Kymera Therapeutics, Inc.

Good morning, and welcome to the Chimera Therapeutics first quarter 2023 earnings conference call. All participants will be in a listen-only mode for the duration of the call, and should you need any assistance during that time, please signal a conference specialist by pressing the star key followed by zero. After today's presentation, there will be an opportunity to ask questions. To ask a question, you may press star, then one on your telephone keypad. And to withdraw your question, please press star, then two. Please note that this event is being recorded today. I would now like to turn the conference over to the Chief Financial Officer, Bruce Jacobs. Please go ahead, sir.

Good morning, everyone, and welcome to the Chimera Therapeutics Quarterly Conference Call. I'm Bruce Jacobs, Chief Financial Officer at Chimera, and I'll be joined today by Nella Manolfi, Founder, President, and CEO, and Jared Golub, our Chief Medical Officer. After our prepared remarks, we will open the call to your questions. To ask a question at that time, please press star 1 on your telephone keypad. And if any time you'd like to withdraw from the queue, you can press star 2. Before I get started, I'd 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 findings with the SEC and any other future findings that the company may make with the SEC. You are cautioned not to place any undue reliance on those forward-looking statements, and Chimera disclaims any obligation to update such statements except as required by law. With that said, I'll now hand the call over to Nello.

Thanks, Bruce, and thank you, everybody, for joining us today. This month marks the seven-year anniversary of our founding. And as Chimera reaches this milestone, I thought I would spend a few minutes reflecting on the progress we've made on our ambitious plans to build the best-in-class, fully integrated global medicines company. Since our funding, we have focused on a target selection strategy that would allow us to use this novel drug modality in target areas that would uniquely benefit from it, and on evolving the platform to reach novel therapeutic hypotheses. Over that time, we've continued to enhance our platform capabilities and advance programs in areas of significant patient needs that cannot be meaningfully addressed by conventional medicines, building a high-value pipeline and demonstrating our ability to design molecules that have the potential to transform disease treatment. Our first-in-class ARAC4 degrader program, KT474, is a molecule we've discovered and developed through Phase I, and its plan to start phase 2 trials conducted by our partner Sanofi. In December of last year, we shared positive early data in both hydrotonitis separativa and atopic dermatitis patients that demonstrated strong translation of our preclinical PKPD and safety models into the clinic. With this program, we have seen for the first time clinical benefits of a hetero-bifunctional degrader in inflammation and immunology indications for the first proof of concept of clinical differentiation of a degrader compared to a small molecule inhibitor. This is a substantial accomplishment for a company that is pioneering a new modality. Sanofi expects to initiate the first phase two study of KT474 in HS this year, followed by a study in AD. Our three oncology programs continue to make progress. Of note, we have initiated the phase one clinical trial of our MDM2 degrader, KT253. The clinical effects of stabilizing P53 and P53 wild-type tumor is a concept that has been pursued extensively in the biopharma industry. There are a handful of MDM2 small molecule inhibitors in the clinic with some activity in a variety of tumor types. Unfortunately, the activity has been limited, given the inhibition of MDM2 leads to a transcriptional feedback loop, which creates more protein that makes it harder for occupancy-driven small molecule inhibitors to block, leading to reduced therapeutic indices. We believe KT253, on the other hand, has the potential to overcome that feedback loop because it removes the protein and does so in a catalytic manner. This makes KT253 a highly effective potent candidate that may be able to induce an irreversible acute apoptotic response with brief exposure while allowing time for the recovery of any normal cells which may be affected, creating an improved therapeutic index. With KT253, we believe we have a degrader that can remove MDM2, stabilize P53, and overcome the feedback loop generated by MDM2 reduction giving us the opportunity to explore the clinical potential of such a powerful mechanism fully. We look forward to sharing more updates as the trial advances, including safety and proof of mechanism data later in the year. Nearer term, we plan to present additional preclinical data on KT253's pharmacological profile at the European Hematology Association Congress next month. Our Arachimid program, KT413, targets Arach4 and the imid substrates, Igoros and Nylos, with a single small molecule and has the potential to be the first precision medicine to treat a genetically defined subset of tumors. KT413 has been designed to target mighty 88 mutant lymphomas, and we're currently in dose escalation of the phase 1 trial in B-cell lymphomas, including BLBCL. We shared some initial data from the trial in December showing that we engaged the target without any dose-limiting toxicities. Our third oncology program, KT333, target STAT3, which has been linked to numerous cancers and inflammatory and autoimmune diseases, and is the first degrader against an undrugged transcription factors to enter the clinic. We're currently in dose escalation of the phase one trial in a broad subset of liquid and solid tumor patients where we've also shown early proof of mechanisms. Our focus in 2023 for both KT413 and KT333 will be the degradation profile and evaluating their biological and clinical impact in the appropriate target patient populations. As discussed today, we plan to provide a clinical update focused on degradation and safety. for KT413 and KT333 at the International Conference on Malignant Lymphoma, or ICML, in June. We intend to present data evaluating anti-tumor activity in the target patient populations for both programs later in the year. In addition, we continue to push the science of TPD forward and identify best and first in class opportunities to transform the treatment of disease. We have several exciting programs in our preclinical pipeline that are designed to address well-validated immunology and oncology pathways in areas of significant patient need and commercial opportunity. These include developing tissue-selective restricted E3 ligase-driven programs, as well as a new generation of molecular glues, exploiting newly identified diagram motifs to expand the reach to high-value undrugged and non-legandable targets. We hope to be able to share more on these efforts later this year or early next. Jared will now cover in more detail the recent progress for each of our disclosed programs before turning the call over to Bruce for a financial update. I will then finish with some concluding remarks before handing the call to the operator for a Q&A session in which Jared, Bruce, and I will be available. Jared?

Thanks, Nello. I'll provide a brief recap of where we stand with our clinical programs and what to expect in the coming months. Turning to our oncology pipeline, I want to update everyone on our disclosed programs, which include our STAT3, Arachamid, and MDM2 degraders. As Noah mentioned, KT253, our MDM2 degrader, received IND clearance from the FDA at the end of last year. We initiated a phase one trial in March and expect to dose our first patient shortly. MDM2 is the crucial regulator of the most common tumor suppressor, P53, which remains intact in close to 50% of cancers. We believe KT253 has the potential to be a highly potent degrader that, unlike small molecule inhibitors, has been shown preclinically to have the ability to overcome the MDM2 feedback loop and rapidly induce apoptosis, even with brief exposures. KT253 has the potential to be effective in a wide range of hematological malignancies and solid tumors with functioning P53. We've shown preclinically that KT253 has superior activity compared to MDM2 small molecule inhibitors and demonstrated greater than 200-fold improvements in both in vitro cell growth inhibition and apoptosis. Additionally, we presented data at the ASH annual meeting last year supporting an intermittent dosing schedule of K2253 in acute myeloid leukemia, AML, which has the potential for improved efficacy and safety using a degrader approach. The phase one trial is evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics, and clinical activity of KT253 in patients with relapse or refractory high-grade myeloid malignancies acute lymphocytic leukemia, or ALL, lymphomas, and solid tumors. Patients in the KT253 phase 1A dose escalation study will receive IV doses of KT253 administered once every three weeks. The open label study is intended to identify the recommended phase 2 dose for KT253 and will be comprised of two arms with ascending doses of KT253 in each arm. The first arm will consist of patients with lymphomas and advanced solid tumors, and the second arm will consist of patients with high-grade myeloid malignancies and ALL. We plan to share initial safety and proof of mechanism data from the phase one clinical trial later this year. Now, turning to our other two oncology trials that are ongoing. STAT3 is a transcriptional regulator that has been linked to numerous cancers as well as to inflammatory and autoimmune diseases. Our phase one clinical trial is evaluating KT333's potential in hematological malignancies and solid tumors. Specifically, the trial is evaluating the safety, tolerability, PKPD, and clinical activity of KT333 in adult patients with relapse and or refractory lymphomas and solid tumors. We reported on the first dose level in December, showing initial proof of mechanism for stat-free degradation in PBMC and no dose-limiting toxicities, with good translation of PKPD from preclinical models to patients. The trial is continuing to enroll, and based on the PKPD we showed in December, with robust target knockdown for 72 hours, followed by recovery, we expect to be at pharmacologically active doses by DL3 or DL4, as previously announced. The trial's second stage will consist of Phase 1B expansion cohorts to further characterize the safety, tolerability, PKPD, and antitumor activity of KT333 in relapsed and or refractory stat-free dependent T-cell malignancies, as well as in solid tumors. Our IRACAMIN program, KT413, is a novel heterobifunctional degrader that targets degradation of both IRAC4 and the imid substrates icrose and ilose. 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 KT333 and is currently in the dose escalation stage of the phase 1 trial, evaluating the safety, tolerability, PKPD, and clinical activity of KT413 in patients with relapsed and or refractory B-cell non-Hodgkin's lymphomas. We reported in December that the first two dose levels have been completed, showing initial proof of mechanism with IRAC4, icorose, and ilose degradation in PPMC and tumor, and no safety signals, with good translation of PKPD from preclinical models to patients. We are continuing enrollment, and similar to KT333, we expect to be at pharmacologically active doses by DL3 or DL4, as previously announced. The trial's second stage will consist of 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. As Nello mentioned, we look forward to sharing updated degradation and safety data on these two programs at ICML in June. We'll present a poster on KT333 at the conference, and an update on KT413 will appear in the ICML abstract book. As we've said previously, we expect to assess the clinical impact of degradation in the respective target patient populations for both KT333 and KT413, and to share that data at a medical meeting later this year. I'll end with our IRAC4 program, KT474. As Nello mentioned, Sanofi will be taking KT474 into Phase II and initiating trials in HS and AD, the first of which in HS is planned to start this year. There is limited additional information I can share with you at this time other than to say the plans in place for starting Phase II are tracking with Sanofi's and our expectations. Finally, with respect to KT474, we look forward to presenting the clinical data from the Phase I program at the EADV Symposium in Seville later this month, which will mark our first time sharing these exciting data at a major scientific meeting. I will now hand the call to Bruce, who will share some brief comments on our financial results for the first quarter.

