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spk08: conference call. Leading the call from management Arnello Mainolfi, founder and CEO, Jared Golub, chief medical officer, and Bruce Jacobs, chief financial officer. After management prepares remarks, we will open the call to your questions. To ask a question, please press star 1 on your telephone. Before we get started, I would like to remind everyone that some of the comments that management may 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 can merit these claims any obligation to update such statements. I will now hand the call over to Nelo Minofi, founder and CEO.
spk06: Thank you, Operator, and thanks, everybody, for joining us on our first quarterly results conference call. We look forward to using this forum every quarter to update all our stakeholders on the progress we're making in building Chimera into a best-in-class, fully integrated, degraded medicine company. Before we transition into the program updates, I just wanted to take a moment to reflect on some of Chimera's achievements since we founded the company. just over five years ago, and also as we near almost our two-year anniversary since our 2020 IPO. When Chemero was founded in 2016, we had both ambitions for the company we wanted to build. As you all likely know by now, the foundation of the company was predicated really on leveraging what at the time was an emerging area of science, targeted protein degradation. While we weren't then and certainly are not now the only company engaged in TPD, I think it's fair to say that we've approached it in a very unique way, and as a result, we believe there are several important points of differentiation with respect to our strategy and our approach that still hold true today. From a target selection standpoint, we've been guided by strict criteria, which we believe has led us to focus on unique high-value targets where there is a clear advantage to using a degrader versus small molecule inhibitor or another technology, several of which you know well and we will discuss today. We remain optimistic. Acutely focused on those targets that address high and met needs, have biology that has been well validated, and where possible, can be addressed with a precision medicine approach. We also embarked on this mission with the belief that to truly harness the full potential of TPD, we needed to invest thoughtfully but aggressively in building our E3LiGASE knowledge, capabilities, and ultimately, our industry-leading E3LiGASE toolbox. We believe our efforts here represent an important competitive advantage that we can and will leverage. While we're building a strong pipeline of oncology-focused degraders, which happens to be the focus also of most of our peers, we believe that there is a great potential in inflammatory conditions, as evidenced by our RAC4 program. But we have not stopped there. as we've engaged with partners to help us target other disease areas, and in doing so, we're building a truly disease-agnostic TPD company. We have also recently unveiled our ongoing investment in targeting high-value undrugged and non-ligandable proteins using small molecule-molecular glues. I think it is fair to conclude that both our pipeline and diverse platform investments position Chimera in a very unique place in the landscape of highly innovative biotech companies. Looking now at the present, from the ambition beginning, we have succeeded in building a company in which the targets that were on top of our list in early 16 and 17 remain our lead programs today. We have entered the clinic with three programs, each of which exemplifies meaningful first in TPD. With our ARAC4 degrader, KT474, which is the first hetero-bifunctional degrader for immune inflammatory indications, we launched the first randomized placebo-controlled trial in healthy volunteers in the TPD industry. With KT333, our STAT3 degrader, we're the first company to bring a hetero-bifunctional degrader against an undrugged transcription factor into the clinic. And KT413, our dual degrader of IRAC4 and IMID substrates, has the potential to be the first therapy in diffuse large B-cell lymphoma targeting a genetically defined subset of patients. And last, but certainly not least, we are excited to continue to progress our MDM2 degrader, KT253, forward to IMD submission later this year. While we have not disclosed much about all the work we're doing in our discovery pipeline, I hope you all appreciate that the four disclosed pipeline programs represent only a fraction of what we hope to deliver from the significant investments we've made in our platform and pipeline over the years. As we highlighted in the press release this morning, 2022 is setting up to be a year rich in data, milestones, and scientific progress at Chimera. Jared will walk you through our recent progress and our goals of 2022 for each of our disclosed programs. Before turning the call to Bruce for a financial update, I will then finish with some concluding remarks. before handing the call to the operator to facilitate a Q&A session in which Jared Bruce and myself will be available. Jared?
