Q3 2024 Kymera Therapeutics Inc Earnings Call
Speaker Change: Good day and welcome to the Timearas therapeutic 3rd quarter 2024 results conference call. All participants will be in listen only mode.
Speaker Change: Should you meet assistance, please significantly conference specialists by pressing the star key followed by zero. After today's presentation, there will be an opportunity to ask questions.
Speaker Change: Last question, you may press star then one on your touch town phone. To withdraw your question, please press star then two. Please note this event is being recorded.
Speaker Change: I would like now to turn the conference over to Justine Koenigsberg, Head of Investor Relations. Please go ahead.
Justine Koenigsberg: Thank you. Good morning and welcome to Chimera's quarterly update call.
Justine Koenigsberg: Joining me this morning are Nello Mainolfi, Founder, President and CEO, Jared Gollob, our Chief Medical Officer, and Bruce Jacobs, our Chief Financial Officer.
Justine Koenigsberg: Please note that during Jared's remarks we intend to reference data from slides in our corporate presentation Which is available within the IR section of our website at ChimeraTX.com
Justine Koenigsberg: Following our prepared remarks, we will open the call to questions. We ask that you please limit your questions to one and a relevant follow-up to assure we have enough time to address everyone's questions.
Justine Koenigsberg: 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.
Justine Koenigsberg: These statements are subject to risks and uncertainties that may cause actual results to differ materially from those projected. A description of these risks can be found in our most recent 10-Q filed with the SEC. Any forward-looking statements speak only as of today's date, and we assume no obligation to update.
Justine Koenigsberg: Any forward looking statements made on today's call. With that, I will now turn the call over to Nello.
Nello Mainolfi: Thank you, Justine, and good morning, everybody.
Nello Mainolfi: We have a lot of important updates today, so let's jump right in. First and foremost, we're extremely excited that we have started the Phase I study of KT621, a first-in-class oral stat-6 degrader and the first stat-6 medicine to ever enter clinical development.
Nello Mainolfi: It's important to highlight that we were able to accelerate the path to the clinic given a recent increased focus of resources and capital that were directing towards our growing immunology pipeline.
Nello Mainolfi: I believe this is also an important moment for the whole industry. We have shown in preclinical species that a STAT6 degrader, like KT621, can block IL4N13 similarly, or even more importantly, than in upstream biologics like dupilumab, in both cellular and in vivo models.
Nello Mainolfi: We've also shown that KT621 was well-tolerated in all safety studies that we have run in a wide variety of preclinical species.
Nello Mainolfi: In summary, we have an investigational drug that has the potential to have a dupigumab-like profile in a daily oral pill.
Nello Mainolfi: Many of you know there are more than 150 million patients just in the U.S., Europe, and Japan who suffer from diseases associated with Th2 inflammation, and according to market data, less than a million of those patients receive dupilumab.
Nello Mainolfi: While one could focus on the roughly million of patients currently on dupilumab, Chimera is focused on expanding access across the tens of millions of patients that are waiting for a convenient, safe, and effective oral pill. One that doesn't require needles, refrigeration, syringes, and frequent trips to the doctor's office.
Nello Mainolfi: We believe KT61 is a medicine that has the potential to transform treatment paradigms in many diseases that affect millions of patients, such as atopic dermatitis, asthma, COPD, EOE, just to name a few.
Nello Mainolfi: In addition, given that Th2 diseases are highly prevalent in children, we believe this has the potential to be a drug that will change quality of life for many families in the future.
Nello Mainolfi: Our next STATSix update is expected to be upon completion of the Healthy Volunteers Study in the first half of 2025, at which point we will share the full results.
Nello Mainolfi: Following the completion of the Phase I study, our plan is to move quickly into patients.
Nello Mainolfi: We have those plans well established and we expect to provide guidance on the next stage of 6-1 clinical development next year.
Speaker Change: Jared will share more details around the ongoing phase one study later in the call.
Speaker Change: I also want to briefly highlight another important update on KT-474, our first-in-class IREC-4 degrader. This is another program where Canera was first to clinic, and its success has influenced the industry, with several companies following our lead with other IREC-4 directed assets.
Speaker Change: We're finally able to share more information on the expanded Phase II studies that are being run by our partner Sanofi.
Speaker Change: As I'm sure you have read in a press release earlier today, the program is transitioning from proof-of-concept-like phase two studies...
Speaker Change: to fully powered Phase IIb studies with those ranging as a mean of accelerating our path to registration of Phase III studies right at the conclusion of the ongoing studies.
Speaker Change: In terms of the specific trial changes, we have basically added one dose group to each study who have enough information to being able to select a dose for the subsequent registration of phase 3 studies.
Speaker Change: We are thankful to our partner Sanofi for the increased confidence in and commitment to this important program.
Speaker Change: Turning to TIK2, we have exciting progress to report as well. At our R&D day in January of this year, we introduced our TIK2 program and our lead molecule, KT294.
