This conference call transcript was computer generated and almost certianly contains errors. This transcript is provided for information purposes only.EarningsCall, LLC makes no representation about the accuracy of the aforementioned transcript, and you are cautioned not to place undue reliance on the information provided by the transcript.
spk14: Welcome to the Chimera Therapeutics quarterly conference call. Leading the call for management are Nello Malby, founder and CEO, Jareb Golub, chief medical officer, and Bruce Jacobs, chief financial officer. After management's prepared remarks, we will open the call to your questions. To ask a question, please press star one on your telephone keypad. If at any point you would like to withdraw from the queue, please press star one again. Before we get started, I would like to remind everyone that some of the comments that management make on this call include forward-looking statements as outlined in the press release. Actual events and results could differ materially from those expressed or implied by any forward-looking statements as a result of various risks uncertainties, and other factors, including those set forth in Chimera's most recent filings with the SEC and any other future filings that the company may make with the SEC. You are cautioned not to place any undue reliance on these forward-looking statements, and Chimera disclaims any obligation to update such statements. I will now hand the call to Nello Manolfi, Founder President, and CEO.
spk11: Thank you, Operator, and thank you, everybody, for joining us today. We're very excited to share with you the progress we've made over the last quarter and how it contributes to achieving our mission to building best-in-class, fully integrated, global, the greater medicine company. We recently completed the patient cohort portion of our KT474 phase one clinical trial, which concludes the phase one campaign for this drug. Jared will share more details in his remarks, but with the study completed, we're currently in the process of collecting and analyzing all the data. We plan to share, as we always do, the data and the analysis of the data with our partner Sanofi. And as announced, we will subsequently share the data publicly on a company webcast on the morning of December 14th, 2022. As we have reiterated in the past, the objective of the patient cohort is to confirm that PKPD and safety in patients with AD and HS is consistent with what was demonstrated in the healthy volunteers, the SAD and MAD cohorts. As we announced last month, We plan to update investors also in our clinical oncology pipeline on the December 14th call. I believe you all know we have two clinical stage programs, the RACIMED KT413 and STAT3 KT333, and one program that we expect to enter the clinic soon, which is our MDM2 degrader KT253. With respect to the ongoing trials, the KT413 and KT333, they're both in those escalating stages of our phase one portion. As a reminder, the objective in these early dose cohorts is to demonstrate what we call a proof of mechanism. which we define as the ability to degrade the proteins of interest, which obviously is STAT3 for 333 and then for 413 is IRAC4 and even substrates, ECOROS and ILOS, with an advanceable safety profile. Again, Jared will share more here as we go into the call. Along with our clinical progress, we continue to work to ensure that we have the resources to build our company in a sustainable way and continue to invest in our clinical programs, discovery pipeline, platform, and teams. To this end, in August, we raised an additional $150 million through a private placement equity financing, which was led by a broad group of really committed, strategically aligned, and long-term oriented investors, each of which demonstrated their confidence in the team and share our optimism in Pemera's future. As a result, we ended the third quarter in a very solid financial position with approximately $596 million in cash. Before I turn the call over to Jared, I also wanted to take a moment to recognize the change we announced today on our board of directors. As many of you have heard me say, we aspire to build Chimera into a fully integrated biotech company and to sustain a leadership position in both PPD as well as in biotech. As we work to achieve this mission, we obviously will continue to build both an employee base as well as a board of directors that bring all the requisite knowledge and experiences to support our success. To that end, we're pleased to announce that Dr. Victor Sandor has joined our board of directors. For those of you who don't know Victor, he has deep expertise in global clinical development of medicines that have significantly impacted lives of patients, especially in oncology. He was most recently the CMO at RA Biopharma prior to his acquisition by Pfizer and has had an impressive career in the biopharmaceutical industry. Importantly, at the same time, I also would like to recognize and thank another director, Don Nicholson, who will be leaving Chimera as director after having served for the past five years and having started just shortly after the company's formation. Don is one of our longest-tenured directors and has been an important contributor to Chimera's growth and success over the last five years. We're very thankful for all of his important contributions and wishing the best. With that said, Jared will now cover in greater details a recent progress for each of our disclosed programs before turning the call over to Bruce for a financial update. I will then finish with some concluding remarks before handing the call back to the operator for a Q&A session in which Jared, myself, and Bruce will be available. Jared?
