KYMR - NASDAQ

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. [Operator Instructions] At this time, 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. [Operator Instructions] 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 positions 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 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 pipeline 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 effective as biologics, given the direct correlation between PK and PD and the need of high drug exposures. As a result, the power -- of the power of protein degradation, we can now 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 for potential of 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 potential to change the quality of life for many patients and family 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 KT-621 Phase I healthy volunteer study, we demonstrated 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 similar 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 in 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 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 of what dupi delivered at 4 weeks in its published studies, including on both EASI score and itch with all the caveats of small ends 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, 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. Jared?

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 lack of tolerance of injection site reactions or phobia of needles. And 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 orals 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. Bruce?

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 comp, 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 comp. The adjusted cash G&A spend of $9.9 million, again, excluding that stock-based comp, 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.

[Operator Instructions] Your first question comes from Geoffrey Meacham, Citi.

I just had a couple of questions. So the first one is, when you look at the upcoming data for KT-621, maybe just highlight, Nello, what are the key characteristics that could enable it to potentially show differential efficacy versus dupilumab at relatively early time points, I think that's probably one of the bigger points of uncertainty with investors. And then the second question is, when you look at the 2 doses of the BroADen study, is the -- the 3 doses, is the expectation that the lower one maybe has a lower impact on degradation and therefore, is subtherapeutic? Or is it to test the upper end of where you'd like to be from a safety tolerability? I'm just trying to get a sense for the selection of the doses and kind of how you would frame that out for what would be the ideal kind of result.

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 dupi-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 difference 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 dupi-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.

Yes. No, Marc, thanks for that. That's a great question. So let me clarify. So there is 2 aspects of this trial. One is the baseline, let's say, the baseline EASI of patients. And then I think what I was referring to back a few minutes ago was the baseline TARC levels. So I think if you study dupilumab TARC reduction over both the AD study, but actually if you study over all the other studies that were run in other indications, whether it's chronic rhinositis (sic) [ rhinitis ], asthma, EoE, et cetera, you see that there is a clear relationship between baseline level of TARC in patients and reduction of TARC. And so that's what I was referring to when I'm talking about baseline level of TARC, baseline levels, I was referring to the TARC baseline levels. And obviously, I'm not going to comment about what the baselines of the study -- of our study are, but obviously, we'll share the data when the time is right. Then there is another element, which I want to clarify, then there is the EASI baseline levels. And I think what we've said in the past, as we've seen generally when dupilumab was developed, it was the first systemic drug for atopic dermatitis. And so if you look at those studies, the baseline EASI were in the high-20s, low-30s. If you look at studies from all companies in the past 5 years or so, you see that the baseline EASI has shifted down in the, let's call it, mid-20s. And that's mostly because the patient population that we're accessing to these trials in the sites that most companies go to, obviously has changed given that these sites in these countries and these regions have access to dupilumab. So generally, the most severe patients are on systemic biologics. Some are not. But generally, the mean number has come down a bit, and that's what we're observing. And so that's kind of another element to the whole study and the outcome of the study. But I just want to separate the point that I was making before where on TARC baseline levels, not necessarily on the EASI baseline level.

Okay. And should we expect that same trend kind of to lower EASI scores, it should apply here. But does that have an impact on TARC level -- likely TARC levels as well, do you think?

I think that's something that we'll discuss when we release the data. I think we understand really well, obviously, the level of TARC at baseline in healthy volunteers, right, where we've seen reduction in the mid to high 30s in many patients on our studies in the healthy volunteers. And we show that also dupilumab when baseline levels were in the range of healthy volunteer at similar reduction. I think, again, as I've said, if you look at other studies, dupilumab level, you see a correlation between baseline level and percent reduction of TARC. And so I think that's the observation that we're sharing looking at those studies. I don't want to preview our study because -- as I mentioned a few minutes ago, I don't think it would be productive to preview some data here versus December.

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

Congratulations on all the progress. I'm wondering how are you guys 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 and 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?

Sure. Yes. I mean we can't give specifics around powering for the Phase IIb. What we can say is -- and we have stated that the end for that study is going to be approximately 200 with there being 4 arms, 3 drug, 1 placebo. So we look very carefully at what the expectations are, what the patterns have been in the past with regard to EASI responses, NRS Pruritus responses, et cetera. And that's all gone into calculating what sort of ends we need to make sure that the study is adequately powered. So we've been very careful in the design of the study to make sure that we are powered to show the desired effect relative to placebo. Another important aim of the study, obviously, is to be able to look across the 3 different doses and to see if we can discern any sort of a dose response. So the study is powered to enable us to do all of those things.

And the doses between AD.

The doses between AD. So right now, so I think what we've guided is that our plan is to -- in the Phase IIb to use the same doses for both AD and asthma across both Phase IIb studies.

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 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.