spk02: Thanks, Melo. Starting with our oncology programs, we are pleased to report that the three disclosed oncology programs, STAT3, Arachamid, and MDM2, are all tracking as expected. First, I will discuss our STAT3 programs. PT333, as mentioned, is our lead STAT3 degrader. As a brief background, STAT3 is a transcriptional regulator that has been linked to numerous cancers and other inflammatory and autoimmune diseases, and it is a target that has long been considered undruggable. Our focus here is on developing selective STAT3 degraders for the treatment of hematological malignancies and solid tumors, as well as autoimmune and fibrotic diseases. We believe our STAT3 degraders have the potential to provide a transformative solution to address multiple STAT3-dependent pathologies. In terms of a clinical update, recall that we received IND clearance from FDA in 4Q21. The first clinical site was activated in 1Q22, and the trial is actively recruiting patients. As a reminder, KT333 is being evaluated in adult patients with relapse, refractory, liquid, and solid tumors, including aggressive lymphomas. Dose escalation is expected to proceed throughout 2022, and we look forward to presenting the first patient data, including preliminary safety and proof of mechanism clinical data, in the second half of 2022. Moving now to Arachamid, KT413 is a novel hetero-bifunctional degrader that targets degradation of both IRAC4 and the imid substrates 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, having received IV clearance from FDA late last year. The first clinical site was activated in 1Q22, and patient recruitment is underway. As a reminder, the Phase I trial for KT413 is focused on adult patients with relapsed refractory B-cell lymphomas, including mighty 88-newton diffuse large B-cell lymphoma, or DLBCL. Our plans remain to present KT413's first patient data, including preliminary safety and proof of mechanism clinical data, in the second half of 2022. Before concluding with an update on our IRAC4 program, I wanted to touch briefly on MDM2, a program we announced for the first time at our R&D day late last year. As we have shared, we are very excited about the potential of this program. MDM2 is the crucial regulator of the most common tumor suppressor, P53, which remains intact or wild-type in more than 50% of cancers. Based on preclinical data, we believe our highly potent MDM2 degrader, KT253, has the ability, unlike small molecule inhibitors, to suppress the MDM2 feedback loop and thus the potential to rapidly induce apoptosis even with brief exposures. We believe KT253 has the potential to be effective in a wide range of hematological malignancies and solid tumors with functioning p53. Just a few weeks ago, we shared preclinical data at AACR highlighting the biological superiority of MDM2 degradation over inhibition. Specifically, we presented preclinical data for KT253 that demonstrated extremely potent in vitro cell killing and in vivo anti-tumor activity with intermittent dosing that is superior to data reported for existing small molecule inhibitors and indicates the potential for improved efficacy and safety with degradation versus inhibition. You can find that poster along with all other publications in the scientific resources section of our website. As planned, KT253 is currently in IND enabling activities to support an IND filing in the second half of 2022. Finally, I will cover our IRAC4 program and our lead candidate, KT474. As previously disclosed, late last year we completed dose escalation in the single ascending dose and multiple ascending dose portions of our phase one clinical trial, where we enrolled over 100 healthy adult volunteers. As reported, initial data demonstrated near complete IRAC4 knockdown in PBMC and skin as well as robust ex vivo inhibition of multiple disease-relevant cytokines with a favorable safety profile. Specifically, in the multiple ascending dose portion of the trial, where subjects received 14 daily doses and we explored a range of doses from 25 to 200 milligrams, robust IRAC4 degradation was seen across all dose levels, with up to 98% reduction in PBMC at steady state between day 7 and 14, plateauing after 100 milligrams. In skin, IRAC4 levels were also reduced to near the lower limit of detection by day 14 at the top dose, but had not yet reached steady state, suggesting that continued dosing beyond 14 days would likely result in further declines in IRAC4 levels at daily doses of 50 to 200 milligrams. Finally, ex vivo cytokine induction by TLR agonists showed greater than 50% inhibition of most cytokines, and maximum inhibition of 85% in the 100 milligram dose group. This robust inhibition was seen in conjunction with greater than 90% IRAC4 knockdown in monocytes. That previously disclosed data as context, I will now comment on our plans for 2022, including a few recent developments. We have selected the dose equivalent of 100 milligrams in the fed state to take into Part C, the patient portion of the Phase I trial. Based on our clinical experience to date, we believe that the 100-milligram dose is the level at which we have maximized the pharmacology of KT474 and which will drive robust IRAC4 degradation leading to TLR-IO1R pathway inhibition in multiple different disease-relevant cell types that can impact inflammation and result in disease-modifying clinical activity. Having observed in SAD an increase in exposure with KT474 in the fed state versus fasted, we are enrolling an additional SAD cohort to determine the 100 milligram dose equivalent in the fed state. Once we have those results, we will then proceed to the patient cohort portion of the trial. With respect to the patient cohort, we have made a modification to the study design. Specifically, we will be extending the dosing duration from 14 to 28 days. This decision was made in conjunction with our partner, Sanofi, and we recently aligned with FDA on this protocol modification. Many of you have asked about our ability to track clinical endpoints in this portion