Q2 2025 Kymera Therapeutics Inc Earnings Call
Speaker #1: Good day, everyone. My name is Olivia, and I will be your conference operator today. At this time, I would like to welcome you to the Kymera Therapeutics second-quarter 2025 results call.
Speaker #1: All lines have been placed on mute to prevent any background noise. After the speakers' remarks, there will be a question-and-answer session. If you would like to ask a question during this time, and if you have joined via the webinar, please use the raise hand icon, which can be found at the bottom of your webinar application.
Speaker #1: 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 Bruce Jacobs, Chief Financial Officer.
Speaker #2: Good morning. I'm Bruce Jacobs, and I'm kicking off this call in place of Justine Koenigsberg, our Head of IR, who is out today. Joining me this morning are Nello Mainolfi, founder, president, and CEO, and Jared Gollob, our Chief Medical Officer.
Speaker #2: Following our prepared remarks, we'll open the call to questions from our publishing analysts. If you'd like to ask a question, please use the raised hand icon, which can be found at the bottom of your meeting window.
Speaker #2: And to help us move efficiently through the Q&A session, we ask that you're ready to unmute your line when called upon. In addition, we ask that you please limit your question to one and refrain from any irrelevant follow-ons to ensure we have enough time to address everyone's questions this morning.
Speaker #2: Before we begin, I'd like 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.
Speaker #2: The 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.
Speaker #2: With that, I'll turn the call over to Nello.
Speaker #3: Thanks, Bruce, and thank you for joining us this morning. As I mentioned at the beginning of the year, we set ourselves up for a very productive and exciting 2025.
Speaker #3: And we're delivering on that promise. The updates we've shared in the first half of the year represent a powerful validation of Kymera's innovative and disciplined approach to drug development within the biopharma industry, while paving the way for future progress across our high-impact immunology pipeline.
Speaker #3: We're committed to leveraging the unique capabilities we've developed to unlock disease biology and deliver groundbreaking oral degraded medicines for areas not served well by existing technologies.
Speaker #3: Today's immunology treatment landscape still leaves millions of patients without adequate options, forcing difficult trade-offs between efficacy, safety, cost, and convenience. Millions of patients with life-altering immune inflammatory diseases don't have access to advanced systemic therapies.
Speaker #3: Mostly injectable biologics. This is true if we look across countries with extremely diverse systems on how they prescribe, reimburse, and deliver these highly effective medicines.
Speaker #3: The issue is really more fundamental than the inefficiencies of the healthcare ecosystems around the world. Simply put, well-tolerated oral drugs that can be as effective as these difficult-to-access injectable biologics have the potential to transform the treatment landscape and, in doing so, impact the lives of millions of patients.
Speaker #3: This is what we're set to do at Kymera. It's an exciting time for the company, and I want take a moment to briefly recap some of the key accomplishments of the first half of 2025.
Speaker #3: Starting with our first-in-class statics program, we completed the first KT621 trial in healthy volunteers and reported positive results that exceeded even our highest expectations, surpassing our target product profile.
Speaker #3: Importantly, the data furthered the risks our path forward and highlights the possibility of KT621s du piloma being appealed profile. As potential first-in-class treatment, we believe KT621 has the ability to be a broadly accessible oral option for many dermatological and respiratory diseases like AD and asthma.
Speaker #3: In addition, for Japanese regulatory purposes, we recently completed a second small healthy volunteer study in Japanese subjects, with results that were consistent with the U.S. study.
Speaker #3: You can expect that we'll present these findings at a future medical meeting. We also wanted to share a few updates regarding the KT621 Phase 1B broadened study in moderate to severe AD patients.
Speaker #3: As noted in the release, the patients' data we plan to share will include data from two different dose groups. While we initially set out to explore a single dose, the speed at the trial enrolled allowed us to evaluate the translation from healthy volunteers into patients more broadly.
Speaker #3: Which we believe gives us an even richer data set to inform our Phase 2b dose choices, which was an important goal of this study.
Speaker #3: The Phase 1B was designed with a flexible protocol that contemplated this scenario, allowing us to make this choice without impacting timelines and, as a result, we were well-positioned to report results in the fourth quarter as planned.
Speaker #3: I'm also happy to share that we have selected and finalized the three doses that we've been included in the two phase 2B studies as well as completed long-term toxicity studies these were really the final important pieces of our planning to start these studies beginning later this year.
Speaker #3: Given we're moving into data collection and analysis mode soon, we're going to limit our comments around the study to what we have said previously until we're able to share the full results in Q4.
Speaker #3: But we can certainly say that we're pleased with the speed at which the trial has enrolled. We're very excited about the trajectory of the program, and we look forward to sharing the full data set when it's available.
Speaker #3: The additional piece of news to share is that we have selected a follow-on statics degrader to KT621. We have strong potency, selectivity, and safety profile and have advanced it through all required I&D enabling studies.
Speaker #3: The degrader is I&D ready should we decide to further advance into the clinic in the future. More broadly, we're building what we believe is the best in industry oral immunology pipeline. Beyond step six, we're also very excited about what's next.
Speaker #3: Early this year, we've unveiled our oral IRF-5 program, which is moving through I&D enabling studies. The compelling preclinical data we've generated showcases that targeting IRF-5 can lead to correcting immune dysregulation across multiple disease pathologies while generally sparing normal cells.
Speaker #3: And it remains our goal to progress our early discovery pipeline of novel immunology programs unveiling one new program per year to expand access to oral systemic advanced therapies for broad patient populations in the space.
Speaker #3: We hope to share more about this next year. Additionally, we announced two important partnership updates in June. First, we're very excited to announce our first oral molecular glue degrader program targeting CDK2, which will be developed under our collaboration agreement with Gilead.
Speaker #3: We have a highly innovative research engine, and the CDK2 program is a great example of this given the challenges of existing technologies to address these highly valued targets.
Speaker #3: With our focus in immunology, this program was an ideal candidate for partnering. We and Gilead believe that a highly specific, safe, and effective CDK2 degrader has exciting potential to meaningfully improve treatment for patients living with breast cancer and other solid tumors that are inadequately treated today.
