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spk04: Welcome to the Chimera Therapeutics quarterly conference call. Leading the call from management are Nello Manolfi, founder and CEO, Jared 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, you may press star then one on your telephone keypad. To withdraw your question, please press star then two. And please note, this event is being recorded. 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 Chimera disclaims any obligation to update such statements. I will now hand the call to Melo Manolfi, founder and CEO. Please go ahead.
spk09: Thank you, operator, and thank you, everyone, for joining us on our second quarter results conference call. We're excited to share with you today the continued progress we're making towards building Chimera into a best-in-class, fully integrated degrader medicines company. As we reach our two-year anniversary as a publicly listed company later this month, we can be really proud of a period of brilliant, outstanding growth and achievement at Chimera. I want to start by saying that the second quarter has been significant for us, particularly in terms of substantial clinical progress we've made by advancing our three lead programs into important stages of their development. Specifically, we dosed the first patients in our three first-in-class clinical programs, including commencing patient dosing in our Part C of our Phase I trial of KT474. This achievement ushers in a new phase for the company as we look forward to demonstrating how targeted protein degradation and these molecules in particular can impact disease and patients' lives. This is just the start of our journey toward treating patients in many disease areas such as adrethronitis separativa, atopic dermatitis through degradation of IRAC4 with KT474, hematological malignancies in solid tumors with KT333, our selective STAT3 degrader, and mighty 88-newton B-cell lymphomas with our arachnid degrader KT413, which has the potential to be the first precision medicine for these conditions. At Chimera, as evidenced by our initial programs, we have the ambitions and capabilities to really broadly apply our platform by expanding the draggable proteome to address inadequately dragged or undragged targets, creating the potential for us to transform the lives of patients, which is really what the company was founded upon and is going towards. We ended the second quarter in a very solid financial position with approximately $482 million in cash, three first-in-class TPD assets in clinical studies, one program KT253, our MD and 2D grader, close to IND filing, and multiple preclinical candidates expected to drive us to our goal of at least one new IND per year, and productive collaborations with our partners Sanofi and Vertec. We have multiple patient data sets expected by year-end, including the Part C data for KT474, our patient cohort. Our plan is to share this data later this year with the medical and investor communities, as well as with our partner Sanofi, to enable their decision around advancing KT474 into Phase II studies. Now, Jared will walk you through our recent progress and goals for 2022 for each of our disclosed programs before turning the call over to Bruce for then 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, Bruce, and myself will be available. Jared? Thanks, Nello.
spk15: We've made substantial progress with our clinical programs this quarter, which I am excited to share. I'll start with our IRAC4 program and our lead candidate, KT474, an orally available potential first-in-class degrader of IRAC4, a key protein involved in inflammation mediated by the activation of Toll-like receptors and IL-1 receptors. A barren deactivation of these pathways is the underlying cause of multiple immune inflammatory conditions. KT474 is being developed for the treatment of TLR, IL-1R-driven immune inflammatory diseases with high unmet medical need, such as hydradenitis seborrheiciva, atopic dermatitis, rheumatoid arthritis, lupus, GI inflammation, and potentially others. AT474 is designed to block TLR-IO1R-mediated inflammation more broadly compared to monoclonal antibodies targeting single cytokines, and to enable pathway inhibition that is superior to IRAC4 kinase inhibitors by abolishing both the kinase and scaffolding functions of IRAC4. We are collaborating with Sanofi on the development of the greater candidates targeting IRAC4, including KT474, outside of the oncology and immuno-oncology fields. Late last year, we completed dose escalation in over 100 healthy volunteers in the single ascending dose and multiple ascending dose portions of the KT474 phase 1 trial, the first randomized placebo-controlled trial for a hetero-by-functional degrader. The data 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. At the SID annual meeting in May, we disclosed that KT474 degrades IRAC4 and inhibits cytokine production in different immune and skin cell types, highlighting the broad impact of KT474 across multiple disease-relevant cell types and supporting the continued development of IRAC4 degraders in patients with HS, AD, and other IONR, TLR-driven autoimmune diseases of the skin, where IRAC4 plays a central role in the pathogenesis of inflammation. You can find that poster along with all our other publications in the scientific resources section of our website. Most recently, as Nello just mentioned, we are excited to share that we commenced dosing patients in the patient cohort part C of the phase one clinical trial. Part C is an open-label study of KT474 that is expected to enroll up to a total of 20 patients with moderate to severe hydradenitis suppurativa or atopic dermatitis to examine the safety, PK, PD, and exploratory biomarker and clinical activity of this first-in-class to greater therapeutic. While we are in the early stages of the patient cohort, we expect enrollment to progress as planned for us to disclose the data before year F. KT474 is being administered daily on an outpatient basis for 28 days, with patients followed through day 42. Patients will receive a daily dose of 75 milligrams of KT474 with food. This dose is expected to provide a plasma exposure that is approximately equal to that achieved with the 100 milligram per day dose in the fasted 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. The goal for this study is to confirm that our PD and safety profile in patients is in line with what we have seen in healthy volunteers. PDM points include 