of the trial, which we had not planned to do with just 14 days of dosing. But with this change to 28 days of dosing and 14 days of follow-up, we have now added several exploratory clinical endpoints. including the eczema area and severity index, or EASI, for atopic dermatitis, total abscess and inflammatory nodule count for hydradenitis separativa, as well as additional measures of symptoms and physician or investigator global assessments for both diseases. We plan to share the results of the patient cohort in the second half of this year as previously guided. Finally, Prior to selecting the dose for the patient cohort, we undertook a comprehensive analysis of all safety data from the SAD and MAD portions of Phase I, which recently included unblinded results. Consistent with what we have previously disclosed, the unblinded safety analysis showed KT474 to be safe and well-tolerated with no serious adverse events and no treatment discontinuations. A full analysis of 24-hour Holter ECGs as well as safety ECGs that were part of the Phase I study did not show any arrhythmias or other ECG adverse events. We did identify a modest, non-adverse, non-dose-dependent 10 to 20 millisecond prolongation of QTC relative to baseline only after multi-dosing in the MAD portion of the trial. This modest effect plateaued by day seven and completely reversed after day 14, following the completion of dosing. Importantly, the QTC interval itself remained less than 450 milliseconds, and therefore the QTC prolongation did not qualify as a grade one adverse event. FDA was informed of the full safety data set, including the comprehensive QTC analysis, and did not object to the proposed dose selection as well as the protocol adjustments to Part C that include 28 days of dosing, both to enable evaluation of exploratory clinical endpoints and to extend safety monitoring. Our broader clinical plans, aside from this adjustment to the patient cohort, remain unchanged and we are excited to advance KT474 through further clinical development. Before Neville concludes the call with some closing remarks, I will hand the call to Bruce Jacobs, our Chief Financial Officer, who will share some brief comments on our financial results for the first quarter. Bruce?
spk13: Thanks, Sherrod. I will keep my comments here brief. For the quarter, we recognize $9.6 million of revenue. This total reflects revenue recognized pursuant to our Santa Fe and Vertex collaborations. At the end of the quarter, our deferred revenue total on the balance sheet was approximately $93 million. That reflects revenue partnership revenue that we expect to recognize over the next several years. With respect to operating expenses, R&D for the quarter was $35.9 million, of which about $3.9 million represented non-cash stock-based compensation. The adjusted cash R&D spend of $32 million, which again excludes the stock-based compensation, reflects about a 5% decrease from the comparable amount in the December quarter. Our G&A spending for the quarter was $10.6 million, $4 million of which was non-cash stock-based comp. The adjusted cash G&A spend of about $6.6 million, again, excluding stock-based compensation, reflects a 2% decrease from the comparable amount in the December quarter. And finally, for my part, we exited 1Q with cash and equivalents of approximately $523 million. That provides a runway based on our current anticipated spending levels into 2025. And please recall, we do not include in our cash runway any payments or milestones that we have not yet received. I'll now turn the call back to Nello for some concluding remarks. Thanks, Bruce and Jared.
spk06: In conclusion, I think I can clearly say that we're very excited about where Chemera is at the moment. We have an exciting first-in-class pipeline that is progressing through the clinic, a best-in-class platform and discovery engine of which we'll continue to hear about as we disclose more programs and data, productive partnerships with Vertex and Sanofi that allow us to extend across multiple disease areas, and as you've heard from Bruce, a very strong cash position that enables us to continue to invest in high-value programs and generate several important data sets in the next few years. 2022, we're looking forward to generating key proof-of-mechanism data in two oncology clinical programs, KT413 and KT333, against two drug targets and pathways, Arachimid and STAT3, both with broad franchise potentials. We're also very excited to add our fourth clinical program later in the year with our MDM2 degrader, KT253, which we believe will have large clinical potential. With regards to 474, as you've heard from Jared, after consultation with the FDA, we've extended our Phase I patient study to 28 days to generate even more potentially de-risking data, including the possibility of early clinical proof of concept. We strongly believe that this mechanism has the potential to be best-in-class small molecule anti-inflammatory drug and excited to explore clinical activity in HICD and eventually in a wide variety of additional indications. I'd like to thank, first of all, Chimera team for every day pushing boundaries in a completely new drug modality and for continuing to execute on our very ambitious goals. I would like to thank our collaborators for enabling us to operate efficiently in a globally challenging landscape, our partners for the rich contributions, and last but not least, all the healthy volunteers and patients that allow us to advance the development of our potentially transformative therapies. Finally, I would like to thank all of you that have taken time this morning for our first quarterly call and looking forward to a rich Q&A. I'll now hand the microphone back to the operator so that we can take your questions. Thank you.
spk08: Thank you. At this point, we will open the call for questions. To ask a question, please press star 1 on your telephone. To withdraw the question, press the pound or hash key. The first question comes from Ellie Merle with UBS. Please go ahead.