spk03: Thanks, Noah. I'm excited to share updates on our three clinical programs. I'll begin with our IRAC-IV program, AT474 is a potentially first-in-class oral degrader of IRAC4, a key protein involved in inflammation mediated by the activation of toll-like receptors in IL-1 receptors. AT474 is being developed for the treatment of TLR, IL-1R-driven immune and inflammatory diseases, such as hydradenitis suppurativa, atopic dermatitis, and potentially others. As you may recall, Part C is an open-label study of KD474 administered daily on an outpatient basis for 28 days with patients followed through day 42. As we shared last month, we've completed dosing in the patient cohort or Part C of our phase one trial for KD474. Additionally, we can confirm today that all patients have completed their last visit or day 42 of the study. The Part C patient cohort followed the dosing of over 100 healthy volunteers in the single ascending dose and multiple ascending dose portions of the Phase I trial. In the SAD and MAD studies, we demonstrated near-complete IRAC4 degradation in peripheral blood mononuclear cells and skin, robust inhibition of multiple ex vivo stimulated disease-relevant cytokines, and a favorable safety profile. Part C includes patients with either moderate to severe hydradenitis suppurativa or atopic dermatitis, and is examining the safety, pharmacokinetics, and pharmacodynamics of KT474, while also exploring early signs of clinical activity. Patients received a daily dose of 75 milligrams of KT474 in the fed state. This dose is expected to provide a plasma exposure that is approximately equivalent to that achieved with a 100 milligram per day dose in the facet state in healthy volunteers in the MAD portion of the trial, which showed maximal or close to maximal degradation in blood and skin and broad disease-relevant cytokine inhibition ex vivo. As previously mentioned, the goal for this study is to confirm that our PK, PD, and safety profile in patients is in line with what we have seen in healthy volunteers. In December, we plan to share data on the impact of KT474 on IRAC4 levels in PBMC and in active HS and AD skin lesions, as well as on the expression of pro-inflammatory gene transcripts in skin lesions and on plasma biomarkers of inflammation. We are also undertaking an exploratory assessment of early impact on clinical endpoints, including eczema area and severity index, or EZ for AD, total abscess, and inflammatory nodule counts, or HS, as well as symptom scores and global assessments of disease severity for both AD and HS. As we have noted in the past, it is important to consider that this is an open-label study without placebo in a small number of patients, and one in which we do not expect to reach steady-state IRAC4 degradation in skin until the second half of the four-week dosing period. And as a result, the data on early signs of clinical activity should be viewed through that lens. We will also be following safety and tolerability in Part C. And as a reminder, in our SAD and MAD studies, KT474 demonstrated no serious adverse events and only a few mild to moderate adverse events. Our December update will include a similar safety analysis including whether the modest non-adverse QTC prolongation that we observed with multi-dosing in healthy volunteers that plateaued after seven days continues to show evidence that it is self-limited, but in this case, out to 28 days. Before I conclude my remarks, I will update everyone on our disclosed oncology pipeline, which includes our SAS3, Arachamid, and MDM2 degraders, the first two of which are in the dose escalation stage of their ongoing phase one trials. As mentioned, our December webcast will include an update on our pipeline. As a quick reminder, STAT-3 is a transcriptional regulator that has been linked to numerous cancers and other inflammatory and autoimmune diseases. Our Phase I clinical trial is evaluating KT333's potential in hematological malignancies and solid tumors. Specifically, the trial is evaluating the safety, tolerability, PKPD, and clinical activity of KT333 in adult patients with relapse and or refractory lymphomas in solid tumors. We have been recruiting broadly in Phase Ia dose escalation across solid and liquid tumors in order to reach pharmacologically active doses as soon as possible, before then focusing on patient populations where we expect to see clinical activity, either as a monotherapy or in combination with other agents. The trial's second stage will consist of four Phase Ib expansion cohorts to further characterize the safety, tolerability, PKPD, and antitumor activity of KT333 in relapsed and or refractory peripheral T cell lymphoma, cutaneous T cell lymphoma, large granular lipocytic leukemia, and solid tumors. In September, KT333 was granted its second orphan drug designation by the U.S. Food and Drug Administration for the treatment of cutaneous T cell lymphoma, following its orphan drug designation for peripheral T cell lymphoma earlier this year. Our arachnid program, KT413, is a novel hetero-bifunctional degrader that targets degradation of both IRAC4 and the imid substrate icorose and ilose with a single small molecule. KT413 was designed to address both the IL-1R, TLR, and the type 1 interferon pathways synergistically to broaden activity against mighty 88 mutant B-cell malignancies. KT413 is on a similar timeline as STAT3 and is currently in the dose escalation stage of the Phase 1 trial, evaluating the safety, tolerability, PKPD, and clinical activity of KT413 in patients with relapsed and or refractory B-cell non-Hodgkin's lymphomas. Similar to the strategy I just described for the KT333 Phase 1, we are enrolling a broad population of B-cell lymphoma patients after which we will focus on patients in whom we expect to see the most substantial clinical activity. Specifically, the second stage will consist of two Phase 1B expansion cohorts in DLBCL to further characterize safety, tolerability, PKPD, and antitumor activity of KT413 in relapsed refractory, MI-D88 mutant, and MI-D88 wild-type DLBCL. Finally, KT253, our MDM2 degrader, has completed IMD-enabling studies and is on track to achieve IMD clearance by year end. MDM2 is the crucial regulator of the most common tumor suppressor, P53, which remains intact in more than 50% of cancers. Chimera is developing a highly potent MDM2 degrader that, unlike small molecule inhibitors, has been shown preclinically to have the ability to suppress the MDM2 feedback loop and rapidly induce apoptosis, even with brief exposures. KT253 has the potential to be effective in a wide range of hematological malignancies and solid tumors with functioning or wild-type P53. We look forward to updating investors on our pipeline in December. I will now hand the call to Bruce Jacobs, our Chief Financial Officer, who will share some brief comments on our financial results for the first quarter.