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 both whole blood ex vivo cytokine induction and plasma biomarkers of inflammation. We are also undertaking an exploratory assessment of early impact on clinical endpoints, including eczema area and severity index, or EASI for AD, total abscess and inflammatory nodule count for HS, as well as symptom scores and global assessments of disease severity for both AD and HS. However, recall that this is an open-label study without placebo in a small number of patients, and we do not expect to reach steady-state IRAC-4 degradation in skin until the second half of the four-week dosing period. The objective of Part C, therefore, is to confirm PK, PD, and safety with the additional information on early signs of clinical activity. With regard to safety and tolerability, which so far has been quite favorable with no serious adverse events and with only few mild to moderate adverse events, we will continue to monitor the safety profile, including whether the modest non-adverse QTC prolongation that we observed with multi-dosing and healthy volunteers that plateaued after seven days continues to show evidence that it is self-limited, but in this case out to 28 days. We look forward to sharing the data from the patient cohort before year end. With respect to Sanofi and their decision to advance KT474 into phase two, We plan to share these patient data with them as soon as they are available and expect a decision on their plans within the timeframe set forth in our collaboration. Moving on to our oncology programs, we are pleased to report that the three disclosed oncology programs, STAT3, Arachamid, and MDF2, are all progressing well. First, I will discuss our STAT3 program. A target long considered undruggable, STAT3 is a transcriptional regulator that has been linked to numerous cancers and other inflammatory and autoimmune diseases. 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. AT333 is a potent and selective heterobifunctional small molecule protein degrader of the STAT3 protein in development for the treatment of liquid and solid tumors. Patient enrollment and dosing are ongoing in our phase one trial, which is evaluating the safety, tolerability, PKPD, and clinical activity of KT333 in adult patients with relapse and or refractory lymphomas and solid tumors. The first stage of the study is exploring escalating doses of KT333. It is important to highlight that in order to expedite dose escalation, we have been recruiting broadly in Phase 1A 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 second stage will consist of four Phase 1B expansion cohorts to further characterize safety, tolerability, PKPD, and antitumor activity, of KT333 in relapsed and or refractory peripheral T cell lymphoma, cutaneous T cell lymphoma, large granular lymphocytic leukemia, and solid tumors. This escalation is expected to proceed throughout 2022, and we look forward to sharing preliminary safety and proof of mechanism data before year end, with the goal, based on the broad population of liquid and solid tumors in phase 1a, of showing that we can attain levels of target degradation associated with anti-tumor activity disease-relevant animal models at doses that are safe and well-tolerated. Recall that we are also exploring STAT3 degradation in immune inflammatory indications using other STAT3 degraders. To that end, at the ULAR Congress in June, we presented data showing that KTX115, a tool STAT3 degrader, selectively and potently degraded STAT3 in human peripheral blood mononuclear cells and whole blood, aggregated stat-free phosphorylation and MCP CCL2 released by human monocytes more potently than JAK inhibition, and inhibited CD4-positive Th17 development and related cytokine production in vitro and prevented collagen-induced arthritis in mice. You can find those posters in the scientific resources section of our website. Moving now to our arachnid program, KT413 is a novel heterolife functional degrader that targets degradation of both IRAC4 and the imid substrates, the carotid myelos, with a single small molecule. KT413 was designed to address both the IONR, TLR, and the type 1 interferon pathways synergistically to broaden activity against mighty 88 mutant B-cell malignancies. KT413 is on a similar timeframe as STAT3, with patient enrollment and dosing ongoing in our phase 1 trial evaluating the safety, tolerability, and PKPD of KT413 in patients with relapsed and or refractory B-cell non-Hodgkin's lymphomas. The first stage is exploring escalating doses of single-agent KT413. Using a similar strategy as I just described for the KT333 Phase I, we are expediting dose escalation of Phase Ia by enrolling a broad population of B-cell lymphoma patients before then focusing 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 the safety, tolerability, PKPD, and antitumor activity of KT413 in relapsed refractory MiD88 mutant and MiD88 wild-type DLBCL. Dose escalation is expected to proceed throughout 2022, and we look forward to sharing preliminary safety and proof-of-mechanism data before year-end. with the goal, based on the broad population of B-cell lymphoma patients in Phase 1a, of showing we can attain levels of target degradation associated with anti-tumor activity and disease-relevant animal models at doses that are safe and well-tolerated. I want 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. Our highly potent MDM2 degrader, KT253, unlike small molecule inhibitors, is able to suppress the MDM2 feedback loop and thereby rapidly induce apoptosis in susceptible P53 wild-type tumors with brief exposure. We believe KT253 has the potential to be effective in a wide range of hematological malignancies and solid tumors with functioning P53. Specifically, our use of biomarkers for an acute episodic response to MDM2 degradation has enabled the identification of several indications where we expect to see robust activity and a favorable safety profile with intermittent IV dosing, such as AML, lymphomas, and multiple different solid tumor types, including but not limited to uveal melanoma, mesothelioma, colorectal, and breast cancer. These all represent potential development opportunities for KT253, with patient selection to be further guided by ongoing work focused on mutation and or gene expression profiles. As planned, KT253 is currently in IND enabling activities to support an IND filing in the second half of 2022. Before Nello wraps up 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.