Speaker Change: Similar to all of our programs, SKT-294 was being advanced through preclinical development. We had parallel work ongoing on other promising compounds.
Speaker Change: One of the compounds we were evaluating demonstrated an even more compelling profile than KT294.
Speaker Change: highlighted by greater in vivo activity and with a similar selectivity and safety profile.
Speaker Change: As a result, we have decided to advance the new compound, KT295, as our lead clinical candidate. Importantly, we believe we can do that without impacting our previously stated TIC-2 development timelines, which assume the Phase I trial start in the first half of 2025.
Speaker Change: Finally, I just wanted to provide everyone with a broader strategic update, and specifically as it pertains to our oncology programs.
Speaker Change: As many of you recall, it was around this time last year we first shared that we had increased our focus in immunology. The rationale was driven by the profoundly impactful profiles.
Speaker Change: We believe we could generate an immunology with oral degraders that could compete with injectable biologics in terms of efficacy and safety.
Speaker Change: As shown with KT474 in the clinic and with our STAT6 and TIK2 efforts preclinically, we think we're positioned to develop a potential vaccine industry portfolio of oral immunology assets with opportunities to impact millions of patients.
Speaker Change: Even more today, with KT474 in multiple Phase IIb trials.
Speaker Change: KT-621 in the clinic and KT-295 close to the clinic and other exciting immunology programs that we will be unveiling starting from next year, we believe that now is the time to focus even more of our resources into this space where we believe we can create outsized value.
Speaker Change: As a result, while we made some encouraging progress with our clinical oncology pipeline demonstrating promising clinical activity in a variety of tumor types,
Speaker Change: As we have completed Phase 1 enrollment, we have made the decision that we will only advance KT333, our STAT3 degrader, and KT253, our MDM2 degrader, beyond Phase 1 with a partner.
Speaker Change: You can expect I will share more on this if and when it makes sense to do so.
Speaker Change: While there are many considerations that contributed to this decision, ultimately we believe our internal resources, both capital and people, are best focused on our expanding immunology pipeline.
Speaker Change: It should be noted that we did not take this decision lightly or made it without thinking about the potential impact on patients.
Speaker Change: We're in fact grateful to patients, families, investigators, and the CHIMERA team who support their studies and these programs.
Speaker Change: In conclusion, as we approach year-end, it is quite exciting to see the trajectory that chimeras had in 2024, especially within our immunology pipeline. We've advanced in the clinic KT621.
Speaker Change: with what could become one of the biggest programs in our industry. We have supported Sanofi to advance KT474 in expanding the Phase II studies. We've developed a TIK2D grader with a compelling profile and are closer to the clinic.
Speaker Change: And we have raised a total of approximately $600 million in just 2024 that has enabled us to have cash into mid-2027 and through several inflection points across our pipeline.
Speaker Change: I will pause here and let Jared share more details on our programs, and Bruce will walk you through the third quarter financial results. I'm looking forward to the Q&A session at the end of our prepared remarks. Jared?
Jared Gollob: Thanks, Nello.
Jared Gollob: As it relates to immunology, I'd like to first recognize our KT621 team for the rapid progression to advance this first-in-class program through IND enabling studies, culminating in the IND clearance and the initiation of the Phase 1 Healthy Volunteers Study earlier this month.
Jared Gollob: As we have not shared many details on the trial design, I wanted to take the opportunity now to provide a quick overview of the Phase I design.
Jared Gollob: The SADMAD Healthy Volunteer Trial includes single and multiple ascending dose cohorts evaluating KT621 as compared to placebo.
Jared Gollob: In the FAD component, each subject receives a single dose of either KT621 or placebo.
Jared Gollob: In the MAD component, each subject receives a daily dose of either KT621 or placebo over 14 days.
Jared Gollob: In terms of data we plan to share, the main objective of the trial is to demonstrate that we can robustly degrade STAT6 in blood and skin at doses that are safe and well tolerated.
Jared Gollob: Based on our preclinical work, we are targeting statistics degradation of 90% or more, which is the level at which we saw strong biologics-like activity in our preclinical models.
Jared Gollob: In fact, levels of pathway blockade, in this case measured by STAT6 levels, are the data that we have shown to be translatable to patient efficacy.
Jared Gollob: As we have said, STAT6 degradation and safety and tolerability are the key readouts from this study.
Jared Gollob: Additionally, as many of you know, we plan to measure certain Th2 biomarkers, specifically IgE and TARC, in the healthy volunteers on our study.
Jared Gollob: We fully expect KT621 to have an impact on these biomarkers.
Jared Gollob: However, we believe the impact is likely to be much more robust and relevant in patients, as is also true for dipilomab.
Jared Gollob: With enrollment underway, we continue to expect to report the full SAT and MAT Phase 1 results for KT621 in the first half of 2025.
Jared Gollob: At or before that time, we will also share our plans for the next stage of KT621's development.
Jared Gollob: I'll now turn to our TICC 2 program.
