Kymera Therapeutics, Inc.

Hello and welcome to the Chimera Therapeutics 4th Quarter 2022 Earnings Conference Call. All participants will be in listen-only mode. Should you need assistance, 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 1 on your telephone keypad. To withdraw from the question queue, please press star, then 2. Please note, this event is being recorded. I would now like to turn the conference over to Bruce Jacobs. Bruce, please go ahead.

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 Neville Manolfi, Founder, President, and CEO, and Jared Golub, our Chief Medical Officer. After our prepared remarks, we'll open the call to your questions. To ask a question, please press star 1 on your telephone keypad. If at any time you would like to withdraw from the queue, please press star 2. Before we 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 filings with the SEC and any other future filings that the company may make with the SEC. Your caution 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 to Nello. Thanks, Bruce.

And thank you, everyone, for joining us today. I thought I would spend a few minutes this morning reflecting briefly on the importance of all the progress we've made in 2022 and what we believe it means for our ambitious objective to build the best-in-class, fully integrated global medicines company. 2022 was an exceptionally important year for Canera's evolution. With those healthy volunteers, patients with HS and AD, which is the first time for a degrader in immune inflammatory indications, patients with lymphomas, leukemias, and solid tumors with our first three investigational drugs. We've seen now across three programs strong translation of our preclinical PK, PD, and safety into the clinic. This is a substantial accomplishment for a company that is pioneering a new modality. In addition, we have seen for the first time clinical benefits of a hetero-bifunctional degrader in immune inflammatory indications and the first proof of concept of clinical differential of a degrader versus a small molecule inhibitor with our KT474 phase 1 data. In fact, KT474 clinical data that we shared late last year from the patient cohort of the Phase I study over Rx4 degrader exceeded our expectations. We were able to replicate the PKPD profile of the healthy volunteer portion of the trial in HS and AD patients. The molecule was generally well-tolerated with no serious adverse events, including a resolution of the QT effect. we demonstrated an encouraging impact on disease-relevant inflammatory biomarkers in blood and skin. And we were able to produce some early but really encouraging signs of clinical activity in HS and AD patients that we think represent strong reasons to believe in the clinical potential of effectively dragging the IRAC4 pathway and in our degrader molecule. And of course, lastly, we reported that our partner Sanofi shares their enthusiasm and will initiate phase two studies in 2023. Jared will share a little bit more on this call regarding the next steps for the program, but obviously this was an important milestone for KT474, a molecule that we believe can have a unique and broad role in raising the standard of care in a wide variety of inflammatory conditions. Assuming the molecule's profile remains consistent, as we tested in larger studies and additional patient populations, we believe a small molecule with the emerging efficacy and encouraging safety profile could be a best-in-class medicine across several diseases. And this year, we're excited for our partner Sanofi to initiate KT474 studies, initially in a chest, followed by AD and potentially other indications. While perhaps somewhat overshadowed by the KT474 results, we made encouraging progress in our first two clinical stage oncology programs, KT413, the arachemide degrader, and KT333, our STAL3 degrader. Both programs are currently in the dose escalation phases of the Phase I clinical studies. In December, we disclosed pharmacodynamic activity in both blood and tumors and knockdown of their targets without any dose-limiting toxicities. Importantly, we've seen fidelity of translation of PKPD and safety from preclinical profiles into these clinical settings, further validating our work and highlighting our ability to replicate our approach to discovering and developing high-value molecules. The promising initial data from these Phase I trials positioned us to share data later this year that we hope will show clinical activity. particularly when we reach the expected active dose levels in our targeted patient populations. Taken together, we believe that these results represent a validation of our R&D approach and strategy. Since we started the company over six years ago now, our funding principles have remained unchanged. Harness the transformative potential of targeted protein degradation to address areas of significant therapeutic need and improve patients' lives. With this goal in mind, we made very intentional choices, which we believe represent a differentiated approach to design in many key areas, including target selection strategies, disease area focus, cutting-edge platform investments, and corporate strategy. This strategy and approach, in conjunction with a clear focus on disease targeting areas of significant patient need, that can't be meaningfully addressed by traditional medicines has led us to targets and markets where protein degradation is the only or the best way to elucidate the desired biology or clinical outcome. I hope that as you reflect on the totality of the data we presented in December and our progress in building the company, you share our belief that we have validated the work and investments we've made over the past seven years, almost seven years. resulting in the high-quality molecular design and platform capabilities and a proven ability to translate our understanding of disease biology, PK, PD, and safety from preclinical models into patients, creating high-value programs that have the potential to become important new medicines. Before I hand the call over to Jared, I should mention that the three programs I just discussed are just the beginning for Chimera. At the end of last year, we also announced that the FDA had cleared the IND for our MDM2 degrader, KT253. MDM2 is a crucial regulator of the most common tumor suppressor, P53, which remains intact in close to 50% of cancers. Jared will share more on our plans for KT253 shortly. We also hinted at several other programs in our early stage pipeline in both oncology and immunology indications earlier in the year. Further evidence of the productivity of our drug discovery engine. These advances have been fueled in part by innovative computational research tools that have enhanced our understanding of disease biology and allowed us to develop new ways to harness TPD. In addition to leadership in the discovery of hetero-bifunctional degraders, we are also identifying novel molecular groups that expand the therapeutic applicability of our platform. And we hope to share more on this later in the year as well. Along with our clinical and scientific progress, we work to ensure that we have the people and resources to build our company sustainably. We recently appointed Ellen Chiniara as Chief Legal Officer and Corporate Secretary. where she'll serve as a key member of our leadership team. Ellen joins us from Alexion Pharmaceuticals with extensive experience overseeing legal activities at biopharmaceutical companies, ranging from discovery phase through commercialization. This month, Rebecca Mosher joined us as our Senior Vice President of Translational Medicine from Mersana Therapeutics, She previously had positions of increasing responsibilities in translational medicine, translational research, and molecular pathology at Novartis, Vertex, and Millennium. We also recently appointed Juliet Williams as Chimera's new head of research. Juliet was previously our head of biology and contributed profoundly to our target selection strategy and drug discovery efforts. She has more than 20 years of drug development experience, including leadership roles at Novartis, Sanofi, Millennium, and Curis. These important roles will help Chimera navigate our next stage of development as we work to bring revolutionary degraded therapies to patients. Finally, we ended the year in a very solid financial position with approximately $560 million in cash. an expanded runway into the second half of 2025, which will allow us to continue to invest in our clinical programs, discovery pipeline, and platform, and importantly, allow us to read up our IREC-IV Phase II Prevo Concept Study and initial proof of concept for the three oncology clinical programs. Jared will now cover in more detail our recent progress for each of our disclosed programs before returning the call over to Bruce for a financial update. I will then finish with some concluding remarks, including covering our key goals for 2023, before handing the call to the operator for a Q&A session in which Jared Bruce and myself will be available. Jared?