spk07: Thank you, guys. Thanks for taking the question, and congrats on all the progress. Maybe just first on the 28-day patient cohort, I guess do you still anticipate enrolling 20 patients or given sort of the lengthening of the study, do you anticipate perhaps enrolling more patients as well? And then if you could just comment on the anticipated mix between atopic derm and HF patients within that cohort. And then second, just on the QT prolongation, can you give us just a little bit more color on what was seen, sort of like the number of patients, which dose levels. I think you said it wasn't considered grade one even. I mean, just any more color there would be helpful. And I guess also when you did the unblinding of the safety data, just maybe what dose levels the mild heart palpitations were seen at. Thanks.
spk06: Cool. Thanks, Ellie. This is Nella here. So maybe I'll just give a brief overview, and then I'll let Jared here comment on the specifics so as we said the extension of the study to 28 days was done mostly driven by our desire to pursue an opportunity to understand even further the PD and potential clinical profile of the molecule given the competitive space and to be honest given the profound pharmacology that we've observed so far Also, after unblinding the study, we wanted to take the opportunity to extend the duration of dosing to further our understanding of the safety, which so far has been actually quite promising. Maybe, Jared, you can comment a bit on... the unblinding and what we've learned as well as I think Ellie's question was also about this modest finding that we have with QCC and which doses and how it was detected.
spk02: Sure, yeah. As we described on the call, we were always planning to unblind and really have a comprehensive look at all the safety data once we decided that we weren't going to dose escalate further and when we were going to then choose our dose to bring into Part C. You know, the unblinding really, you know, showed that really the adverse events that we saw with the blinded analysis still remained the primary adverse events that we saw, you know, in a relatively small proportion of patients, including headache that was predominantly mild, palpitations that were also predominantly mild and self-limited, as well as several subjects with with nausea. It turned out that these adverse events, you know, these in particular were seen, you know, in the drug arm, not in the placebo arm, and that was not, you know, unexpected. And again, just to note that these were relatively few in number. They were self-limited, and they were predominantly mild. Now, in terms of the, you know, QTC findings, As we described, this was not seen in the SAD portion of the study, and it was not seen following the first dose of the MAD. It was only seen after multi-dosing. This was a modest effect. This 10 to 20 millisecond increase is a modest effect. This change in QTC is well below the 60 millisecond threshold that is associated with risk of arrhythmia. And also importantly, the QTC interval itself remained less than 450, which is essentially within the normal range, which is also well below the 500 millisecond threshold, which confers risk of arrhythmia. So, you know, we note this modest change in QTC, but it's important to note that this is, you know, well away from the threshold associated with any sort of, you know, possibility of sort of clinical adverse events such as arrhythmia.
spk06: Okay, thanks. Maybe I will just add one thing as we go. Bruce, if we go to the next question here. So why are we sharing a non-adverse event in this call today as obviously never made to the table of adverse events and actually we only learned it afterwards? And the reason that we're doing so is just because we want to keep our kind of style of communication transparent and continue to maintain high level of rigor and credibility. Obviously, we can discuss for the next half an hour this particular finding, but hopefully we get to talk about the other things as well.
spk08: Thank you. Your next question is from Brad Canino with Stifel. Please go ahead.
spk10: Good morning. I appreciate the updates. On the newly added clinical endpoints for KT474, you know, I've seen data with the TNFs and IL-1 agents in HS particularly where improvements don't max out until about eight weeks. So do you have any HS benchmarks in mind when you're thinking about the four-week time point? I'm especially asking in consideration of Pfizer's announcement to discontinue their IRAC4 small molecule this morning. And then looking forward to the other development opportunities for 474, I'd like to ask about your takeaways from the recent Nature publication that implicated TLR7 as the central signaling pathway in lupus and whether that might change your disease development. prioritization at all. Thank you. Yeah. Thanks, Brad.
