Kymera Therapeutics, Inc.

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 Chimera Therapeutics third quarter 2025 results call. All lines have been placed on mute to prevent any background noise. After the speaker's remarks, there will be a question and answer session. If you would like to ask a question during this time and you have joined via the webinar, please use the raise hand icon, which can be found at the bottom of your webinar application. If you have joined by phone, please dial star nine on your keypad to raise your hand. At this time, I would like to turn the call over to Justine Konigsberg, Vice President of Investor Relations.

Good morning and welcome to Chimera's quarterly update. Joining me this morning are Nello Manolfi, founder, president, and CEO, Jared Golub, 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. If you would like to ask a question, please use the raise hand icon, which can be found at the bottom of your meeting window. And to help us move efficiently through the Q&A session, we ask that you are ready to unmute your line when called on. In addition, we ask that you please limit your question to one and a relevant follow-on to be sure we have enough time to address everyone's questions this morning. 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 10Q filed with the SEC. Any forward-looking statements speak only as of today's date, and we assume no obligation to update any forward-looking statements made on today's call. With that, 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 two years since unveiling our STAT6 program, we have demonstrated exceptional progress in advancing our first-in-class STAT6 degrader KT621. To recap, we completed a healthy volunteer study ahead of schedule with impressive results. We enrolled and completed dosing in the Phase 1b trial in AD patients, with data coming in December. We initiated a first of two Phase 2b trials, brought in two in AD, and we're on track to start the breath Phase 2b asthma trial in the first quarter of 2026. We were also featuring two recent late-breaking presentations, which have helped us maintain high level of visibility with the medical and scientific communities, where there continues to be a 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 KT579 IND enabling studies and remain on track to initiate the first clinical trial in healthy volunteers early in 2026. In addition to RF5, we continue to advance an earlier stage undisclosed immunology pipeline, and our goal remains to address many of the major immunology indications with oral medicines. Importantly, we believe that 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 that direct correlation between PK and PD and the need of high drug exposures. As a result 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 a STAT6 program, KT621 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 populations, 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 families around the world. We moved our statistics program at a rapid pace from preclinical to IND to initial clinical proof of concept, and we're now embarked on our first global face-to-be trials. In fact, we filed our IND in September of 2024, and by the fourth quarter of 2025, we've already launched our first face-to-be study. This progress is a strong testament to the speed, focus, and execution of excellence of our team in driving this program forward. Looking back at KT621 Phase 1 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 broadened Phase 1b trial, which we initiated in the spring. To remind you, the trial was designed to achieve three 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 four dimensions we're evaluating KT621 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've seen in the phase one 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 four-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 four weeks. which is the bar we set for KT621, assuming generally comparable baseline levels. In skin, we also plan to assess KT621'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 KT621 blocks IL4N13 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 broadened study expecting clinical activity of KT621 to be in the range of what Doopie delivered at four weeks in its published studies, including on both easy score and itch, with all the caveats, 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 Chimera. He's a seasoned life science executive with deep industry experience, bringing more than two 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. 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 KT621, 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. KT621 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 injective 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 KT621 and Healthy Volunteers, we have developed an accelerated clinical development strategy, including conducting a small Phase 1b biomarker-focused trial in moderate to severe atopic dermatitis patients that we initiated earlier this year. The key aim of the 28-day broadened study is to show that robust stat6 degradation, in blood and skin lesions by KT621 has a dupilumab-like effect on multiple Th2 biomarkers in the blood and skin. We will also assess KT621's effect on clinical endpoints such as EZ 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 1B study was not gating to the start of the parallel Phase 2B dose range-finding trials in AD and asthma, which in turn are designed to enable subsequent Phase 3 registrational studies across multiple indications. This quarter, we initiated Broaden2, our Phase 2b AD study, a global randomized double-blind placebo-controlled trial to evaluate KT621 in approximately 200 patients with moderate to severe atopic dermatitis. This study is designed to evaluate three different doses of KT621 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 easy 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 EASY 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 EZ50, EZ75, a validated investigator global assessment score of 0 to 1, and at least a four-point improvement in peak pruritus NRS. We expect top-line results from the Phase 2B study will be available by mid-2027. In addition to atopic dermatitis, we plan to initiate the breath Phase 2B 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 STATS 6 program, we have completed IND-enabling studies with KT579, our IRF5 degrader, which we plan to advance into a phase one healthy volunteer study early next year with data expected in 2026 as well. Last month, we shared incremental updates in two posters at the ACR meeting in Chicago. In several preclinical efficacy models of lupus and RA, KT579 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, N10Q, 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 non-cash 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 non-cash 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 KT621 Phase 2B trials in AD and asthma, cover startup costs in the initial Phase 3 activities for the STAT6 program, advance KT579 through initial POC testing, and advance our research pipeline as we scale and grow Chimera. Just a quick reminder, our runway calculations exclude any unearned milestones from our collaborations with Sanofi and Gilead. Regarding Sanofi, we expect that they will advance KT485 into Phase I testing in 2026, which would trigger a development milestone payable to Chimera. 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 IRAC4 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.