Speaker Change: As Nello mentioned, we made the decision to advance a new development candidate, KT295, into the clinic, which we believe we can do without impacting our stated timelines of the first half of 2025 for the start of the Phase I study.
Speaker Change: I thought I would take a few minutes to share some details around KT295, particularly a comparison to KT294 that influenced our decision.
Speaker Change: You can also reference the TIC-2 program slides in our corporate presentation, which is available on our website.
Speaker Change: Asides 48 and 49 of our corporate deck, you can see that in preclinical testing, KT295 demonstrated picomolar degradation potency and potent inhibition of the IL-23, IL-12, and type 1 interferon pathways.
Speaker Change: showing its potential to recapitulate the biology of human TIK2 loss-of-function mutations.
Speaker Change: Like KT294, on slide 50, KT295 did not impact any of the other JAK proteins and spared IL-10 signaling, a feature important in the treatment of inflammatory bowel disease.
Speaker Change: Importantly, KT295 had greater in vivo activity compared to KT294 as shown back on slide 48.
Speaker Change: With this profile, KT-295 has the potential to replicate the TIK2 loss-of-function profile and achieve biologics-like activity at lower doses than what was predicted for KT-294.
Speaker Change: And as a reminder, the goal of the previously announced decision to expand the Phase II program was to structure the hydradenitis effertiva and atopic dermatitis trials with the necessary regulatory perspective to enable dose selection and advancement directly to pivotal Phase III studies.
Speaker Change: ultimately with a meaningfully shorter timeline.
Speaker Change: To support this strategy, the size of the studies has increased with additional doses being evaluated in both trials.
Speaker Change: There are no changes to study endpoints.
Speaker Change: Specifically, the HS Phase 2 trial has been expanded from 99 to 156 patients and will evaluate two doses of KT474 versus placebo versus just one active dose previously.
Speaker Change: The AD Phase 2 trial has increased from 115 to 200 patients and will evaluate three doses of KT474 compared to placebo versus just two active doses previously.
Speaker Change: These changes drive the primary completion dates to the first half of 2026 and mid-2026 for HS and AD respectively.
Speaker Change: While that obviously extends the time before the complete phase 2 data readout, we expect that it will meaningfully reduce overall development timelines for the KT474 program by allowing a faster path to pivotal studies.
Speaker Change: We're energized by the progress and potential impact of our immunology programs, each representing pipeline and a product opportunities.
Speaker Change: And, we believe that our oral degraders are uniquely positioned to have both the efficacy and safety of biologics with multiple development opportunities and large high event need indications.
Speaker Change: Finishing up on oncology, I will not add too much more to what Nello said earlier, but I did want to remind everyone that we will be sharing the totality of the phase one data for our STAT3 degrader, DT333, at ASH in December.
Speaker Change: As a reminder, our latest enrollment was focused on Hodgkin's lymphoma patients, given the promising responses we observed in that population, and those results will be included in the poster presentation.
Speaker Change: I'll stop here and ask Bruce to review the third quarter financial results. Bruce?
Bruce Jacobs: Thanks, Jared. As we have a lot to cover on this call, and I'm sure you all have many questions.
Bruce Jacobs: I'm going to provide a quicker than normal overview of our financials and then refer you to the financial statements in the press release in our 10-Q, which we filed this morning.
Bruce Jacobs: In the quarter we recognized $3.7 million of revenue, that was all attributable to Sanofi and the collaboration.
Bruce Jacobs: Combined spending of R&D and SGA excluding cash-based, non-cash, stock-based compensation.
Bruce Jacobs: was $61 million in the quarter and that's down about 2% sequentially from the June quarter. And then finally we ended the quarter with $911 million of cash on our balance sheet providing a cash runway to mid-2027.
Nello Mainolfi: I'll now turn the call back to Nello. Thanks, Bruce and Jared. Before we open the call to questions, I just want to reiterate that we're more enthusiastic than ever about the opportunities in front of us. Advancing KT61 in the clinic is a significant milestone for Chimera and the industry.
Nello Mainolfi: And we're doing so with a very exciting drug profile based on our preclinical finding. We're executing on the rest of our immunology pipeline, and we look forward to sharing updates on TIC2 and providing more visibility on other pipeline programs, which we have yet to disclose, likely next year.
Nello Mainolfi: We're well-resourced to advance our best-in-industry pipeline of degraded therapeutics and look forward to keeping you updated with our progress. The next six to 12 months will provide multiple value-creating catalysts, and we look forward to sharing these with you.
Nello Mainolfi: Finally, I wanted to thank the Chimera team and our collaborators for continuing to deliver on very ambitious goals and first-in-industry endeavors. I'll pause here and ask the operator to open the call to questions.
Nello Mainolfi: Thank you.
Speaker Change: We will now begin the question and answer session.
Speaker Change: To ask a question, you may press star then 1 on your touchtone phone. If you're using a speakerphone, please pick up your handset before pressing the keys. If at any time your question has been addressed and you would like to withdraw it, please press star then 2. We ask that you limit yourself to one question and one follow-up. At this time, we will pause momentarily to assemble our roster.