Thanks, Jared. I'll quickly cover the financials before turning the call back to Nello for some concluding remarks. Before getting into the specific financial results for the quarter, I wanted to briefly address the events surrounding Silicon Valley Bank as it relates to Chimera At the time of the receivership of SBV, we had very limited exposure to the bank, and in response to the events in March, we removed all of our excess operating cash that was held there and moved the outstanding letter of credit that was also there that is held to support our new lease. At this time, we have modest cash at SBV to support our current operating needs. And as a brief reminder, Chimera's investment policy prioritizes protection of principal and our liquidity needs above all and limits our investments to government securities and highly rated corporate bonds. This policy guides our investment approach, and it's been coupled with the recent expansion of our banking and asset management relationships to further diversify our financial risk. That said, back to the financials for the quarter, we recognize $9.5 million of revenue. This total reflects revenue recognized pursuant to our Sanofi and Vertex collaboration. At the end of the quarter, our deferred revenue total on the balance sheet was approximately $57 million. That reflects partnership revenue we expect to recognize over the next several years excluding the receipt of any potential future milestones. With respect to operating expenses, R&D for the quarter was 42.2 million, of which 4.7 million represented non-cash stock-based compensation. The adjusted cash R&D spent of $37.5 million, including stock-based comp, reflects about a 3% decrease from the comparable amount in the fourth quarter of 22. Our SG&A spending for the quarter was 12.6 million, of which 4.7 was non-cash stock-based compensation, The adjusted cash G&A spend of $7.9 million, also excluding stock-based comp, reflects a 10% increase from the comparable amount in the fourth quarter of 2022. And finally, we exited the first quarter with cash and equivalents balance of approximately $516 million. As we shared earlier in the year, we believe our cash runway extends into the second half of 2025, a projection which includes milestones only related to the start of the first two Phase II trials for KT474. I will now turn the call back to Nello.

Thanks, Bruce. I'd like to conclude by reminding everybody that Chimera was founded to harness novel therapeutic approaches to revolutionize the way we treat diseases. Over our seven-year history, we've built best-in-class discovery engine capable of identifying new drug candidates at accelerated pace and delivering at least one DCIND every year. We now have a pipeline of four clinical stage assets across different disease areas. We continue to invest in the future and evolve our disease agnostic discovery platform so that we can expand the possibilities of what we can do to improve patients' lives. Propelling a rigorous scientific approach is a relentless desire to do what hasn't been done before. to push the boundaries of our science, expand our capabilities to support a rapidly maturing company, and build a culture that enables us to achieve what may seem impossible. We look forward to sharing exciting updates on our clinical programs, platform, and company in the coming months. At this point, I'd like to thank the Chimera team as well as our partners and the patients participating in our clinical trials for sharing this journey with us. Finally, thank you all for participating in our call, and I look forward to your questions. I will now hand the microphone back to the operator so that we can take your questions.

We will now begin the question and answer session. Again, to ask a question, you may press star, then 1 on your telephone keypad. If you're using a speakerphone, please pick up your handset before pressing the keys. If at any time your question has been addressed and you would like to withdraw your question, please press star, then 2. We ask that you please limit yourself to one question and one follow-up for today's call. At this time, we will pause just momentarily to assemble our roster.

And our first question here will come from Vikram Pirohit with Morgan Stanley.

Please go ahead with your question.

Good morning, everyone. This is Gospel on Pope Vikram. We have one question. So for KT413 and KT323, you have mentioned that you would expect those levels 3 and 4 in each program to demonstrate clinical activity. When this data is available, what do you think is going to be the best way to interpret the data to gauge the strength of the clinical activity for each molecule? What is your benchmark for determining a good outcome versus a more mixed one? Thank you.

Thanks for the question.

So first, I'd like just to be clear. We said in December that we expect dose level three and dose level four to be at clinically active exposures and level of degradation. Obviously, the question will be at those doses, do we see clinical activity, just to be clear. So just to remind everybody, these are first-in-class mechanisms. And for both mechanisms, for 413 and 333, we've shown some really compelling preclinical data. Remind you, for 413, we've shown that if you degrade IRAC4, egonose, and ilose for about 72 hours, anywhere between 50 and 90% across the three proteins, we can drive mighty 88 mutant tumors to complete remission. For 333, we've shown that if you degrade STAT3 for about 90%, for about 48 hours, we're able to drive some subset of liquid tumors. We've talked about CTCL, PTCL, LGL leukemias, to at least in some preclinical models that we were able to run to complete remissions. So the question that we want to ask, we always look at clinical translation from two perspectives. The first one, is the molecule able to translate what it was designed to do? And so we ask of these two molecules to replicate our preclinical degradation profile. So as I mentioned, what we believe to be clinically relevant is this 50% to 90% degradation for 413 and 90% degradation for for 333 for, you know, as I said, 72 hours for one program and 48 hours for the second. So as we continue to explore PKPD and safety in the clinic, and in fact what we said is that we're going to give an update at ICML on that, you know, we want to make sure that our molecules are able to reach those degradation profiles at tolerated doses and exposures and with a tolerated profile. And then the second part of the clinical translation de-risking is that particular degradation profile, as he had done in the preclinical studies, translating into anti-tumor effect. And that's going to be the question that we're going to try and answer and show data later this year, I think we said. It's hard for us to set a bar because, just to be clear, we're running a relatively broad phase one dose escalation studies in terms of patient population, so we will have probably a handful of patients that fit the right criteria in terms of disease and type of tumor types. And so what we would like to see in those patients is, the ability of translation of anti-tumor effect. And so I think we're staying away right now on comparing and setting a bar just because we're still early in the clinical development. Jared, anything you want to add to that? No, I think that covers it all.

Thank you. And our next question will come from Michael Schmidt with Guggenheim.

Please go ahead with your question.

Hey, guys. Good morning. Thanks for taking my questions. Just a follow-up on 333 and 413. You know, as we think about this upcoming update at the ICML conference, can you talk about a bit, you know, how far in you are in those two phase one studies now beyond dose over one or two? You know, how many patients' worth of data, you know, do you have at this point? And how are you tracking towards identifying a recommended phase two dose? And then on 413, I think you already had 95% to 100% knockdown of Icarus and Iolos last December. I guess, you know, how much higher do you need to go and how confident are you in not seeing, you know, issues around potential on-target toxicities related to those two targets if you go, you know, much higher? Thanks so much.

Yeah, thanks for the questions, Mike. You know, we really haven't been guiding externally in terms of where we are right now with regards to enrollment across both the studies. You know, as we showed back in December, you know, we presented data on DL1, the first dose level for KD3D3, and on the first two dose levels for KD413. And all we can really say is that we're continuing to enroll across both studies. And when we do present updates in ICML, you know, at that time we'll be able to really update on numbers and where we are in terms of which dose levels. Oh, in terms of the knockdown question, yes, you're right, that, you know, with regard to 413 and icrosanilose knockdown, we did show very robust knockdown of greater than 90, 95% in peripheral blood. In particular, you know, with those first two dose levels, the data we shared back in December, you know, for IRAC4, I think at that time we had approximately 40% knockdown of IRAC4 in the blood. You know, we had one serial, a set of tumor biopsies from the first dose level where we showed around 60% knockdown of icrosanilocin tumor and around 20, 25% knockdown of IRAC4. And so I think, you know, what we want to be able to show in subsequent dose levels is continued strong knockdown of icrosanilocin in the blood. We'd like to see further knockdown, you know, of IRAC4, you know, getting up into that 50 to 70% range that Nello alluded to earlier that's associated with anti-tumor activity in our preclinical models. And if it's possible, you know, where we can get voluntary two-room biopsies to also continue to show activity there as well.

Thanks, Jared. I just want to add one thing, Michael, and probably for everyone's benefit. You know, I think it's an exceptionally exciting time to be at Chimera. We have the luxury of witness what is, you know, first-class in mechanisms, translation into patients. We've done it with ARAC4, and now we're doing it with three other mechanisms. So I don't think we're trying to deflect questions. It's really like we are observing new biology at play here. And so especially for SAD3, there is a wealth of opportunities that we want to be thoughtful on how we're exploring.

And our next question will come from Brad Canino with Stiefel. Please go ahead with your questions.

morning, and I apologize. I feel like I'm going to ask Michael's questions in a different way because I just want to check on the upcoming Lugano presentation. Will that include additional patient numbers and dose cohorts relative to last December's disclosure? And then a specific question on KT413 is we watch these safety data evolve through the rest of the year. As you dose escalate, do you have a range of neutropenia across grades that you're going to be comfortable with, especially when you think about marching this drug eventually to earlier lines in the treatment paradigm, which will be in combination with the DLBCL standards of care? Thank you.

Yeah, no, and that's a great... Thanks for asking again, because maybe... We weren't clear enough. Yes, there will be more data, obviously. Otherwise, we wouldn't be presenting an ICML. There will be meaningfully more data on the programs that we present. Maybe I'll let Jared comment on the neutropenia question. I just want to repeat something we've said before, which is the opportunity with 413 is the ability to translate synergistic biology between IRAC4 and Icarus and ILOs. And that's really the question. The question is, is this synergistic biology that we've seen preclinically being able to drive profound anti-tumor effect driven by an immediate apoptotic response that only required 72 hours of knockdown? Is that going to translate in the clinic? If it is, I think we will be able to navigate much better than other programs the question around neutropenia because we have this pulsatile dosing, which allows us to capture this immediate apoptotic response in the first few days and then allow any potential on-target safety coming from the immediate part of the pharmacology here to be managed by, again, the alternative dosing paradigm. Jared, anything you want to add on the actual kind of grade type of neutropenia here?

Yeah, in terms of neutropenia, I mean, clearly we're referring to the neutropenia that is seen with IMiDS, especially with potent IMiDS. And as we noted back in December, with the first two dose levels in 413, we didn't see any neutropenia adverse events. You know, we do expect, you know, based on our preclinical animal tox data, to see lowering of neutrophils as we continue to dose escalate. The issue isn't whether we'll see lowering a neutrophil, the issue is really, you know, what is the recovery time? And because we have this every three-week dosing, which is one IV infusion every three weeks, in our GLP-Tox studies, we saw that that gave us adequate time to see recovery of neutrophils after they were suppressed, as well as recovery of lymphocytes. And so I think the key here for us will be, you know, as we escalate, you know, we do expect to see some lowering of neutrophils. Will we see recovery, you know, prior to each dose? And I think that will tell us a lot about the therapeutic index and tolerability and the ability of this intermittent dosing regimen to mitigate that particular toxicity, which is seen commonly within them.

And our next question will come from Chris Shibutani with Goldman Sachs. Please go ahead with your question.