spk14: Bruce? Thanks, Jared. I'll keep my comments brief. For the quarter, we recognized 11.5 million of revenue. This total reflects revenue recognized pursuant to our Sanofi and Vertex collaborations. And at the end of the quarter, our deferred revenue total on the balance sheet was approximately 84 million. That reflects partnership revenue we expect to recognize over the next several years, excluding the receipt of any potential future milestones. On operating expenses, R&D for the quarter was $41.3 million. Of that, $4.8 million represented non-cash stock-based compensation. The adjusted cash R&D spend of $36.5 million, which excludes this stock-based compensation, reflects a 14% increase from the comparable amount in the March quarter. On the G&A side, our spending was $11 million, of which $4.9 million was non-cash stock-based compensation. There, the adjusted cash G&A spend was 6.1 million. That reflects 8% decrease from the comparable amount in the March quarter. And then finally, we exited the second quarter with a cash and equivalence balance of approximately $482 million. That provides a runway based on our current anticipated spending levels into 2025. And recall that it's our policy not to include in our cash runway any payments for milestones that we have not yet received. With that, I'll turn it back to Noah for some concluding remarks. Thanks, Ruth and Jared.
spk09: So in conclusion, we're clearly very excited about all that we've accomplished this year at Chimera, as well as by all that is in front of us. We're in a strong position with an exciting first-in-class pipeline that is progressing through the clinic, a best-in-class platform and discovery engine, about which you will continue to hear as we disclose more programs and data, productive partnerships with Vertex and Sanofi, that allow us to extend across multiple disease areas, and a very strong cost position that you just heard from Bruce that enables us to continue to invest in high-value programs and generate several important data sets in the next few years. We're poised to deliver key clinical insights in the second half of this year and continue to demonstrate the potential of our approach to targeted protein degradation to improve the lives of patients. In the second half of the years, in fact, as you've already heard, we look forward to generating for the first time key patient data in HSNAD from our KT474-IRAC4 degrader program, as well as key proof-of-mechanism data in the two oncology clinical programs, KT413, a Raracumib degrader, and KT333, a STAT3 degrader. We mentioned earlier our key goals for this dataset, but to just summarize briefly, For KT474, we're looking to confirm that healthy volunteer PD and safety profile in this patient cohort, which we believe could be a game-changing profile in the world of small molecule oral anti-inflammatory drugs. In oncology, we want to demonstrate that these molecules are behaving as predicted based on our preclinical studies, and the translation of degradation and safety is happening in a predictable way. If we can do this well, which we have confidence in, then we can set clear expectations of clinical activity starting from 2023 and beyond, once we would be focusing on our responders' population. We're also very excited about the prospect of adding our fourth clinical program later in the year with our MDM2 degrader KT253, which we believe will have significant clinical potential. We have also several earlier programs with clear degraded rationale and large commercial opportunities that we're advancing towards the clinic and will be disclosing as we approach clinical investigation. With the tremendous progress that we've made in mind, I want to thank the Chimera team, our collaborators, our partners, and last but not least, all the healthy volunteers and patients which allow us to advance development of our potentially transformative therapies. Finally, I would like to thank all of you who have taken time this morning for our call. I look forward to a great Q&A discussion. And for that, I will hand the microphone back to the operator so that we can take your questions. Thank you again.
spk04: We will now begin the question and answer session. To ask a question, you may press star then one on your telephone keypad. If you are using a speakerphone, please pick up your handset before pressing the keys. To withdraw your question, please press star, then two. And we also ask that you please limit questions to one question and one follow-up.
spk03: We will pause momentarily now to assemble our roster. The first question comes from Brad Canino with Stifel.
spk04: Please go ahead.
spk07: Good morning. On KT474, can you share any additional findings from your preclinical investigations of the potential mechanism behind the QTC effect and why it becomes saturated as you've observed in phase one? I think you previously discussed the cardiomyocyte assay around the 1Q call, but is there anything else to add that you've done? And then on KT413, the Arachamid Some of your peers have had recent difficulty finding a therapeutic window for these given the on-target IKZF1 neutropenia. Can you talk about your confidence in achieving the required IRAC4 degradation within a feasible window, and then maybe discuss the likelihood of observing any anecdotal clinical activity in MITEI 88 mutated patients that might be enrolled within that all-comer group? Thank you.
spk09: Thanks, Brad. So technically those were two questions, but we'll let it go this time. So just to address at some level, and then I'll let Jared also jump in. So maybe I'll start with the second one. So what is our approach with the arachnid degrader? As we said early on, the hypothesis there is to have a synergistic cell autonomous anti-cancer effect, meaning that the biology of IREC4 degradation and the biology of Icarus and Ilus degradation intersect in myD88 news and lymphoma to provide a very substantial synergistic anti-tumor effect, both in vitro and in vivo. The way that we managed the combination in a single molecule has been to really understand fully the kinetics of degradation the impact on the right cell type, and then the potential management of the well-known IMID pharmacology, which, as we all know, is well characterized, both the wanted and unwanted. I think we have two major differences from what's been done in the past. One is that from IREX4 degradation, we expect to see no contribution to unwanted pharmacology, meaning we know that IREX4 degradation is well-tolerated. So the only, let's say, pharmacology that we need to monitor is from the IMID part. And as we know, our drugs actually behave quite differently from any other drug that has been tested in with this mechanism. We dose our drug once every three weeks, and we have a PKPD profile that allow us to have profound degradation for the first two to three days, and then we see a recovery of targets as well as a recovery of some blood cell type, which we know can be impacted by image biology. And so the combination of kind of PKPD and our ability to dose infrequently, even that we're able to drive really strong apoptosis in the early days, and we don't need to continue to dose, allow us to have A safety profile that is, we think, very manageable. I mean, we've studied this extensively in non-human primates, and we expect that profile to translate well in the clinic. I will only also add one more thing, which we said in meetings, maybe this is an opportunity to share broadly. We are, I guess, a company that focuses on translation of PKPD, which is the core of the technology. You're looking at protein levels, and so that's really what we're translating in the clinic. And so when we've selected our starting doses, in all of our trials, we have been targeting a PKPD profile or a degradation profile that we believe will allow us to both understand the translation and de-risk the translation. So in all of our oncology trials, especially learning from KT474, we've been able to translate in a degradation profile that we believe was quite conservative and de-risked so that we would learn in human the kinetics in a safe and in a productive manner. On the 474, and then I'll pass it to Jared to comment on both, I don't know that we have any particular updates. I think what we've said in the past very clearly is that This QT finding is, first of all, non-adverse. So, obviously, we're talking about a non-adverse event, which, you know, we brought it up, so we're happy to discuss it. But that's the context. It's non-dose responsive, and it is self-limiting, and we believe it's saturated. based on the fact that we have a mild affinity for the HERK channel that seems to be saturated by how the molecule distributes in tissues. And I think the fact that this finding is non-dose responsive and non-concentration responsive is the most important aspect that de-risks the profile of the molecule going forward, because really what we are avoiding is the excursion of QT that goes into areas where the risk of arrhythmia is higher, which in no cases we've seen so far. But Jared, maybe you want to contextualize a bit the mechanism based on the latest?