Speaker #3: Secondly, Sanofi announced that they officially opted into the ARC4 program and will assume full responsibility for the development activities of KT485, our second-generation oral ARC4 degrader.
Speaker #3: Which we expect to advance into phase one testing next year. Based our preclinical results, KT485 has greater potency, broader distribution, and a general improved overall profile than KT474, our first-generation degrader.
Speaker #3: As a result, Sanofi made the decision not to advance 474 into further development, as KT485 has the greatest potential benefit for patients. Both of these collaborations have the potential to realize significant milestones for Kymera.
Speaker #3: Which Bruce will cover later in the call, and we're appy to collaborate with two industry leaders on this novel program. Finally, to support all we have ahead of us, we've extended our cash runway into the second half of 2028.
Speaker #3: We raised approximately $288 million in the follow-on offering that we launched at the end of June and received the upfront payment from Gilead, increasing our cash position to $1 billion as of the end of July.
Speaker #3: Our well-capitalized balance sheet should allow us not only to take KT621 through the planned phase 2B studies in AD and asthma, but also to prepare for and initiate several phase 3 studies across multiple indications.
Speaker #3: While also progressing our earlier stage pipeline. As you've heard me say before, our strategy centers on combining the unique power of targeted protein degradation with carefully selected targets and pathways to create transformative new class of medicines.
Speaker #3: By focusing on immunology, we're not only addressing large patient populations, but also meeting a significant unmet need to create effective, safe oral therapies. We believe our approach has the potential to deliver, for the first time in our industry, biologics-like efficacy with the ease and convenience of an oral pill.
Speaker #3: Again, I couldn't be more excited about the foundation we've built and what we're doing. I'm looking forward to the Q&A discussion, but let me pause here for Jared to discuss KT621 and our pipeline.
Speaker #3: Jared?
Speaker #2: Thanks, Nello. Looking back on the last quarter, we were excited to share the first KT621 clinical data, which we believe greatly de-risks the next stage of development.
Speaker #2: We identified clear goals for the Phase One healthy volunteer study, and the data not only hit the mark but, in many instances, exceeded our expectations with compelling translation from preclinical studies to humans.
Speaker #2: The primary objective in the healthy volunteer study was to show that we can robustly degrade STAT6 in blood and skin, which we define as a reduction of 90% or more at doses that are safe and well tolerated.
Speaker #2: As shown here, the results exceeded our expectations across every measure. We showed more than 95% degradation in both skin and blood at very low doses.
Speaker #2: The safety profile was undifferentiated from placebo. We are encouraged by the biomarker profile, which we believe is at least comparable to what dupilumab showed in healthy volunteers or patients, and in some cases, is superior.
Speaker #2: That said, I'd like to take a few minutes this morning to recap the results and next steps with KT621. Which we believe has the potential to profoundly alter how TH2 diseases are treated by delivering an oral drug with a biologics-like profile.
Speaker #2: For the full data set, please reference the slides presented in early June, which are available on our website. As a reminder, we enrolled 118 volunteers in a randomized, double-blind, placebo-controlled study to assess single and multiple ascending doses of KT621 across a range of doses from 6.25 to 800 milligrams in SAD and from 1.5 to 200 milligrams in MAD.
Speaker #2: In all SAD cohorts, including the lowest dose of 6.25 milligrams, KT621 degraded STAT6 by 90% or more, and at doses of 75 milligrams or greater, achieved complete degradation.
Speaker #2: With greater than 95% mean STAT6 reduction and STAT6 levels below the lower limit of quantitation in multiple subjects after just a single dose.
Speaker #2: In MAD, where volunteers were dosed daily over two weeks, we were able to completely degrade STAT 6 in both blood and skin at doses of 50 milligrams and above.
Speaker #2: In fact, to establish the lower end of the dose response curve, we had to go back after the initial cohorts and add the 1.5 milligram MAD cohort given none of the initially planned doses had less than 90% degradation.
Speaker #2: The robust degradation of STAT6 led to functional inhibition of the IL-413 pathway, as demonstrated by median reductions of up to 37% for TARC and up to 63% for Eotaxin-3 at day 14.
Speaker #2: A result that was comparable or superior to what has been observed for dupilumab, either in healthy volunteers or in patients with TH2 diseases.
Speaker #2: Importantly, whether treated at the lowest or highest dose, or anywhere in between, the safety profile was undifferentiated from placebo. There were no serious adverse events, very few treatment-related adverse events that were mild, no treatment-related discontinuations, and no clinically relevant changes in vital signs, laboratory tests, or ECGs.
Speaker #2: With daily dosing up to 200 milligrams, which is 16-fold above the lowest MAD dose with greater than 90% degradation. As many of you have asked, we are also happy to share that we recently completed our four-month GLP toxicology study, and consistent with our earlier non-GLP and GLP tox studies, we do not see any adverse events of any type at all of the doses tested.
Speaker #2: This study completes the necessary preclinical work to allow us to initiate the Phase 2B trials planned to start later this year and early next.
Speaker #2: Prior to reporting the healthy volunteer data, we initiated a 28-day Phase 1B trial named BROADEN, which was designed to enroll approximately 20 moderate to severe atopic dermatitis patients.
Speaker #2: We've had a high level of engagement from sites on the trial and are pleased to report that we are on track to share data in the fourth quarter.
Speaker #2: As a reminder, the key study aim 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, TARC being the most relevant in AD patients, as well as on the TH2 transcriptome of active AD skin lesions.
Speaker #2: We will also assess KT621's effect on clinical endpoints, such as ease and pruritus NRS. Beyond the Phase 1B BROADEN study, which is designed as a streamlined biomarker-focused study, we are planning parallel Phase 2B dose range binding als to enable subsequent registrational Phase 3 studies across multiple indications.
Speaker #2: As Nello mentioned, we have selected the three doses for the studies. Our Stat 6 team has done a remarkable job keeping this program moving at a rapid pace.
Speaker #2: Including all the necessary work to initiate two global Phase 2B trials. The AD Phase 2B trial will begin in the fourth quarter this year, and the asthma study is expected to initiate in the first quarter of 2026.
Speaker #2: And quickly, on the IRF-5 program. Historically, in undrugged transcription factor and genetically validated target, IRF-5 is a master regulator of innate and adaptive immune response pathways involving pro-inflammatory cytokines, B cell activation and autoantibody production, and type 1 interferons.