Great. Thank you very much. Following some of those specific questions on the assets, Nello, you noted the anniversary. Perhaps can you comment on a couple of things in terms of how you're thinking about the next phase of strategically optimizing your portfolio development and capital allocation. When we think about the oncology assets, there's kind of a fleet of them that seem to be going in tandem. You know investors like to pay attention to kind of like a lead steer as kind of a catalyst driver. Do you anticipate that the timing of these oncology assets will also be kind of in this couplet or the trio? And then in terms of next areas that you could roam, You have the Sanofi relationship for the first immunology asset, but there's other potential immunology indications. I believe you brought on board someone more with the sort of business development, strategic investment banking role in-house. How are you thinking about taking that next tranche of assets so that you can optimize the capital that you have?

Thanks, Chris. This is a great question, which I could spend a day on, but I'll try to do it in a couple of minutes. First, I'd like to recognize the path that we've taken from an early company that was sitting on a potentially transformative new drug modality and decided to commit to building a real company. I use often this definition of real company, meaning committed to seeing programs through the different phases of development and eventually commercialization. Because we believe that in order to capitalize on the power of this really, really strong new modality, you have to commit to see it through. You cannot depend on other industry partners to do so, because that's what history has taught us. New modalities have been developed in biotech companies and biotech companies only at best. So that's our commitment. Now, you know, the first seven years have been years full of execution but also learning. We learned the type of targets that best benefit from this technology, and we've shown we were fortunate enough that our early targets have played out, I would say, extremely well into early clinical development, demonstrating the power of the technology. We've also learned, maybe not discussed broadly enough, the type of targets that don't work well with this technology. And I think we've been focused and we've been really good at understanding early on the type of targets that is not worth applying this technology against. And so our first wave of targets, I think, are well positioned to demonstrate with a catalyst-rich sequence the power of degrading targets in human patients, and then the power of that degradation impacts on human disease and human condition. So I would say the next two years, we will see proof of concept across four clinical programs that we have in our pipeline. We will see proof of concept of KT474 in HS and AD. We will see proof of concept of KT413 in lymphomas. We'll see proof of concept of KT333 in several disease types or cancer types and potentially outside of oncology. And we will see MDM2, I think, final realization of full potential. But Chimera could not be the type of company we want to build if we stop there. And so our investment has been in actually the learnings that we've taken from the first, let's say, six years or five years since our founding into applying this technology to a new generation of targets. And we have decided for a new generation of pipeline to focus heavily on on two areas that we believe will define the success of biotech going forward, which is an area where there is larger clinical need, large commercial opportunities, with a maybe slightly higher focus in immunology, where we've learned ahead of everybody else. We were the first company to take a degrader into immunology. We've already shown the meaningful clinical data. We haven't really talked about all the platform learnings that we have learned from, that we have been able to amass through the development of that asset. And we're able to translate that to a series of of novel immunology programs that we will be disclosing in the next few months. I think we're also not naive enough to believe that we can do all of that on our own. I think that would be impossible, just to be clear. For the type of indications and programs that we want to develop, it would be impossible to commercialize eight programs on our own in the next five years. or seven years. So the question is, how do we optimize the synergies that one can build in this biopharma ecosystem, which is obviously the best in the world in terms of businesses? And as we've done with Sanofi for 474, I suspect there will be other partnerships that will maximize value creation here. We're just not in the position to talk about them because I don't think we're quite there yet. We're focused on now really translating these programs in the clinic and advancing a new generational program in the clinic, into the clinic. And then maybe as we progress on this path, share more on what are the strategic choices that we have in front of us.

And our next question will come from Mark Fromm with TD Cowan. Please go ahead with your question.

Thanks for taking my questions. Maybe just to start one question. Right after ICML, you have the guidance for initial MDM2 data in the middle of the year. Can you just walk through again the target degradation profile there, both in terms of depth, but also kind of the timing of that degradation?

So this is MDM2, right? So MDM2, just to be clear, will not be presenting an ICML. Maybe I misunderstood, but so my ICML will be right after. Yeah.

Yeah.

So I think what we're presenting in the short term on MDF-2 is some preclinical data at the IHA conference. Later in the year, we will be presenting early clinical data. And what we call it, this proof of mechanism, is just to be clear is, you know, how much degradation we see in early cohorts and what is the safety profile, which, you know, for this program is going to be meaningful because, you know, In a way, all MDM2 programs in the past have suffered from ability to engage the target fully and managing the right safety profile. So we haven't really actually talked deeply about what is the degradation profile and the extent of degradation needed to achieve kind of full biological response in preclinical species. And I believe we're presenting more data also later in the year on these, again, preclinical data. It's really elegant work that the team has done. And even at EI, I believe, we will talk about how dose and dosing type will impact the biology in this pathway. But what I will say is in order for us to overcome we call a feedback loop of MDM2 transcription regulation, we need to have a deep MDM2 degradation that is actually limited, I would say in terms of hours, not even days. Once we are able to knock down MDM2 for a short period of time, but deeply, we see a profound commitment to cell death of a wide variety of tumor types. And we have seen, we have observed that that commitment to apoptosis is enough to not require another dose for weeks. In fact, we're going into the clinic with this program with once every three weeks dosing. So what we're trying to do in the first, again, innings of this program is to demonstrate, again, that we're seeing this profound degradation in the early few hours, and we're also seeing a manageable safety profile, which in preclinical species we've characterized and we feel really confident around.

Okay, that's helpful. And then maybe back to the 333 and 413 trials. As you mentioned earlier, the enrollment criteria is pretty broad and not necessarily in its early parts focused entirely on the patient populations who might have the most robust single-agent activity. But are you seeing, you know, a real bias kind of in the enrollment just given that there is some testing, particularly from ID88, you know, out there towards those target populations? Or should we think the epidemiology is really what we'll see?

Yeah, thanks for the question, Mark. I think, as you've noted, you know, the 413 study, you know, is broadly enrolling B-cell non-Hodgkin's lymphoma on Phase 1A. You know, we do have sites, you know, that are enrolling patients, and these are sites that have the ability to identify mighty 88 mutant patients as well, either with DLDCL or Waldenstroms. And so as we get into higher doses, you know, those sites know that those are patients of interest. And as Nello alluded to earlier, we'd like to be able to have some of the target indications enrolled onto the study as we get into those higher doses to give us an opportunity to show initial antitumor activity. Okay. And likewise, for the STAT3 program, you know, we're broadly enrolling solid tumors as well as B and T cell lymphomas on phase 1A. But likewise, we also have a number of sites that do have CTCL, PTCL, and LDL patients. And those sites, you know, are capable of putting those patients onto the trial, especially as we get, again, into those higher pharmacologically active doses. So once again, we would have an opportunity to show anti-tumor activity in those target indications.

And our next question will come from Mike Kratke with SVB. Please go ahead with your question.

Yeah, hi, everyone. Thanks for taking our question. Regarding the KT474 data to be presented at EATB, will there be any new analyses included in these results, and what incremental new info could we expect to get?

Thanks. Yeah, so in our oral presentation, I think it would be a summary of data that we've already shared. What I will say is that, as we said in the past, you know, we're working on a manuscript that will have maybe more insights into the data. But for the presentation, I would expect it to be what we've shared in the past, given that it's also a relatively short presentation.

Thank you. And our next question will come from Eric Joseph with JP Morgan.

Please go ahead with your question.

Hi, good morning. This is Hannah on for Eric. Thanks for taking the question. Just wondering how many dose levels you're planning to evaluate in the KT253 dose escalation study. And based on that, at which levels would you expect to be at pharmacologically active doses? And are you commenting on the specific doses that are being evaluated in that study? And then secondly, can you comment at this time on the expected biomarkers that are being used to evaluate MDM2 degradation, and how quickly do you expect these to begin to change in response to degradation?

Yeah, thanks for the question. We haven't really commented publicly on how many dose levels are in that study or the doses that we're actually planning to prosecute. I mean, whenever we bring, you know, doses into our phase one studies, it's based on our preclinical data and our GLP-Tox studies, and we usually have an expectation that you know, even the lower dose levels will have the potential ability to result in some downregulation of the target, but we really haven't provided specifics on that. With regard to sort of measuring pharmacology, in addition to looking at MDM2 downregulation, you know, we do have other biomarkers that are included in the study that help us look at P53 pathway activation, because as you know, If we're hitting MDM2 the way we want to, we should see upregulation of P53 pathway and the various biomarkers that are associated with that activation. So we've built this into our phase one study that will be able to measure these different biomarkers in the blood as we proceed with dose escalation.

Yeah, maybe the only thing to add, I would say, if you look at all the programs we've disclosed so far, the first dose has always been a dose with measurable levels of degradation. So I think we expected that to be in line, obviously, but we have to run the study to see.

And our next question will come from Zhisheng Xu with Barenburg. Please go ahead with your question.

Hi, thank you for taking the question. This is Andy on for Z. The first question is, so for your STAT-3 program, I think you communicated the knockdown or the degradation window. And I'm just wondering, like, what's the ideal therapeutic window that you're targeting and if there's any clinical rationale for that? And the other question is, your STAT-3 and IRACMET program, what's your ability or willingness to make them orally available? Thank you.

Okay, so the first question is, so we've said this in the past. Empirically, through lots of work that we've done preclinically, we've shown that a degradation profile where you have about two days or 48 hours of deep degradation, around 90% or even more, and then recovery of that degradation over the course of the duration of the week or even two weeks, is sufficient to drive strong anti-tumor effect in a wide variety of tumor types. And that profile is also really well tolerated. So this is the hypothesis that we're bringing into the clinic. Once a week, we could actually dose even once every two weeks, but we decided to start with once a week. and being able to drive that profound degradation in the first 48 hours or so of that particular program. And so that's what we're bringing forward. That is both effective and really well tolerated in preclinical species. With regards to oral, I mean, this is really around, when we start the program, we usually, you know, start with the TPP, based on the mechanism. And if the mechanism is unknown, it usually is driven also by what we learn along the way. So in both of these programs, the biological and translational hypothesis has been infrequent dosing because we need to manage both the activity as well as the recovery of the target and the building of the therapeutic index. And the fact that we were able to use the distribution and the PK of these compounds to maintain degradation for multiple days with a single dose. So naturally, that type of profile led to this infrequent dosing, which is a lot more manageable if you do it by a parenteral administration. These two programs are not IV because these molecules are not orally bioavailable. At least we've shown for the 413, this actually started as an oral drug and we were dosing it every day in preclinical species early on in the development of the program. And then we switched it to a different dosing paradigm. Again, to manage both the activity and the safety.

And our next question will come from Ellie Merle with UBS. Please go ahead with your question.