spk15: Yeah. In terms of the mechanism from the in vitro work with the iPSC cardiomyocytes, I think What's been encouraging to us is that what we've seen in vitro really does mirror what we've seen in vivo in healthy volunteers in that, you know, the effect we see on current in these cardiomyocytes that's due to this mild effect on HERD is delayed, which is consistent with the delayed effect that we see in vivo. Also importantly, it really does appear to be, you know, compound specific, not due to any on-target effect. I think we've definitively shown that the effect we're seeing on HERG is not due to degradation of IRAC4. We've been able to show that by using, you know, another IRAC4 degrader in this in vitro system that degrades IRAC4 quite well but has no impact whatsoever on HERG. You know, coming back, Brad, to your question on whether we're going to be able to see any activity in MITEI 88 mutant lymphoma during dose escalation, You know, as I mentioned, you know, we are enrolling a broad population of B-cell lymphoma in Phase Ia to really help to expedite moving through dose escalation. Our goal, you know, we know from our preclinical studies that 60% to 80% knockdown of IRAC4 in the imid substrate, icrosanilose, is what is required for anti-tumor activity in mighty adiabatic lymphoma. So while we are enrolling a broad population of B-cell lymphoma in Phase Ia, once we get up to doses that are giving us that 60 to 80% knockdown. We probably will start to make an effort to bring on more DLBCL patients and maybe even a few MiD88 mutant patients. So it's possible as we get through toward the end of Phase Ia, we may have some anti-tumor activity in MiD88 mutant populations. But really our primary goal is to really focus on anti-tumor activity in Phase Ib, where we then specifically enroll MiD88 mutant and wild-type DLBCL. And that will really happen next year. So our goal for what we plan to report out later this year is really focused on, as Nella was saying before, that we can obtain the desired sort of knockdown of these three targets that is associated with anti-tumor activity pre-clinically, and we can do it at doses that are safe and well-tolerated.
spk09: Yeah, and really de-risking the molecule, right? As I said in the remarks earlier, it's about making sure that the molecule has the profile that is in line with what we see to be really active preclinically. If we can show that, basically, the degradation and safety then we've erased the molecule. Then the biological and clinical question will be asked once we focus more on MiD88 mutant patients, which will be, you know, as soon as we can, most likely in 2023 and beyond. Thanks, Brad.
spk03: The next question is from Michael Schmidt with Guggenheim.
spk04: Please go ahead.
spk08: Hey, guys. Thanks for taking my questions. I had a couple on KT474 as well, and You know, on the QT signal, you know, assuming that, you know, this non-adverse, you know, level of QT prolongation is being confirmed in the patient study, you know, I guess what is your expectation how that might potentially affect the longer-term clinical potential of the drug? You know, is there an expectation, for example, that, you know, that would preclude certain patients down the road from potentially using the drug or certain combinations that might be affected by that? And the other question I had is just on Part C, on the exploratory clinical endpoints. Obviously, understanding that it is, you know, non-medical. placebo-controlled and, you know, as you said, the steady-state knockdown is only reached sort of in the second half of this sort of four-week period. But I guess is there a certain level of efficacy that, you know, based on these outcomes in AD and HS that one would expect or hoping to see based on that PK, PD of the drug? Thanks so much.