Speaker Change: The first question comes from Mark Fram of TD Koenigsberg.
Mark Fram: Thanks for taking our questions.
Mark Fram: Thanks for taking my questions.
Mark Fram: Maybe thinking to the 621 Healthy Volunteer data, and thanks for the clarity on exactly where the target profile is, but maybe thinking through to the TH2 biomarkers, investors seem to be really trying to comp this to what was seen with Dupy, as you alluded to. How reliable do you think those
Mark Fram: changes, this percent changes in IgE and TARC from the Healthy Volunteer Study, you know, almost a decade ago, really are, you know, how comparable and how tight of a range do you think you need to get to?
Speaker Change: Yeah, maybe I'll start and Jared, please jump in.
Speaker Change: So first, Jared, I think, explained that the main goal of the Phase I study, for any program but especially for us, is first to demonstrate that we have predictable
Speaker Change: a direct biomarker. So don't forget lots of other modalities and companies use downstream biomarkers because they're not able to have a proximal biomarker. So we have the most proximal biomarker, which is
Speaker Change: STAT-6 protein levels.
Speaker Change: So we can look at STAT6 protein levels in blood and skin to show that we're able to block I4-13 pathway fully. That's the goal of the study. That is the only biomarker that has been correlated to disease impact.
Speaker Change: Again, blocking the pathway has been correlated to disease impact. In fact, actually there was a recent paper, sorry if I'm digressing a bit, where actually there were humans where they found partial loss of function variant of STAT6 that was protective against...
Speaker Change: So that's actually now for the first time even correlating protein function, protein levels to protection in TH2.
Speaker Change: So now, many companies, including Regeneron back in the day, and you also saw other companies with this long-acting biologics, obviously look at downstream levels, again, because you can't really measure your direct biomarkers. As you know,
Speaker Change: You know, people have looked at IG and TARC. I feel like IG has been mostly detected by the Dupilumab data, and I think it's from recent publication from other companies, I actually haven't seen IG data out there, but mostly TARC and phosphostatics for other companies.
Speaker Change: But so it's important to understand that they're modestly elevated in active volunteers, right? You're trying to measure something that is just around the baseline. There is inter-subject variability, so it makes it difficult to predict the degree of reduction.
Speaker Change: So if you look at, for example, if you look at the published paper of the Primad that you were referring to in Healthy Volunteers
Speaker Change: the data also from the long-acting IL-13 biologics that is being evaluated in Phase 1.
Speaker Change: So I think, you know, that kind of sets the range.
Speaker Change: I would just discourage people from trying to understand the exposure.
Speaker Change: ability to suppress pathway signaling. Then, you know, again, we have confidence that we'll change the biomarkers and I'm sure they will be in the range of what has been seen for these agents that have been in the clinic.
Speaker Change: talk through with the continuing prioritization of the immunology side. Are there kind of any savings of that from the oncology or it's all going to be redeployed into immunology?
Speaker Change: Yeah, thanks, Mark. It's a good question. So, I mean, there are savings, yes, in aggregate because of the fact that obviously some of the clinical development plans that we contemplated we won't be undertaking on our own.
Speaker Change: However, we do imagine that a meaningful part of that, if not all, would be invested in our immunology pipeline.
Speaker Change: both the clinical development of the programs you know about and the ones that we haven't yet disclosed but will in the future. So, while there might be a modest
Speaker Change: change, you know, in the ultimate cash runway, not enough to change the guidance. I think most of it, you should assume, will be reinvested in our immunology programs.
Speaker Change: Our next question comes from Kalpit Patel from B. Reilly. Please go ahead.
Speaker Change: Yeah, hey, good morning, and thanks for taking the question. Maybe just one on the STAT6 program here. I'm curious if you've made comparisons to DUPI.
Speaker Change: pre-clinically if you've looked at the change in ear thickness in the atopic derm model the the MC 930 and as a follow-up I think the 32 milligrams per kilogram showed the most reductions in IgE so I'm curious what that dose
Speaker Change: Translating to humans. Thank you.
Speaker Change: Yeah, thanks, Calpit. Great question. So let's start with the second. So if you look at the slides that have been up for now close to 12 months,
Speaker Change: So in the mouse...
Speaker Change: To reach 90% degradation, because that's really what we're looking at, we use basically what you said, 30-32 mg per kg dose. In monkeys or in dogs, you actually need a much lower dose, in the single-digit mg per kg.
Speaker Change: So the reason why in mouse you need a larger dose is because actually plasma protein binding in mouse is higher than it is in dogs.
Speaker Change: in monkeys and in humans.
Speaker Change: So, when you do those projections, you should look at maybe more the dog and the monkey data. I would say the dog would show more data than using the mouse. So, we don't talk about those projections. What we've said in the past…
Speaker Change: is that the doses that we've explored in the IREC-IV programs, broadly, are probably, again, broadly what we would be exploring in this program as well. So it's relatively low doses.