Thank you. At this time, if you would like to ask a question, please click on the raise hand button, which can be found at the black bar at the bottom of your screen. If you have joined by phone, please dial star nine on your keypad to raise your hand. When it is your turn, you will receive a message on your screen inviting you to join as a panellist. Please accept and wait until you are promoted to panellist. Please unmute your audio, turn on your camera and ask your question. As a reminder, we are allowing analysts one question and one follow-up related question today. We will now pause a moment to allow this queue to assemble. Your first question comes from Jeffrey Meacham, Citi. Please unmute and ask your question.

Okay, great. Hey guys, thank you very much. I just had a couple of questions. So the first one is, when you look at the upcoming data for KT621, maybe just highlight Nello, what are the key characteristics that could enable it to potentially show differential efficacy versus dapilumab? 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 two doses of the broadened study, you know, is the expectation, or the three doses, is the expectation that the lower one, you know, maybe has a lower impact on degradation and therefore is sub-therapeutic? Or is it to test the upper end of where you'd like to be from a safety tall ability? 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 results.

Great. Thanks, Jeff, 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 I4N13 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 IL-13, as well as upstream biologics. In all the studies that we've run, again, preclinically, as I said, 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 the pilumab in a pill-like profile It's 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 dupuy-like activity. In our phase one 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 a KT621 is going to be better than dupilumab or worse than dupilumab. All we've seen so far, they were 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 two profiles will evolve and where they will differentiate. We're talking about, obviously, an injectable biologics versus a small molecule degrader. So you will see probably small differences or larger difference here and there. But a priori, it's very difficult for us to like set the expectation one way or the other. I would be the head, probably the happiest CEO in the world if we're able to deliver a dupli-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 gonna answer your question is, so we selected two doses for the Phase 1b 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 three doses for the phase 2b. The only thing I'm going to say right now is that the two doses of the phase 1b as well as the three doses for the phase 2b are all within the doses that we started in the healthy volunteer study. And generally our approach for The phase IIb is to evaluate a range in which we see maximum pharmacology at the top dose, or some would call it superpharmacology, 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. Thank you. Thank you very much.

Thank you. Your next question comes from the line of Mark Fram, TD Cohen. Please unmute and ask your question.

Thanks for taking my questions. Maybe just on the phase one B, you know, in your comments, you mentioned the kind of target of 70 to 80% tar production. But with that caveat of assuming similar baseline characteristics, you know that you've enroll the patients, you know, with a group of, you know, 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, you know, 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.

