarter. And overall, adjusted operating expenses were down slightly from the prior sequential quarter. We ended September with a cash balance of $978.7 million, providing a cash runway into the second half of 2028. This runway allows us to complete both KT-621 Phase IIb trials in AD and asthma, cover start-up costs in the initial Phase III activities for the STAT6 program, advance KT-579 through initial POC testing, and advance our research pipeline as we scale and grow Kymera. Just a quick reminder, our runway collaborations, calculations, I should say, exclude any unearned milestones from our collaborations with Sanofi and Gilead. Regarding Sanofi, we expect that they will advance KT-485 into Phase I testing in 2026, which would trigger a development milestone payable to Kymera. As for the Gilead collaboration, upon exercising its option for a CDK2 glue, we are entitled to a milestone payment. As previously announced at the time of signing the Gilead collaboration agreement, we are eligible to receive a total of $85 million in upfront and option payments, with approximately half of this already received as the upfront payment in the last quarter. We look forward to the continued progress of both the IRAK4 and CDK2 partnered programs. With that, we'll pause here so we can convene in our main conference room and open the call for your questions. Thank you.

Your first question comes from Geoffrey Meacham, Citi.

I have a couple of questions. First, could you highlight the key characteristics of KT-621 that might allow it to demonstrate different efficacy compared to dupilumab at earlier time points? This seems to be one of the main uncertainties for investors. Second, regarding the doses in the BroADen study, is the expectation that the lower dose may have a lesser effect on degradation and thus be subtherapeutic? Or is it intended to assess the upper end of the desired safety tolerability? I’m looking for clarification on the dose selection and how you envision the ideal outcome.

Great. Thanks, Geoff, for the question. So on the first one, let me just take a step back. So in all the work that we've done with our STAT6 program for multiple years now, we've been working on this program for a very long time. We were able to demonstrate, I think, convincingly in all the preclinical studies that when you degrade STAT6, you're able to block IL-4 and 13 signaling as well as an upstream biologics, whether it's an IL-4 receptor blocking drug like DUPIXENT or even an IL-13 drug. So generally, we're actually the only oral drug that is able to block IL-4 and 13 as well as upstream biologics. In all the studies that we've run, again, preclinically, as I said a few minutes ago, both in vitro and in vivo, we've seen comparable activity. And I think this speaks to the biology of the pathway. Whether you block the receptor or you block the specific transcription factor for the receptor, you see the same biology. So the reason why we say the opportunity here is to have dupilumab in a pill-like profile is not because it's actually what we hope to see. Obviously, we hope to see that. But it's because it's the activity, the biology that we've seen so far. So as a data-driven company as we are, we're reporting the observation of so far, we've seen dupilumab-like activity. In our Phase I healthy volunteer study, where we measured, as you remember, biomarkers in blood in healthy volunteers, we were able to show also in those biomarkers that we were generally comparable, some would say even numerically superior to dupilumab. So for me, it's really hard to say KT-621 is going to be better than dupilumab or worse than dupilumab. All we've seen so far that we're generally blocking the pathway the same way. Hence, that's where the expectations are set. Now as a data-driven drug development company with, I think, astute people in the company, we're very keen to see how the 2 profiles will evolve and where they would differentiate. We're talking about obviously an injectable biologic versus a small molecule degrader. So you will see probably small differences or larger differences here and there. But our priority is very difficult for us to like set the expectation one way or the other. I would be probably the happiest CEO in the world if we're able to deliver a dupilumab-like profile. Going to your second question, I think I understand what you're saying, what you were asking, but maybe not. So you can correct me if I got it wrong. So maybe the way that I'm going to answer your question is, so we selected 2 doses for the Phase Ib study because we wanted to really understand well what was the translation of healthy volunteer degradation profile into patients to then have a high level of confidence in selecting the 3 doses for the Phase IIb. The only thing I'm going to say right now is that the 2 doses of the Phase Ib as well as the 3 doses for the Phase IIb are all within the doses that we studied in the healthy volunteer study. And generally, our approach for the Phase IIb is to evaluate a range in which we see maximal pharmacology and, at the top dose or some would call it super pharmacology and then in the bottom dose, a dose that reaches less than the optimal pharmacology and then obviously, a dose in between. So that's the general philosophy without going into details.

Your next question comes from the line of Marc Frahm, TD Cowen.

Maybe just on the Phase Ib. Nello, in your comments, you mentioned the kind of target of 70% to 80% TARC reduction, but with that caveat of assuming similar baseline characteristics. Now that you've enrolled the patients with a group of 10 per dose level, there's always some chance that you end up with a little bit of a skewed population relative to the comparators. Just anything you'd highlight there based on the patients that have actually enrolled that might be a little bit different than the historical DUPIXENT comparators? And then I'll probably have a follow-up.