spk09: Thanks. So maybe just to address a couple of questions here from Michael. So the first one, and then I'll pass it to Jared, maybe more for the second one. So we've done, as you can imagine, extensive work on trying to contextualize this non-adverse event QT finding for, you know, for moving forward this drug towards clinical and commercial success. And so our view is this. If the finding remain within the range that we have observed so far, We expect that there will be no impact on clinical, regulatory, or commercial success of this drug. And I'll explain a bit where we're coming from. So for a 10 to 20 millisecond, especially in the absence of concentration dependency and large excursion, then what we're talking about is something that slightly modifies, let's say, the baseline of subjects that never really reaches area of really high risk of arrhythmia. So from our early exploration both with our experts as well as with interaction with FDA, we expect that we can advance this molecule in a broad variety of disease indications regardless of kind of background. And then, you know, Jared will comment on which specific small number of patients might not be, you know, suited for this particular drug with this profile. So then going back to regulatory, so what we've seen based on FDA-based databases as well as work that we've done ourselves is that for 10 to 20 milliseconds QT changes usually what we've seen as maybe the most impactful kind of label impact, we've seen some warning and precaution statement that says usually, you know, this drug can extend the QT. Be aware in case you take other drugs that can extend QT. And in terms of commercial success, I mean, what we've seen is, I mean, also talking to prescribing doctors in this space is that with this type of there is no expectations of having to have monitoring associated with prescription of the drug. And in the absence of monitoring, then I think the uptake should be just as any other drug that might not have this particular finding. And maybe, Jared, you can comment on what are the subset of patients that we might be not selecting in our clinical development plans
spk15: Yeah, I mean, I think we feel as though this should affect very few patients in the targeted indications. You know, patients who have, you know, a prolonged QT at baseline, and there are rare patients with sort of hereditary syndromes resulting in QT prolongation, or patients who are on other drugs that they cannot come off of that are clearly shown to prolong the QT intervals. Those would be the sort of patients that would not be able to, you know, go on to our study. It might be excluded from use of the drug, you know, if approved and commercially available. But we expect that to be a very small fraction of the total patients who would be eligible for this sort of treatment.
spk09: And then going back to the Part C, you know, again, maybe we'll double team here as well. Just at the high level, I just want to reiterate that. The goal of the study, as we've been saying for now two years, although obviously the focus has been more recently, given that now the study is in progress, but we've always said that the desire here, the goal was to demonstrate that transitioning this technology from healthy volunteers to patients, and I just want to remind everybody, we actually haven't said that, but I've said it on social media, this is the first drug that has gone in patients outside of oncology coming from a hetero-bifunctional degrader mechanism. So the actual reason for running these patient studies, exactly for that reason, we wanted to see that going from healthy volunteer to patient where, again, there is a plethora of cell types that contribute to the pharmacology, we wanted to make sure that degradation profile was maintained. So this was the initial design reason for designing the study. And, you know, I'll remind everybody, the initial study design was 14 days. Now, we've learned from the healthy volunteer study new things. And so we adapted the study to the new things that we've learned. So we moved from a 14 days to 28 days. And the reason for moving from 14 days to 28 days has been because for two reasons. One, we've seen that Skin degradation in two weeks has not reached steady state. And so we wanted to make sure we reach steady state so that when we select phase two dose, we do with that information in hand. The second one, we uncovered this QT finding in the healthy volunteer study. We saw that between day seven and day 14, we had reached steady state or plateau of this mechanism. we wanted to confirm by extending the study by two more weeks so that we would de-risk running a 12 to 16 weeks phase two study. So this is really the backdrop. So the goal is confirming PPE and confirming safety. Now, given that, we've extended to 28 days, and given other data with other molecules where in 28 days there has been some early sign of clinical efficacy, we have added this exploratory clinical endpoint. But again, our focus is on the PD and safety, and we'll be happy to collect and share any data on efficacy, but as Jared said earlier, given that you know, we expect to reach maximal pharmacology only in the back second, you know, in the back two weeks of the study, it would be unfair to set expectations from that point of view. But again, we remain committed to sharing that data and we'll share with all of you.
spk03: The next question is from Chris Shibutani with Goldman Sachs.
spk04: Please go ahead.
spk13: With the Part C study for KT474, on dosing and on patient selection, you made the modification to do the 75 milligrams in the fed state. Can you just make sure that we all understand the basis for that selection of the change? And then secondly, with the two types of patients, HS and AD, will the Should we be differential in terms of the kinds of exploratory responses that you might see from this Part C group based upon your understanding of the kinetics of degradation? as well as kind of the kinetics of the pathophysiology of the different diseases states. I realize that we're only going out to 28 days, but if there's any basis for thinking that there might be a difference between those two patient types, that would be helpful to know. And will you share that and break out that data based upon those patient types? Thanks.
spk09: Thanks, Chris.
spk15: Maybe Jerry, do you want to take this one? Yeah. Hi, Chris. Maybe starting with your first question, why the 75 milligram dose? Just to clarify, which is that Our aim all along has been to bring in what we call the sort of minimally efficacious dose into Part C, meaning the smallest dose that gives us maximal pharmacology that we think would be associated down the road with clinical activity. From the Part B MAD, we determined that the 100 milligram dose, which was administered in the fasting state, was giving us maximum knockdown in the blood, near-maximal knockdown in the skin, and also significantly impacting ex vivo cytokine induction. So we really saw that as our minimally effective dose. Now, in the Healthy Volunteer Study, you know, these subjects were all treated on an inpatient basis. In Part C, in patients, this is all going to be done on an outpatient basis, 28 days of dosing. So it's not practical really to dose those subjects in the fasting state. So we wanted to make sure we could dose them in the fed state. We did observe a very modest food effect that led to a modest increase in plasma exposure in the presence of food. So we did an additional SAD food effect cohort to determine what is the dose in the fed state that would give us the same plasma exposure as 100 milligrams in the fasting state. And we found out from that cohort that that dose is 75 milligrams, and that's the dose that we're therefore bringing into Part C. With regard to your question around AD versus HS and the ability to detect a clinical signal, you know, we note that, you know, in studies using active agents where these subjects are treated for a long period of time, 12 to 16 weeks, you can see signs of clinical response as early as 28 days in either AD or HS. So we don't expect, if we were to see any clinical signal, for there to be any advantage of AD or HS, which is why we're planning on accruing approximate equal number of AD and HS patients to Part C, restricting the enrollment to patients with moderate to severe disease.