Hi, this is Jasmine on for Ellie. Thanks so much for taking our question. On the MDM2 program, We know that RNR-AML has been disclosed as a particularly sensitive tumor type to MTM2 degradation. So when we're thinking about other tumor types that could also be potentially sensitive to this mechanism, can you give any color that would help us understand the characteristics of the kinds of tumors these might be? Thanks.

Do you want to take this? I think the question was around probably AML. Yeah, well, I know, I think the question was that AML, you know, we've shown that to be a sensitive tumor in our model systems. You know, what are we doing on solid tumors? And even though we haven't presented as much data on solid tumors, what we can say is that we've been doing a lot of work preclinically to identify those solid tumor types that have the same sort of exquisite sensitivity to MDM2 degradation that AML has, where we can dose intermittently as we can with AML once every three weeks in tumor models and see profound tumor regressions. And so we have identified, you know, various solid tumor cell lines. And we perhaps will later this year be able to reveal what some of those are at presentations. But we have been, number one, looking at those different solid tumor types to determine those that are very sensitive to this mechanism. And number two, we've also, you know, had an active effort in trying to nail down potential biomarkers that are associated with the most responsive subsets of those different solid tumor types that could allow us to then use that to select patients moving forward as we go beyond phase one. So I think this is an active area of research for us and very important that for us it's not just going where other MDM2 inhibitors have gone before in terms of solid tumors. It's really forging our own path based on our preclinical data, making sure this is a data-driven decision which guides which solid tumor types we end up exploring as we get beyond phase one.

Yeah, and I would also add that, you know, encourage everybody to kind of follow, as we disclose, more preclinical data. I think for both, for these broad mechanisms, both KT333 with SAD3 and MDM2 with 253, these are both broad applicable mechanisms in a wide variety of systems. We're uncovering some really, really fascinating data. I would call it almost new biology, both alone and in combination with interesting agents where you can see really meaningful paths of patient impact when you have this new modality that can be combined with existing mechanisms. So stay tuned and you'll see much more of of those in the upcoming medical meeting.

And maybe also just to quickly add that, you know, again, in our phase one study, we have a one arm, which is solid tumors and lymphomas, and then a second arm, which is, you know, AML and ALL and other high-grade myeloid malignancies. We then plan in phase 1B on having expansion cohorts. One of those will certainly be AML, but we also plan to have expansion cohorts and select solid tumors based on activity that we see. in Phase Ia and also based on activity that we're seeing in our preclinical models.

And our next question will come from Timur Ivankov with Raymond James. Please go ahead with your question.

Hi. Thank you for the question. So I just wanted to come back to Q2C prolongation for a moment. So recently one of the players in TPD reported a Grade 4 prolongation event in their study of synovial sarcoma. So could you just remind us in your preclinical testing for the newest assets like 413, 333, and 253, did you see an interaction with ion channels preclinically? And I think in the past you've talked about a potential saturation effect on interaction with ion channels. Do you still believe that's the case?

Yeah, no, thanks for the question. So I would say that we can say with confidence that QT prolongation is not class effect. I mean, as you know, QT prolongation or QTC prolongation is something that we've seen in the industry for the past 20 years since we discovered, and actually we understood more since we discovered the HERT channel, and it's impacted many small molecules. So I think this is a molecule-specific phenomenon that... you know, we have seen in the industry, and I suspect we will continue to see, I think I want to remind you that there have been several degraders in the clinic, and I think the example you bring up is just one out of several examples where we have not seen QTC prolongation. With regards to KT474 and Chimera, I think what we've said is that we've seen something that is very unique, which is And... It's a time-limited effect where we see appearance of the subclinical QT that then resolves spontaneously with continuous dosing, and that's a very atypical phenomenon. And we believe it's driven by a compound distribution that requires some time to reach steady state, and it might initially have higher exposures around the intracellular compartment of cardiomyocytes that express the HERP channel. That's just in hypothesis. But this is not the typical QT prolongation, which is often those responsive and concentration-responsive, which is what you see with most molecules. I don't know enough about what happened in the other company with that particular drug. I suspect that it's a different, probably it's a different mechanism, given that they've seen it only at the high dose. I remind you that we've seen kind of the same subclinical finding, obviously not a grade four, it was subclinical, across all the four doses in our MAD study. So again, saying that This was a different mechanism than a normal QT driven by hurricane emission.

And our next question will come from Kelly Shi with Jefferies. Please go ahead with your question.

Hi, this is Sean on for Kelly. Thanks for taking our question. We have a question on HS with a rapidly evolving landscape. Can you share how your thoughts and positioning of KD474 have evolved in light of the recent development in this space. Specifically, has any of the recent competitor data been factored into the Phase II trial design, the selection of efficacy endpoint, et cetera? Thank you.

Yeah, no, thank you. It's a great question, talking about patients also. You know, HS is a high-end need, we all know. I don't believe that HS is driven by a single cytokine. So I'm pleased to see that IL-17 agents work. I don't believe that IL-17 is the solution to HS. But it is going to be a great tool in the arsenal of tools that doctors and patients will have. So I think it's great to see this evolving class of antibodies and the likes that have been developed in the space. This is a broad inflammatory disease, local and systemic, that we believe requires a broad anti-inflammatory agent. And we believe that IRAC4 is uniquely positioned to be both active and well-tolerated and have and obviously be an oral agent. our view of the unmet need and the opportunity for an oral active agent has not changed. There is still high unmet need, and we believe we can have an opportunity to have a broad impact in this disease. In terms of how we think about trial design, I wouldn't think that we have learned what we've seen from, you know, elegant studies that have been run is really validation of what are the key primary and secondary endpoints that one wants to see to confirm activity of drugs. And I don't believe we've learned anything that has changed our view on how we want to design our clinical study, which, you know, obviously we've done in collaboration with Sanofi on phase two. So I think it's great to see, again, other agents being active. The opportunity is totally still there for a neural active drug in that space that is, again, active and well-tolerated.

And we have time for one more question which will come from Rich Law with Credit Suisse. Please go ahead with your question.

Hi, this is Grace on for Rich. Thank you for taking our question. The first one is what's the development path and timelines for the STAT III program in combo with PD-1? And do you see any other combo regimens that will make sense?

Yeah, no, thank you. So, yes, the answer to the second question is yes, we see several combo opportunities here. And this is a bit what I was referring to earlier. At the beauty of working with a new mechanism, we are learning also with some of our academic collaborators that have published and will continue to publish on this. what STAT3 biology can be combined with to drive synergistic anti-tumor effects. With regards to timing, so we're now focused, as you know, on dose escalation as single agent, and we're obviously learning Also, when we can, when patients allow for biopsies, also what's happening in the tumor microenvironment, at least that's one of the goals that we have. And any combo will be part of later expansion cohort, which will happen after we conclude phase 1A.

Operator, we probably can take one or two more, so if you want to go to the queue, that'd be great.

Absolutely. Our next question here will come from Jeff Meechan with Bank of America. Please go ahead with your question.

Good morning. This is Hao calling in for Jeff Meechan, and thank you so much for squeezing in for the question. So I think you touched on this, so just a follow-up. For KT413, could you talk about the choice of the Q3W? You know, we see recovery of Acros, Iolos, and to some extent, IRAC4. If it's helpful for the neutral opinion, could you talk about the data, maybe some implication on the efficacy side that you have seen? Thank you.

I mean, we've shown in our preclinical models, and we've run multiple preclinical xenograft models with both CDX and PDX models of MyD88 mutated DLBCL. And very consistently in those models, we've shown that at once every three weeks, IV infusions results in complete responses that are durable. So I think we're feeling, you know, fairly confident in the ability of a once-every-three-week regimen to elicit activity in the target patient population. And that comes back to what we've learned even in vitro in washout experiments where we know that these mighty 88 mutant cell lines, if you knock these targets down for about 72 hours, that commits these cells to apoptosis. And that's why we think we're seeing these profound antitumor responses in the xenograft models. With regard to the every three-week dosing and safety, you know, we've learned from our GLP talk studies that when we do see a drop in nutritional counts, which is really driven by the imidactivity of the drug, we can see nice recovery of those counts, you know, prior to the next dose three weeks later. And that's why we think that we anticipate, you know, having an acceptable therapeutic index with an every three-week dosing regimen while at the same time still being able to maximize clinical activity even with that sort of intermittent dosing schedule.

And our last question here will come from Kalpit Patel with B. Riley. Please go ahead with your question.

Yeah, hey, good morning. Thanks for taking the question. Maybe one for IRAC4 degraders, the landscape. There have been other recent collaborations in the industry for developing IRAC4 degraders. I guess from the available information for these other molecules, Are there any specific points of differentiation that you want to highlight? And maybe what early metrics do you think it might be crucial to focus on when making comparisons? Thank you.

Thanks, Abid. I will say we're very proud of having initiated a new field here with ARAC4, and I'm being serious. So I think it's good to see that the mechanism has been finally recognized once you have the right approach, and in this case, with the degrader approach. You know, we have a drug that is quite exceptional. You know, we can degrade the target 95% plus. We can degrade it in the skin and in the blood. We've seen some really exciting early data in both HS and AD. It's a profile that is going to be hard to match. I don't know which molecules others are advancing. I know that there is a collaboration in which a molecule was, I think, optioned at DC, so clearly at least a couple of years behind. I think there are also other molecules. We just don't know what those molecules are. look like. We haven't seen any presentations of any type of data. So it's hard for me to point to something besides saying, you know, we have a really, really good molecule. It would be hard to match PK, PD, activity, and safety. And obviously, we're also further ahead in competition.

And this concludes our question and answer session. I'd like to turn the conference back over to Nello Manolfi for any closing remarks.

Well, thanks. I want to thank everybody for joining our call today. It's been an exciting first quarter for 2023, starting from early in the year when we announced some of the strategic choices that we've made in terms of where we're taking our discovery engine and platform with some tease on the new programs. Also, we've been talking about where and when we will be disclosing our oncology data across our pipeline, both preclinical and clinical. We'll have in the next seven weeks actually presentation across the whole clinical pipeline, 474 at the ADB. Then we'll have MDM2 preclinical, in this case at EHA. And then we have both KT413 and 333 at ICML. And then we have more data in the second half of the year. And this is really what this company will continue to be, you know, producing data clinical data in first-in-class mechanisms with broad clinical potential. And, you know, expect that in the next two, three years, we'll have a large pipeline with continued cadence of clinical readouts. So it's an exciting time. The first seven years of CAMERA have been It's been a fun ride, but the more exciting will be the next seven. So thank you very much for being on the call and looking forward to more interactions in the next few weeks.

The conference has now concluded. Thank you very much for attending today's presentation. You may now disconnect your lines. you Bye.