spk02: Bruce? Thanks, Jared. For the quarter, we recognize 9.6 million of revenue, a total that reflects revenue recognized pursuant to our Sanofi and Vertex collaborations. At the end of the quarter, our deferred revenue total on the balance sheet was approximately 77 million. That reflects the partnership revenue we expect to recognize over the next several years, excluding the receipt of any future potential milestones. With respect to operating expenses, R&D for the quarter was $43.9 million. About $4.9 million of that represented non-cash stock-based comp. The adjusted cash R&D spend of $39 million, which again includes the stock-based comp, reflects a 7% increase from the comparable amount in the June quarter. With respect to G&A spending for the quarter, it was $10.6 million, of which $4.2 million represented non-cash stock-based comp. That adjusted cash G&A spend of $6.4 million, again, excluding stock-based comp, reflects a 5% decrease from the comparable amount in the June quarter. We exited the second quarter with a cash and equivalence balance of approximately $596 million. Recall that we do not include in our cash runway any payments for milestones that we have not yet achieved. Our guidance for cash runway of at least into 2025 incorporates the completion of our $150 million pipe, but we do plan to update this runway guidance, in particular the specifics around the extended runway extension driven by the financing closer to year-end. With that, I'll turn the call back to Nello for some concluding remarks.
spk11: Thanks, Bruce and Jared. As we look forward to providing a clinical update on our December webcast, it's clear that Chimera has successfully transitioned into a new phase, one in which we can observe our signs in actions in patients. We are excited to begin to assess the impact that three of our programs may have in patients with cancer and immunological conditions, and to finally demonstrate the advantages of our platform over traditional medicines. With all the progress made this quarter, we're just getting started. In addition to our three clinical programs, we're on track to clear an IMD for MDM2-degrader KT253 this year. And we're advancing several earlier programs with clear, degraded rationale and significant commercial opportunities. With the productive partnerships in place with Berserk and Sanofi, with our recent financing, we continue to maintain an array of pipeline investment opportunities to maximize the potential of our best-in-class platform and discovery engine. At this point, I'd like to thank the Chimera team, as well as our partners, the patients who are participating in our clinical trials, And finally, all of you for participating in this call, and I look forward to your questions. I will now hand the microphone back to the operator so we can take your questions. Thank you again.
spk14: At this point, we will open the call for questions. To ask a question, please press star 1 on your telephone keypad. If at any point you would like to withdraw from the queue, please press star 1 again. We will take a moment to render our roster. Your first question comes from the line of Brad Canino from Stiefel. Your line is open.
spk08: Good morning. First, can you tell us when you expect to deliver the data package to Santa Fe in relation to that December 14th date you've set up? And will the package be based on the 28-day data cut or include the two extra weeks of follow-up? And then, Nell, I want to go back to your R&D day last year. You said a ambitious suite of goals for 2022, which included the first tissue-restricted E3 ligase-enabled program in development. Can you just update us on that status and perhaps share any comments regarding the critical decision points remaining for the target and E3 ligase selection for that first candidate? Thank you.
spk11: Great. Thanks, Brad. Two great questions. So one at a time. So the first one, so we plan to deliver to Sanofi the complete data package. So obviously that will include also the follow-up period of the extra two weeks of observation. I think today We're saying, and it's also on the clinicaltrial.gov, that we have completed that phase as well. So that's when we say the study is completed, we mean that every patient has gone through also the two weeks of follow-up. What we've also said today, that we're still collecting and analyzing data. So the phase of data collection is not completed yet. As soon as we complete that phase, we will share the totality of the data with our partner. So we haven't said when that will happen because, to be honest, we haven't completed all the work that we're doing internally. Maybe the only thing I would add, we've always had a very close relationship and communication with the Sanofi team, so... So we try and be as helpful as possible also in this time when we're still collecting data to make sure that we share anything meaningful as we collect things. To your second question, so we, as I said, we have several programs in the preclinical stage many of which are actually close to entering preclinical development. And, you know, one of those programs entail the use of an E3 ligase that has a restricted expression in the body that will allow us to actually overcome those limiting toxicity of a well-known oncology target. I think our plan, although we haven't firmed it up yet, is to provide an update at some point next year on where those programs are. Maybe we'll disclose. We'll see one or two of them, depending on which stage of development they are. So I guess it's not super satisfying, but I'll say stay tuned as more information will be shared on that.
spk14: Operator, can we go to the next question, please? Your next question comes from the line of Chris Shibutani from Goldman Sachs. Your line is open.