spk06: It's always, you know, great questions. So I'll take a bit of it, and then I'll let Jared comment on the more specific point. I just would like to kind of reiterate the 28-day. So we're not running a 28-day study to produce definite proof-of-concept data. I think, as we said, we have given our preclinical talk studies, we have opportunities to extend the duration of those into 28 days to firm up PKPD as well as early sign of clinical efficacy with also the safety profile. And to really fully, maybe not fully, but to further appreciate the risk-reward profile of the molecules. So I would not comment specifically on other drugs in four weeks of study, but I think it's fair to say both across, say, the NHS, then within four weeks, active drugs, you start to see some separation from placebo in well-controlled studies. And so we feel like it will be probably short-sighted of us not to measure clinical endpoints. Again, not the expectation for us to say we have clinical proof of concept, just because I want to reiterate this would be an open-label study, but just to start to further create a strong relationship with RPD and, again, as I said, early potential clinical endpoints. So it's to further that relationship that we've been trying to build from the early days of the development of these programs. And I'll let Jared comment on where are the comps that he's keeping an eye on. I wanted to address, you made the Pfizer point and the other indications. With regard to Pfizer, yes, we've learned it today as well, 20 minutes ago, I think, half an hour ago, that maybe just not to correct you but to specify, I think their HS study, their HS development seems to be halted, but the RA trials continues to move forward. I don't want to speculate, especially not on this call. Clearly, the important thing doesn't seem to be, at least based on the fact that other studies are ongoing, a safety concern, and then we really don't know the data in H.S., versus that, the three-arm study with the JAK and Ibizir and TIK2. So I don't know whether there's been some prioritization in that pipeline, but we'll have to see. And then, you know, with regards to the breadth of opportunities, as you know, we have a slide on our deck that points to several opportunities in TH1, TH17, TH2 biology. Yes, we're well aware of TLR7. recent human genetics data point into a really strong correlation to lupus. Lupus is one of those diseases that we're exploring with our partner Sanofi in terms of priorities. And so as we continue to advance the program, we will do our best to exploit fully the potential of these mechanisms. Jared, any comment on the, you know, let's say the comms?
spk02: Yeah, maybe just to touch on this in terms of why extending also to 28 days. I think one of the main drivers for our decision to extend to 28 days of dosing came from our review of the pharmacodynamic data where we saw that while knockdown in peripheral blood really reached steady state after seven days of dosing, in skin we had not reached steady state after 14 days of dosing. And so being able to extend dosing to 28 days would give us the opportunity to dose long enough to reach steady-state knockdown in the skin. And since, in Part C, what's very important to us is now obtaining skin biopsies of active inflamed skin lesions and being able to show not just knockdown of BIORAC4 in the skin, but also impact on disease-relevant inflammatory biomarkers in the skin, we thought it was important to extend to 28 days to give us the best chance of really showing that sort of pharmacology in diseased skin. Now, in terms of the comps, at 28 days, we know, for example, in the Humira pivotal studies in HS and the Dupixent pivotal studies in AD, if you look at the curves for their various primary endpoints or even their secondary endpoints, you can see that at 28 days, as Nella was saying, you can start to see separation clearly from placebo. So we think that there is a potential opportunity to detect an initial sort of exploratory signal of clinical efficacy, and what would be nice for us is to be able to sort of connect a signal of efficacy with pharmacodynamic effect, a group of biology showing impact on IRAC4 and inflammatory biomarkers in both the skin and the blood. So being able to make that connection in Part C, we think would really help to further de-risk the program.
spk08: Thank you. And your next question comes from Michael Schmidt with Guggenheim. Please go ahead.
spk11: Hey, good morning. This is Paul on for Michael. Thanks for taking our questions. I have one on your iracomid. You know, there's been some renewed focus recently on tolerability with the neuroendocrine generation of imids, particularly on neutropenia. So just wanted to get a sense of your expectations around initial safety for 413, given how you've designed the molecule and any read-through, if any, from the competitive landscape. And then secondly, you know, you mentioned STAT3 has some potential in inflammatory and fibrotic diseases. Just wondering if there's any gating factors that you're thinking about potentially initiating development outside of oncology, and if there's something we can expect if the PD and safety data from the data one look good. Thank you.
spk06: Yeah, thanks, Paul. So, great question. So, the first one, I'll just share some thoughts. So, I think everybody's well aware of the pharmacology of image, right? and I think we're well aware of the strategies that, you know, Celgene or now Bristow has taken to develop those drugs. So I'm personally not, you know, surprised by, you know, seeing the pharmacology of the image play out in different clinical studies depending on the potency of the compound. And I think as we've said in the past, our goal has been to maximize the synergistic pharmacology between the ARAC4 degradation and the IMID degradation in a way that we would be able to maximize activity while managing safety. And in fact, based on the potency, the PK, the distribution profile of our molecules, we've optimized these molecules to be dosed once every three weeks, which is obviously very different than how image are dosed. So we feel very confident going into the study that we'll be able to really explore and understand how the preclinical study will translate into clinical both safety and activity. And we believe that we spent a lot of time running non-human primates study to really understand how to walk the line between efficacy and safety. So we're confident going into the study. And, again, before the end of the year, we will be updating that. everybody on how the data is evolving on the stat 3 question so we've invested heavily on that program there was a nice review the other day out there on all the other efforts that are in the space, and I think it's probably fair to say that our selective degrader is probably the most de-risked approach to targeting selectively and specifically STAT3. We also spent, I would say, a couple of years, actually, trying to fully understand the pharmacology and safety of STAT3 degradations. running multiple efficacy and safety studies across many type of disease states. And so the reason why we separated oncology from non-oncology indications is because we have come to the conclusion that the degradation profile needed in oncology is actually quite different than the degradation profile needed outside of oncology. And so the reason why a molecule that will be developed outside of oncology is our slightly behind is because we're, again, firming up the PKPD safety to then advance that approach towards the clinic. So I don't know if that's a satisfying answer, but that's really the story to the STAT3 program right now.