spk09: Maybe I just want to add a couple of things. Just to clarify, so we expect 75 mixed dose to have the same activity in terms of PD of the 100 mixed dose in the MAD cohort. That's the goal. It's pure math, actually. It's nothing to do with us. The math of the exposure 75 is the same as the exposure 100, whether you eat food or don't. depending on the two doses. The other part is obviously, on the second part, the pathophysiology is very different. The kinetics of erectile degradation's impact on pathophysiology of those two diseases might be different. So we actually don't know, right? The question is, That's why the 28-day study has to be focused on does the molecule do what it's supposed to do? Does it degrade and is it well tolerated? Because we want to leave the real answer to your question in a 12 to 16-week study, to be fair.
spk15: And the other maybe key point here is that one reason why we are not sort of placing our focus so much on the clinical endpoints, more on the PDM points, is what's most important in either AD or HS in Part C, is that we are able to observe with IRAC4 knockdown, you know, in the skin, which we want to achieve at least 85% or greater knockdown, we can see an impact on the expression of pro-inflammatory gene transcripts. And those gene transcripts that are elevated at baseline could be different in AD versus HS, but the key is that we want to see downregulation of those transcripts in conjunction with downregulation of IRAC4 protein expression. If we see that in AD as well as in HS, regardless of what we see in terms of clinical endpoints at four weeks, that will give us confidence moving forward that we should be able to impact the natural history of the disease for either of those diseases with studies of longer duration that we would be able to test in phase two.
spk04: The next question is from Richard Law with Credit Suisse. Please go ahead.
spk12: Hi, guys. Good morning. Can you talk more about the type of patients that you're recruiting for the Phase I Part C study regarding the use of prior? Any additional information on this type of patients that you're recruiting will be great. And also a follow-up question would be, you mentioned earlier that the 10 to 20 millisecond would not meet monitoring. Is there a threshold for QDC prolongation that you would meet monitoring from the FDA?
spk06: Thank you.
spk15: I think in terms of your first question, in terms of the patient population for Part C, these will be, you know, HS and AD patients with moderate to severe disease. They could be treatment-naive patients, or they could be patients who have had prior treatments, including prior biologic therapies. If patients are on biologic therapies, or really any therapies at the time that they're screened for the study, they would need to come off of those treatments, and we have an appropriate washout period for different therapies that are written in the protocol. So they will not be able to come on to the study and be on concurrent medications. They'll have to come off of those before they can go on to KT474. The other question was about the QT. Oh, yes, I'm sorry. In terms of the QT and what sort of QT excursions will be required for monitoring, you know, as Nella said, We've had extensive discussions with our cardiology consultants, and they all, I think, unanimously believe that for a 10 to 20 millisecond change, there would be no need for cardiac monitoring. Probably an excursion that is routinely sort of going beyond, say, 40 milliseconds or greater is a level that might require some degree of cardiac monitoring. But again, it really all depends on You know, what's happening to the QT interval itself? Is it going beyond, you know, 500 milliseconds? What is the risk of a cardiac arrhythmia? That would all have to be looked at in totality by FDA ultimately in order to determine what would be the labeling implications and whether any sort of cardiac monitoring would be necessary.
spk03: The next question is from Vikram Puri with Morgan Stanley.
spk04: Please go ahead.
spk10: Good morning. Thanks for taking my questions. So maybe looking at your earlier stage pipeline beyond 474, could you comment a bit on the intended development plan for 253 once the IND is filed later this year and what you expect the news flow for the MDM2 program to look like in 2023? And then secondly, could you give us an update on your efforts with the molecular glue programs you've alluded to before and when you anticipate having a development candidate there to talk about?
spk09: Thanks. Yeah, thanks, Vikram. Maybe I'll try and answer this question more broadly, and then if we need to go into specifics, Jared can help me. So the reason why we started the MDM2 program is because we felt it was an area of clinical investigation and commercial opportunity that has been untapped by the space. I think the biology of p53 as a tumor, as a key tumor suppressor gene and the ability to stabilize p53 in a variety of tumor has been, you know, the focus of many efforts, but I think it's been, maybe from a not the appropriate, not using the appropriate technology. So we discovered that in order to replicate the cancer genetics, really removal of MDM2 was needed. And so the applicability of this concept of removing MDM2 to stabilize p53 and impact a broad variety of tumor is large. What the team is focusing on at the moment is how we select and prioritize indications. So I think as Jared mentioned earlier, there is the very, very strong case for degrading MDM2 in AML, given existing data, given cancer genetics, and given some preclinical data that we've generated that very, very elegantly demonstrates that MDM2 degradation is up there in AML as the mechanism to go after, especially in refractory or resistant to venetoglax patients, which is an area that we're trying to expand. But obviously, we would not develop this asset if AML was the only place to go. And so, we're expanding our investigation in many other tumors, both liquid and solid, and we'll disclose more data as we commit to those areas of investigation. So, I would say our first kind of first in human study will start, you know, towards end of the year, early next year with probably both the solid and AML approach, and then there would be expansion cohorts in different indications. I expect that in terms of news flow, we will have, again, a molecule de-risking early on. So as we've done, as we've been discussing for 413 and 333, is 253 degrading the target with kinetics and safety that we believe, based on preclinical model, is therapeutically relevant. So there will be the early proof of mechanism, which, you know, I don't want to start now setting up expectations, but I expect that that will be something that we'll focus on next year. And then soon after that, we'll be talking about in which indication we expect to see proof of concept. Going back to your broader question, so we have broad activity in each novel E3 legacy discovery that is applied both to novel E3 ligase-enabled hetero-bifunctional degradation as well as novel E3 ligase-enabled molecular glue-driven degradation. I think it is fair to say that these programs are still in the discovery stage, and I think once we're ready to disclose a program, I think it will be when we're close to the clinic. So we're going to we're going to choose to keep our cards close to the vest on the early discovery pipeline because it's a highly competitive space. And to be honest, I don't think we're given any credit for anything that is early. So I think it's probably not a smart thing to share at this point.