spk15: Thank you very much. Good morning. Just to be clear in terms of the optionality for Sanofi and the decision that they'll make, we may hear from them that they would proceed with both programs one or sequentially. the way that you've structured your relationship there, just so that we can frame the different scenarios that could play out that would be helpful. And secondly, on the KT333, there is scientific premise for pursuing indications outside of oncology. Any thinking there in terms of how you would pursue that? Would that be with partnerships? And does Sanofi have any opportunity to explore that as well? Thank you.
spk11: Chris, if you can stay on the line for one more second. Can you clarify your first question when you said two programs? I'm not sure I fully understood the question.
spk15: Yeah, no, just thinking about the two indications for AD and HS. And so perhaps clarifying that we shouldn't be thinking that the decision from Sanofi is singular and binary, but that there's sort of an option set.
spk11: Yeah, yeah. Sorry, Chris. I missed that. So thank you. So going back to the question then. So as you know, we are in this partnership with Sanofi on IREP4 degraders outside of oncology and immunology. That's actually the spirit of the contract. And both Sanofi and Chimera have large ambitions. We believe that this mechanism has potential to be one, if not the best, small molecule anti-inflammatory drug in a wide variety of diseases. Obviously, we'll have to generate data to support our beliefs here, but that's what we're doing. So when Sanofi will make the decision to transition, if and when make the decision to transition KT474 into phase, into what we call a late development, it's a decision to invest into the global development of the drug. And so it's not indication-based, but it's in the late development. We, as a partnership, we've always been aligned that the reason for Sanofi and Chimera to partner is to use and benefit, at least from Chimera point of view, benefit from the broad both clinical and commercial footprint that Sanofi has built in immunology. And as they say publicly, they want to be the number one immunology company in the world. And so the spirit of the collaboration has always been to try and pursue several indications. But obviously, we would like to... look at the data, and then with Sanofi decide how to prioritize indications going forward. But I would say their decision is in global development of, you know, we hope to be multiple indications. Great, and on three things. Yeah, yeah, sorry, stat three outside of oncology. So we have been talking about this program For a couple of years, we've released data in different conferences. This is something we're very keen on, and I think we'll share some data as we firm up our kind of clinical strategy around this asset. For now, this is something that Chimera is leading independently from any other existing or any potential new partner, but obviously time will tell if things go in different ways. Thank you. We'll look forward to December 14th. Thanks, Vince.
spk14: Your next question comes from the line of Divya Rayo from Cohen and Company. Your line is open.
spk05: Morning. This is Divya on for Mark. Thanks for taking our question. We have one on the oncology program and then one on KT474. So just for the oncology programs, what data can we expect at the R&D day and then Could you remind us what level of degradation you would expect to see to translate into clinical activity? And then for 474, with the Part C now completed, I know that you guys are doing some analysis and that is still ongoing, but is there anything else data-wise that still needs to be generated before presenting the data package to Sanofi this quarter? Thanks.
spk11: Great.
spk03: Jada, do you want to take the oncology question? Sure. Yeah, for both oncology programs, the aim is for us to be able to show what we call proof of mechanism, which is knockdown of the intended targets, you know, to a level, you know, that, you know, hopefully is associated with preclinically, you know, anti-tumor activity and to show that we can accomplish that knockdown at doses that are safe and well-tolerated. Your question around what are the target levels of knockdown for the various programs, for the Arachnid program, We've seen that knockdown of IRAC4 and the imid substrates icorose and ilose in the 60% to 80% range is sufficient to give us activity in MIT88-mutated DLBCL. So that's a level of knockdown that ultimately we'd like to see in that program. For STAT3, we've shown in STAT3-dependent lymphomas that greater than 90% knockdown maintained for several days is sufficient to also induce significant tumor regressions in that context. So those are the sort of benchmarks that we'd like to ultimately see. But from the standpoint of what we'll be presenting at R&D day, our hope will be that we'll be through enough dose levels to be able to show initial proof of mechanism at doses that are safe and well-tolerated.
spk11: And maybe the other, I'll take the other question on 474. I just want to maybe take the opportunity to remind what the purpose of the study was and is. And it's really to demonstrate that transitioning from healthy volunteer to patients were able to maintain a good both PD, PK-PD relationship and safety profile to advance the drug into phase two. And so that means that our key goal is to actually collect data to demonstrate that there is a continue to be a strong relationship between exposure and PD that can inform our phase two dose selection. that the PD has now defined, let's say, as aerosol degradation in blood and skin, that PD results into impact on disease-relevant, pathway-relevant, chemokines or cytokines that we believe will create that new now correlation, given that in Healthy Volunteer we weren't able to do that. So correlation between, we call it, let's say, target engagement and something that is disease relevant as the biomarkers. And then as we said, just so that I obviously don't dismiss it completely, we also said that we will be collecting clinical endpoints with the goal of trying to establish a potential correlation again with some PD, some biomarker, anything that can be tied to a clinical endpoint that obviously would be highly exploratory given the size and the design of the study. Now, going back to your question, sorry, we are actually still collecting data. So there is some data that you can imagine is easily accessible in an open-label study, And then there's some data, especially with regards to PD, that takes weeks to generate. So we are generating data. We're not just analyzing data. And so it would take us more time to fully collect all the data. And that's the only reason. for having a December call because we want to have the totality of the data in hand before sharing it again, both with Sanofi to get their approval to share the data and then with all of you.