spk08: Thank you. Your next question comes from Vikram Purohit with Morgan Stanley. Please go ahead.
spk03: Good morning, everyone. This is Daspo on for Vikram. We have two questions. So the first one pertains to Sanofi. I mean, could you walk us through the mechanics of how your decision-making process with Sanofi will unfold following the release of the KT474 data in second half of 2022? Specifically, I mean, how long does Sanofi have to review the package, and how will you be working with them to prioritize the indication to evaluate in phase two? And when do you think this disclosure could be provided to the street? And then how are you thinking about the timing and process for your opt-in decision? Thank you.
spk06: Okay, thanks. So first question, what's the process? So as we've shared in the past, nothing has changed. We are in very close communication with our partners. We do that with every one of our partners. And so they're obviously well aware and they're part of, you know, key, whether it's a regulatory interactions or an internal decision. And so when we complete, when we will complete the patient cohort that we just, you know, described that, we've extended to generate even more data. I strongly believe to generate hopefully key de-risking data. Then we will be very quickly, you know, presenting Sanofi with a full data package which just to remind everybody includes all preclinical as well as phase one data. So it's actually a large, large document. And then we haven't disclosed how many days, but they have X number of days. it's not like half a year, it's definitely less than that, to make the decision of whether to advance 474 into phase two. We expect that at least our firm goal is to present that complete data set to Sanofi before the end of the year, and then hopefully that decision will be swift as, again, they're up-to-date with all the development of the program. Then I think there was a question about chimeras opting, if I understood well. And so the mechanism for that is if and when, hopefully, Sanofi decides to advance KT474 into a randomized placebo-controlled phase-to-study or multiple phase-to-studies. then at the end of the first one, with proof of concept study in hand, Chimera will have the opportunity to decide if we want to co-develop and co-commercialize in the U.S., sharing profit and losses 50-50. And that decision will have to be made before the beginning of Phase 3 so that we can operationally and financially contribute to Phase 3 studies. Thank you.
spk08: Your next question comes from Kalpit Patel with B. Reilly. Please go ahead.
spk12: Yes, hi. Good morning, and thanks for taking my question. Just one question on your IREC-INMID program. I think another drug developer, Curis, had a clinical hold placed recently on their IREC-IV inhibitor on safety concerns for rhabdo. I guess, does that in any sense impact your thinking about how you're advancing this iRecAdmit program? You know, from my understanding, that Curis' drug is more of a dirty kinase inhibitor that might have been responsible for the safety concerns, but do you have any evidence of elevated, you know, CK levels in your preclinical studies with the iRecAdmit program?
spk02: Yeah, thanks for the question. No, I think it's a good question. I think, as you mentioned, you know, the QRIS compound, you know, is a multi-kinase inhibitor. And in addition to IRAC4, one of its key targets is FLIP3. And there have certainly been published reports of with other FLIP3 inhibitors. So we think it's highly likely that the rhabdomyolysis that they're seeing and that's problematic and potentially dose-limiting for them is because of the FLIP3 targeting. With regard to IRAC4 targeting, you know, we and others have not seen any rhabdomyolysis with either IRAC4 targeting or the use of Arachemid in our preclinical studies. You know, as you know, in our IRAC4 studies, Phase one, we are engaging the target quite robustly and knocking out the target by 98%. We have not seen any rhabdomyolysis. We're not aware of any reports of rhabdomyolysis from Pfizer with their IRAC4 kinase inhibitor in their various clinical trials. And as you also probably know, there are IRAC4 null individuals who, as adults, really have no clinical phenotype and certainly have no muscle pathology. So we don't think that there's a connection between IRAC4 targeting and rhabdomyolysis, and that's what curious is seeing, again, is probably due to off-target effects and most likely FLT3 targeting. Thank you.
spk08: Your next question comes from Divya Rao with Cowan and Company.