Speaker Change: with regards to your first question. So when we run these models we focus on
Speaker Change: driven disease outcomes and so that's why we looked at
Speaker Change: Again, in those models, IG and other.
Speaker Change: and other measures of TH2 inflammation, and for dc.com, we look more at the asthma model where we can look at...
Speaker Change: both lung and infiltrator cells in the lungs as well as other TH2 biomarkers. That model is not only TH2, so ear thickness is not something we...
Speaker Change: we kind of monitor either for DUPI or for R-degrader just because it's a more composite outcome that is non-TH2 as well.
Speaker Change: Okay, got it. Thanks for taking the questions.
Speaker Change: Thank you. Bye. Bye.
Speaker Change: Operator, next question. Our next question comes from Kripa Devarakonda from Truist Securities. Please go ahead. Hi, this is Alex Xenakis on for Kripa. A question I'm going to take two...
Speaker Change: We've had some conversations with investors about what they would describe as a slow launch for SOTIC2, citing some efficacy, good efficacy and indications like psoriasis and maybe some challenges and others like IBD.
Speaker Change: Do you think that a degrader could address these issues and provide additional benefit? And when you think about future enrollments for the studies, would you consider...
Speaker Change: enrolling in TIK2 inhibitor experienced patients in the trial as an extended opportunity. Thanks.
Speaker Change: Yeah, maybe I'll address the first one and I'll let Jared address the recruitment one.
Speaker Change: So, I mean, you obviously bring the point of...
Speaker Change: at the current commercial.
Speaker Change: success of TIK2 inhibitors. I'm going to answer it a bit differently, but hopefully still addressing your point. So what we have right now in the industry, we have a genetically validated target, TIK2, that has been drugged by, you know, multiple molecules from different companies. One has been approved by BMS and there are at least
Speaker Change: you know, two or three other companies in different stages of development.
Speaker Change: We believe strongly at Chimera and I think people that understand TIK2 biology would tend to agree with us that all these inhibitors are going to be difficult to be differentiated because they address only partial function of TIK2.
Speaker Change: Tick-2 has a well-characterized scaffolding function.
Speaker Change: that actually is important in receptor signaling.
Speaker Change: IL-23, IL-12, type 1 interferon. By removing the protein we are going to completely block a TIK2 signaling and we're able to near complete block three of these pathways.
Speaker Change: So obviously, if the profile of our degrader looked like the inhibitor, we would obviously have failed. That's not the type of profile that we're looking for. We're looking for something that can compete with biologics.
Speaker Change: in many of those indications. And I actually believe that...
Speaker Change: If we're able to translate the preclinical profile, we have an even more active molecule with 295 because, again, full target degradation is the name of the game in this particular program. I think that we're going to have a really transformative drug, and I think
Speaker Change: At this point, it's been missed right now because there is a bit of general, maybe fatigue in the TICTU space. But Jared, is there a comment about recruitment? Yeah. I think, you know, for the initial proof of concept study in patients...
Jared Gollob: We would likely not put on patients who had been on prior TIK2 and had progressed.
Jared Gollob: Whereas, you know, we might include patients who have been on a prior TIK2 inhibitor, but have come off due to tolerability issues.
Jared Gollob: Further down the road, once we've gone through initial proof of concept, we might be interested in understanding the activity of our drug, even in those patients who have progressed after prior TIK2 inhibitors, but we probably wouldn't do that in the first study.
Speaker Change: Next question, operator.
Speaker Change: Our next question comes from Brad Canino of Stiefel.
Speaker Change: Please go ahead.
Brad Canino: Hi, good morning.
Brad Canino: But Dupilumab replication in Th2 patients is the major question. Is there a particular type of Th2 disease where this test
Brad Canino: is best to conduct, I guess, how much duration of testing is likely needed, and do you need hard clinical endpoints, or will biomarkers in patients be sufficient to accelerate mid-to-late stage development? Thank you.
Speaker Change: Yeah, Brad, great question. So I would kind of say it this way. I think the goal of the Phase I study is to demonstrate that you can reach
Speaker Change: statistics degradation levels that we believe are therapeutically relevant, which as you said actually anywhere between 70 and 90% we've shown that it's therapeutically relevant, but 90% is where we see maximal activity in a safe manner.
Speaker Change: I believe that Regeneron and Sanofi have done an excellent job actually doing studies of what does Dupilumab do in the blood and skin especially of AD patients with regards to
Speaker Change: And I think that one...
Speaker Change: very briefly get into that type of context and demonstrate that you're able to.
Speaker Change: to have a relevant biomarker signature that shows that statics degradation blocks the pathway, at least as well as an IL-4 receptor antagonist.
Speaker Change: So you could imagine a biomarker study in patients to be exceptionally telling of the profile of the drug.
Speaker Change: And that will probably allow you to move into a large...