Speaker #2: We believe IRF-5 degradation has the potential to be the first broad anti-inflammatory mechanism that effectively addresses immune dysregulation while sparing normal cell function. KT579, our potent selective al degrader, has the potential to be the first IRF-5 targeted therapy to deliver a completely novel and potentially transformative treatment option, in many cases superior to pathway biologics, in a range of autoimmune and rheumatic indications such as lupus, RA, Sjögren's, and others.
Speaker #2: This program is progressing in I&D enabling studies, and we expect to advance KT579 into phase 1 testing in early 2026, with what we believe will be the first oral IRF-5 degrader to enter the clinic.
Speaker #2: Across our portfolio, we see strong potential to advance multiple first-in-class oral degraders that address major market opportunities in immunology. Our stat 6 and IRF-5 programs represent significant advancements not only for our pipeline but for the industry and patients as we look to deliver the first oral therapies with biologics like profiles in immunology.
Speaker #2: We're excited about their continued progress and remain focused on our goal of expanding access to transformative treatments for millions of patients. So let me pause here, and Bruce will review our second quarter financial results and provide a collaboration overview.
Speaker #2: Bruce? Thanks, Jared. I will quickly run through our results for the quarter, also because this past quarter has been busy with collaboration and financing activity.
Speaker #2: I wanted to provide a brief summary of our recent news as well. As I walk through the second quarter results, please reference the tables found in today's press release and 10-Q, which was filed this morning.
Speaker #2: Revenue in the second quarter of 2025 was $11.5 million, all of which was attributable to the Sanofi collaboration. With respect to operating expenses, R&D for the quarter was $78.4 million.
Speaker #2: Of that, approximately $8 million represented non-cash stock-based compensation. The adjusted cash R&D spend of $70.4 million, which excludes that stock-based compensation, reflects a 3% decrease from the comparable amount in the first quarter of 2025.
Speaker #2: On the G&A side, our spending for the quarter was $17.6 million of which $7.4 million was non-cash stock-based comp. The adjusted cash G&A spend of $10.2 million again excluding that stock-based compensation reflects a 6% increase from the comparable amount in the prior quarter.
Speaker #2: And overall, adjusted operating expenses in total were down slightly from the prior sequential quarter. When in June with the ash balance of $963 million, our quarter-end cash balance included the base proceeds from our $250 million follow-on offering that closed at the end of June.
Speaker #2: The June total does not include either the additional proceeds from the underwriter's overlapping option, which was fully exercised in July, or the first payment that we received from Gilead as part of our recently signed CDK2 partnership, both of which were received in July.
Speaker #2: As a result, we ended the month of July with a cash balance of approximately $1 billion, providing a cash runway into the second half of 2028.
Speaker #2: Just a quick reminder that our runway calculations exclude any unearned milestones. And with that in mind, I'd like to take you briefly through the key financial terms of our two collaboration agreements.
Speaker #2: Starting with Gilead, under the collaboration, we're eligible to receive up to $750 million in total payments, in addition to tiered royalties on net product sales that range from the high single digits to the mid-teens.
Speaker #2: This $750 million includes $85 million related to the upfront payment, which was received in July, and you can see on our balance sheet shown as deferred revenue and the potential option exercise.
Speaker #2: If Gilead chooses to exercise its option for an exclusive license, they will assume global rights to develop, manufacture, and commercialize all products arising from the collaboration.
Speaker #2: Turning to Sanofi and the development of KT485, under the existing collaboration, we could earn up to $975 million in clinical, regulatory, and commercial milestones for KT485.
Speaker #2: We retain the right to opt into a 50/50 cost and profit share in the U.S. prior to the first Phase 3 trial, in addition to international royalties.
Speaker #2: If we decide not to opt in, we would instead be entitled to worldwide royalties ranging from the low double digits up to the high teens.
Speaker #2: To conclude, as you've heard today, there's a great deal of momentum across our programs. And importantly, we have the resources in place to continue executing on our development strategy and the progression of our earlier stage pipeline.
Speaker #2: With that, we'll pause here so we can convene in the conference room, at which point we'll open the call to questions. Thank you.
Speaker #1: Thank you. At this time, if you would like to ask a question, please click on the "raise hand" button, which can be found on the black bar at the bottom of your screen.
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Speaker #1: Please accept and wait until you are promoted to panelist. Please unmute your audio, turn on your camera, and ask your question. As a reminder, we are allowing analysts one question and one related follow-up today.
Speaker #1: We will now pause a moment to assemble the queue. The first question is from Michael Schmidt from Guggenheim. Please unmute yourself and begin with your question.
Speaker #3: Hey, guys. It's Paul on for Michael. Thanks for taking our question. I had one on the dose levels that you're exploring for 621. Maybe first, could you provide some color on that decision to add the second dose in the Phase 1B study?
Speaker #3: I think it's probably safe to assume that both the doses fall within the broad range that achieve complete static degradation, but just wondering how you're thinking exploring both the high and low dose versus perhaps two doses in the higher range.
Speaker #4: Yeah. Thanks, Michael. I want to make sure we're you can hear us. So as we said today, so the doses, both doses are within the range that we that we explore in the phase 1 healthy volunteer study.
Speaker #4: And as we also said, as you're aware, we had initially decided to explore one dose, thinking that, you know, roughly 20 patients would be enough to give us the data to speak to what the profile of that one dose is.
Speaker #4: And then obviously, as we were moving along with the enrollment and given how quickly it was going, and you know, given that we were able to assess the performance of that one dose, we decided to explore an additional dose so that we'll get even more robust translation from healthy volunteers to patients of, you know, STAT6 degradation.
Speaker #4: I think it's important to keep in mind that in the healthy volunteer data, we had multiple doses. I would say almost all doses, besides one, met our target product profile.
Speaker #4: And so we wanted to confirm that that really, ally robust profile could be translated into patients with the same level of fidelity and so I think we're happy that we did that.
Speaker #4: Obviously, I'm not going to speak to high, low, medium, et cetera. Rest assured that the main goal was really to refine the phase 2B dose selections.