spk05: That's helpful. Thank you.
spk14: Your next question comes from the line of Joseph Eric from JP Morgan. Your line is open.
spk12: Thanks. Good morning. It's Eric Joseph from J.P. Morgan. No, I'm assuming that some of the additional data you're gathering is perhaps the intermittent dosing data in Healthy Volunteers. I know you added this additional cohort looking at biweekly or every other day dosing. Is that specifically the data that you're gathering? And I guess what should we expect those data to be presented at December 14th. And then, I guess, can you just talk about the rationale for evaluating that regimen specifically with 474? Thanks.
spk11: Yeah, thanks, Eric, for bringing that up, actually. So the answer to your first question is no. I mean, we were focused on the patient cohort. And as I said, just maybe to be even more transparent, in these studies, You can get initial read on safety and clinical endpoint quickly. There is obviously a data lock and a cleanup that takes time even to do that. And what is taking longer, as it does and as it's done in the past, is generating all the PD and biomarker data. These are not simple assays. In fact, these are cutting-edge data. things that we're doing in industry. I don't believe other companies have ever done what we're doing in HSND patients, and I have to thank Jared and his team for all the work that they've done in actually designing and executing and hopefully eventually generating the data. With regards to the infrequent dosing, as I've said in the past, this was a PK-PD experiment that we wanted to run before the eventual transition of the program to Sanofi, where we will lose the ability to run clinical studies. And this was a study that we wanted to learn not just for KT474 and learning given that in the sad, we learned that had extended degradation after a single dose. So we wanted to learn, you know, how far and how reliable it would be, you know, dosing less frequently, but also for us was a big platform question. But I don't expect that that will be, you know, part of, you know, our disclosure. I think we'll be focused on, unless there is anything relevant to that, to the development of the program, but we'll be focused on the patient data and how, hopefully, that will be informing further development.
spk12: Okay, great. I appreciate that. Maybe just a follow-up, if I could, on the oncology programs. And thanks for sort of setting... You can't hear.
spk11: I don't...
spk12: Oh, excuse me. Can you hear me now?
spk11: Yeah, again.
spk12: Okay, good. Thanks for just a follow-up on the oncology programs, and thanks for framing expectations into December 14th. I'm just wondering whether, as part of the presentation, you might be at a point where you can detail a recommended phase 2 dose. Really, how close of line of sight do you have on when you might start enrolling the expansion cohorts for 333 and 413. Thanks.
spk11: Yeah, I think it's – first of all, at this point, it's probably not appropriate for us to comment, so we might comment on this in December. But what I would say is, you know, we're still in the dose escalation phase, and we're focused on – just maybe to take a step back. The beauty of this technology and the reason why many of us are here is because it allows you to do drug development in a completely different way. It allows you to do a data-driven drug development where you know at any given point in your clinical trials, if you design them right, where are you versus your expectations or versus your prediction or your data-driven expectation of What kind of degradation do you need to achieve the type of efficacy that you're looking for? So the ability that we have in dose escalation, instead of blindly escalating to an MTD, we have an opportunity to escalate and learning where we are versus our expectations on level of degradation needed to achieve efficacy. So the goal of this year is really to see is the translation of the PKPD as, you know, let's say as good as we've seen with KT474, where we degrade the protein in a reliable, predictable, and dose-responsive way, and the safety that goes with the degradation profile is in line with what we've seen preclinically. Because if that is the case, we will have really... bullish prospect on the potential clinical success of these drugs because the mechanisms are well known in oncology and here is really getting the PD and the safety right for both of these drugs in oncology. And I think if we can show that, I think it will be a large de-risking event for this program moving forward. Now, I don't want to dismiss your question. I think we will comment on there, but I suspect that Next year, we will continue to do both some escalation and some expansion at a time that maybe we will discuss more in December.
spk14: Your next question comes from the line of Vikram Perhohi from Morgan Stanley. Your line is open.
spk04: Hi, good morning. Thanks for taking my questions. Following up on KT474, I just wanted to see if there had been any more exploratory work done on the palpitation and QTC signals that you reported earlier with the Healthy Volunteer Data Set. And if so, if there's any update to communicate out here on anything more you might have learned versus your prior update on what the mechanistic rationale for these findings could be. And then secondly, on the same program, going back to your prepared remarks, you mentioned you won't be seeing steady-state degradation until the second half of the dosing interval in Part C. So given that, how would you advise people to interpret the efficacy data here versus some other 28-day dermatology data sets that are available in the space? Thanks.
spk11: Great. Thanks, Vikram. Maybe, Jared, if you want to comment on the first question. The only thing I will say, maybe before passing it on to Jared, we have never... draw a line of correlation between palpitation and QT. So, but I'll let Jared comment on anything else that, you know, we want to share on our understanding of that mechanism.