Thank you. Good morning, and welcome to the Chimera Therapeutics first quarter 2023 earnings conference call.

All participants will be in a listen-only mode for the duration of the call. And should you need any assistance during that time, please signal a conference specialist by pressing the star key followed by zero. After today's presentation, there will be an opportunity to ask questions. To ask a question, you may press star, then one on your telephone keypad. And to withdraw your question, please press star, then two. Please note that this event is being recorded today. I would now like to turn the conference over to the chief financial officer, Bruce Jacobs. Please go ahead, sir.

Good morning, everyone, and welcome to the Chimera Therapeutics quarterly conference call. I'm Bruce Jacobs, chief financial officer at Chimera, and I'll be joined today by Nella Manolfi, founder, president, and CEO, and Jared Golub, our chief medical officer. After our prepared remarks, we will open the call to your questions. To ask a question at that time, please press star 1 on your telephone keypad. And if any time you'd like to withdraw from the queue, you can press star 2. Before I get started, I'd 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 findings with the SEC and any other future findings that the company may make with the SEC. You were cautioned not to place any undue reliance on those forward-looking statements, and Chimera disclaims any obligation to update such statements except as required by law. With that said, I'll now hand the call over to Nello.

Thanks, Bruce, and thank you, everybody, for joining us today. This month marks the seven-year anniversary of our founding. And as Chimera reaches this milestone, I thought I would spend a few minutes reflecting on the progress we've made on our ambitious plans to build the best-in-class, fully integrated global medicines company. Since our funding, we have focused on a target selection strategy that would allow us to use this novel drug modality in target areas that would uniquely benefit from it, and on evolving the platform to reach novel therapeutic hypotheses. Over that time, we've continued to enhance our platform capabilities and advance programs in areas of significant patient needs that cannot be meaningfully addressed by conventional medicines, building a high-value pipeline and demonstrating our ability to design molecules that have the potential to transform disease treatment. Our first-in-class ARAC4 degrader program, KT474, is a molecule we've discovered and developed through Phase I, and its plan to start phase 2 trials conducted by our partner Sanofi. In December of last year, we shared positive early data in both hydrotonitis separativa and atopic dermatitis patients that demonstrated strong translation of our preclinical PKPD and safety models into the clinic. With this program, we have seen for the first time clinical benefits of a hetero-bifunctional degrader in inflammation and immunology indications for the first proof of concept of clinical differentiation of a degrader compared to a small molecule inhibitor. This is a substantial accomplishment for a company that is pioneering a new modality. Sanofi expects to initiate the first phase two study of KT474 in HS this year, followed by a study in AD. Our three oncology programs continue to make progress. Of note, we have initiated the phase one clinical trial of our MDM2 degrader, KT253. The clinical effects of stabilizing P53 and P53 wild-type tumor is a concept that has been pursued extensively in the biopharma industry. There are a handful of MDM2 small molecule inhibitors in the clinic with some activity in a variety of tumor types. Unfortunately, the activity has been limited, given the inhibition of MDM2 leads to a transcriptional feedback loop, which creates more protein that makes it harder for occupancy-driven small molecule inhibitors to block, leading to reduced therapeutic indices. We believe KT253, on the other hand, has the potential to overcome that feedback loop because it removes the protein and does so in a catalytic manner. This makes KT253 a highly potent candidate that may be able to induce an irreversible acute apoptotic response with brief exposure while allowing time for the recovery of any normal cells which may be affected, creating an improved therapeutic index. With KT253, we believe we have a degrader that can remove MDM2, stabilize p53, and overcome the feedback loop generated by MDM2 reduction giving us the opportunity to explore the clinical potential of such a powerful mechanism fully. We look forward to sharing more updates as the trial advances, including safety and proof of mechanism data later in the year. Nearer term, we plan to present additional preclinical data on KT253's pharmacological profile at the European Hematology Association Congress next month. Our Arachimid program, KT413, targets Arach4 and the imid substrates, Igoros and Nylos, with a single small molecule and has the potential to be the first precision medicine to treat a genetically defined subset of tumors. KT413 has been designed to target mighty 88 mutant lymphomas, and we're currently in dose escalation of the phase 1 trial in B-cell lymphomas, including BLBCL. We shared some initial data from the trial in December showing that we engaged the target without any dose-limiting toxicities. Our third oncology program, KT333, target STAT3, which has been linked to numerous cancers and inflammatory and autoimmune diseases, and is the first degrader against an undrugged transcription factors to enter the clinic. We're currently in dose escalation of the phase one trial in a broad subset of liquid and solid tumor patients, where we've also shown early proof of mechanisms. Our focus in 2023 for both KT413 and KT333 will be the degradation profile and evaluating their biological and clinical impact in the appropriate target patient populations. As discussed today, we plan to provide a clinical update focused on degradation and safety. for KT413 and KT333 at the International Conference on Malignant Lymphoma, or ICML, in June. We intend to present data evaluating anti-tumor activity in the target patient populations for both programs later in the year. In addition, we continue to push the science of TPD forward and identify best and first in class opportunities to transform the treatment of disease. We have several exciting programs in our preclinical pipeline that are designed to address well-validated immunology and oncology pathways in areas of significant patient need and commercial opportunity. These include developing tissue-selective restricted E3 ligase-driven programs, as well as a new generation of molecular glues, exploiting newly identified diagram motifs to expand the reach to high-value undrugged and non-legandable targets. We hope to be able to share more on these efforts later this year or early next. Jared will now cover in more detail the recent progress for each of our disclosed programs before turning the call over to Bruce for a financial update. I will then finish with some concluding remarks before handing the call to the operator for a Q&A session in which Jared, Bruce, and I will be available. Jared?

Thanks, Nello. I'll provide a brief recap of where we stand with our clinical programs and what to expect in the coming months. Turning to our oncology pipeline, I want to update everyone on our disclosed programs, which include our STAT3, Arachamid, and MDM2 degraders. As Noah mentioned, KT253, our MDM2 degrader, received IND clearance from the FDA at the end of last year. We initiated a phase one trial in March and expect to dose our first patient shortly. MDM2 is the crucial regulator of the most common tumor suppressor, P53, which remains intact in close to 50% of cancers. We believe KT253 has the potential to be a highly potent degrader that, unlike small molecule inhibitors, has been shown preclinically to have the ability to overcome the MDM2 feedback loop and rapidly induce apoptosis, even with brief exposures. KT253 has the potential to be effective in a wide range of hematological malignancies and solid tumors with functioning P53. We've shown preclinically that KT253 has superior activity compared to MDM2 small molecule inhibitors and demonstrated greater than 200-fold improvements in both in vitro cell growth inhibition and apoptosis. Additionally, we presented data at the ASH annual meeting last year supporting an intermittent dosing schedule of K2253 in acute myeloid leukemia, AML, which has the potential for improved efficacy and safety using a degrader approach. The phase one trial is evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics, and clinical activity of KT253 in patients with relapse or refractory high-grade myeloid malignancies acute lymphocytic leukemia, or ALL, lymphomas, and solid tumors. Patients in the KT253 phase 1A dose escalation study will receive IV doses of KT253 administered once every three weeks. The open label study is intended to identify the recommended phase 2 dose for KT253 and will be comprised of two arms with ascending doses of KT253 in each arm. The first arm will consist of patients with lymphomas and advanced solid tumors, and the second arm will consist of patients with high-grade myeloid malignancies and ALL. We plan to share initial safety and proof of mechanism data from the phase one clinical trial later this year. Now, turning to our other two oncology trials that are ongoing. STAT3 is a transcriptional regulator that has been linked to numerous cancers as well as to inflammatory and autoimmune diseases. Our phase one clinical trial is evaluating KT333's potential in hematological malignancies and solid tumors. Specifically, the trial is evaluating the safety, tolerability, PKPD, and clinical activity of KT333 in adult patients with relapse and or refractory lymphomas and solid tumors. We reported on the first dose level in December, showing initial proof of mechanism for stat-free degradation in PBMC and no dose-limiting toxicities, with good translation of PKPD from preclinical models to patients. The trial is continuing to enroll, and based on the PKPD we showed in December, with robust target knockdown for 72 hours, followed by recovery, we expect to be at pharmacologically active doses by DL3 or DL4, as previously announced. The trial's second stage will consist of Phase 1B expansion cohorts to further characterize the safety, tolerability, PKPD, and antitumor activity of KT333 in relapsed and or refractory stat-free dependent T-cell malignancies, as well as in solid tumors. Our IRACAMIN program, KT413, is a novel heterobifunctional degrader that targets degradation of both IRAC4 and the imid substrates icrose and ilose. 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 KT333 and is currently in the dose escalation stage of the phase 1 trial, evaluating the safety, tolerability, PKPD, and clinical activity of KT413 in patients with relapsed and or refractory B-cell non-Hodgkin's lymphomas. We reported in December that the first two dose levels have been completed, showing initial proof of mechanism with IRAC4, icorose, and ilose degradation in PBMC and tumor, and no safety signals, with good translation of PKPD from preclinical models to patients. We are continuing enrollment, and similar to KT333, we expect to be at pharmacologically active doses by DL3 or DL4, as previously announced. The trial's second stage will consist of 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. As Nello mentioned, we look forward to sharing updated degradation and safety data on these two programs at ICML in June. We'll present a poster on KT333 at the conference, and an update on KT413 will appear in the ICML abstract book. As we've said previously, we expect to assess the clinical impact of degradation in the respective target patient populations for both KT333 and KT413, and to share that data at a medical meeting later this year. I'll end with our IRAC4 program, KT474. As Nello mentioned, Sanofi will be taking KT474 into Phase II and initiating trials in HS and AD, the first of which in HS is planned to start this year. There is limited additional information I can share with you at this time other than to say the plans in place for starting Phase II are tracking with Sanofi's and our expectations. Finally, with respect to KT474, we look forward to presenting the clinical data from the Phase I program at the EADV Symposium in Seville later this month, which will mark our first time sharing these exciting data at a major scientific meeting. I will now hand the call to Bruce, who will share some brief comments on our financial results for the first quarter.