Speaker #4: And so all that happened so quickly that now between the healthy volunteer data and whatever data we have access from this study, we're able to firm up and select the phase 3 the phase 2B doses even in the absence of completing the phase 1B study.
Speaker #3: Great. And if I got a quick follow-up on that point, and mostly on just what factors into the dose selection for the Phase 2 studies, was it predominantly the healthy volunteer data you presented?
Speaker #3: Was there anything emerging from the Japanese studies or GLP tox? Can you say if there's a range of doses being explored between the AD and the asthma studies?
Speaker #3: Thank you.
Speaker #4: Yeah, no. So, that’s a great question, actually. As you saw, it was a very, very busy Q2. I don't think we've had a busier Q2 in the history of the company given everything that we've accomplished.
Speaker #4: So I will say that if you look back at the healthy volunteer data, there was a dose selection based on this data. Everything else that we've done confirmed was able to confirm our initial instinct.
Speaker #4: We didn't arn to be honest, anything new. That made us change the initial instinct, let's say, on those selection, but it was highly encouraging that everything that we've seen in healthy volunteer was supported by obviously the four-month off, which we said was completely clean.
Speaker #4: The Japanese study, which was very much in line with the U.S. study and the early, let's call it early data for the Phase 1B.
Speaker #3: Great. Thanks very much.
Speaker #1: The next question is from Derek Achila at Wells Fargo. Please unmute yourself and begin with your estion.
Speaker #5: Hey, good morning. And thanks for taking the estion. Congrats on the progress here. So just one and a follow-up. So basically, just want to understand maybe following up on this line of estioning just in terms of what you would expect to see at these at these additional doses that you're looking at in the phase 2B.
Speaker #5: Ultimately, like we saw very good degradation and pretty quick. So I guess, you know, how do you think some the doses will differentiate? And then just a follow-up to that, you ow, what do you actually expect to see with the follow-on stat 6 that you're ing?
Speaker #5: What sort of optionality are you really looking for with that molecule? Thanks.
Speaker #4: Great question, Derek. So the first one I just want to confirm we're talking about the dose for the Phase 2B. I think the important thing for a drive, obviously, is to find a dose that has the best risk-reward profile.
Speaker #4: And so I think what we want ask in a, you know, in a 16, let's say for AD, a 16-week study is what is the maximal or we believe close to maximal at that point level of clinical activity that we will see.
Speaker #4: And what is the safety profile at different levels of degradation? Obviously, we will explore maximal degradation, which we call complete. Which, again, is where really we see in most subjects, stat 6 level be below the lower limit of quantitation.
Speaker #4: So, we want to ask that question: What is the clinical profile of maximal degradation? And then, obviously, we want to ask the question at a couple of lower doses just to, again, at the end of the study, be sure that we're taking into Phase 3 the profile that we believe has the best risk-reward.
Speaker #4: So it's obviously a necessary step that we need to take as a company to fulfill regulatory requirements to do those ranging studies before selecting a Phase 3 dose.
Speaker #4: You know, I think we have bets in the company on what that phase 3 dose will be already, but we've got to the studies and make sure that we do all the right steps to de-risk the program.
Speaker #4: With regards to the follow-on molecule, so that's something many of you that has followed us for years know that every program we always have a next generation molecule.
Speaker #4: As you saw for IRC4, Sanofi decided to focus the efforts on the follow-on. And we call it the next generation molecule, KT485. For stat 6, to be honest, we didn't really have a particular goal with the next generation compound given how well KT621 has performed.
Speaker #4: And this is the reason why you ow we've advanced a very good molecule that in many ways looks at least in terms of profile very much like KT621 is, you ow, potent, extremely well tolerated, very active in vivo.
Speaker #4: And the principle is, you ow, to support the franchise for one is for the eventual unlikely scenario that we need another molecule or for a for a strategic choice of eventually advancing another molecule should we choose to do for a different severities or different indications.
Speaker #4: I think given how well KT621 is doing, we have decided for now to keep this follow-on molecule I&D ready, meaning that we have everything we need to file an I&D, but we're not planning to file an I&D in the in the short term.
Speaker #4: I think another important point in this highly competitive space, as stated in Q6, is becoming having a molecule IND-ready probably ahead of any other, let's call it, competitor that is behind us.
Speaker #4: So we have two molecules ahead of every other competitor. I think it also sends a message about how committed the company is to this franchise.
Speaker #4: And to the potential of this franchise.
Speaker #5: Excellent. Thanks, Nello.
Speaker #4: Thanks, Derek.
Speaker #1: Question is from Andrea Newkirk at Goldman. Please unmute yourself and begin with your question.
Speaker #6: Hi, guys. Good morning. Thanks so much for taking the question. Two for me as well. Maybe the first, recognizing the primary objective of the Phase 1B data is to show a duplicate profile here on biomarkers.
Speaker #6: But I was hoping you ight be willing frame your expectations on what you'd like see on the clinical efficacy measures, particularly EC75 as well as NRS.
Speaker #6: And then secondly, just noting the completion of the GLP tox studies that you mentioned and obviously your phase 1 healthy volunteer also looked really clean, but if you could just speak to the potential safety risks of degrading stat 6 completely, what type of signals are you looking for in the phase 1B to really feel fortable here with the safety profile as you move forward?
Speaker #6: Thanks so much.
Speaker #4: Well, thanks. Great question. Jared, I thought maybe you could take at least the first one, if not both.
Speaker #3: Yeah. In terms of on the clinical expectations, I think you know we've emphasized always that the primary objective here is to show robust stat 6 degradation in the blood and an active AD skin lesions.
Speaker #3: And to show that that results in a duplicate biomarker effect both in blood and in skin, where in skin we're looking at the TH2 transcriptome and we want to see a duplicate effect there.
Speaker #3: You know, we have sort of set our expectations around biomarkers. I think TARC is the most important blood biomarker probably in AD. Duplicate studies have shown that even at 28 days, there is about a 70-plus percent reduction with dupilumab.
Speaker #3: So that's a general ballpark that we would expect to see in patients who liken those duplicate AD studies had greatly elevated TARC levels at baseline.
Speaker #3: We'll be looking at other biomarkers in the blood as well as these you know various you know transcriptional biomarkers in the skin. In terms of clinical endpoints, again, we've always emphasized that in the absence of a placebo control, these are more exploratory.