Thanks, Melo. I'll provide a brief recap of where we stand with our clinical programs and what to expect in 2023. I'll begin with our IRAC-IV program. As you all know, in October, we announced the completion of dosing of the patient cohort portion, Part C, of the KT474 Phase 1 clinical trial, and we shared the full data set in December. I won't go over all of the data here today, but if you are interested, you can find the replay of our December meeting on our website. The data are also included in our updated corporate presentation. That said, I did want to share our expectations for the progress of the program in 2023. As you know, Sanofi will be taking KT474 into Phase 2. Just as they were closely involved in the Phase 1 trial that Chimera ran, we jointly discussed the plans for the Phase 2 program. As we shared in December, Sanofi is committed to Phase 2 trials in at least two initial indications, beginning with HS, and followed by AD. As for timing, it is too early to guide to the expected phase two start dates, but as we have said in the past, at least the first phase two is planned to start in 2023. Turning to our oncology pipeline, I want to update everyone on our DISCLOSE programs, which include our STAT3, IRACAMID, and MDM2 degraders. Focusing first on our new trial activity, KT253, our MDM2 degrader, received IND clearance from the FDA in December. MDM2 is the crucial regulator of the most common tumor suppressor, P53, which remains intact in close to 50% of cancers. Chimera is developing a highly potent MDM2 degrader that, unlike small molecule inhibitors, has been shown preclinically to have the ability to 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 or wild-type p53. We plan to initiate dosing patients soon in the phase one trial of KT253. The phase one study will evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, and clinical activity of KT253 in adult patients with relapsed or refractory high-grade myeloid malignancies, acute lymphocytic leukemia, lymphoma, and solid tumors. The open-label dose escalation study is intended to identify the recommended phase two dose. It 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. Now, turning to our two ongoing oncology trials, VAT3 is a transcriptional regulator that has been linked to numerous cancers and other 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. Based on the PKPD we have shown to date, with robust target knockdown for 72 hours followed by recovery, we expect to be at efficacious doses by dose level 3 or dose level 4. This year, we expect to show clinical impact of stat-free degradation on tumor burden in the target patient populations, such as peripheral T-cell lymphoma, cutaneous T-cell lymphoma, and LGL leukemia. 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 stat3-dependent T-cell malignancies, as well as in solid tumors. And finally, our Arachamid program, KT413, is a novel heterobifunctional degrader that targets degradation of both IRAC4 and the image substrates agarose and ilose with a single small molecule. KT413 was designed to address both the IL-1R TLR and the type 1 interferon pathways synergistically to broaden activity against mighty 88 mutant B-cell malignancies. KT413 is on a similar timeline as VAT3 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, icarose 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 expect to be at efficacious doses by dose level three or dose level four. And as with KT333, later this year, we expect to show clinical effect of arachnid degradation on tumor burden in MiD88 mutant patients. 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. We look forward to sharing more progress on these programs throughout the year. I will now hand the call to Bruce, who will share some brief comments on our financial results for the fourth quarter.