spk01: On for Mark. First one is, could you talk about what you mean for degradation for IRAC4 in the ADHS population? And then do you think the levels of IRAC4 needed to drive this meaningful clinical benefit is different between the two? And then just like a little bit more broadly, are you willing to comment on the venues you plan to present the updates on all three clinical updates coming later this year? Would it be like a medical meeting or possibly another R&D day? Thank you.
spk06: Great. So you broke up at a point, so I'm going to repeat the question. Hopefully I got it right. So the first part was, do you expect the degradation profile needed to be different between the chest and AD? I'll let Jared take that one. And then I want to answer the presentation venues. So we have always said that we like to present scientific data at scientific or medical meetings. We've also said that our commitment to timelines And, again, going back to the point that I made about transparency and credibility, it's paramount. So if we said that we're going to present the data before the end of the year, which is true for all three programs, we're going to try our best to do it in a medical meeting. If not, if for timeline reasons of abstract submission, et cetera, we won't be able to do, then we'll find another venue, whether it's an R&D day or it's a focus meeting. It's not our preference by far, but again, I just want to say that as a company, we like to commit to the timelines that we give, unless, obviously, some operational issue arises and we can't deliver on the timelines, which is not the philosophy we have at Chimera. Jerry, do you want to comment on the degradation profile?
spk02: Yeah, I think it's a really important question. I think that we anticipate that the degradation that we need for clinical impact should be similar for AD and HS. We've learned from our preclinical mechanistic models of inflammation that 85% or greater degradation really has an impact on inflammation and the induction of various inflammatory cytokines that drive inflammation. We've also learned from our phase one healthy volunteer study so far that a similar threshold, 85% or greater degradation is associated with an impact on ex vivo cytokine induction. So we think that really what's important is how much degradation is needed to impact the function of the TLR-ILR1R pathway, and importantly, you know, the particular function that we're interested in is the induction of pro-inflammatory cytokines and chemokines. And so we anticipate a similar, you know, threshold of knockdown, at least 85 percent or greater, you know, in blood and in skin for us to really be able to impact inflammation in both of these diseases. And we feel from what we've seen so far in the Healthy Volunteer Study, with the dose that we plan on taking into Part C, that we should be able to readily attain those levels of IRAC4 degradation.
spk08: Thank you. Your next question comes from Eric Joseph with JP Morgan. Please go ahead.
spk00: Hi, good morning. Thanks for taking the questions. I wanted to revisit the first question on QT, specifically the dose levels where you observed the extension or the prolongation and how it resolved. I guess, did it resolve on consistent dosing or was dosing modified in any way? And do you anticipate having to conduct a QT, a thorough QT study as part of the phase one package prior to handover?
spk06: Thanks, Eric. Great question. I think it's great an opportunity to clarify this point. So I just want to clarify one thing, and then I'll pass it to Jared. So I think what we've said, that this is a non-dose responsive, self-limiting, modest finding that never happens. became an adverse event, not even a great one for QCC. And again, I'll repeat, the reason why we're sharing it is for being transparent as a company. Maybe, Jared, you can comment on those adjustments, resolution, and all that stuff.
spk02: Yeah, I think importantly, during the conduct of the SAD and MAD, again, there were no ECG adverse events. There were no changes in QTC interval that rose to the level of being an adverse event. It was only after we completed those parts and then undertook a more thorough analysis of ECGs prior to selecting the dose for Part C that we noted this modest QT prolongation. Again, that was not adverse I think importantly, as I mentioned earlier, this was not associated with prolongation that reached any sort of threshold that would be associated with arrhythmia. I think it's also important to note, as we said, in order to be open and transparent with FDA, we did share these data with them. and we have to go ahead to go into Part C with a very robust dose, 100 milligrams, and that should help us to really maximize pharmacology. We're continuing with daily dosing. We're now extending dosing to 28 days and including clinical endpoint. I think in terms of your question around whether we need a thorough QT study, I mean, it's very common for companies to do thorough QT studies. Sometimes the TQT studies can be bypassed by having enough ECG information from your phase one study to be able to determine whether there is any sort of QT effect. It is a possibility that we might do a thorough QT study. I think that will depend in the future on what we see in part C, but I think that certainly is on the table. But at least we have some understanding right now that whatever QT effect we're seeing is very modest and currently has not met the threshold for being adverse. It's not even close to that.
spk08: Thank you. Your next question comes from Richard Law with Credit Suisse. Please go ahead.