Yeah, no, thanks for that. That's a great question. So let me... So there is two aspects of this trial. One is the baseline, let's say the baseline easy 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, the TARC reduction over both the AD study, but actually if you study over all the other studies that were running other indications, whether it's chronic rhinositis, 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, you know, I'm not going to comment about what the baselines 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 easy baseline levels. And I think what we've said in the past as we've seen generally when the pilumab was developed, it was the first systemic drug for atopic dermatitis. And so if you look at those studies, the baseline easy where in the high 20s, low 30s. If you look at studies from all companies in the past five years or so, you see that the baseline easy has shifted down in the, let's call it mid 20s. And that's mostly because the patient population that were 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. But I just want to separate the point that I was making before where on TARC baseline levels, not necessarily on the easy baseline level.

Okay. And should we expect that same trend kind of to lower easy scores? Yeah, 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, you know, something that we'll discuss when we release the data. I think We understand really well, obviously, the level of target baseline in healthy volunteers, right, where we've seen reduction in the, you know, 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 empty volunteer at similar levels. I think, again, as I've said, if you look at other studies, the Piedmont level, you see a correlation between baseline level and percent reduction of tarp. 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.

Okay, thank you.

Your next question comes from the line of Brian Abrahams, RBC. Please unmute and ask your question.

Hey guys, thanks so much for taking my question and 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 2B AD study, just considering the population you expect to enroll, the mix of biologics and experience, the 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 terminologic diseases. I was wondering if you could elaborate a little bit more about what you think are the important considerations around that. Thanks.

Sure.

Yeah. I mean, we can't, you know, give specifics around powering, you know, for the phase 2B. What we can say is, and we have stated at the end for that study, you know, it's going to be approximately 200, you know, with there being four arms, three drug, one placebo. So we look very carefully at, you know, what the expectations are, what the patterns have been in the past with regard to easy responses, anorethritis 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 three 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 that. Dr. Oh, the dose of 280 depth so right now, so I think what we've got is that our plan is to interface to be to use the same doses, you know for both ad and asthma across both phase to be studies.

Dr. And then, maybe just to add that, then the phase three doses or those that will be. use for AD phase three and asthma phase D 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.

Got it. That's really helpful. Thanks so much. Thank you. Thanks.

Your next question comes from Brian Cheng, JP Morgan. If you'd like to unmute yourself and ask your question.

Hey guys, thanks for taking our questions this morning. Some of the color you're providing here for the December readout is pretty much in line with what you already messaged. I'm just curious, just given the gap between the time you selected your three doses for the phase two Bs and when phase one B 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 three doses and have a follow-up?

Well, so I like to maybe clarify, I think what we said before is the same thing that we've been color. So I just want to clarify, when we selected the doses for the phase 2b was actually a few months before October, right? We started the study recently, the phase 2b study, but in order to submit the protocol and do startup 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 1B and less, but still some data from the second dose in the phase 1B. 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 2b doses.

Thanks, Nelo. In a prepared remarks, in a broadened to 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 the investors think about comparing the bond to future data against other benchmarks?

Yeah, 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 KT621 and our STAT6 program is a 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're 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, I-4, I-13, JAX, will not come onto our study. So they will have to have responded to those therapy, then decided not to continue, and then jump on our six to one study. So for those two main reasons, and also I would say for the experience that we had in the phase 1B, we believe the majority of patients would be naive. And I would also add, hopefully I will not be proven wrong, that we don't believe there'll 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 this study in North America, Europe, Australia, and Japan, with the majority of sites actually being ex-US. So ex-US in particular, they're going to be a number of patients who don't have access to 2B. And so that's another reason why we expect a substantial proportion of patients on 2B to be 2B-naive. Thanks for the call, Eric. Thank you. Thanks, Ryan.

Your next question comes from the line of Mayank Mamthani. B. Reilly, if you'd like to unmute yourself and ask your question.

Yes. Good morning, team. Thanks for taking our questions and congrats on the progress. Could you give us a little bit more detail on the asthma breath? I think you're calling it trial considerations in terms of, you know, 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, you know, 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, you know, timelines for data readout for the asthma and atopic dump. Will they be stacked together in 2027? And then I have a quick follow-up.