Thank you for that question, Marc. Let me clarify. There are two aspects of this trial. One is the baseline EASI of patients, and the other is the baseline TARC levels. Previous studies on dupilumab have shown a clear relationship between the baseline level of TARC in patients and the reduction of TARC across various conditions like chronic rhinositis, asthma, and eosinophilic esophagitis. I won't comment on the specific baseline levels of our study, but we will share the data when appropriate. The second element I want to address is the EASI baseline levels. Historically, when dupilumab was developed as the first systemic drug for atopic dermatitis, the baseline EASI scores were in the high 20s to low 30s. In studies from the past five years, this baseline has shifted down to the mid-20s. This change is primarily due to the patient populations participating in these trials, as many of them have access to dupilumab now. Generally, the most severe patients are on systemic biologics, although some are not. Overall, we have seen a slight decrease in the mean baseline EASI, which is important for understanding the outcomes of the study. I wanted to emphasize the distinction between TARC baseline levels and EASI baseline levels.

Okay. Should we expect that same trend of lower EASI scores to apply here? Do you think that has an impact on TARC levels as well?

I believe we'll address that when we release the data. We have a strong understanding of the baseline TARC levels in healthy volunteers, where we've observed reductions in the mid to high 30s across many patients in our studies. Additionally, dupilumab showed similar reductions when baseline levels were comparable to those of healthy volunteers. Furthermore, in other studies involving dupilumab, there is a noticeable correlation between baseline levels and the percentage reduction of TARC. This is the main observation we're presenting from those studies. I prefer not to preview our study findings now, as I don't think discussing specific data here would be beneficial compared to what we will share in December.

Your next question comes from the line of Brian Abrahams, RBC.

Congratulations on all the progress. I'm wondering how you guys are thinking now that it's been initiated about the powering overall for the Phase IIb AD study, just considering the population you expect to enroll, the mix of biologics experienced and naive patients and your expectations for effect size? And then just as a follow-up, it sounds like you're thinking about maybe different doses for asthma and respiratory diseases versus dermatologic diseases. I was wondering if you could elaborate a little bit more about what you think are the important considerations around that.

Jared, do you want to take that?

We can't provide specific details about the power for the Phase IIb study. However, we can confirm that the study will have approximately 200 participants, divided into four groups: three receiving drugs and one receiving a placebo. We have carefully considered expectations and previous patterns regarding EASI responses and NRS Pruritus responses while calculating the necessary endpoints to ensure the study is adequately powered. The study's design is precise to ensure we can demonstrate the desired effect compared to the placebo. Additionally, it is essential for the study to assess the three different doses to determine any potential dose response. Therefore, the study is structured to allow us to achieve these objectives.

And the doses between AD.

The plan for our Phase IIb studies is to use the same doses for both AD and asthma.

And then maybe just to add, then the Phase III doses or dose that will be used for AD Phase III and asthma Phase II might be different based on the dose ranging. To be honest, our expectation is that it will not be different, and we will use one dose for all studies. But that's why we're running different dose ranging in different diseases with different target tissues so that we actually understand what the right dose will be.

Your next question comes from the line of Brian Cheng, JPMorgan.

Some of the color you're providing here for the December readout is pretty much in line with what you already messaged. But I'm just curious, just given the gap between the time you selected your 3 doses for the Phase IIb and when Phase Ib finished enrollment around early October, what could be additive to what you already know in the December readout? Or do you think the data is most likely going to be in line with the data that you had already seen when you picked the 3 doses? And I have a follow-up.

I would like to clarify that what we've communicated over the past several months remains the same. When we selected the doses for the Phase IIb trial, this was done a few months prior to October. We recently began this Phase IIb study, but the selection of doses needed to occur earlier to allow for protocol submission and start-up activities. I have mentioned previously that at the time of selection, we had some partial data for both doses from the first dose in the Phase Ib study, and limited data from the second dose. While we did not have complete data, our focus on translation of degradation and safety provided us with sufficient information to make an informed decision regarding the Phase IIb doses.

In the prepared remarks, in the BROADEN2 trial design, I think you mentioned that you expect a substantial number of patients to be naive to advanced therapy. So I'm just curious what's the driver behind that? And how should we take that into account as investors think about comparing the BROADEN2 future data against other benchmarks?