Speaker #3: However, we think we do have an opportunity to look at endpoints like easy and pruritus NRS and IGA because we know from duplicate that you can see impact on those biomarkers as early as 28 days.
Speaker #3: And we're really giving specific numbers where that bar would be set. I think the published data are out there with duplicate and one can look at those published data at 28 days and get a sense for what we mean by sort of being in the ballpark with regard to those clinical endpoints.
Speaker #3: In terms of your second question around safety risks, as you noted, we’re very pleased with what we’ve seen in our GLP tox studies.
Speaker #3: We've now completed our four-month toxicology studies, as Nello indicated, and we've seen no safety signals whatsoever. That's very much in line with our four-week GLP toxicology studies and our prior non-GLP toxicology studies.
Speaker #3: We are very encouraged by the fact that our safety profile was undifferentiated from placebo. The healthy volunteers received two weeks of dosing, so that's very encouraging.
Speaker #3: And now we'll be looking safety with four weeks of dosing, of course, in the phase 1B. I think overall this is in line with our expectations.
Speaker #3: Based on our mechanism of action and the fact that it appears that STAT6 is highly selective for the IL-4 and IL-13 pathways in human genetics, this has pointed not just to the phenotype of abnormalities in STAT6, but also to the safety of knocking down STAT6, as supported by mouse knockout studies.
Speaker #3: And so, this is all in line with what is expected for our transcription factor that is very specific for IL-4 and L13, and for a drug like ours that is highly selective just for STAT6.
Speaker #4: I would only thank Jared. I wouldn't say anything differently. I will only add one thing, just to be clear. Again, as Jared said on the clinical endpoints, it's difficult to compare.
Speaker #4: You know, it's also difficult to compare placebo-controlled randomized studies, like the industry's full of these arguments over comparing placebo-controlled studies. So it's even more difficult to compare non-controlled studies.
Speaker #4: But I just want to say our expectations are that we will have a very active drug. I don't want to hide behind the impossibility to compare.
Speaker #4: We expect that this mechanism is going to be on par with what du pilomab has shown. And that's the bar for us without talking about numbers.
Speaker #6: Okay. Understood. Thanks, guys.
Speaker #1: The next question is from Faisal Kershid at Lee Rink. Please unmute yourself and begin with your question.
Speaker #7: Hey, good to see you guys. Thanks for taking the question. Just want to ask on the doses for the phase 1B and the phase 2B, are you able to confirm if the dose that you added to the phase 1B is higher or lower than the dose that you originally went in with?
Speaker #7: And could you also confirm if either or both of these doses are part of the three that you're selected for Phase 2B?
Speaker #4: So, I don't want to get into the higher or lower because I think whatever I say is going to be viewed one way or the other.
Speaker #4: What I can say is that both doses have been tested in the healthy volunteer studies. I don't want to talk about what our doses are for the 2B because I think we might choose to keep that as I've said in other venues.
Speaker #4: To keep that close to the vat for as long as we can. Only for competitive reasons. All I can say that you know we have several doses in the healthy volunteers that performed really well.
Speaker #4: And so really the main driver here are these doses going to perform as well in patients given that I actually don't remember the number.
Speaker #4: Bruce will know better. But we're spending tens, if not hundred-plus millions of dollars in these two studies. And we're not going to optimize over you know for these studies on you know making or thinking that we selected the right doses.
Speaker #4: These are consequential decisions. And so, given that we had the time to do it, we said, "Let's make sure." So, that's really what's behind this.
Speaker #4: And you ow I think once we'll share the data, we can add a bit more color to what came first.
Speaker #7: Got it. Makes sense. And then could you confirm if it's still 20 patients for the phase 1B? And then also like between the two doses, would you like to or do you have to see dose response between those two doses?
Speaker #4: Great question. So I think what we said is that the goal of the 1B was approximately 20 patients, and that's still the case. I don't want to get into the dose response.
Speaker #4: I think we'll talk about it once we share the data.
Speaker #7: Sounds odd. Thanks for taking the questions.
Speaker #1: The next question is from Alex Thompson at Stifel. Please unmute yourself and begin with your question.
Speaker #8: Hey, good morning. Thanks for taking my question. I guess another question on the next-gen STAT6: you know how different is the scaffold binding to STAT6 than to 621?
Speaker #8: Is that a key part of this decision-making? And when might you consider potentially splitting indications here? Is that a near-term decision, or are you going to wait quite a while for that to come down?
Speaker #8: Thanks.
Speaker #4: Yeah. So what I can say, thanks, that's a great question, Alex. So we have several scaffolds, let's call it, across actually all binding molecules, whether it's E3 ligase or it's STAT6.
Speaker #4: We have plenty of chemistry. Some you know patterns have been published from us. As many have seen, there is plenty that hasn't yet. So, we have a plethora of chemistry in this program that covers everything that you can imagine.
Speaker #4: So maybe I'll leave it at that. On the indication splitting, it's a bit obviously challenging to think about that particular endgame given kind of the evolving landscape right now in terms of pricing and reimbursement, and global versus U.S.
Speaker #4: So, I think we want to keep maximal optionality, and that's kind of the goal behind everything that we're doing. But it's difficult for us right now to at least disclose what the latest thinking on that is.
Speaker #4: But you know as we get closer to phase 3, which you know which actually with the recent raise hopefully was clear from from our remarks earlier now with the money we have in hand, we can actually initiate multiple phase 3 studies.
Speaker #4: So I think as we get closer to those, we'll be able to disclose more about what our indication sequence and strategy will be.
Speaker #5: Great. Thank ou.
Speaker #1: The next question is from Tuzine Ahmed at Bank of America. Please unmute yourself and begin with your question.
Speaker #6: Hi, guys. Good morning. Thanks for taking my question. Going back to the data that you're going to have by year-end, I just wanted to ask. You've talked about your expectations for what data you're going to show.
Speaker #6: Should I assume that you're also going to be able to show some level of pitch data? I ask because some doctors have indicated that, in addition to, let's say, EC scores, that is something that they feel is important when they're trying to make a decision in a real-world setting about what potential options they might choose.