Speaker Change: the studies in all the important relevant population. So I think that could be an interesting sequence of events. I think we're not quite ready to share what our plans are, but those are important opportunities to validate this mechanism.
Speaker Change: Thank you.
Speaker Change: Our next question comes from Vikram Parohit from Morgan Stanley. Please go ahead.
Speaker Change: and I'm sure that partnership is something we're expecting in the near term. Thank you.
Speaker Change: Yeah, great question. So, yeah, we're not going to comment on the, you know, ongoing or hypothetical conversations that obviously, you know, happen at
Speaker Change: at any time in the lifetime of companies.
Speaker Change: But what I will say is we've shown across our oncology pipeline that we've been able to demonstrate
Speaker Change: a really impeccable translation of our PK, PT, and safety into the clinic.
Speaker Change: across the different programs, and we've shown some exciting...
Speaker Change: early clinical activity across different indications. And Jared mentioned we'll have an ASH poster on 333, which I encourage people to look out for. And so the activity we've shown has been, in many cases, in heme indications. So in order to maximize value in those patient populations,
Speaker Change: I think a partner there is.
Speaker Change: that has franchised both clinical and commercial in those areas, I think will be able to create most values.
Speaker Change: And, you know, for us, it's really how do we help patients in the most effective way, and that's what's going to drive some of our decision making, given that our focus will be, again, our internal resources in immunology.
Speaker Change: The next question comes from Kelly Shee of Jeffries. Please go ahead.
Kelly Shee: Congrats on the progress and thank you for taking my questions.
Kelly Shee: I would appreciate your insights on what are the major differentiations of targeting status six compared to targeting interleukin-413 or ox40 from a biology perspective.
Kelly Shee: For example, STAT6 is also known involved in innate immunity besides L413 signaling. So what do you see the breadth of indications that the STAT6 program could pursue based on its MOA? Thank you.
Speaker Change: Yeah, Jared, I'll take a bit of this but maybe you can you can help me. So yeah, great question. So what we've shown in our studies pre-clinically that
Speaker Change: Almost all, if not all, is driven from IL-4 receptor signaling, so IL-4N13.
Speaker Change: and we've shown that if you block L4-13, as others have shown, you reduce phosphostat-6.
Speaker Change: levels. If you reduce that six, you reduce alpha receptor level again.
Speaker Change: I don't want to keep quoting this recent paper, but if you read this recent paper on the
Speaker Change: partial loss of function variant of STAT6 actually shows the same that there is reduction of IF4 receptor signaling.
Speaker Change: If you look at gain of function in humans, again, I'm talking about human people.
Speaker Change: Also there, the IF-SAT6 gain-of-functions have severe allergic diseases, TH2 biology. So, we kind of expect...
Speaker Change: and we've seen that, you know, impact, you know, both in our in vivo models.
Speaker Change: where we see efficacy that's comparable to DUPI in the asthma and AD models. And we've seen it in multiple cell types, even in a recent EADV presentation where we looked at
Speaker Change: transcripts involved in itch and pain, which are key symptoms in AD. So we think...
Speaker Change: You know, STAT6 targeting really, you know, has an advantage in addition to the unique pharmacology of being able to, you know, degrade STAT6 by over 90%, sort of 24-7 could give us pharmacology that may be unique and differentiated from what can be achieved with the upstream monoclonal antibody biologics.
Speaker Change: Great, thanks.
Speaker Change: Our next question comes from Jeff Jones of Oppenheimer.
Speaker Change: Please go ahead.
Jeff Jones: Good morning, guys, and thanks for taking the question. I guess I'll stay on 621 in Stat. 6. Clearly, you guys aren't the only ones targeting Stat. 6, and your IRAC4 partner Sanofi is working with both Recludix and Nurex.
Jeff Jones: Could you comment on the differentiation between a degrader approach here for STAT6?
Jeff Jones: versus the small molecule approach and maybe any differentiation between your degrader platform and Nurex's. Thank you.
Speaker Change: Yeah, so great question. So first I would say that we're the only company that has actually generated a wealth of data comparing six to one and statistics degradation to approved medicines.
Speaker Change: And while all the data so far has been preclinical, so there's always the caveat of preclinical, we've shown that STAT6 degradation can phenocopy in a variety of models what dupilumab does.
Speaker Change: both in terms of breadth of activity, and some would argue that we've seen even more activity than the pitomab in some of these models, but so that's that. I think what we believe is that degrading STAT6.
Speaker Change: is the only pharmacological way to block this pathway as fully as a saturating dose of an IF4 receptor alpha antibody.
Speaker Change: you can use a small molecule inhibitor to block SAT-6.
Speaker Change: But blocking the pathway, given that these are occupancy-based, there is the challenge of PK and PD correlations.
Speaker Change: We believe that the degree that there is both highly potent and catalytic, that doesn't require the correlation between PK and PD, has a much more profound impact in terms of pathway blockade. I would also...