spk04: The next question is from Mark Frame with Cohen. Please go ahead.
spk11: Thanks for taking my questions. I wanted to just start off on 474. Given the degradation dynamics and that you're really not maybe going to get maximal degradation in the skin for two weeks, is it appropriate to compare to four-week data for all sorts of other programs that have happened in AD and HS, or should we be thinking more like two- to three-week endpoints for those trials?
spk09: Well, Mark, that's a great question. I'll only spend 10 seconds, and I'll pass it to Jared. The reality is we just don't know. First of all, we're early in the trial, so we really don't know. And then second, I think it's a very good question, and I think only our ability to assess how the data evolve will tell us and teach us. I think what we're seeing here is to see maximal skin pharmacology we need to wait for the second part of the 28-day study. So maybe week three is not week four. And again, the study is small. There is no placebo. So I want to just be transparent. We're not trying to downplay the expectation. Like nothing has really changed from the last quarter. What we're only saying is we can't set the expectation on a study where there are so many variables which make the study based on expectation on efficacy completely unpowered. What we're saying is let's focus on things that we put a lot of expectations on, critical go-no-go expectations on, which is PD and safety. And the other, let's keep it exploratory. I fully appreciate that the investor community would like to have clear targets for those exploratory endpoints, but we're just being very transparent in saying that it's really hard for us to do that.
spk03: The next question is from Zjikwam Xu with Barenburg.
spk04: Please go ahead.
spk15: Great. Good morning. thanks for taking my questions first also on the QT prolongation you mentioned this this one is probably related to specifically to the molecule I was wondering if you have identified any liable structures within the molecule within the compound that go for this and I guess the question is really ask whether other compounds in your pipeline have this liable structure. A quick follow-up on the potential efficacy of this IRAC4 class. Can you help us understand, kind of frame the efficacy expectation for IRAC4 in AD and HS? I'm not looking for guidance, but just kind of broadly speaking in terms of different I think Sanofi talked about they're not looking for as efficacy as a biologic, but they see a great potential for oral therapy.
spk02: Thanks very much.
spk09: Thanks. So to the first question, we understand really well what drives this very weak affinity for the HER channel. And I want to reiterate in case I haven't said it before, we do not degrade ion channels. We only degrade IREC4 also in cardiomyocytes. We understand really well. We have no concern about this impact of any other program, including the backup program. So we know exactly what we need to do and what we've done for other programs in our pipeline. With regards to efficacy, maybe just at the high level, I think that the IL-1 TLR pathway has shown impact in a wide variety of diseases. By blocking either single cytokines, we have data with IL-1, IL-33, IL-36, in some cases even IL-18. We have data with IRAC4 inhibitor in RA, and to some extent, maybe some early data in HS. So this is one of the most validated innate immune pathways out there. What we're offering here is a molecule that can block the pathway, I would say almost completely, if not completely, that should afford superior efficacy to all the other agents that I mentioned so far. So the question is not You know, it's not whether this is my opinion, I want to say. This is not whether this is going to be active or not. The question is where it's going to be active and how much and in which diseases. So is this going to be the best in class in HS and an active drug in AD, best in class in lupus and an active drug in GI inflammation? I'm just, you know, putting things out there. It's just... I think clinical investigation will be needed to assess the level of activity needed. And I think the comments that were made by other companies, including our partner, has There is different expectations if you have a neural drug with a good safety profile where you're going to be driving your penetration on different expectations than a biologics where really the only case for biologics for high penetration has to be exceptional activity given the modality barrier that has with patient compliance. But Jared, any thoughts on this?
spk15: No, no, I mean, I think I agree with what you said. I mean, our aim ultimately is for, you know, this drug to have a, you know, transformative activity, you know, in patients with these diseases with high unmet need. But as Nella was saying, you know, having an oral drug with a very favorable safety profile, one can definitely see these drugs, you know, being taken up and commercialized and being successful, you know, even if the activity is not necessarily superior to what's out there right now. But our expectation is that for certain indications, we should have superior activities that should be, again, transformative for patients.
spk09: So we're told we got to move quickly. So let's do some quick Q&A from now on. We have two minutes left.
spk04: The next question is from Ellie Merle with UBS. Please go ahead.