Yeah, no, thank you for the question. Unfortunately, as we've said, we're going to talk more about the phase 2b BRAT study when we're in the startup 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 we can get 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? Thanks for taking your questions.

Yeah, 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 Chimera has that solution using targeted protein degradation. So if you look at human genetics, the top four places where one would go directly are you know, generally lupus, SLE, and other subcategories of this disease. Some other interferon-related pathologies, RA, IPD. So those are where human genetics point to, our preclinical data point to. I think when we're closer to the phase one study, we'll be able to share more about our development plans. Jared, anything you want to add? Thank you.

Your next question comes from the line of Sudan Loganathan from Stevens. Please unmute and ask your question.

Hi, good morning, Chimera team. Thank you for taking my question. Looking back at the healthy volunteer data for KT621, 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, on these levels when the patients were off of KT621, as you showed. My question is, how important is the durability for the AD and asthma patients' quality of life outcomes? And will KT621's daily oral 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 I4N13 continuously at steady state. The beauty of our drug is that you can stop and start when you want, if needed. without, you know, long worship 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 biologics 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.

Yeah, and maybe coming back to your comment around the phase one A, just to clarify, you know, patients were on a 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 seven versus day 14, levels were actually continuing to go down, TARC and eotexin-3 between day seven 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 eotexin-3 until dosing was stopped after day 14, and then you see a gradual recovery. So that just speaks to what Nella was referring to in terms of the durability of the effect as evidenced by organ and healthy volume here is a durable effect on the virus. Thank you. Thank you. Thanks.

Thank you. Due to time restraints, we are now limiting analysts to one question only. Your next question will come from Andy Chen, Wolf Research. If you'd like to unmute yourself and ask your question.

Hey, this is Brandon on for Andy. And thank you for taking our question. 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 easy shifting from, let's say, early 30s to mid-20s, I think it's almost physiological to have seen an increase placebo rates. I think, though, there are ways in which one can minimize the effect, and maybe, Judd, you can speak to it. Sure.

Yeah, I think, you know, as far as we see it, I think this is based on the general learning from prior studies. There are really three 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 select 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 if they are enrolled, are going to have, you know, a contribution to placebo rate. A second important thing is to select, you know, very experienced sites because you want the raters, the people who are assessing the endpoints that 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, you know, assess easy, for example, consistently and accurately. And then finally, it's really important that there be close sponsor oversight of the sites involved and also the CRO that's helping to execute on the study. You know, that oversight is really up 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.

Thank you.

Thank you. Your next question comes from Kripa Devarakonda, tourist. If you'd like to unmute yourself and ask a question.

Hey guys, can you hear me?

Yeah.

Yeah, thank you so much for taking my question. 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 StatSix de-grader fit into this context? Thank you.

Thanks, Kripa. So obviously, yes, we're aware of other companies that I think we've enabled with our amazing data 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 KT621 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. You know, I think others will have to talk about their differentiation versus KT621. I'm not familiar with many of the other programs because there haven't been any publications on 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, degraded 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 86 to 1 a double-digit billion-dollar drug in the TH2 space.

Thank you so much. Thank you. Your next question comes from Jeff Jones Oppenheimer. If you'd like to go ahead and ask your question.

Good morning, guys, and thanks for taking the question. 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 one data from 5, 7, 9 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 one HETI 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.

Thanks, guys.

Thank you. Your next question comes from the line of Jeet Mukherjee, BTIG, if you'd like to ask your question.

Great. Thanks for taking my question. You know, you folks have spoken at length about the niche and the opportunity for KT621 and the atopic derm space, but could you just elaborate a bit further on how you see it fitting within the asthma landscape? Thank you.

Yeah, 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. It's 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 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 caring 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. 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 we can talk more medically.

Yeah, no, I think in addition to the, I think, important opportunity in pediatric patients, I think also, you know, in you know, the adolescent and adult patients, you know, 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, you know, adult and adolescent space as well. you know, with our drug for those patients who might have disappeared because now we have a world drug, which hopefully if it's as, if it's comparable to do being as efficacy and safety, it could really transform, you know, how these adult and adolescent patients are also treated with asthma. Thanks guys.