spk03: Yeah, no, I think what we had, what we've described previously, right, based on our in vitro data, you know, is that with, you iPSC cardiomyocytes, we have been able to see, you know, an effect on current that's consistent with a mild, you know, herd effect at high concentrations, you know, that is somewhat delayed and that is sort of consistent with the sort of effect that we saw in the clinic where we have a delayed effect that's not, in the clinic anyway, a dose or exposure dependent and appears to plateau. after day seven and then remain steady until the end of the dosing period at 14 days. And so we don't really have anything new to report, you know, on those lines in terms of our understanding mechanistically of what's going on. I think what will be important for us in part C is to really, as we continue to observe now out to 28 days of dosing past 14 days that we did in part B, do we continue to see sort of a plateauing of that QT effect. And I think that will, you know, further inform us as to,
spk11: you know, what sort of, you know, clinical impact, if any, there is of this subclinical, not adverse QT effect that we saw in Part B. And maybe to then to get back to you on the efficacy question, I mean, the question you asked is really why we continue to say that expecting, you know, clear efficacy readout from this study is I think kind of unfair for how we've designed the study and the purpose of the study and it's really difficult for us kind of scientifically to take the eventual data set and compare it to other agents given that this is a different mechanism new pathway small numbers, no placebo, and again, for a new mechanism, relatively very short time. But I think what we want to be able to do, if possible, and again, we'll have to generate the data and see, is to see if there is, if there are any trends between what we see in terms of PD and biomarker changes, any early signs of differences in clinical endpoints. It would be really hard, if not impossible, for us, one way or the other, to say that the drug works or doesn't work in HSNAD based on comparison with other studies, just because this is a different study.
spk14: Your next question comes from the line of Ellie Merrill from UBS Financial. Your line is open.
spk01: Hey, guys. Thanks for taking the question. On MDM2, maybe if you could just elaborate on what a potential initial trial design would look like and any commentary on data timelines, say, if we could, assuming IMD clearance the data next year. And then also just in terms of the biology, how you're thinking about what tumor type this would make the most sense in and be best suited for as you would plan an initial dose escalation and thinking about expansion cohorts that you might be looking at things.
spk11: Thanks, Ellie. I enjoy talking about also other programs on our pipeline. So for MDM2, we're really excited about this program, obviously not more or less than others, but it's really, I think, another program that we built to demonstrate that this technology can be used to do things that other technologies cannot do. And as hopefully everybody appreciates, that has been our philosophy in terms of target selection all the time. And when we disclose our next three, four programs that are you know, in a really good stage preclinically, you'll see that that philosophy continues to be true. So with MDM2, this is not a super small molecule. This is just a different biological intervention at that pathway that is looking to eventually and finally replicate the cancer genetics data that shows that absence of MDM2 generates high level of sensitivity in p53 wild-type tumors, which is not what has been seen with small molecule inhibitors. And as we said, the one way that we're able to do is because we remove the protein quickly, we overcome this feedback loop and we drive cell to apoptosis in a way that small molecules are not able to do. So I'll let Jared comment on the clinical trial design, although it's something we haven't fully disclosed, but maybe he can give you a high-level overview. But what I would say, our strategy there is to focus on indications where we see a very rapid apoptotic response that allows us to maximize efficacy and safety for this mechanism. And what I will say is that we have several indications in both liquid tumors and solid tumors that have this type of response. And I believe today our ASH abstract is out, I believe at 9 a.m., highlighting a bit more work on AML, which will be one of the indications of interest. Jared, do you want to give maybe just a high-level example?
spk03: Yeah, definitely. Just to give a high-level overview. And just as a reminder that because of the unique mechanism of action of degrading as opposed to just small molecule inhibition, we're able to sort of dose intermittently. So we're planning on bringing in an intermittent IV dosing, so infrequent IV dosing into the Phase I. And the trial design, it will be sort of a standard Phase Ia dose escalation followed by Phase IB expansion. But importantly, you know, the Phase Ia will be able to set us up to understand safety, tolerability, and PD, both in hemolygnases as well as in solid tumors. And we will have opportunities to put on, you know, indications of particular interest, both in hemolygnases and solid tumors within Phase Ia. And then eventually, you know, once we do come up with a either recommended Phase II dose or maximum tolerated dose to then bring that into Phase Ib expansions, that will likely involve expansions in hemolignancies, especially AML, but potentially others, including lymphoma, as well as in solid tumors. Thanks, Joe.
spk14: Your next question comes from the line of Jeff Meacham from Bank of America. Your line is open.
spk10: Hi, all. This is Joe on for Jeff Meacham. Thanks for taking the question. On KT253, are you hoping to achieve a tumor agnostic label, and can you provide any additional information on patient selection and your breakdown between liquid and solid tumors? Thank you.
spk11: Yeah, Joe, that's a great question. We unfortunately are not in the position to comment on the specifics, but rest assured that that is one of our ongoing translational work. being able to potentially get to that type of tumor agnostic development and approval. But we're not in the position right now to comment on where we are. And this is something we hope to share at different meetings, you know, hopefully next year. I know the team is working on obviously generating data and also identifying the right medical meetings to start to discuss what our translational strategy is.