Speaker #6: Thanks.
Speaker #4: Yeah, Tuzine, it's a great question. And as Jared said, yes, we will show easy pruritus NRS. And so H is going to be an important factor.
Speaker #4: As you know, H probably has the biggest impact on the quality of life of these patients. And so it's something that we're watching very closely.
Speaker #4: So we will share their data as well.
Speaker #6: And will that be for all the patients that you're going to show, or will it be a subset?
Speaker #4: Well, I mean, if we have collected the data, yeah, so we will share it. So yes, it should be all patients.
Speaker #6: Okay. Thank ou.
Speaker #4: Yeah.
Speaker #1: The next question is from Kelly Shea at Jefferies. Please unmute yourself and begin with your question.
Speaker #9: Congrats on the quarter. So, one question on stat 6. Conjunctivitis is believed to be an on-target adverse event of Dupixent. Do you expect to see a similar level of conjunctivitis in the KT621 Phase 1B trial?
Speaker #9: Likely one or two patients. And also could a daily oral drug be differentiated in safety profile versus injectable due to a potential remote blood PK curve?
Speaker #9: Thanks.
Speaker #4: Maybe I'll start, and then I'll pass it to Jared, who can speak more to the medical part. I mean, our view at Kymera is that stat 6—and hopefully it’s just here at Kymera.
Speaker #4: Stat6 is the selective transcription factor of IL-4 and IL-13. We have shown preclinically, early clinically, and hopefully will show in Q4 that if you block Stat6, you can phenocopy dupilumab.
Speaker #4: So if conjunctivitis, which is actually mostly, if not only, seen in atopic dermatitis patients, is really a feature of the disease and these IL-4 and IL-13 biologics.
Speaker #4: So again, if conjunctivitis is a mechanism event, an adverse event for IL-4 and IL-13 biology, then we expect to see it. If it's due to the receptor or the cytokines, then we wouldn't see it.
Speaker #4: So it's for us to know. Maybe Jared, you can speak to, you know, is it seen after only four weeks? I don't know.
Speaker #3: Yeah. I mean, you know mechanistically, it's really known why some patients, especially AD patients, do develop conjunctivitis. If you look at the dupilumab studies, where you do see conjunctivitis, oftentimes you'll see it within the first, say, four to eight weeks or so of treatment.
Speaker #3: And then over time, it actually tends to diminish. You know, it is an adverse event that one does see with duplicate. It's not a dose-limiting adverse event.
Speaker #3: And most of the cases, the duplicates are sort of in the mild to moderate range. I think importantly, you know we haven't seen it preclinically in our tox studies.
Speaker #3: We haven't seen it in healthy volunteers, and we really wouldn't expect to see it there in healthy volunteers since this appears to be something unique to AD patients.
Speaker #3: But, as Nello said, you know we don't have any reason to believe that we'd see other less or more in AD patients compared to what du Pilomab has seen.
Speaker #4: But yeah, we're watching it because it's an interesting, obviously, feature of many of these drugs, right? It's not only dupilumab; all the IL-13 drugs have it.
Speaker #4: So we're watching that very closely and see if we see it in our four-week studies. And we'll obviously share all the data in Q4.
Speaker #4: And then you talked about the safety difference between one's oral daily and a biologic. I mean, from what we have both understood, and what we've empirically derived in our preclinical studies, du pilomab has a very, very robust pathway blockade.
Speaker #4: I would compare du pilomab pathway blockade pretty much in line with the level of pathway blockade we see from our 500, to make those 200, you know, the complete degradation type of pathway blockade.
Speaker #4: I would put it on that kind of level of pathway blockade. So, if that's the case, then I don't see why pathway blockade coming from STAT6 degradation should look different from pathway blockade from an IL-4 receptor alpha blockade.
Speaker #4: So anyway, I think that's another feature and another part of the analysis that we will do again. I'll repeat in our preclinical study. Now we're adding the four-month talk.
Speaker #4: KT621 has been exceptionally well tolerated. And so we'll continue to, again, watch everything that happens in the clinic.
Speaker #1: Thank you for your help. Thanks. The question is from Judah Ferma at Morgan Stanley. Please unmute yourself and begin with your question.
Speaker #10: Yeah. Hi, guys. Thanks for taking the question. Just one for us. I guess, can you comment a little bit further on enrollment progress and the success you're having there?
Speaker #10: Maybe what feedback is from investigators? Is the, you know, oral administration of the drug resonating and curious if if you think, you know, you'd have similar success if there were a placebo arm in a trial?
Speaker #10: Thanks.
Speaker #4: Yeah, it's a great question. You know, the challenge over the 28-day study, remember, is that the patients are not going to be on the drug beyond day 28.
Speaker #4: We don't have an extension arm to the study. So it's, I would say, before we started the study, we were nervous because, you know, there are a huge amount of incentives for patients to come onto the study.
Speaker #4: Besides knowing they'll be on an active drug, and that's part of the reason why we decided not to have a placebo. We thought we would have an impact on our enrollment rate.
Speaker #4: As we expected, part of our expectation was that patients do want an oral drug. And so, I think we are seeing that in our study, and the data has allowed us to, you know, meet our enrollment goal.
Speaker #4: I would say we will even exceed our enrollment goal for sure. And maybe that's where I'm going to have it. I think once we start seeing more differentiation, it's probably going to be in the face-to-face study where now you're offering 16-week, potentially OLE.
Speaker #4: And so, that would be interesting to see our enrollment versus biologics and whether it's telling us also something about what patients are looking for in the market.
Speaker #3: Great. Thanks.
Speaker #1: The next question is from Krippa Devrakonda at Jewish. Please unmute yourself and begin with your question.
Speaker #6: Hey, guys. Thank you so much for taking my question, and congrats on the progress through the quarter. So, I'll ask one non-stat question. Congratulations on your CDK partnership with Gilead.
Speaker #6: I know that you diversified your pipeline into oncology, where you've been focused a little bit more on the INI in the recent past. But given the data we've seen so far with CDK2 inhibitors, can you talk a little bit about how you think the degrader could be differentiated based on the data that you have?
Speaker #6: And what is the strategy of development? And then I have a follow-up.