Speaker Change: I encourage you to be patient as you'll hear more from us on this particular topic in the near future. With regards to us...
Speaker Change: and other companies, it's hard for me
Speaker Change: Again, I think no other company has shown any data. No other company has compounded even in
Speaker Change: for what we understand.
Speaker Change: that have made past or at development candidates. So, I mean, those two companies you cited are just two out of many that are doing preclinical work in stat six. I think since we...
Speaker Change: share their data. I've heard of many other companies that are attempting to do what we've done. Again, I'll encourage you to continue to follow us. You'll hear more about our efforts in StatSix, even beyond 6-to-1, as we progress this program.
Speaker Change: Appreciate the update guys. Thank you.
Speaker Change: Thank you.
Speaker Change: The next question comes from Eric Joseph of JP Morgan. Please go ahead.
Eric Joseph: Hi, good morning. Just picking up on the phase 1 trial with 621, I'm sorry if I missed it, but can you give us a sense of sort of the number of dose cohorts and patient numbers that you're evaluating?
Eric Joseph: and Matt components, or maybe a partial readout thereof, and yeah, and the extent to which sort of the prior phase one with the IRAC-IV is a useful roadmap here.
Speaker Change: On the group side, you didn't miss anything, Eric. So Jared can tell you more about at least what we've done at this point about your question. Yeah, I mean, we can't provide a whole lot of color around the actual number of those cohorts, but I think your comparison to the IRAC-IV Phase I SAD-MAD, you know, probably is within the ballpark in terms of how we plan to interrogate, you know, both the SAD and MAD portions. And just as a reminder, these are...
Speaker Change: placebo-controlled cohorts, you know, of healthy volunteers.
Speaker Change: going across a full range of doses of both SAD and MAD and we plan on doing that.
Speaker Change: efficiently with Healthy Volunteers. And as we mentioned, the data readout in the first half of next year will include both the SADD and MADD portions. So it will be the full data set from the Healthy Volunteers SADD-MADD that we reveal in the first half of next year.
Speaker Change: Thank you.
Speaker Change: Sorry, Eric, just to add, because it's going to show up on clinicaltrials.gov in a few days, anytime, I think we say there that the total number of patients in SADM is roughly 120, or up to 120, so that's...
Speaker Change: That's the additional piece of info we can share today. Go ahead, do you have a follow-up?
Eric Joseph: Yes, thanks for that detail. Yes, we were looking for the...
Eric Joseph: targets programs here in that space over the next year or so.
Speaker Change: Yeah, I mean, for sure. So we've, you know, it's been three-plus years that
Speaker Change: We have focused
Speaker Change: are research and now development experts in immunology. We're working on many, many programs.
Speaker Change: We have multiple development candidates.
Speaker Change: that are being nominated in the next few months. So we'll be happy to share as again, as we've done in the past, when we're close to the clinic, we're happy to share next targets. I think we've also learned from our
Speaker Change: previous experiences that maybe we should wait a bit longer before sharing our target and data package for competitive reasons, so maybe we'll share one more a bit closer to the clinic than in the past, but you should expect next year at least one disclosure.
Speaker Change: The next question comes from Ellie Murrell of UBS.
Speaker Change: Please go ahead.
Speaker Change: Hey, it's Sam on for Ellie. I guess can you just touch on a little bit your level of confidence for IRAC-IV's efficacy in HS versus atopic derm heading into those C2 readouts in 26?
Speaker Change: How quickly do you expect to move into patients following the FADMAD portion and any expectations for timing on that? Thanks.
Speaker Change: So maybe I'll take the second and I'll let Jared take the first one. So as we said, I think we've said it today, that we expect to go into patients soon after the phase one. To be honest, mostly for competitive reasons, we're not sharing those plans yet. We have them, we've had them for months.
Speaker Change: if not for years, but we'll be able to share as we're closer to those studies what the plans are, both in terms of near-term development and eventually long-term development.
Speaker Change: Jared is on the IREC floor. Yeah, I think in terms of your question around our level of confidence and being active in HS versus AD, I think we have, and Sanofi as well, have a high level of confidence in potentially being active in both of these indications. I mean mechanistically, for example, HS, you know, we know is driven by IL-36, IL-1, total like receptor activation. AD, we know there's an important component of IL-1, IL-33, and total like receptors.
Speaker Change: I think there's a mechanistic basis for believing that IRAC-IV targeting should be effective there. And I think also if you look at our phase one study where we did have.
Speaker Change: in both of those diseases impacting pain significantly in HS and pruritus and AD, these being the number one symptoms that affect quality of life in these patients. And so, I think in addition to that phase 1 study, we showed modulation of pro-inflammatory pathways and skin biopsies from both of those patients. So I think we have confidence in both and look forward ultimately to the clinical readouts from the phase 2b trials, which will ultimately answer that question.
Speaker Change: The next question comes from Michael Schmidt from Guggenheim.
Speaker Change: Please go ahead.