spk14: Your next question comes from the line of Rich Law from Credit Suisse. Your line is open.
spk13: Rich, are you there? Oh, yeah, sorry. I was on mute. Yeah, thanks for taking my question. Can you comment on what were the stopping rules in place for Part C, and can we rule out all Grade 3 or Grade 4 adverse effects? And also a follow-up question is that you mentioned earlier that you are still preparing data for Sanofi. Can you confirm that Sanofi hasn't seen any of the data yet and there was no piecewise data or real-time safety data that they already saw when the study was ongoing?
spk11: What was the first part? So, you know, I think we've said it in the past. We can't really comment on the specifics. Obviously, if there were events that that impacted the study's success, we would have obviously had to share them. With regards to Sanofi, we really are not in the position to share what we have or haven't shared with them. But again, as I said earlier, you can assume that we're in constant communication as we've been throughout the collaboration. So I'll leave it at that.
spk14: Your next question comes from the line of Michael Schmidt from Guggenheim. Your line is open.
spk09: Hey, guys. Good morning. Just a couple from us. On KT333, which is, you know, your STAT3 program, you know, other than on target degradation in this Phase I study, are there any other PD markers related to STAT3 that you're looking at that could, you know, potentially further validate this target?
spk11: Do you want to take that one?
spk03: Thanks, Michael. Yeah, thanks for the question, Michael. Yes. So in addition to looking at STAT3, yes, we are also looking at, you know, the impact of STAT3 degradation on the actual STAT3 pathway. We'll have the best opportunity to look at that in serial tumor biopsies. We can look at the impact either looking at phosphostat3 or looking at, you know, gene expression profiles for STAT3 pathway activation. So that will give us an opportunity to show not only that we can hit the target, but that by hitting the target, we're able to impact the pathway itself. We'll also be doing genotyping of these patients in order to see whether specific genotypes, for example, pathway mutations or other mutations affecting the pathway, correlate at all with clinical responses as we get into higher doses when we can start to assess the clinical responses and where we can start to bring on the target patient population, especially those patients with T cell malignancies.
spk11: So expect that to be part of a kind of a global assessment of you know, a comprehensive phase one study. Obviously, it's not something that we can do in every patient.
spk09: Yeah. All right. Got it. And then a question on your MDM2 program. It sounds like you are focusing on AML and then perhaps other solid tumors as well. And, you know, I know with this class of drugs, there has been some on-target toxicity, in particular myelosuppression drugs. And I was just wondering, you know, with the degrader mechanism, and I think you mentioned the intermittent dosing, you know, schedule that you're looking at. I guess just given the, you know, the PK and PD around degradation, do you think you can, you know, avoid some of those safety issues that have been associated with some of the other drugs in the class?
spk11: Yeah, so just to clarify, Michael, AML is one of the indications of interest, not the main indication. It's just one that we've generated, let's say we're sharing data of, and will obviously, as we said, be part of our clinical strategy. Going back to your question, I mean, that's the point, the second part of your question. That's the point that I was trying to make before. We want to use protein degradation to do things that small molecules or antibodies or RNAIs or gene editing technologies cannot do. In this case, actually have a safe and effective therapy, at least much more effective than you can do with other agents. And let's say the trick there is really to have a very profound effect very early on, very, very quickly, which again, small molecules cannot have, and then allow for recovery. So Jared mentioned with those infrequently, so with those once every three weeks. And we have seen that that's enough to lead tumor cells to extremely rapid apoptosis. And we also see healthy cells being able to recover because they're obviously less sensitive to cancer cells. And so we're able to manage the safety with maximizing efficacy. In a way, although not exactly similar, but how we're developing our Arachimid and how we're managing neutropenia with the IMID part is theoretically or philosophically exactly the same way. And this is why we built these drugs to be dosed infrequently. These are drugs that have been designed at the molecular level to have extended PD so that you can dose them infrequently, but also with a dosing paradigm that will allow recovery of non-cancer cells. So what we're doing at KMR is not just pushing the envelope of protein degradation in immunology, but what we're trying to show is that actually you can push the envelope on cancer biology through probably very, very thoughtful drug development, using the technology to change the paradigm on how one can think about affecting the biology in tumors.
spk14: Your next question comes from the line of Kelly Shi from Jefferies. Your line is open.
spk06: Thank you for taking my questions. A follow-up question regarding the efficacy rate out of 747 is, so how many lines of prior biologics actually allowed for the trial according to protocol? And do you expect that most of the patients had a prior depiction to also mirror treatment for AD and HS patients, respectively, and to further complicate the efficacy interpretation besides the difference of PKPD and also the administration route of 474 compared to other AD and HS drugs. Thank you.