Thanks, Jared. I'll quickly cover the financials before turning the call back to Nello for some concluding remarks. Before getting into the specific financial results for the quarter, I wanted to briefly address the events surrounding Silicon Valley Bank as it relates to Chimera At the time of the receivership of SBV, we had very limited exposure to the bank, and in response to the events in March, we removed all of our excess operating cash that was held there and moved the outstanding letter of credit that was also there that is held to support our new lease. At this time, we have modest cash at SBV to support our current operating needs. And as a brief reminder, Chimera's investment policy prioritizes protection of principal and our liquidity needs above all and limits our investments to government securities and highly rated corporate bonds. This policy guides our investment approach, and it's been coupled with the recent expansion of our banking and asset management relationships to further diversify our financial risk. That said, back to the financials for the quarter, we recognized $9.5 million of revenue. This total reflects revenue recognized pursuant to our Sanofi and Vertex collaborations. At the end of the quarter, our deferred revenue total on the balance sheet was approximately $57 million. That reflects partnership revenue we expect to recognize over the next several years, excluding the receipt of any potential future milestones. With respect to operating expenses, R&D for the quarter was 42.2 million, of which 4.7 million represented non-cash stock-based compensation. The adjusted cash R&D spent of $37.5 million, including stock-based comp, reflects about a 3% decrease from the comparable amount in the fourth quarter of 22. Our SG&A spending for the quarter was 12.6 million, of which 4.7 was non-cash stock-based compensation, The adjusted cash G&A spend of $7.9 million, also excluding stock-based comp, reflects a 10% increase from the comparable amount in the fourth quarter of 2022. And finally, we exited the first quarter with cash and equivalents balance of approximately $516 million. As we shared earlier in the year, we believe our cash runway extends into the second half of 2025, a projection which includes milestones only related to the start of the first two Phase II trials for KT474. I will now turn the call back to Nello.

Thanks, Bruce. I'd like to conclude by reminding everybody that Chimera was founded to harness novel therapeutic approaches to revolutionize the way we treat diseases. Over our seven-year history, we've built best-in-class discovery engine capable of identifying new drug candidates at accelerated pace and delivering at least one DCIND every year. We now have a pipeline of four clinical stage assets across different disease areas. We continue to invest in the future and evolve our disease agnostic discovery platform so that we can expand the possibilities of what we can do to improve patients' lives. Propelling a rigorous scientific approach is a relentless desire to do what hasn't been done before. to push the boundaries of our science, expand our capabilities to support a rapidly maturing company, and build a culture that enables us to achieve what may seem impossible. We look forward to sharing exciting updates on our clinical programs, platform, and company in the coming months. At this point, I'd like to thank the Chimera team as well as our partners and the patients participating in our clinical trials for sharing this journey with us. Finally, thank you all for participating in our call, and I look forward to your questions. I will now hand the microphone back to the operator so that we can take your questions.

We will now begin the question and answer session. Again, to ask a question, you may press star, then 1 on your telephone keypad. If you're using a speakerphone, please pick up your handset before pressing the keys. If at any time your question has been addressed and you would like to withdraw your question, please press star, then 2. We ask that you please limit yourself to one question and one follow-up for today's call. At this time, we will pause just momentarily to assemble our roster.

And our first question here will come from Vikram Pirohit with Morgan Stanley.

Please go ahead with your question.

Good morning, everyone. This is Gospel on Pope Vikram. We have one question. So for KT413 and KT323, you have mentioned that you would expect those level 3 and 4 in each program to demonstrate clinical activity. When this data is available, what do you think is going to be the best way to interpret the data to gauge the strength of the clinical activity for each molecule? What is your benchmark for determining a good outcome versus a more mixed one? Thank you.

Thanks for the question.

So first, I'd like just to be clear. We said in December that we expect dose level three and dose level four to be at clinically active exposures and level of degradation. Obviously, the question will be at those doses, do we see clinical activity, just to be clear. So just to remind everybody, these are first-in-class mechanisms. And for both mechanisms, for 413 and 333, we've shown some really compelling preclinical data. Remind you, for 413, we've shown that if you degrade IRAC4, egonose, and ilose for about 72 hours, anywhere between 50 and 90% across the three proteins, we can drive mighty 88 mutant tumors to complete remission. For 333, we've shown that if you degrade STAT3 for about 90%, for about 48 hours, we're able to drive some subset of liquid tumors. We've talked about CTCL, PTCL, LGL leukemias, to at least in some preclinical models that we were able to run to complete remissions. So the question that we want to ask, we always look at clinical translation from two perspectives. The first one, is the molecule able to translate what it was designed to do? And so we ask of these two molecules to replicate our preclinical degradation profile. So as I mentioned, what we believe it to be clinically relevant is this, you know, 50 to 90% degradation for 413 and 90% degradation for for 333 for, you know, as I said, 72 hours for one program and 48 hours for the second. So as we continue to explore PKPD and safety in the clinic, and in fact what we said is that we're going to give an update at ICML on that, you know, we want to make sure that our molecules are able to reach those degradation profiles at tolerated doses and exposures and with a tolerated profile. And then the second part of the clinical translation de-risking is that particular degradation profile, as he had done in the preclinical studies, translating into anti-tumor effect. And that's going to be the question that we're going to try and answer and show data later this year, I think we said. It's hard for us to set a bar because, just to be clear, we're running a relatively broad phase one dose escalation studies in terms of patient population. So we will have probably a handful of patients that fit the right criteria in terms of disease and type of tumor types. And so what we would like to see in those patients is, the ability of translation of anti-tumor effect. And so I think we're staying away right now on comparing and setting a bar just because we're still early in the clinical development. Jared, anything you want to add to that? No, I think that covers it all. Thank you.

And our next question will come from Michael Schmidt with Guggenheim.

Please go ahead with your question.

Hey, guys. Good morning. Thanks for taking my questions. Just a follow-up on 333 and 413. You know, as we think about this upcoming update at the ICML conference, can you talk about a bit, you know, how far in you are in those two phase one studies now beyond dose over one or two? You know, how many patients' worth of data, you know, do you have at this point? And how are you tracking towards identifying a recommended phase two dose? And then on 413, I think you already had 95% to 100% knockdown of Icarus and Iolos last December. I guess, you know, how much higher do you need to go and how confident are you in not seeing, you know, issues around potential on-target toxicities related to those two targets if you go, you know, much higher? Thanks so much.

Yeah, thanks for the questions, Mike. You know, we really haven't been guiding externally in terms of where we are right now with regards to enrollment across both the studies. You know, as we showed back in December, you know, we presented data on DL1, the first dose level for KD3D3, and on the first two dose levels for KD413. And all we can really say is that we're continuing to enroll across both studies. And when we do present updates in ICML, you know, at that time we'll be able to really update on numbers and where we are in terms of which dose levels. Oh, in terms of the knockdown question, yes, you're right, that, you know, with regard to 413 and icarotin-ylose knockdown, we did show very robust knockdown of greater than 90, 95% in peripheral blood. In particular, you know, with those first two dose levels, the data we shared back in December, you know, for IRAC4, I think at that time we had approximately 40% knockdown of IRAC4 in the blood. You know, we had one serial, of tumor biopsies from the first dose level where we showed around 60% knockdown of icrosanilocin tumor and around 20, 25% knockdown of IRAC4. And so I think, you know, what we want to be able to show in subsequent dose levels is continued strong knockdown of icrosanilocin in the blood. We'd like to see further knockdown, you know, of IRAC4, you know, getting up into that 50 to 70% range that Nello alluded to earlier that's associated with anti-tumor activity in our preclinical models. And if it's possible, you know, where we can get voluntary two-room biopsies to also continue to show activity there as well.

Thanks, Jared. I just want to add one thing, Michael, and probably for everyone's benefit. You know, I think it's an exceptionally exciting time to be at Chimera. We have the luxury of witness what is, you know, first-class in mechanisms, translation into patients. We've done it with ARAC4, and now we're doing it with three other mechanisms. So I don't think we're trying to deflect questions. It's really like we are observing new biology at play here. And so especially for SAD3, there is a wealth of opportunities that we want to be thoughtful on how we're exploring.

And our next question will come from Brad Canino with Stiefel. Please go ahead with your questions.

morning. And I apologize. I feel like I'm going to ask Michael's questions in a different way because I just want to check on the upcoming Lugano presentation. Will that include additional patient numbers and dose cohorts relative to last December's disclosure? And then a specific question on KT413 is we watch these safety data evolve through the rest of the year. As you dose escalate, do you have a range of neutropenia across grades that you're going to be comfortable with, especially when you think about marching this drug eventually to earlier lines in the treatment paradigm, which will be in combination with the DLBCL standards of care. Thank you.

Yeah, no, and that's a great... Thanks for asking again, because maybe... We weren't clear enough. Yes, there will be more data, obviously. Otherwise, we wouldn't be presenting an ICML. There will be meaningfully more data on the programs that we present. Maybe I'll let Jared comment on the neutropenia question. I just want to repeat something we've said before, which is the opportunity with 413 is, the ability to translate synergistic biology between IRAC4 and Icarus and ILODS. And that's really the question. The question is, is this synergistic biology that we've seen preclinically being able to drive profound anti-tumor effect driven by an immediate apoptotic response that only required 72 hours of knockdown? Is that going to translate in the clinic? If it is, I think we will be able to navigate much better than other programs the question around neutropenia because we have this pulsatile dosing, which allows us to capture this immediate apoptotic response in the first few days and then allow any potential on-target safety coming from the immediate part of the pharmacology here to be managed by the, again, the alternative dosing paradigm. Jared, anything you want to add on the actual kind of grade type of neutropenia here?

Yeah, in terms of neutropenia, I mean, clearly we're referring to the neutropenia that is seen with IMiDS, especially with potent IMiDS. And as we noted back in December, with the first two dose levels in 413, we didn't see any neutropenia adverse events. You know, we do expect, you know, based on our preclinical animal tox data, to see lowering of neutrophils as we continue to dose escalate. The issue isn't whether we'll see lowering a neutrophil, the issue is really, you know, what is the recovery time? And because we have this every three-week dosing, which is one IV infusion every three weeks, in our GLP-Tox studies, we saw that that gave us adequate time to see recovery of neutrophils after they were suppressed, as well as recovery of lymphocytes. And so I think the key here for us will be, you know, as we escalate, you know, we do expect to see some lowering of neutrophils. Will we see recovery, you know, prior to each dose? And I think that will tell us a lot about the therapeutic index and tolerability and the ability of this intermittent dosing regimen to mitigate that particular toxicity, which is seen commonly within them.

And our next question will come from Chris Shibutani with Goldman Sachs. Please go ahead with your question.