Yes. I’ll start, and Jared can jump in. The reason we believe this will be the case is multi-faceted. First, we think that KT-621 and our STAT6 program aim to increase patient access to advanced systemic therapy. Currently, the use of advanced biologics among moderate to severe patients is below 10%. While some companies claim it is higher, let's agree on 10% to avoid disputes with others. This indicates that most patients do not have access to advanced systemic therapy, which is our focus. Additionally, we've discussed that patients who have undergone systemic therapies that failed, including IL-4, IL-13, and JAKs, will not be included in our study. They must have responded to those therapies but opted not to continue before enrolling in our 621 study. For these two primary reasons, and based on our experience from Phase Ib, we believe most patients will be treatment-naive. I also hope to be correct in stating that we don’t anticipate difficulties in finding naive patients, as they urgently need an effective systemic oral therapy that is safe.

The only thing I would add would be just as a reminder that this is a global study. And so we're running the study in North America, Europe, Australia and Japan, with the majority of sites actually being ex U.S. So ex U.S., in particular, there are going to be a number of patients who don't have access to those advanced therapies. And so that's another reason why we expect a substantial proportion of patients on IIb to be treatment-naive.

Your next question comes from the line of Mayank Mamtani, B. Riley.

Congrats on the progress. Could you give us a little bit more detail on asthma BREADTH? I think you're calling it trial considerations. And in terms of if you're looking at a 12- or 24-week FEV1 endpoint or a longer duration exacerbation, you could be looking at both, but just wondering in terms of which is your primary endpoint? And then also curious about the kind of patients you're thinking to enroll there and the allowance of background therapies. And obviously, the question is around timelines for data readout for the asthma and atopic derm. Will they be stacked together in 2027? And then I have a quick follow-up.

Yes. No, thank you for the question. Unfortunately, as we've said, we're going to talk more about the Phase IIb BREADTH study when we're in the start-up mode, when we're close to dosing our first patient. So give us a few more weeks, and then we'll provide all the color that you're asking for. So why don't you ask the follow-up so that at least we have a question.

And maybe just to talk a little bit beyond 621 and about your pipeline beyond that. Just on the 579, could you maybe give us some color on what the initial targeted indications would be just given the broader inflammation cascade that you're targeting there?

Yes. Maybe just high level. So thanks for asking about IRF5. This is a program that I think has mostly been unparalleled in the industry where you have a highly validated genetically validated transcription factor that has been, I think, the object of many drug development efforts in the biopharma industry for a decade or so, but has remained elusive where Kymera has that solution using targeted protein degradation. So if you look at human genetics, the top 4 places where one would go directly are generally lupus, SLE and other subcategories of this disease, some other interferon-related pathologies, RA, IBD. So those are where human genetics point to our preclinical data point to. I think when we're closer to the Phase I study, we'll be able to share more about our development plans. Jared, anything you want to add?

No.

Your next question comes from the line of Sudan Loganathan from Stephens.

Looking at the healthy volunteer data for KT-621, I observed that the median percent change in serum TARC and IgE levels were comparable to the outcomes seen with dupilumab in healthy volunteers on treatment. There was a noticeable rebound increase when patients were off KT-621, as you mentioned. My question is regarding the significance of durability for quality of life outcomes in patients with atopic dermatitis and asthma. Will the daily oral dosing of KT-621 compensate for any potential deficiencies in durability compared to dupilumab? Also, does the administration method and systemic effects of dupilumab naturally lead to more durable outcomes?

It's a great question. So I mean, I will answer part of it, and then I'll let Jared also speak to part of all of it. So the beauty about our drug is that it's a once-a-day oral that allows you to block IL-4 and 13 continuously at steady state. The beauty of our drug is that you can stop and start when you want, if needed without a long washout period. The beauty of a once-a-day oral drug is that as long as you continue to take the drug once a day orally, you will see profound effects or at least the effect that the underlying biology will have. I don't believe that if these drugs are taken as prescribed, obviously, we're still very early to compare to dupilumab, that you have more or less duration of the effect. The only main difference that I will say between an injectable biologic and a once-a-day oral degrader, not small molecule inhibitor, is that the once-a-day oral degraders allow you to have steady-state complete pathway blockade. I believe with dupilumab, a couple of days before your next dose, you're not maximizing the pharmacology as much. So you might actually have less pathway blockade, continuous pathway blockade than a once-a-day oral degrader. Now what would that mean from a therapeutic perspective? Obviously, well, time will tell and studies will tell.