spk03: Yeah, thanks for the question. You know, we actually did not restrict number or type of prior treatments for either AD or HS patients. So the Part C of the Phase I allowed patients either who had not received prior therapy or prior systemic therapy, as well as patients who had received prior therapy, including biologics. If patients had received any prior systemic therapies, they required a washout period before coming onto the study. So we did not allow concurrent therapy along with our degrader. That would have confounded the results. You know, again, because this is a small open-label study, we were not trying to control, you know, baseline characteristics in terms of prior treatment that would have been difficult to do and probably not appropriate for such a small study. And because, you know, clinical efficacy is not, you know, the primary endpoint of Part C, we didn't feel it necessary to do that. However, when we do look at the results, we will, of course, you know, pay attention to what the prior treatments, if any, were for patients with either AD or HS. And as we interpret results, especially exploratory endpoint results, we will certainly keep that in mind.
spk11: Yeah, thanks, Jared. Just to confirm, so we do not expect or we know that we won't have any impact from previous therapy because every patient, if they were on previous therapies, would have been washed out. And so there would be no previous drug on board when they receive KT474.
spk14: Your next question comes from the line of Mike Kratzke from SVB Securities. Your line is open.
spk00: Hi, everyone. Thanks for taking our question. So having completed the dosing portion in Part C, can you provide any details on the split between the total number of AD versus hydradenitis patients in the study and whether those baseline characteristics are largely consistent with your expectations?
spk11: Well, I mean, I think we're close enough to sharing the data at this point. We're just going to not comment on the split. I think baseline characteristics, Jared, we've always said moderate to severe, right? So I think that's consistent. Right. Yeah.
spk14: Got it.
spk11: Thanks, though.
spk14: Your final question comes from Zhang Xu from Barenburg. Your line is open.
spk03: Good morning. Thanks for taking the question. The first one I was wondering if you can tell us more about the difference in terms of biology between HS and AD. And I guess on your December data set, would you be able to differentiate the potential in these two type of disease and provide prioritization at that point? And then the second set of questions around the safety, given you have been exploring the less frequent dosing schedule in your Healthy Volunteer Mass Study. Can you comment on any change or any safety signal in terms of QT prolongation in that cohort? And finally, on that also related to QT, can you confirm for your oncology programs, that's three and four, and also IREC image, that the QT elongation signal should not be expected. Thank you very much.
spk11: Thanks. So, maybe I'll start from the last, and then maybe, Jared, if you can comment on the first, on the HSAB biology. So the last one is easy. We don't expect that QT has anything to do with the platform, the program broadly. As we've shared already, we have characterized for KT474, this weak acidity for her channel that we believe is compounded by a higher than expected exposure in the cardiac tissues in humans that leads to this A very, again, as we said, very atypical, non-dose responsive, non-CMAX-driven QT prolongation that, again, we believe has no impact, in our view, no impact on clinical development of this drug, assuming it stays within the range that we've seen in healthy volunteers. uh we've also said in the past that we've been able to replicate this change of current in cardiomyocytes i believe jared said it even earlier today and we we've also shared that in that particular assay we've demonstrated that we can take another iraq 4 degrader and and show that we don't change current so we know it's a molecule specific effect um Going back to infrequent dosing and safety, I mean, all we will say is that if there is anything out of the study that is worth sharing, we will share. I guess as I've said it in the past, the reason why we've never discussed this study is because we had almost little or no expectation that it will have an impact on the development of KT474. It will be informative, again, for the drug. It will be informative for the platform. Again, if there is data from the study that is worth sharing, we will share it. in December, but I continue to advise and guide on low expectations there. And then on HS and AD, Jared, if you want to comment on the biology.
spk03: Sure. Yeah, in terms of the biology, you know, even though HS is classically thought of as a Th1, Th17 disease, and AD as a Th2 disease, in reality, there have been very interesting sort of gene expression analyses of skin lesions showing that the inflammation is actually quite mixed in both of these diseases. Even in AD, in addition to Th2, you see Th1 and Th17 elements. And in NHS, you can also see some Th2 elements. In reality, both of these diseases, importantly, are driven by toll-like receptor activation. You know, bacterial colonization of the skin, which activates toll-like receptors, is important in both diseases. And both diseases have also been shown to be driven by multiple different IL-1 family cytokine members. And so there's probably more in common, you know, pathophysiologically between those diseases than one might suspect. And therefore, we think both of these diseases are really prime indications for targeting with an IRAC4 degrader. Great.
spk11: Thanks, Jared. So maybe just to conclude, thanks, everybody, for joining today. I want to say... From myself and the whole team, we appreciate the engagement from the community, from both our analysts and investors we've had. I don't know, hundreds of meetings this year, so we appreciate that there is interest in what we're doing. As you know, we're always available to follow up with many of you that are interested in understanding the facts and the science at Chimera. We're excited about what we're doing. I think that the sky's the limit for the technology, and it's really our responsibility to develop drugs and to build the company that can really capitalize on the power of it. So we look forward to seeing you, hopefully all of you, in December. And some of you may be at that conference where we'll be present in the next few weeks.
spk14: This concludes today's conference call. You may now disconnect.
Disclaimer