Thanks, Jared. I will quickly cover the financials before turning the call back to Nello for concluding remarks. For the quarter, we recognized $16.1 million of revenue. This total reflects revenue recognized pursuant to our Santa Fe and Vertex collaborations. At the end of the quarter, our deferred revenue total on the balance sheet was approximately 63 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 43.1 million, of which 4.5 million represented non-cash stock-based compensation. The adjusted cash R&D spent of 38.6 million, excluding stock-based comp, is essentially unchanged from the comparable amount in the September quarter. Our G&A spending for the quarter was $11.6 million, of which $4.4 million represented non-cash stock-based compensation. The adjusted cash G&A spend of $7.2 million, excluding stock-based compensation, reflects a 13% increase from the comparable amount in the September quarter. Finally, on cash, we exited the fourth quarter with a cash and equivalence balance of approximately $560 million. As we shared earlier in the year, we believe that our cash runway extends into the second half of 2025, a projection that now includes milestones related to the Phase II start. I'll now turn the call back to Nello.

Thanks, Bruce. With our accomplishments last year, it's clear that Chimera has made considerable progress in its evolution and begun to demonstrate the incredible potential of this modality in our company to make a meaningful difference in patients' lives. We're excited to have the opportunity this year to assess the impact that our four programs may have for patients with cancer and immunological conditions and to further demonstrate the potential advantages of our technology and platform have over traditional medicines. We feel that we're just getting started and energized by the opportunity we have in front of us. As I said earlier, 2023 will be a busy year. We have a lot that we expect to achieve, much of which was discussed earlier in the call. But just to quickly state our key 2023 goals, we will collaborate with Sanofi to initiate the first KT474 phase 2 study. We're also working to publish the results of the phase 1 trial in a top-tier journal. We intend to evaluate the effects of our Arachimid and STAT3 programs on tumor-burdening patients in our phase one studies. We plan to initiate the KT253 phase one trial in solid and hematological tumors in order to demonstrate proof of mechanism in patients. And with respect to our pipeline, our objective is to deliver at least two new VCs INDs from the preclinical pipeline and also continue our expansions of our novel molecular glue franchise. At this point, I'd like to thank the Chimera team as well as our partners and the patients participating in our clinical trials and 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 to the operator so that we can take your questions.

Thank you. At this point, we will open the call for questions. As a reminder, to ask a question, please press star 1 on your telephone keypad. If at any time you would like to withdraw from the queue, please press star 2. We will now take a moment to review our queue. Today's first question comes from Eric Joseph with J.P. Morgan. Please go ahead.

Thanks. Good morning, and thanks for taking the questions. Just a couple questions on the MDM2 program, if we could. I guess first, what is... Can you lay out what proof of mechanism looks like with KT253 later this year? And does it look similarly in liquid tumors as it does in solid tumors? And then secondly, with respect to the anticipated AE profile with the drug, do you anticipate any differences, I guess, relative to... competitor MDM2 inhibitors, particularly on the aspect of myelosuppression, any potential to sort of reduce rates of grade 3 neutropenia with this compound? Thank you.