Great. Thank you very much. Following some of those specific questions on the assets, Nello, you noted the anniversary. Perhaps can you comment on a couple of things in terms of how you're thinking about the next phase of strategically optimizing your portfolio development and capital allocation. When we think about the oncology assets, there's kind of a fleet of them that seem to be going in tandem. You know investors like to pay attention to kind of like a lead steer as kind of a catalyst driver. Do you anticipate that the timing of these oncology assets will also be kind of in this couplet or trio? And then in terms of next areas that you could roam, You have the Sanofi relationship for the first immunology asset, but there's other potential immunology indications. I believe you brought on board someone more with the sort of business development, strategic investment banking role in-house. How are you thinking about taking that next tranche of assets so that you can optimize the capital that you have?

Thanks, Chris. This is a great question, which I could spend a day on, but I'll try to do it in a couple of minutes. First, I'd like to recognize the path that we've taken from an early company that was sitting on a potentially transformative new drug modality and decided to commit to building a real company. I use often this definition of real company, meaning committed to seeing programs through the different phases of development and eventually commercialization. Because we believe that in order to capitalize on the power of this really, really strong new modality, you have to commit to see it through. You cannot depend on other industry partners to do so, because that's what history has taught us. New modalities have been developed in biotech companies and biotech companies only at best. So that's our commitment. Now, you know, the first seven years have been years full of execution but also learning. We learned the type of targets that best benefit from this technology, and we've shown we were fortunate enough that our early targets have played out, I would say, extremely well into early clinical development, demonstrating the power of the technology. We've also learned, and maybe not discussed broadly enough, the type of targets that don't work well with this technology. And I think we've been focused and we've been really good at understanding early on the type of targets that is not worth applying this technology against. And so our first wave of targets, I think, are well positioned to demonstrate with a catalyst-rich sequence the power of degrading targets in human patients, and then the power of that degradation impacts on human disease and human condition. So I would say the next two years, we will see proof of concept across four clinical programs that we have in our pipeline. We will see proof of concept of KT474 in HS and AD. We will see proof of concept of KT413 in lymphomas. We'll see proof of concept of KT333 in several disease types or cancer types and potentially outside of oncology. And we will see MDM2, I think, final realization of full potential. But Chimera could not be the type of company we want to build if we stop there. And so our investment has been in actually the learnings that we've taken from the first, let's say, six years or five years since our founding into applying this technology to a new generation of targets. And we have decided for a new generation of pipeline to focus heavily on on two areas that we believe will define the success of biotech going forward, which is an area where there is larger clinical need, large commercial opportunities, with a maybe slightly higher focus in immunology, where we've learned ahead of everybody else. We were the first company to take a degrader into immunology. We've only shown the meaningful clinical data. We haven't really talked about all the platform learnings that we have learned from, that we have been able to amass through the development of that asset. And we're able to translate that to a series of of novel immunology programs that we will be disclosing in the next few months. I think we're also not naive enough to believe that we can do all of that on our own. I think that would be impossible, just to be clear. For the type of indications and programs that we want to develop, it would be impossible to commercialize eight programs on our own in the next five years. or seven years. So the question is, how do we optimize the synergies that one can build in this biopharma ecosystem, which is obviously the best in the world in terms of businesses? And as we've done with Sanofi for 474, I suspect there will be other partnerships that will maximize value creation here. We're just not in the position to talk about them because I don't think we're quite there yet. We're focused on now really translating these programs in the clinic and advancing a new generational program in the clinic, into the clinic. And then maybe as we progress on this path, share more on what are the strategic choices that we have in front of us.

And our next question will come from Mark Fromm with TD Cowan. Please go ahead with your question.

Thanks for taking my questions. Maybe just to start one Right after ICML, you have the guidance for initial MDM2 data in the middle of the year. Can you just walk through again the target degradation profile there, both in terms of depth, but also kind of the timing of that degradation?

So this is MDM2, right? So MDM2, just to be clear, would not be presenting an ICML. Maybe I misunderstood, but so my ICML would be right after. Yeah.

Yeah.

So I think what we're presenting in the short term on MDM2 is some preclinical data at the IHA conference. Later in the year, we will be presenting early clinical data. And what we call it, this proof of mechanism, is just to be clear is, you know, how much degradation we see in early cohorts and what is the safety profile, which, you know, for this program is going to be meaningful because, you know, In a way, all MDM2 programs in the past have suffered from ability to engage the target fully and managing the right safety profile. So we haven't really actually talked deeply about what is the degradation profile and the extent of degradation needed to achieve kind of full biological response in preclinical species. And I believe we're presenting more data also later in the year on these, again, preclinical data. Some really elegant work that the team has done. And even at EI, I believe, we will talk about how dose and dosing type will impact the biology in this pathway. But what I will say is in order for us to overcome we call a feedback loop of MDM2 transcription regulation, we need to have a deep MDM2 degradation that is actually limited, I would say in terms of hours, not even days. Once we are able to knock down MDM2 for a short period of time, but deeply, we see a profound commitment to cell death of a wide variety of tumor types. And we have seen, we have observed that that commitment to apoptosis is enough to not require another dose for weeks. In fact, we're going into the clinic with this program with once every three weeks dosing. So what we're trying to do in the first, again, innings of this program is to demonstrate, again, that we're seeing this profound degradation in the early few hours and we're also seeing a manageable safety profile, which in preclinical species we've characterized and we feel really confident around.

Okay, that's helpful. And then maybe back to the 333 and 413 trials. As you mentioned earlier, the enrollment criteria is pretty broad and not necessarily in its early parts focused entirely on the patient populations who might have the most robust single-agent activity. But are you seeing, you know, a real bias kind of in the enrollment just given that there is some testing, particularly from ID88, you know, out there towards those target populations? Or should we think the epidemiology is really what we'll see?

Yeah, thanks for the question, Mark. I think, as you've noted, you know, the 413 study, you know, is broadly enrolling B-cell non-Hodgkin's lymphoma on Phase Ia. You know, we do have sites, you know, that are enrolling patients, and these are sites that have the ability to identify mighty 88 mutant patients as well, either with DLDCL or Waldenstroms. And so as we get into higher doses, you know, those sites know that those are patients of interest. And as Nello alluded to earlier, we'd like to be able to have some of the target indications enrolled onto the study as we get into those higher doses to give us an opportunity to show initial antitumor activity.

Okay.

And likewise, for the STAT3 program, you know, we're broadly enrolling solid tumors as well as B and T cell lymphomas on phase 1A. But likewise, we also have a number of sites that do have CTCL, PTCL, and LDL patients. And those sites, you know, are capable of putting those patients onto the trial, especially as we get, again, into those higher pharmacologically active doses. So once again, we would have an opportunity to show anti-tumor activity in those target indications.

And our next question will come from Mike Kratke with SVB. Please go ahead with your question.

Yeah, hi, everyone. Thanks for taking our question. Regarding the KT474 data to be presented at EATB, will there be any new analyses included in these results, and what incremental new intro could we expect to get?

Thanks. Yeah, no, so in our oral presentation, I think it would be a summary of data that we've already shared. What I will say is that, as we said in the past, you know, we're working on a manuscript that will have maybe more insights into the data. But for the presentation, I would expect it to be what we've shared in the past, given that it's also a relatively short presentation.

And our next question will come from Eric Joseph with JP Morgan.

Please go ahead with your question.

Hi, good morning. This is Hannah on for Eric. Thanks for taking the question. Just wondering how many dose levels you're planning to evaluate in the KT253 dose escalation study. And based on that, at which levels would you expect to be at pharmacologically active doses? And are you commenting on the specific doses that are being evaluated in that study? And then secondly, can you comment at this time on the expected biomarkers that are being used to evaluate MDM2 degradation, and how quickly do you expect these to begin to change in response to degradation?

Yeah, thanks for the question. We haven't really commented publicly on how many dose levels are in that study or the doses that we're actually planning to prosecute. I mean, whenever we bring, you know, doses into our phase one studies, it's based on our preclinical data and our GLP-Tox studies, and we usually have an expectation that you know, even the lower dose levels will have the potential ability to result in some downregulation of the target, but we really haven't provided specifics on that. With regard to sort of measuring pharmacology, in addition to looking at MDM2 downregulation, you know, we do have other biomarkers that are included in the study that help us look at P53 pathway activation, because as you know, If we're hitting MDM2 the way we want to, we should see upregulation of P53 pathway and the various biomarkers that are associated with that activation. So we've built this into our phase one study that will be able to measure these different biomarkers in the blood as we proceed with dose escalation.

Yeah, maybe the only thing to add, I would say, if you look at all the programs we've disclosed so far, the first dose has always been a dose with measurable levels of degradation. So I think we expected that to be in line, obviously, but we have to run the study to see.

And our next question will come from Zhisheng Xu with Barenburg. Please go ahead with your question.

Hi, thank you for taking the question. This is Andy on for Z. The first question is, so for your STAT-3 program, I think you communicated the knockdown or the degradation window. And I'm just wondering, like, what's the ideal therapeutic window that you're targeting and if there's any clinical rationale for that? And the other question is, your STAT-3 and IRACMET program, what's your ability or willingness to make them orally available? Thank you.

Okay, so the first question is, so we've said this in the past. Empirically, through lots of work that we've done preclinically, we've shown that a degradation profile where you have about two days or 48 hours of deep degradation, around 90% or even more, and then recovery of that degradation over the course of the duration of the week or even two weeks, is sufficient to drive strong anti-tumor effect in a wide variety of tumor types. And that profile is also really well tolerated. So this is the hypothesis that we're bringing into the clinic. Once a week, we could actually dose even once every two weeks, but we decided to start with once a week. and uh being able to drive that profound degradation in the in the first uh 48 hours or so of that particular uh program um and so that's what we're bringing forward that that is both effective and really well tolerated in preclinical species with regards to oral i mean this is really around when we when we start the program we usually uh you know start with the tpp based on the mechanism. And if the mechanism is unknown, it usually is driven also by what we learn along the way. So in both of these programs, the biological and translational hypothesis has been infrequent dosing because we need to manage both the activity as well as the recovery of the target and the building of that therapeutic index. And the fact that we were able to use the distribution and the PK of these compounds to maintain degradation for multiple days with a single dose. So naturally, that type of profile led to this infrequent dosing, which is a lot more manageable if you do it by a parenteral administration. These two programs are not IV because these molecules are not orally bioavailable. At least we've shown for the 413, this actually started as an oral drug and we were dosing it every day in preclinical species early on in the development of the program. And then we switched it to a different dosing paradigm. Again, to manage both the activity and the safety.

And our next question will come from Ellie Merle with UBS. Please go ahead with your question.

Hi, this is Jasmine on for Ellie. Thanks so much for taking our question. On the MDM2 program, We know that RNR-AML has been disclosed as a particularly sensitive tumor type to MTM2 degradation. So when we're thinking about other tumor types that could also be potentially sensitive to this mechanism, can you give any color that would help us understand the characteristics of the kinds of tumors these might be? Thanks.