Thank you. Your next question comes from Clara Dong with Jefferies. Please unmute and ask your question.

I think we can't hear you.

Yeah, 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. Thank you, Alex. If you'd like to go ahead and ask your question.

Great. Thanks for all the updates here. I guess on the phase 2B AD study, again, you mentioned obviously patients that had experience with biologics. And I think, Nell, 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? Thank you.

Yeah, there would be no cap. Again, as long as you have not failed advanced systemic therapies that block this pathway, L4, L13, and even JAX, there will be no cap 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. Sounds good. Thank you. Thanks, Alex. Thanks, Alex.

Thank you. Our next question comes from Faisal Khurshid, LIRINC. If you'd like to go ahead and ask your question.

Hey, guys, thank you for the question. So I know you've put kind of a benchmark out there of 70 to 80 percent on a 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 and 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 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. So we're honestly saying, you know, for TARC, assuming the baseline levels are in the range of what we've seen with the dupilumab study, we expect to see that 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 easy reduction on a 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 Dupuy, 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, day 28, to be in that ballpark because we know that CKD621 blocks the pathway as well as the PILMAR. So here is how we've always characterized it, and we're not going to change it now a month from the data disclosure.

I appreciate it. I look forward to the data next month.

Thank you. Thank you. Our next question comes from Judah Frommer, Morgan Stanley. If you'd like to ask a question.

Yeah. Hi, guys. Thanks for taking the question. Maybe just one, if there's anything you can share on early recruitment trends, even anecdotally for Broad and 2, obviously, you know, the phase 1B was tougher to recruit just given the 28 days dosing here. You know, you can get patients on drug for a year plus and curious about just awareness of the healthiest data and how all that might be helping in recruiting patients and what investigator feedback is. Thanks.

Yeah, I mean, high level, again, we just started the study. We just, you know, activated a few sites. So we're very, very early into that process. You know, I think what we believe right now is even on the phase 1B, there was a lot of excitement. by science and investigators and eventually patients, we believe, in accessing an oral option. And obviously the 28-day study was not set up to get patients excited because it's a short study without an OLE. So the face-to-be, it's a whole different value proposition. And I believe between that and hopefully the data that we'll disclose in December, I think 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 Judd 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 two or four. So that's where we're coming from, but hopefully we'll be able to share more about, you know, your question as we get deeper into the study.

Thank you. We would like to invite Clara Dong to try one more time. If you'd like to unmute yourself and ask your question.

Good morning, 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 1B 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 you, in your view, are relatively less affected by the treatment duration and which, if

And why do you think it's more complex to interpret because of the cloud design? Thank you.

Yeah, 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 the week before. 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.

Thank you. Thank you. Our next question comes from Brad Canino, Guggenheim. If you'd like to go ahead and ask your question.

Hey, great to see everyone again. Maybe just 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 KT621, the name pipeline and the platform to really maximize value for Camara at this juncture?

Yeah, 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 8621 on their own fully. So we appreciate this is a unique both opportunity and responsibility to do capital allocation the right way. I would also say that if we became a stat six only company, we would 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, a happy medium between going all in on six to one 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 one.

Thank you. Our final question of today comes from Joe Catanzaro, Mitsuho. If you'd like to go ahead and ask your question.

Perfect. Thanks so much. Appreciate you guys taking my question here. 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 1b, but maybe more importantly, looking towards the phase 2b. and 16 weeks of dosing, what you guys can do to ensure a high level of compliance there?

Thanks. Yeah, no, it's a great question. So obviously with an oral drug, you know, industry data will tell you that getting 100% compliance is, you know, it's 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, you know, 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 out of time. The beauty about a degraded drug is that you can actually skip a dose and maintain maximum 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 adherence. the benefit to patients.

Thank you.

Great question.

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 930 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 Chimera, and we have one and a half 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.