Thanks, Eric. So I'll start, and then I'll let Jared comment more on the proof of mechanism. But maybe I'll take the second question first, just because it actually points to the core thesis for our investment in the MDM2 program, which is creating for allowing us to create a larger therapeutic index that will allow us to finally interrogate this mechanism in the clinic fully. And as you heard this said in the past, the rationale is really based on cancer genetics. If you look at data that's been published over the years and that has fueled all the drug development programs in this pathway, we know that p53 is wild-type, in more than 50% of cancers. In those type of cancers, both liquid and solid tumors, if you delete MDM2, if you genetically delete MDM2, with genetic tools that we have preclinically, you see a high dependency of these tumors on the presence or absence of MDM2. And that basically genetic removal of MDM2 leads to rapid apoptotic response in those tumors that have p53 wild type. And if you look on one of those plots that have been generated, it's probably one of the most impressive sensitivity plots that we've seen in cancer genetics. Now, I think the field has made the assumption, and that has been true for many programs in oncology in the past 20 years since we started to understand, you know, the human genome and the relationship with the human proteome. We made the assumption that inhibiting MDM2 will lead to that kind of response. And what we've learned is actually that's not true. We've learned that if you inhibit MDM2-P53 interaction, you are able to actually stabilize p53, but not fully, and mostly because the inhibition of that interaction leads to an upregulation of MDM2. So as you're inhibiting the interaction, you see more MDM2 that gets produced, and the small molecule has a hard time fighting that. And so you end up having to dose longer, and that creates a very narrow window, if at all, between your anti-tumor effect and your impact on bone marrow-derived cells, which are one of the most sensitive cell types to MDM2 absence. What we have been able to do with degrading MDM2 is to remove the protein quickly, and we see in the first two to four hours a rapid commitment to apoptosis. And that leads cancer cells that are sensitive to this mechanism to die quickly, while healthy cells, while they might have an initial impact, have time to recover between the first and the second dose. And so that creates, in tumors that are highly sensitive, I want to be sure that's clear, a therapeutic index that no small molecule has seen before in our hands. And so what we're talking about, and I think Garrett commented on it before, and this is work that we're still doing, obviously I think it's not fair to assume that all P53 wild-type tumors will have this wider therapeutic index. I think that's scientifically not true based on our experimentation. But we have found subsets of tumor types within the p53 wild-type larger set, there are highly sensitive. And the ones that are highly sensitive have this increased therapeutic index. So our hypothesis going into the clinic is that we'll have a drug that is well-tolerated while it's being effective in the patient populations that are sensitive to it. The only indications that we have shared so far where we've seen this high sensitivity are AML, including the patients that are refractory to the existing line therapies. So that's an exciting area for us to explore. Lymphomas and some solid tumors that we will be disclosing later in the year or as we go into the expansion cohort. So maybe I'll let Jared comment more on what the proof of mechanism is going to look like and whether, I think your question was also whether it's going to be different between liquid and solid tumors.

Yeah, and maybe if I can just quickly comment also on the question around myelosuppression. You know, the fact that we have this unique mechanism of action that Nella laid out allows us to dose infrequently, given the drug is an IV infusion once every three weeks. And that infrequent dosing, we think, is going to give us this unique therapeutic index that will allow us to mitigate myelosuppression by allowing plenty of time for normal cells in the marrow to recover in between doses. Coming back to proof of mechanism, our aim for showing proof of mechanism, at least this year, is to focus on impacting the MDM2 P53 pathway in peripheral blood mononuclear cells, which we can do essentially in all of the patients on the study. We've done this with our prior programs, 413, 333, looking at impact on the target in PBMC and where available in tumor as well. Here, I think in the MDM2 phase one trial, the initial focus will be PBMC. And then I think when there is tumor available for biopsy or once we're in R and B where we're treating high-grade myeloid malignancies including AML, we may have more opportunities there to also show impact on the pathway in malignant cells including leukemia.

The next question comes from Ellie Merle with UBS. Please go ahead.

Hi, this is Jasmine on the line for Ellie. Thanks very much for taking our question. So you've been mentioning your work in molecular glues, so we just have a couple questions there. First, what's your perspective on the ability of molecular glues to be selective for a single target protein as you think about target selection? And then second, non-cerebron-based glues, is this something you think could be feasible over the next few years, or is this more a longer-term focus for you? Thanks.