Speaker #4: Yeah. Yes. Thank you. So just to be clear, our discovery engine has been very focused on immunology. We have programs that we were working on from the earlier days, and one of our programs was CDK2.
Speaker #4: And so, with our strategy shift to focus on developing immunology drugs, we decided that it was best to place a very exciting CDK2 program, from a development standpoint, in the hands of a partner that was committed to that space.
Speaker #4: So that's a bit to the strategy. The reason why we have that program is because we firmly believe that small molecule inhibitors of CDK2 are really not able to selectively target CDK2.
Speaker #4: They all inhibit CDK1 to a larger extent at pharmacologically active doses, but to different degrees. This leads to clinical doses that are probably not optimally blocking CDK2.
Speaker #4: Again, for the risk of hitting CDK1. Another important aspect for us to develop this drug was to have a brain-penetrant asset so that we would also address potential brain secondary tumors or metastasis from breast cancer.
Speaker #4: And so our degrader program, the molecular group degrader program, is highly specific. CDK2 also reaches the CNS, and we believe it's going to have the potential to be best in class.
Speaker #4: If I look at the small molecules out there, it's by far superior. Obviously, I'm not aware of other programs that are in early discovery, early development.
Speaker #4: So, I can't say obviously for sure. But with regards to the development, that's a question you have to ask Gilead. We can't speak for them on that particular front.
Speaker #6: Okay, thank you so much. And just following up on Tuzine's question about its relief—and this is something that we've heard from KOLs too—it’s really important to see rapid itch relief.
Speaker #6: Will we get a sense of that when we see the data, the rapidity of response?
Speaker #3: Yeah, we. I mean, you know, as Nello already mentioned, looking at it through a pruritus NRS is a key part of the sort of suite of clinical endpoints.
Speaker #3: And we'll be looking at it, you know, fairly regularly as we'll be looking at ease. So, we'll have a good sense of the kinetics of impact on itch as on ease, and will be something part of the profile that we share once we have those data in Q4.
Speaker #4: Yeah. I think you'll see, hopefully, that will be the case. But it will be, you know, we'll show Day 7, Day 14, Day 21, and Day 28.
Speaker #4: So you'll be able to see the kinetics of all of these parameters.
Speaker #6: Thank you so much.
Speaker #1: Hello. Each questioner can ask one question now. No follow-up questions. The next question is from Mayank Mantani at the Riley. Please unmute yourself and begin with your question.
Speaker #11: Yes. Good morning. Thanks for taking our questions, and congrats on the progress, team. Any color you're able to provide on the baseline easy scores of the patients you're enrolling or have enrolled? And I wonder, always, about the screen failure rate for the topic dump trial sites.
Speaker #11: And maybe just remind us how you're measuring degradation in skin tissue. There's obviously a couple of ways to do that. And lastly, anything you've learned on the degradation from the four-month GLP tox studies you completed?
Speaker #4: Oh, yeah. Four questions in there. That's a way to.
Speaker #3: I will not ask a follow-up, I promise. No follow-up.
Speaker #4: Yeah. Well, you asked for four. So let's see how I go. Let's see if I remember. So the first one was the easy. Yeah, we're not going to comment on the baseline easy, but I will refer you to our entry.
Speaker #4: So the baseline criteria for entering the studies is easy: 16 or above. There is obviously itch as well. There is PSA: more than 10%.
Speaker #4: So we have a strict criteria that really overlap with what has been done with du pilomab. On the, again, on the failure rate, again, I don't know if we'll speak when we release the data.
Speaker #4: All I can say is that our team is watching the study very closely, and we've worked very, very hard to make sure that patients entered into our study actually have atopic dermatitis.
Speaker #4: We should be shocked that, you know, this could be possible if you don't watch the study closely. That, you know, their disease is active.
Speaker #4: And obviously that their lab work is, you know, in line with making sure we're not, you know, taking sick patients on our study. So I think when you take all of that, that results in obviously screen failures that, again, are not able to comment on today.
Speaker #4: On the degradation in the skin, as we've done in many of our studies, we are fortunate enough to have patients in our study willing to take biopsies, which, as you know, adds an additional layer.
Speaker #4: That's why we're so impressed with how we were able to enroll patients again quickly, because we asked patients to undergo biopsies at baseline and Day 28.
Speaker #4: To measure stat 6 with the mass spec. So that's how we're going to assure it.
Speaker #3: Anything you learned from the GLP tox study on degradation?
Speaker #4: I am, I mean, all we learned in these studies is that, obviously, at these toxic doses, there is no STAT6 anywhere to be found.
Speaker #4: You know, we degrade it completely. That's maybe all I can say. Yeah, if the question is, does the STAT6 degradation wind off after some time, obviously the answer is no.
Speaker #4: We see STAT6 degradation all throughout the study.
Speaker #3: That's great to hear. Thank you.
Speaker #1: The next question is from Jeet McCarry at BTIG. Please unmute yourself and begin with your question.
Speaker #5: Great. Thanks for taking my question. I know we're a long way out, but can you speak to payor willingness to cover therapies in the dermatology space given alternative administration formats like an oral option with Dupixent-like efficacy for KT621?
Speaker #5: Or is there a bar for truly superior efficacy versus standard of care options? Thank you.
Speaker #4: Well, no, it's a great question. We believe that when you make the case for an oral option first, you will hear from prescribers that actually you don't even need to have dupilumab-like activity for expecting a substantial adoption in the market.
Speaker #4: It just speaks to the fact that there is a need for flexible, easy-to-prescribe, reimbursable, and takeable medicines. So the reason why we say 'duplicate-like' in appeal is because all the data we've seen so far speaks to that.
Speaker #4: And so that's why our bar has always been there. And hopefully, we'll continue to be there. Again, I think when you make the case for having a therapy even with the same activity, you're telling actually insurance companies and prescribers and patients that this drug has a much bigger impact on their quality of life and asking for a lot less, right?
Speaker #4: In terms of visits to the doctors, testing, you know, needing or lack thereof of, you know, cold storage of the drug, needles, injection sites, and reactions.
Speaker #4: So I think that's the value case that, you know, a drug like this will have. And especially, if you compare it to, for example, the only drug that right now is approved in AD, it's a drug with a black box.