Well, so I'd like to maybe clarify. I think what we said before is the same thing that we've been saying for 9 or 10 months. But that's maybe just my small additional color. So I just want to clarify, when we selected the doses for the Phase IIb was actually a few months before October, right? We started the study recently in the Phase IIb study. But in order to submit the protocol and do start-up activities, you had to actually have chosen the doses much earlier. And I think I've said this many times, I believe, publicly that when we selected the doses, we had visibility into partial data for both doses for both the first dose in the Ib and less but still some data from the second dose in the Phase Ib. And again, we did not have access to the totality of the data, but we -- because we're focused mostly on the translation of degradation and obviously, safety, which is understood, we had enough information to make the right selection for 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. So I'll start, Jared, please jump in. So the reason why we believe that will be the case is multifold. But I will start with -- we believe KT-621 and our STAT6 program is -- the whole value proposition is to expand patient access to advanced systemic therapy. The penetration of these advanced biologics in moderate to severe patients is less than 10%. Some companies claim it to be more than 10%. Maybe we align on, let's say, 10%. So we don't have to argue with other companies. So the majority of the patients do not have access to advanced systemic therapy. That's where we are coming from. Then another part, which we've discussed as well is patients that have gone on to systemic therapies that have failed systemic -- pathway systemic therapy, IL-4, IL-13, JAKs will not come on to our study. So they will have to have responded to those therapy, then decided not to continue and then jump on our 621 study. So for those 2 main reasons, and also, I would say, for the experience that we had in the Phase Ib, we believe the majority of patients will be naive. And I would also add, hopefully, I will not be proven wrong, that we don't believe there will be issue out there finding naive patients because those patients are in dire need of an active systemic oral safe therapy.

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 IIb. And so that's another reason why we expect a substantial proportion of patients on IIb to be dupi-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 the 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 wonder 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 time lines 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 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 maintained -- 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 back at the healthy volunteer data for KT-621, I noticed that the median percent change in the serum TARC and the IgE were similar to that of dupilumab healthy volunteer outcomes for those same levels when on treatment. There was a noticeable rebound higher, obviously, whenever these -- on these levels when the patients were off of KT-621, as you showed. My question is how important is the durability for the AD and asthma patients' quality of life outcomes? And will KT-621's daily oral dose -- dosing regimen make up for any deficiencies and maybe durability outcomes that it could have compared to dupi? And does dupilumab mode of administration and systemic effects just inherently lend to a more durable outcome?

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 long washout period. The beauty about 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 biology -- 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 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 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. So obviously, yes, we're aware of other companies that -- I think we've enabled with our amazing data, right, over the past couple of years, which is obviously always great to see, at least from an industry perspective. So first, let me start with -- this is not just about being first. I think this is about being first and best because that's what is going to almost guarantee commercial success, right? You're ahead of the competition, which is important. But more importantly, you have a drug that is going to be extremely difficult, if not impossible, to do better than. And that's what KT-621 is. It's a drug that is exceptionally potent as we've seen, exceptionally well-tolerated with a profile that we believe would allow us to go in any potential indications of patients with Th2 diseases. I think others will have to talk about their differentiation versus KT-621. I'm not familiar with many of the other programs because there haven't been any publications or presentations with actual data. What I will say going on record here is I believe a small molecule inhibitor STAT6 is impossible to reach the level of pharmacological effect that our degrader will have, mostly because we'll not be able to block this pathway 24/7 almost completely or completely as we do. And we believe that, that's required to have biologics-like activity. On the other, obviously, degrader programs, again, I don't know enough. But the important thing here is that we have confidence in our drug. We're years ahead of competitors. And so our team mandate here, including us around the table, is to execute flawlessly in the next few years so that we can accomplish the commercial success that will make KT-621 a double-digit 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 question. 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 study 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 mean I'll start with -- actually, there's a more fundamental issue, I think, in the asthma space, and I'll let Jared speak to the medical part of it. I just want to talk strategically. So Th2 asthma, eosinophilic asthma, which obviously we expect this drug to address, right, just to level set, is a disease that starts very early in life. And actually, it turns out that if you're not able to impact the disease until or before your lung fully develops, you're actually going to have reduced lung function for the rest of your life. And children, young adults are on non -- on therapies that do not address the underlying Th2 inflammation for many years before they are graduated to systemic biologics. I think there is a paradigm that needs to change because we're actually putting kids' lives at risk or we're not carrying as much as we should or do for the best quality of life possible of children and young adults with Th2 inflammation. So that's where an oral drug with, hopefully, the safety and the efficacy that we expect should fit in, in the treatment paradigm, that help patients earlier in their trajectory. I'm not saying that this is a patient for mild asthma, a drug for mild asthma, but this is an opportunity to change the treatment landscape in respiratory diseases, given that this is a disease of young people, and we need to change how this disease is treated. Maybe, Jared, you can bring us back to earth and maybe talk more medically.

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 dupi 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.

I think you're on mute.

Clara, we can't hear you.

Now?

No.

Yes. Maybe, operator, do you want to put her back in queue and we go to the next one and she can try to sort that out.

Your next question will come from Alex Thompson. Please bear with us as we invite him to be panelist.