Do you want to take this? I think the question was around probably AML. Yeah, well, I know, I think the question was that AML, you know, we've shown that to be a sensitive tumor in our model systems. You know, what are we doing on solid tumors? And even though we haven't presented as much data on solid tumors, what we can say is that we've been doing a lot of work preclinically to identify those solid tumor types that have the same sort of exquisite sensitivity to MDM2 degradation that AML has, where we can dose intermittently as we can with AML once every three weeks in tumor models and see profound tumor regressions. And so we have identified, you know, various solid tumor cell lines. And we perhaps will later this year be able to reveal what some of those are at presentations. But we have been, number one, looking at those different solid tumor types to determine those that are very sensitive to this mechanism. And number two, we've also, you know, had an active effort in trying to nail down potential biomarkers that are associated with the most responsive subsets of those different solid tumor types that could allow us to then use that to select patients you know, moving forward as we go beyond phase one. So I think this is an active area of research for us and very important that for us it's not just going where other MDM2 inhibitors have gone before in terms of solid tumors. It's really forging our own path, you know, based on our preclinical data, making sure this is a data-driven decision which guides which solid tumor types, you know, we end up exploring as we get, you know, beyond phase one.

Yeah, and I would also add that, you know, encourage everybody to kind of follow, as we disclose, more preclinical data. I think for both, for these broad mechanisms, both KT333 with SAD3 and MDM2 with 253, these are both broad applicable mechanisms in a wide variety of systems. We're uncovering some really, really fascinating data. I would call it almost new biology, both alone and in combination with interesting agents where you can see really meaningful paths of patient impact when you have this new modality that can be combined with existing mechanisms. So stay tuned and you'll see much more of of those in the upcoming medical meeting.

And maybe also just to quickly add that, you know, again, in our phase one study, we have a one arm, which is solid tumors and lymphomas, and then a second arm, which is, you know, AML and ALL and other high-grade myeloid malignancies. We then plan in phase 1B on having expansion cohorts. One of those will certainly be AML, but we also plan to have expansion cohorts and select solid tumors based on activity that we see in Phase Ia and also based on activity that we're seeing in our preclinical models.

And our next question will come from Timur Ivankov with Raymond James. Please go ahead with your question.

Hi. Thank you for the question. So I just wanted to come back to Q2C prolongation for a moment. So recently one of the players in TPD reported a Grade 4 prolongation event in their study of synovial sarcoma. So could you just remind us in your preclinical testing for the newest assets like 413, 333, and 253, did you see an interaction with ion channels preclinically? And I think in the past you've talked about a potential saturation effect on interaction with ion channels. Do you still believe that's the case?

Yeah, no, thanks for the question. So I would say that we can say with confidence that QT prolongation is not class effect. I mean, as you know, QT prolongation or QTC prolongation is something that we've seen in the industry for the past 20 years since we discovered, and actually we understood more since we discovered the HERT channel, and it's impacted many small molecules. So I think this is a molecule-specific phenomenon that you know, we have seen in the industry, and I suspect we will continue to see, I think I want to remind you that there have been several degraders in the clinic, and I think the example you bring up is just one out of several examples where we have not seen QTC prolongation. With regards to KT474 and chimera, I think what we've said is that we've seen something that is very unique, which is And... And... It's a time-limited effect where we see appearance of the subclinical QT that then resolves spontaneously with continuous dosing. And that's a very atypical phenomenon. And we believe it's driven by a compound distribution that requires some time to reach steady state. And it might initially have higher exposures around the intracellular compartment cardiomyocytes that express the HERP channel. That's just in hypothesis. But this is not the typical QT prolongation, which is often those responsive and concentration responsive, which is what you see with most molecules. I don't know enough about what happened in the other company with that particular drug. I suspect that it's a different, probably it's a different mechanism, given that they've seen it only at the high dose. I remind you that we've seen kind of the same subclinical finding, obviously not a grade four, it was subclinical, across all the four doses in our MAD study. So again, saying that This was a different mechanism than a normal QT driven by hurricane emission.

And our next question will come from Kelly Shi with Jefferies. Please go ahead with your question.

Hi, this is Sean on for Kelly. Thanks for taking our question. We have a question on HS with a rapidly evolving landscape. Can you share how your thoughts and positioning of KD474 have evolved in light of the recent development in the space. Specifically, has any of the recent competitor data been factored into the Phase II trial design, the selection of efficacy endpoint, et cetera? Thank you.

Yeah, no, thank you. It's a great question, talking about patients also. You know, HS is a high-end need, we all know. I don't believe that HS is driven by a single cytokine. So I'm pleased to see that IL-17 agents work. I don't believe that IL-17 is the solution to HS. But it is going to be a great tool in the arsenal of tools that doctors and patients will have. So I think it's great to see this evolving class of antibodies and the likes that have been developed in the space. This is a broad inflammatory disease, local and systemic, that we believe requires a broad anti-inflammatory agent. And we believe that IRAC4 is uniquely positioned to be both active and well-tolerated and have and obviously be an oral agent. our view of the unmet need and the opportunity for an oral active agent has not changed. There is still high unmet need, and we believe we can have an opportunity to have a broad impact in this disease. In terms of how we think about trial design, I wouldn't think that we have learned what we've seen from, you know, elegant studies that have been run is really validation of what are the key primary and secondary endpoints that one wants to see to confirm activity of drugs. And I don't believe we've learned anything that has changed our view on how we want to design our clinical study, which, you know, obviously we've done in collaboration with Sanofi on phase two. So I think it's great to see, again, other agents being active. The opportunity is totally still there for a neural active drug in that space that is, again, active and well-tolerated.

And we have time for one more question which will come from Rich Law with Credit Suisse. Please go ahead with your question.

Hi, this is Grace on for Rich. Thank you for taking our question. The first one is what's the development path and timelines for the STAT III program in combo with PD-1? And do you see any other combo regimens that will make sense?

Yeah, no, thank you. So, yes, the answer to the second question is yes, we see several combo opportunities here. And this is a bit what I was referring to earlier. At the beauty of working with a new mechanism, we are learning also with some of our academic collaborators that have published and will continue to publish on this. what STAT3 biology can be combined with to drive synergistic anti-tumor effects. With regards to timing, so we're now focused, as you know, on dose escalation as single agent, and we're obviously learning Also, when we can, when patients allow for biopsies, also what's happening in the tumor microenvironment, at least that's one of the goals that we have. And any combo will be part of later expansion cohort, which will happen after we conclude phase 1A.

Operator, we probably can take one or two more, so if you want to go to the queue, that'd be great.

Absolutely. Our next question here will come from Jeff Meechan with Bank of America. Please go ahead with your question.

Good morning. This is Hao calling in for Jeff Meechan, and thank you so much for squeezing in for the question. So I think you touched on this, so just a follow-up. For KT413, could you talk about the choice of the Q3W? You know, we see recovery of Acros, Iolos, and to some extent, IRAC4. If it's helpful for the neutral opinion, could you talk about, you know, data, maybe some implication on efficacy side that you have seen? Thank you.

I mean, we've shown in our preclinical models, and we've run multiple preclinical xenograft models with both CDX and PDX models of MyD88 mutated DLBCL. And very consistently in those models, we've shown that at once every three-week IV infusion, results in complete responses that are durable. So I think we're feeling, you know, fairly confident in the ability of a once-every-three-week regimen to elicit activity in the target patient population. And that comes back to what we've learned even in vitro in washout experiments where we know that these mighty 88 mutant cell lines, if you knock these targets down for about 72 hours, that commits these cells to apoptosis. And that's why we think we're seeing these profound antitumor responses in the xenograft models. With regard to the every three-week dosing and safety, you know, we've learned from our GLP talk studies that when we do see a drop in nutritional counts, which is really driven by the imidactivity of the drug, we can see nice recovery of those counts, you know, prior to the next dose three weeks later. And that's why we think that we anticipate, you know, having an acceptable therapeutic index with an every three-week dosing regimen while at the same time still being able to maximize clinical activity even with that sort of intermittent dosing schedule.

And our last question here will come from Kalpit Patel with B. Riley. Please go ahead with your question.

Yeah, hey, good morning. Thanks for taking the question. Maybe one for IRAC4 degraders, the landscape. There have been other recent collaborations in the industry for developing IRAC4 degraders. I guess from the available information for these other molecules, Are there any specific points of differentiation that you want to highlight? And maybe what early metrics do you think it might be crucial to focus on when making comparisons? Thank you.

Thanks, Abid. I will say we're very proud of having initiated a new field here with ARAC4, and I'm being serious. So I think it's good to see that the mechanism has been finally recognized once you have the right approach, and in this case, with the degrader approach. You know, we have a drug that is quite exceptional. You know, we can degrade the target 95% plus. We can degrade it in the skin and in the blood. We've seen some really exciting early data in both HS and AD. It's a profile that is going to be hard to match. I don't know which molecules others are advancing. I know that there is a collaboration in which a molecule was, I think, auctioned at DC, so clearly at least a couple of years behind. I think there are also other molecules. We just don't know what those molecules are. look like. We haven't seen any presentations of any type of data. So it's hard for me to point to something besides saying, you know, we have a really, really good molecule. It would be hard to match PK, PD, activity, and safety. And obviously, we're also further ahead in competition.

And this concludes our question and answer session. I'd like to turn the conference back over to Nello Manolfi for any closing remarks.

Well, thanks. I want to thank everybody for joining our call today. It's been an exciting first quarter for 2023, starting from early in the year when we announced some of the strategic choices that we've made in terms of where we're taking our discovery engine and platform with some tease on the new programs. Also, we've been talking about where and when we will be disclosing our oncology data across our pipeline, both preclinical and clinical. We'll have in the next seven weeks actually presentation across the whole clinical pipeline, 474 at the ADB. Then we'll have MDM2 preclinical, in this case at EHA. And then we have both KT413 and 333 at ICML. And then we have more data in the second half of the year. And this is really what this company will continue to be, you know, producing data Clinical data in first in class mechanisms with broad clinical potential. And, you know, expect that in the next two, three years, we'll have a large pipeline with continued cadence of clinical readouts. So, it's an exciting time. The first seven years of CAMERA have been a fun ride, but the more exciting will be the next seven. So, thank you very much for being on the call and looking forward to more interactions in the next few weeks.

The conference has now concluded. Thank you very much for attending today's presentation. You may now disconnect your lines.