Thank you for the question. It's a great question because it allows us to talk about, I think, one of the key differentiators for this company, which has always been to go after hard problems. So as you've heard, and I know your team has paid a lot of attention to what we said in the past on this particular topic, we've said that we are using molecular glues to go after problems that hydro-bifunctional degraders cannot solve. So maybe just a step back, what are hetero-bifunctional degraders solving for? They're solving for undrugged or poorly drugged targets where you have inability to bind to that particular disease-causing protein. And we've shown that you can go after transcription factors, scaffolding proteins, et cetera. So again, there's plenty of targets out there that obviously hetero-bifunctional degraders can solve meaningful clinical problems. But there are also many validated targets in oncology, in immunology, in rare disease, in cardiovascular, in CNS, where you don't have an opportunity to find discrete binders to those proteins, mostly because those are, let's say, disordered proteins or difficult to ligand proteins. And so you either choose not to go after them or you choose to build capabilities that to go after them. And we chose, again, the hardest part, which is developing technologies to go after them. And so we take an E3 ligase agnostic approach. So yes, the answer to your second question is yes, there will be molecular glues that don't use cerebron. And in fact, I think there are already examples out there in the literature pointing to those possibilities. But we take, as I've always said in the past, the translational medicine approach. We think about what are the clinical problems we're trying to solve for and what are the molecular mechanisms that will enable us to do that. And so I have to give, again, kudos to our team led by Juliet and others in our platform team that have uncovered actually a whole new series of proteins that we can go after using a completely new background motif that we can engage with an E3 ligase and with some molecular designs that we made. And it turns out that these proteins that we've already identified that are multiple are key un-drugged, un-ligandable proteins, many of whom are in immunology and some are in oncology. And I think it's unlikely that we would be disclosing the molecular mechanism because we feel this could be, you know, the beginning of a completely new era of molecular glue. I would kind of look back at when the IMID and Cereblon were discovered and how many targets have then subsequently been drugged by that interaction. I suspect that what we've uncovered here could lead to that type of discoveries. And so we're just at the beginning. We're very excited. I think we have our first program that is already in lead optimization. driving towards the development candidate. And we'll continue to talk about this. And as the program moves into development, we'll talk about what target it is. But probably unlikely that we'll be disclosing the molecular mechanism or even D3 ligase.

The next question comes from Brad Canino with Stiefel. Please go ahead.

Good morning. Thanks for the updates. Two questions for me. First, I guess with the recent announcement for the departure of the global head of R&D at Sanofi, John Reed, and the company searching for a new successor, I'd just like to hear your optimism that KT474 has enough advocates or champions, so to speak, at Sanofi so that the program will continue to be prioritized even with any future shakeup of portfolio strategies and initiatives from a new R&D head. And then for Jared, on KT413, can you remind us the type of DL-BCL patients that are being recruited in terms of likely prior therapies? Are these patients post-Polivi, CAR-T, bispecifics, et cetera? And if so, what is your confidence in the ability to recapitulate the preclinical model results in such a heavily pre-treated population, particularly with a MI-D88 mutation? Thank you.

Great. Brad, that was a perfect question for our colleagues at Sanofi. So I will try and answer it, obviously understanding that I cannot speak for them. First, you gave me the opportunity to thank John that has been an amazing partner along the way from the beginning, which was when we started to talk about a partnership on KT474 all the way through his last day. I will say that we've had the fortune to connect with several leaders in the company without naming names at the executive level that have continued along the way to be excited, to be helpful, to be supportive of the partnership and understanding and appreciating the value of 474. So again, speaking for Chimera, I have no doubt that the molecule is in the right hand, and there is the excitement, commitment, and appreciation of what this molecule can do for, to be honest, millions of patients out there. And I expect that there will be no change of priorities or commitment going forward. Regarding the second question, again, I'll leave it to Jared to answer.

Yeah, thanks, Brad. You know, on the 413 study, you know, we are recruiting B-cell malignancies, including DLBCL, and including, you know, patients with MI-D88 mutations. You know, as you noted, you know, many of the patients will have had prior therapies, and we anticipate that many of these patients, you know, will have had, especially if they had DLBCL, you know, perhaps prior CAR-T, if they were eligible, maybe prior Polivir or bispecifics or even TAFA. But I think what's important here to note is our unique mechanism of action. You know, the fact that with 4 and 3, we're drugging IRAC4, and we're also drugging the IRF4 pathway with the IMID activity. It makes this a unique mechanism of action, and so we don't expect there to be cross-resistance to these other therapeutics like cellular therapies or like bispecifics. And so I think we're confident that with the right patient population, especially those with a mighty 88 mutation, sort of regardless of prior therapies or how many prior therapies, we still expect that the mechanism of action here should yield you know, significant anti-tumor responses with WOMEN3.