I guess on the Phase IIb AD study again, you mentioned obviously, patients that had experience with biologics. And I think, Nello, you also mentioned JAK inhibitors. Is there going to be a cap for how many of those advanced therapy experienced patients you might have in the study? And then on rescue therapy, how are you dealing with that as well?

Yes, there would be no cap. Again, as long as you have not failed advanced systemic therapies that block this path to IL-4, IL-13 and even JAKs, there will be no cut for those. And I don't think we're discussing rescue therapy. Obviously, there is a system on how we're going to deal with it, but I don't believe we're going to disclose it at this point.

Our next question comes from Faisal Khurshid, Leerink.

So I know you've put kind of a benchmark out there of 70% to 80% on TARC reduction from baseline. Could you talk to us about what you would -- what efficacy endpoint you think people should focus on, given that people are focused on this, given that you already showed nice TARC in healthy volunteers? And then if you're not willing to put out a numerical benchmark, can you just clarify for investors why that's the case?

No. So thanks. That's a very good question, actually. So we're just basically stating the facts. And we've said that this is a biomarker-focused study mostly because we -- I think we can gather from the data that there is very little, if almost no, let's call it, placebo effect on biomarkers. So the absence of placebo should not impact the interpretation of biomarkers, right? So we're honestly a bit more comfortable saying for TARC, assuming the baseline levels are in the range of what we've seen with the dupilumab study, we expect to see the 70% plus, 70% to 80%. That's a fact, right? That's what dupilumab has seen. Now you would say it's also a fact that the EASI reduction on day 28, there is a number to it. The reason, again, why we've been shy about putting a number on that is because, as you know, clinical endpoints are much more noisy and much more impacted by the potential placebo effect. And so I think we like to be data-driven and science-first company, as you know as well. And I think we'll put out things when we can confidently say that those numbers are something that we can scientifically then follow and adhere to. What we said, again, we're not going to hide behind it. The numbers are out there for dupi, right? I don't have to say what the numbers are. The numbers are out there. The treatment arm numbers are out there. We expect in this study at day 28 to be in that ballpark because we know that, say, KT-621 blocks the pathway as well as dupilumab. So here is how we've always characterized it, and we're not going to change it now a month from the data disclosure.

Appreciate it. We look forward to the data next month.

Our next question comes from Judah Frommer, Morgan Stanley.

Maybe just one, if there's anything you can share on early recruitment trends, even anecdotally for BROADEN2. Obviously, the Phase Ib was tougher to recruit just given the 28 days dosing here, you can get patients on drug for a year plus. And curious about just awareness of the healthy data and how all that might be helping in recruiting patients and what investigator feedback is.

Yes. I mean high level, again, we just started the study. We just activated a few sites. So we're very, very early into that process. I think what we believe right now is even on the healthy people -- on the Phase Ib, there was a lot of excitement by sites and investigators and eventually patients, we believe, in accessing an oral option. Obviously, the 28-day study was not set up to get patients excited because it's a short study without an OLE. So the Phase IIb, it's a whole different value proposition. And I believe between that and hopefully, the data that we'll disclose in December, I think it will be -- we are confident that this will be a study that we can recruit in a timely manner. Now recruiting the study as fast as possible is not our goal. Our goal is to recruit the study as fast as possible with the right patient. Going back to what Jared was saying earlier, we have a paranoid oversight of this whole study because we want to try and control the placebo rates as much as possible, even if that has to be at the expense of a week or 2 or 4. So that's where we're coming from. But hopefully, we'll be able to share more about your question as we get deeper into the study.

We would like to invite Clara Dong to try one more time.

Can you hear me now?

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

Thank you for letting me try again. So my question is on the Phase Ib trial. So this trial has a relatively short follow-up for weeks of patients. So among all the key endpoints like biomarkers, clinical efficacy and safety, which ones are -- in your view, are relatively less affected by the treatment duration and which endpoint do you think is more complex to interpret because of the trial design?

Yes. So I think very quickly because we're almost running out of time. If you look at the dupilumab study, I don't believe -- and hopefully, I'm not wrong, Jared, correct me. I don't believe there was any endpoint that reached maximal effect at week 4. So I think it's hard for me to say which one is going to be less or more impacted by this 28-day duration. I think we'll look at all the data together in December and answer the question better.

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?

Yes, great question. So I probably need half an hour for this. But in 30 seconds is, I think there has never been a biotech company that has developed a program like KT-621 on their own fully. So we appreciate this is a unique both opportunity and responsibility to do capital allocation in the right way. I would also say that if we became a STAT6-only company, we will not be fulfilling the mission that we have of a global company that develops drugs that impact patients across the world with different diseases. Obviously, there is a medium -- and happy medium between going all in on 621 and spending a lot of money on the other programs. And I always believe that we need to earn the right to invest more. So our ability to invest more in 621 will be driven by the success of 621. Our ability to invest more also in other programs will depend on also our ability to have success with our clinical pipeline. So we don't do resource allocation because we have money. We allocate capital because we earn the right to do more. And that's the strategy since day 1.

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 with regarding to 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 about 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 to patients.

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