spk00: Hey, guys. Thanks so much for taking the question. Moving just to stat three, I guess, what are you expecting to see from a PD perspective and proof of mechanism perspective, such as the percent degradation at the update later this year just based on the doses you're studying. I understand that it's still in dose escalation. And then just in terms of STAT3, I guess what have we learned from other STAT3 clinical programs, whether it's inhibitors or antisense programs targeting STAT3, just from a clinical perspective in terms of any efficacy seen? in the oncology setting and, you know, lessons learned there, and I guess kind of, you know, what we've learned about why it's so important to degrade versus inhibit STAT3. Thanks.
spk09: Thanks, Ellie. So we'll do this really quickly. So preclinically, we've seen that if we get around 90% degradation of STAT3 in a patient population that is dependent on that target for a couple of days, we can then dose again either a week after or two weeks after. So having a profile that is, you know, approaching that or around that or that, you know, that level of degradation with a good safety profile for us would be a huge de-risking event for this program. In terms of external landscape, to be honest, I haven't seen any real good agent out there. So it's difficult to I don't think there are real statutory agents that engage the target specifically, and so it's hard to compare apples to oranges there.
spk06: Talpate, next.
spk03: The next question is Talpate Patel. Please go ahead.
spk02: Oh, hey. Good morning. Thanks for squeezing me in here. on the STAT3 program. Another drug developer recently demonstrated clinical activity in late-line liver cancer with their inhibitor-based approach as a monotherapy. I guess based on these recent learnings, should we expect you to enrich that solid tumor arm with liver cancer patients, or are there other solid tumors that you're eyeing or prioritizing for this program?
spk15: Jared, do you want to take that quickly? Yeah, Talbot, I mean, we've been exploring multiple different sort of solid tumor types preclinically, and, you know, we use those data to then drive ultimately whether we decide to enrich for those populations. So I think that'll be based on really on our preclinical data. And also, you know, again, you know, within solid tumors, you know, our data so far suggests that, you know, combination of our drug with anti-PD-1 agents maybe the most effective way to use the drug in solid tumors, whereas in liquid tumors like T and NK cell malignancies that are stat-free dependent, we're expecting a significant activity with our degrader as a monotherapy.
spk09: But yeah, the liver data is intriguing, so obviously we'll follow up on that. Debbie, let's do two quick questions, and then we'll wrap.
spk04: Yeah, the next question comes from Eric Joseph with JP Morgan. Please go ahead.
spk05: Hi, good morning, guys. Just to follow up on stat three, can you talk a little bit about anticipated therapeutic index? Any expectations around myelosuppression or neutropenia based on either mechanism or what we're seeing in the preclinical tox package? And then from a PD perspective, particularly in solid tumors, can you just clarify if you're taking serial biopsies, will you be able to look at not only target aggravation in the periphery, but also in distribution or activity in... impact in tumor samples as well. Thanks. Yeah.
spk09: So, you know, we have options for biopsies in the dose escalation. This is not mandated, given that this is an early dose escalation. So we're relying on really patients to help us there. And so we can't commit that we'll have the data, but we're trying to collect the And as you know, we are very keen on, as I've said, on translation, so also the correlation between PK and PD in blood and in tumor is important. So we'll try and get there, hopefully. I think the first question was on safety. I mean, at pharmacologically active doses, these compounds are quite well tolerated preclinically. So we expect to see a similar profile in the clinic, but we will continue to monitor things and obviously report if there are things to be concerned about.
spk06: Sounds like last question.
spk04: Yes, the next question is from Mike Kratky with SVP. Please go ahead, SVP. Yeah, hi, everyone.
spk01: Really appreciate you fitting me in here. In terms of the previously disclosed QT finding, is there any plan to run a thorough QT, QTC study and then have a follow-up on efficacy? Can you just clarify whether you'll be reporting the mean reductions in EZ at day 28, and if you may be reporting any other metrics such as EZ50 or 75 or 90 in those atopic dermatitis patients? Thank you.
spk09: Judge, why don't you take that one?
spk15: Yeah, in terms of the endpoints themselves, you know, we'll be analyzing, you know, those endpoints in a number of different ways. We haven't finalized exactly how we'll be looking at those endpoints, such as the EZ and AD, so really we'll provide more color on that, you know, once the data emerge. The first question was? The thorough QT study. Oh, thorough QT. Yeah. You know, the fact that, you know, within our phase one, we've had extensive ECG monitoring in the healthy volunteer portion, including culture monitoring, and we detected this, you know, subclinical modest QT finding. I think that sort of precludes the need for any thorough QT study in the future. We essentially know sort of what we're dealing with, and we'll be able to sort of do routine sort of ECG monitoring to sort of follow that finding.
spk09: Great. Thanks, Jared. Maybe to wrap up, we're out of time, so no more questions. I know we're past our time, so I'll be very brief. I just wanted to thank everybody for joining in on our call and for all the really good questions. We are excited, you know, beyond our expectation to be here in 2022 dosing patients with HSAD, lymphoma, solid tumors, leukemias, with programs that were all de novo first-in-class programs developed at Chimera within our team. So this is an amazing accomplishment. Obviously, we haven't accomplished anything until we impact the lives of patients. So we're focused on how to do that in the most responsible, data-driven, and thoughtful way, and to continue to engage with you to make sure that there is continued communication with the external community so that we can advance these, hopefully, game-changing therapies and all the new generation programs that we haven't disclosed yet and make Chimera this fully integrated commercial stage company in the next few years. So thanks again and have a good day.
spk04: The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.
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