Michael Schmidt: What are learnings from stat six knockout animal models? Thanks so much
Speaker Change: Yeah, thanks, Mike. So...
Speaker Change: So in terms of what we know is that STAT6 degradation and even 40 fold above the exposure in which we reach
a full septic degradation, we have not seen in preclinical species any adverse events. Our molecule, as you've seen, 6-to-1, is an exceptionally selective molecule in both proteomics as well as any other biological testing that we've done.
Speaker Change: So we do not expect
to have any off-target activity. So, you know, I don't have an answer for you. What we expect is in terms of...
Speaker Change: safety flag. The reality is that so far we haven't seen anything. We hope not to see anything in the clinic also. In terms of what we know from genetics, so we know that knockout mice are
Speaker Change: are normal and fertile.
Speaker Change: We know gain-of-function statistics, people have...
Speaker Change: severe atopic diseases, which
signaling through the R4 receptor alpha pathway. Again, I mentioned already twice this is also this partial loss of function. Humans, which also are protected, they don't have any phenotype.
Speaker Change: So, I would say that if we look at the totality of our data, it is, you know, the perfect target and we hope we're right.
And just a quick follow-up. So in terms of subsequent studies, how do you think about prioritizing potential indications? Would you...
Speaker Change: move into AD first, perhaps? I know there's a lot of work on STAT6 out there in lung inflammation, so asthma is at the top of the list. How do you plan on prioritizing potential opportunities? Yeah, I mean, look, again, as I mentioned earlier, we were not going to disclose our clinical development plan, not because we don't have it, it's just premature at this point, but I can say that, you know, we believe this is a Th2 drug.
Speaker Change: This is not an AD drug or an asthma drug. This is a Th2 drug. So this drug has the opportunity to work in all these indications that DuPilumab has worked in. So we're talking now 7-8 indications with also the most recent data.
Speaker Change: would likely be the primary indications, but we are committed to helping all patients of all ages, of all severity of diseases. That's our mission and vision for this program, for this franchise, I should say.
And so we are going to do as much as possible to help as many people as possible, unlike the biologics that are now on the market or soon to be on the market.
The next question comes from Faisal Khurshid from Learing Partners.
Please go ahead.
Hey guys, thanks for taking the question. I realize this might be premature but wanted to ask anyways. So how are you thinking about partnership opportunities on KT621 and when do you think the best time for that would be?
One answer would be we're not thinking about that, but to answer, it is a good question, it's not premature actually. Not because we're planning to do so, but it's good to discuss. So we believe we're best positioned to develop KT621 and our franchise through the next inflection point. We believe it will be, I believe personally, it will be exceptionally premature to have these discussions.
in the near future. I think we have a great development plan that will take us through.
some compelling, hopefully, Phase II B studies. I think as we're nearing commercialization and Phase III and commercialization, you know, the questions will be based on our cost of capital, our pipeline, what is the best way to create value and impact patients.
One part would be to, you know, go all in.
and become, you know, these amazing companies that commercialize this product everywhere. Another path would be to find a partner that helps us.
Speaker Change: commercialized this drug in particular regions, but it's going to be an extremely high bar for us to partner CET6 and we've been asked multiple times it's probably an understatement.
Speaker Change: Great. Thank you.
The next question comes from Andy Chen from Wolf Research. Please go ahead.
Andy Chen: Thank you.
Can you guys hear me?
Yeah, yeah, I think we got to... yeah, did you have anything else? I think you stopped at some point. Yeah, it sounded like it cut off for a second. So let's say first we assume that the new doses are higher in both trials because the efficacy can go higher, or are we thinking of this wrong?
So it's a great question actually. So let's take a step back because actually maybe we because we've talked about this for so many times we didn't today. So I will remind everybody that how we got to this point that Sanofi decided elected to do a safety efficacy IA early in the year.
to look at the profile of the drug to that point and decided to use that data set to make an investment decision or not actually and the data and again early data in both safety and efficacy
will support DEVOLVE and increase investment to accelerate the overall development timeline.
And so what we haven't said...
It's a lower or higher dose. I think, you know, you can speculate a thousand things. I think what we've said, though, publicly, is that the need or the desire to add another dose was driven from regulatory needs.
to conduct dose ranging studies before selecting a dose for phase 3.
and so it's probably neither of your hypotheses, it's more they wanted to add another dose so that you've checked that box.
in order to move into late development, into phase three studies, and maybe less about was it not safe or too safe. I think the data that we both saw was compelling enough that it was about accelerating the study.
Got you, got you. Makes sense. Thank you.
So, I think this was the last question. I wanted to thank everybody for joining our call. As you all know, we're easily reachable if there is any follow-up questions from...
Andy Chen: our stakeholders externally. I want to thank our team again because they continue to do some amazing work.
and, you know, looking forward to an exciting year, year-end and early next year. We've probably never been busier at Chimera and so I think everybody says busy is good. So looking forward to the next update.
This concludes today's presentation. You may now disconnect.