Yes. And maybe coming back to your comment around the Phase Ia, just to clarify, patients who were on the MAD portion were getting 14 daily doses. And so when we look at the effect on TARC and Eotaxin-3 in particular, that suppression or inhibition was seen throughout the entire 14-day dosing period. In fact, if you looked at day 7 versus day 14, levels were actually continuing to go down TARC and Eotaxin-3 between day 7 and 14, which suggested that if we had continued dosing beyond day 14, we might have seen more suppression. So there was no recovery of TARC and Eotaxin-3 until dosing was stopped after day 14, and then you see a gradual recovery. So that just speaks to what Nello was referring to in terms of the durability of the effect as evidenced by even in healthy volunteers, a durable effect on those biomarkers.

Your next question will come from Andy Chen, Wolfe Research.

This is Brandon on for Andy. Within BROADEN2, are you doing anything to control the rising trend of placebo that we're seeing in atopic dermatitis where recent trials have seen a higher placebo response?

Thanks for the question. So I just want to answer the first part, and then Jared will address it. So I think that's an important point. I think as I was speaking earlier, I think with a drifting of patients with EASI, shifting from, let's say, early 30s to mid-20s, I think it's almost physiological to have seen an increase of the placebo rates. I think though, there are ways in which one can minimize the effect. And maybe, Jared, you can speak to it.

Sure. Yes. I think as far as we see it, I think this is based on the general learnings from prior studies. There are really 3 main things that one can do to try to limit that placebo rate. One is making sure that you have the right protocol design and site selection so that you're making sure you actually have patients with atopic dermatitis, not other skin diagnoses, and that you make sure you have moderate to severe patients that you're not somehow also getting mild patients. The milder patients, the more mild patients you have who should not really be enrolled in these studies, but they are enrolled, are going to have a contribution to the placebo rate. The second important thing is to select very experienced sites because you want the raters, the people who are assessing the endpoints to have the right expertise, the right derm expertise here for AD. And you also want to have the proper training of those raters to make sure they're able to assess EASI, for example, consistently and accurately. And then finally, it's really important that there'll be close sponsor oversight of the sites involved and also the CRO that's helping to execute on the study. That oversight is really our study conduct, and the sponsor has to really be all over study conduct. So I think all of those elements combined, I think, are important in helping to mitigate the placebo rate, and those are all things that we're addressing in our study.

Your next question comes from Kripa Devarakonda, Truist.

Can you hear me?

Yes.

I was actually wondering how you think about the evolution of the competitive landscape for 621. I know you guys are significantly advanced in terms of the clinical development. There are competitors, whether you talk about degraders or some inhibitors. But based on what you've seen, how important is the fact that you're ahead in development versus any potential areas of differentiation? And where does the next-gen STAT6 degrader fit into this context?

Thanks, Kripa. We are indeed aware of other companies that we've supported with our exceptional data over the years, which is great to see from an industry perspective. I want to emphasize that being first is important, but being both first and best is what will truly drive commercial success. It places us ahead of the competition, which is crucial, but more importantly, it means we have a drug that will be extremely difficult, if not impossible, to surpass. KT-621 is that drug; it is remarkably potent and well-tolerated, and we believe its profile allows us to target any potential indications for patients with Th2 diseases. Other companies will need to address their differentiation compared to KT-621, but I'm not well-acquainted with many of their programs due to a lack of publications or presentations with real data. I believe that a small molecule inhibitor of STAT6 cannot achieve the level of pharmacological effect that our degrader will provide, primarily because they won't be able to block this pathway continuously as we can. We believe that this continuous blockade is necessary to achieve biologics-like activity. Regarding other degrader programs, I don't have enough information. The key point is that we have confidence in our drug. We are years ahead of our competitors. Our team’s goal is to execute flawlessly in the coming years so we can achieve the commercial success that positions KT-621 as a multi-billion-dollar drug in the Th2 space.

Your next question comes from Jeff Jones, Oppenheimer.

We've been talking about TARC, Eotaxin and some of the other critical biomarkers for the STAT6 program. Can you comment on key biomarkers we should be focusing on for the IRF5 program when we see that data? And should we be expecting healthy volunteer data in 2026?

Yes. Jeff, you always ask very orthogonal questions. I love it. So yes, we expect to have Phase I data from 579 in 2026, next year. It's a bit early to speak to the biomarkers. But as you know us, as you do know us well, we tend to run Phase I healthy volunteer studies that are quite rich in terms of information. So as we get closer to the start of the study, we'll share more about our biomarker strategy.

Your next question comes from the line of Jeet Mukherjee, BTIG.

You folks have spoken at length about the niche and the opportunity for KT-621 in the atopic derm space. But could you just elaborate a bit further on how you see it fitting within the asthma landscape?