spk05: Hi, good morning. I have two questions. So regarding the QTEC observation, did the FDA ask for any mitigation plans if that would occur again? And at what point would that trigger some sort of intervention? And then the second question I have is that on KT474, can you share with us any updated changes to timeline or any preliminary discussions
spk04: You have a set of things regarding the Phase II plans, like in terms of what type of patients will you be exploring, and also you mentioned the RCT trials. Would that be any head-to-head study with biologics? Thank you.
spk06: Yeah, no, thanks. I just want to clarify, again, the first point. So we actually did not have to share this QCC information. finding with FDA, but we decided to do, we have a really strong relationship. Our regulatory group is really strong. We've had, you know, four, almost four, close to four IMD submissions, several other follow-ups. So we tried to be also, as we do also with FDA, transparent and collaborative. We obviously had to engage them to amend the protocol, and when we did, we also submitted all the safety, PK, PD, and all the data that we generated. We really didn't receive much of comments with regards to how we're proposing. We continue to explore the safety of the drug. I think they generally align with our proposed plans, and there was no particular mitigation plan that was discussed. This was our study design protocol, and there was a general alignment in the big picture. With regards to Sanofi, we, again, we are very close to the team, to the development team, and I think where we are today is that, as we've always said, we have some really high priority indications. There are several, but what we've discussed often is HS, AD, RA. We talked last week a lot about lupus, for example. And I think we agree, and it makes sense. We're both data-driven companies. We will continue to see how data emerge from this patient study. Obviously, now this patient study is much more powered in terms of data that we generate, and I think with that data in hand, we will refine the strategy and the selection for the right dose, sorry, for the right priorities that we'll have for Phase II and beyond.
spk08: Thank you. Your next question comes from with Berenberg. Please go ahead.
spk14: Great. Thank you. I have two questions. First one on the STAT3 program. In the past, you have communicated potential accelerated rate approvals based on the data you've seen, or have you continued to hold that view? And also on that program, that I see you have amended the protocol to include a combo study. Can you discuss more, provide more color on how you want to go with that combo study?
spk06: Yeah, it was a bit noisy, but I think, Jared, the question was, What is the path to potential accelerated approval that we're planning with STAT-3? And then the combo, like what is the plan on how to develop the company?
spk02: Yeah, I think in STAT-3, you know, we see the rapid development opportunities in STAT-3-dependent email lignancies, especially online. certain T-cell malignancies like peripheral T-cell lymphoma, cutaneous T-cell lymphoma, and LGL leukemia, where you tend to see activating mutations in STAT3 or in JAKs or even just hyperactivation of the pathway. So our preclinical animal model data where we've seen very robust anti-tumor activity with STAT3-degrader as a monotherapy, and because these are areas with very high unmet medical need, we think there are rapid approval or accelerated approval opportunities with our STAT3-degrader KTE333 as a monotherapy. In terms of combination, we tend to think more about combination in solid tumors where we have shared very interesting data where the immunomodulatory properties of STAT3 synergize with anti-PD1 drugs to show sort of synergistic anti-tumor activity in various solid tumor models and genetic tumor models such as colorectal cancer. So we think there could be an even larger opportunity for combination development with checkpoint inhibitors in solid tumors. Those paths, you know, may not be as accelerated because those are combination studies as monotherapy paths, but we think that those are also very attractive and represent even larger opportunities for the degrader.
spk14: Great. Thank you. And maybe if I could follow up there on this battery and also your IRAC in-med program. Have you seen... I know it's early days. Have you seen any QDC findings in those programs?
spk06: Yeah, so far we're early in, and we just opened our phase one, so we're not in possession of any human safety data. Generally, what I would say is that QTC prolongation is not a signal that we've had to deal with within our pipeline, so it's not something that is present in our portfolio molecules broadly.
spk08: Thank you. And I'm not showing any further questions in the queue. I would like to turn the call back to Nello Mainolfi for his final remarks.
spk06: Yeah, so thank you. First, I want to thank everybody for tuning in today. I realize it was a very busy day. in the biopharma space in terms of calls. So thanks for calling in. I just want to reiterate, so we're a company that is almost six years in, we have a rich pipeline of programs across a variety of indications. Again, we've talked about HSAT, T-cell lymphoma, T-cell leukemia, solid tumor, diffuser HB cell lymphoma, and then soon with MDM2, other indications. So you see that We're obviously a company that is trying to build into a fully integrated business that takes protein degradation into the space where it should be, which is really changing people's lives. We're here for any follow-up, for any questions that others might have during the day or in the next few days. I want to thank the team here, Bruce and Jared, and the team at Chimera for continuing to generate information really best-in-class data every quarter, and, you know, wish everybody a good day.
spk08: Thank you, ladies and gentlemen, for participating in today's call. You may now disconnect. Have a wonderful day.
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