Speaker #4: And that drug actually is doing quite well. I think that speaks. And then it's a drug that requires testing before you start that therapy. And it speaks to the hunger that this market has for an oral drug.
Speaker #4: And I think you've seen it all in all markets. Oral drugs and multiple effective therapies are needed to expand access and penetration. Now, you know, especially the topic of dermatitis market is really dominated by a single player.
Speaker #4: I would say mostly with du pilomab. But it still has less than 15% penetration, I would say. If you look at all moderate to severe, it's less than 10%.
Speaker #4: And so, I think we need these options to expand access dramatically in the U.S. and all over the world.
Speaker #5: Appreciate . Thanks, guys.
Speaker #1: The next question is from Jeff Jones at Opco. Please unmute yourself and begin with your question.
Speaker #11: Good morning, guys. And thanks for taking the question. One question from us on IRC4. Can you provide any additional detail behind what drove the exchange of 474 for the 485 candidate?
Speaker #11: You know, given the specificity differences, was there something that was being seen with 474 that was concerning?
Speaker #4: Great question, Jeff. Thanks for asking about this. So just a reminder, everybody, the decision was made by Sanofi to focus all the resources of the IRC4 collaboration on KT485.
Speaker #4: Based on preclinical data, KT485 seems to be superior to 474 on both potency distribution and has also demonstrated a complete lack of the subclinical QT finding that we had seen with 474 in our clinical studies.
Speaker #4: I will also reiterate that that particular finding was self-resolving with continued dosing, meaning that it will go away as you continue to dose. And we didn't learn anything, even in the ongoing Phase 2 studies, that spoke negatively regarding the safety of the drug beyond what we'd already shared.
Speaker #4: So, I think it was really focused on the fact that 485 overall seemed to have a better profile, and we believe both clinically and maybe commercially more competitive.
Speaker #4: But since you asked me about IRC4, I thought it was also interesting to see how the landscape is evolving. I don't know if you all have seen AstraZeneca starting a big Phase 2 study in COPD after they've run a small earlier study, which we haven't seen data for. However, they've shared that they're going to release that data for their IRC4 inhibitor in COPD.
Speaker #4: So that's another indication that we at Kymera thought IRC4 could be well-positioned for. It's exciting that a big company is, I think, 400 patients.
Speaker #4: No, it's more than that. Yeah, a 1,000-patient study. So anyway, just the field continues to learn and evolve. And, you know, we're cited to have a great asset out there that hopefully could also go towards that direction.
Speaker #4: That's something that we need to obviously discuss with Sanofi.
Speaker #1: The next question is from Andy Chen at Wolf Research. Please unmute yourself and begin with your question.
Speaker #12: Hey, thank you for taking the question. On IRF5, is there a reason for degradation inside the kind of induction and all that to not translate into humans?
Speaker #12: It looks like your STAT 6 degrader has more than translated. Wouldn't all of that read through to IRF5? Or is there still something special about that molecule that makes you think that you're still maybe semi-concerned and that the de-risking steps are still ahead of you?
Speaker #12: And also, what are the top two or three safety signals that you'll be watching for in humans? Thank you.
Speaker #4: Yeah, great question. So for IRF5, I mean, what are the stages? To be honest, we’ve been here for a while. All of our programs have translated really well.
Speaker #4: You can argue whether you like the target and the biology that translate, but all of our programs have translated really well in the clinic.
Speaker #4: So we expect IRF5 to translate just as well as KT621. Also, for IRF5, KT579 in non-GLP tox, we've seen no adverse event of any type.
Speaker #4: And we went up to 200-fold above the expected 90% degradation of human exposure. We are in the midst of buying the enabling studies. I'm confident we'll continue to see an exceptionally well-tolerated drug.
Speaker #4: So we're excited about that drug. We're working really hard not only to prepare for the healthy volunteer study that will start early next year, but the team has been spending the past few months working on and planning our patient study that will start soon after the healthy volunteer study, where we're prioritizing indications.
Speaker #4: We're talking to KOLs and refining protocols. So, yeah, we're working under the assumption that the translation will be happening just as well as it did for 621.
Speaker #12: Thank you, Nello. We're just about up against time. Operator, I'll try to just move really quickly to these last few.
Speaker #1: One moment while we wait for questioners. The next question is from Elly Mill at UBS. Please unmute yourself and begin with your question.
Speaker #6: Hey, guys. Thanks so much for taking the question. Just another one on IRC4. I guess, can you elaborate a little bit on what was seen clinically with the first-generation IRC4?
Speaker #6: And I guess what gives you the confidence and the efficacy of this target in AD and HS? I mean, I heard your comments on AstraZeneca.
Speaker #6: I mean, any difference now in terms of how you might think about the opportunity set across indications now for IRC4? And then also just a follow-up on CDK2.
Speaker #6: Can you elaborate on some of the learnings on working with molecular glues versus heterobifunctional degraders? And your confidence in the selectivity for CDK2 with these programs?
Speaker #6: Thanks.
Speaker #4: Yeah. So on IRC4 quickly, we can't speak about what we've seen or not seen in the studies. Unfortunately, that is Sanofi's guidance on that. On the indications, again, this is another question for Sanofi.
Speaker #4: But as mentioned, COPD has always been on the high priority list for that biology. Obviously, we're talking about non-eosinophilic COPD, which is a huge patient population.
Speaker #4: And with CDK2, so we again, historically said that these two, the heterobifunctional degrader and molecular glue, are two complementary technologies, and they're not one the next generation of the other.
Speaker #4: Although many companies seem to go in that direction, we use molecular glues where we believe that the binding site and the ability to bind to the target is either not feasible or not with the selectivity.
Speaker #4: If you use specific binding to CDK2, it's really difficult to find selectivity against CDK1. And that's why we built our CDK2 degrader, which does not have any kind of cross-binding with CDK1.
Speaker #4: That's how we, that's why we went in that direction.
Speaker #6: Great. Thanks.
Speaker #1: There are no more questions at this time. I would now like to turn the call over to Nello Mainolfi for closing remarks.
Speaker #4: Well, thanks, everybody. Sorry we went a bit too long today. Another exciting quarter. We're here. For any follow-up questions, you know where to find us.