Yes, I'll start by addressing a fundamental issue in the asthma space, while Jared can provide more details on the medical side. Strategically, Th2 asthma, specifically eosinophilic asthma, is a condition that typically begins early in life. It's crucial to impact the disease before or as the lungs fully develop, as failing to do so can lead to diminished lung function for the rest of a person's life. Young patients often remain on therapies that do not tackle the underlying Th2 inflammation for years before advancing to systemic biologics. We need to change this paradigm, as we are putting children's lives at risk and not doing enough to ensure the best quality of life for those with Th2 inflammation. An oral drug with the expected safety and efficacy could fit into the treatment paradigm, helping patients earlier in their disease progression. While I'm not suggesting this drug is for mild asthma, it presents a chance to transform the treatment landscape for respiratory diseases in young people, and we need to reconsider our approach to treating this condition. Jared, perhaps you can provide more detailed medical insights.

Yes. No, I think in addition to the, I think, important opportunity in pediatric patients, I think also in the adolescent and adult patients with asthma, I think being able to access a much greater proportion of those patients with moderate to severe disease, right, who have a significant unmet need, but just are not going on injectable biologics for all the reasons around market access or concerns about being on an injectable or a biologic to be able to really penetrate the adult and adolescent space as well with our drug for those patients with moderate to severe because now we have an oral drug, which hopefully, if it says if it's comparable to dupilumab in its efficacy and safety, it could really transform how these adult and adolescent patients are also treated with asthma.

Your next question comes from Clara Dong with Jefferies.

Can you hear me?

We can hear you. We see somebody else, we can hear you. Go ahead.

Thank you for allowing me to ask again. My question is regarding the Phase Ib trial. This trial has a relatively brief follow-up period for the patients. Among the key endpoints like biomarkers, clinical efficacy, and safety, which ones do you think are less influenced by the treatment duration, and which endpoint do you find more challenging to interpret due to the trial design?

I believe that there wasn't any endpoint in the dupilumab study that reached its maximum effect by week 4. Therefore, it's challenging for me to determine which aspects will be more or less influenced by the 28-day duration. We plan to review all the data collectively in December, which will help us provide a clearer answer.

Our next question comes from Brad Canino, Guggenheim.

Maybe just to close out on a capital allocation question for Nello because you're in the most comfortable cash position you've ever been in with the company, but also have the highest capital demands ever faced by the company. So how do you think about deployment of each incremental investor dollar across KT-621, the name pipeline and the platform to really maximize value for Kymera at this juncture?

Thank you for the question. This is a complex topic that I could discuss at length, but to summarize, there hasn't been a biotech firm that has independently developed a program like KT-621. We recognize this as a unique opportunity and obligation for responsible capital allocation. If we were to focus solely on STAT6, we wouldn't be fulfilling our mission as a global company committed to creating treatments for patients with various diseases worldwide. We need to find a balanced approach between investing heavily in 621 and adequately funding our other programs. I believe we must justify any increased investment. Our capacity to expand our investment in 621 will rely on its success, and similarly, our investment in other areas will hinge on the achievements of our clinical pipeline. We don't allocate resources simply because we have them; we do so based on the merit of our potential. This has been our strategy since the beginning.

Our final question of today comes from Joe Catanzaro, Mizuho.

Maybe a follow-up sort of along the lines of duration of effect. Wondering if you could say anything about the level of compliance that you observed in the Phase Ib, but maybe more importantly, looking towards the Phase IIb and 16 weeks of dosing, what you guys can do to ensure a high level of compliance there?

Yes. No, it's a great question. So obviously, with an oral drug, industry data will tell you that getting 100% compliance is difficult just because we all forget to take one pill one day. And with biologics, you can ensure compliance asking patients to be injected in the site. So obviously, we're aware of it. We're actually using novel technologies to increase as much as we can adherence to the study protocol regarding taking the drug. And we're confident that, that will deliver what we need. I will add one last thing. I know we're way out of time. The beauty of a degrader drug is that you can actually skip a dose and maintain maximal pharmacology, assuming you have the right dose that reaches complete degradation that you will never see with a traditional occupancy-based small molecule inhibitor. So we have a bit of a cushion on the adherence question. But obviously, we're not sitting on it. We need to ensure as much as we can 100% adherence because we want to maximize the benefit for patients.

Thank you. I'd now like to turn the call over to Nello Mainolfi for closing remarks.

Okay. Thank you. I'm sorry, we ran beyond the 9:30 goal that we had. I want to thank everybody. Obviously, lots of questions. We are always available to continue to engage. This has been the most exciting year of Kymera, and we have 1.5 more months or so to go. So stay close. I think it's going to be an exciting time in the next few years developing this really once-in-a-generation drug and the broader pipeline. So thank you again today, and we'll talk more soon.