The next question comes from Vikram Parohit with Morgan Stanley. Please go ahead.

Hi, good morning. Thanks for taking our questions. So we had two, one on 474 and then one on your STAT3 program. So going back to your relationship with Sanofi, just wondering if you could provide some more color on And what are some of the considerations that you're thinking through with Sanofi when you explore indications beyond HS and AD for Phase II development for this molecule? And then for STAT3, I was just curious to get an update on where efforts stand with evaluating a STAT3 degrader in autoimmune and fibrotic conditions and when we could expect to hear an update on that effort. Thanks.

Thanks, Vikram. So first question is, So if you actually look historically at how we've developed the molecule and this program, you know, there is a slide that actually we haven't changed in a couple of years in our deck, which are clinical opportunities that could be realized by targeting the L1-TLR pathway. And we've, you know, usually shared these kind of Th1, Th17-driven diseases like HS, like RA, like lupus, IBD, and others. And then we've shown the Th2 type diseases, you know, like AD, asthma, COPD, and others. And we said that, you know, with validation of this mechanism in some of those diseases representing kind of these two, slightly kind of differentiated ways to thinking about immunology, then you can think about expanding further. And so I believe that at the high level, both Sanofi and Chimera are looking at the opportunity in that way. Now, practically, what we have prioritized, as you know, is HS and AD, and we've been fortunate, I have to say, that even with small patient numbers in a study design land and even study design generally that was not set up to look for clinical activity, we've been fortunate to have seen really early validation of this mechanism in both HS, again, Th1, Th17, AD, Th2 type inflammation. you know, obviously we look for further validation in a placebo-controlled randomized face-to-study, and we go into this study with high degree of confidence and expectations based on the data we've seen so far. So the conversations that obviously are happening and will continue to happen is, you know, what are the next type of indications that we will go after? What I will say that I can't again, speak for the collaboration in terms of particular indication. What I will say from our perspective and even from my perspective, there is such a high need in many of those indications where there are really no small molecules with an activity and safety profile that we can match with the IRAC4 degrader. Obviously, I'll start with AD. I don't think there is one. Going to HS, I don't think there is one. I go to IBD, large amine. I don't believe there is a good molecule now that can really help patients go through a horrible experience. I look at Array, which is commercially quite crowded. But again, I think there is an opportunity for a well-tolerated active drug. I look at Lupus, which is an unsolved disease. And then I look on the other side, on the Th2 type inflammation. Again, there are really no good small molecules in those indications that I mentioned earlier, like asthma, COPD, pruritus, and others. So I think we have a large opportunity. I think we have to be rational with how we select the opportunities, and we have to be data-driven. I suspect we will be updating, you know, you all on as we make those determinations. And clearly, initial proof of concept in a randomized study in phase two will be the drivers of those further selections downstream of these initial two diseases. But, you know, I think we have a unique opportunity here in the landscape to help millions of patients, as I said earlier, Let's not forget, and I don't want to spend the whole 20 minutes on this, but let's not forget that the unique value proposition of KT474 is that this is a systemic anti-inflammatory molecule with broad anti-inflammatory effect with local anti-inflammatory also effect. The molecule has demonstrated systemic anti-inflammatory efficacy as measured by also biomarkers across a wide variety of downstream cytokines and chemokines. It's also shown, as you know, a preferred distribution in tissues, especially as you've seen in skin, as well as, as we know, an anti-TLR activation, anti-inflammatory effect. So it has this really unique combination of both molecular properties as well as pathway engagement properties that makes it a very unique molecule in the landscape. We're excited to continue to develop the molecule to explore further, you know, how many other diseases we can potentially develop it in. The other question. Yeah, the STAT3S. So STAT3I and I, as I said, you know, relatively recently, there is an area that we are continuing to do work. You know, we plan to be able to update further later in the year. I can't live it. share more than what we said recently.

The next question comes from Michael Schmidt with Guggenheim. Please go ahead.

Good morning. This is Paul. I'm from Michael. Thanks for taking our question. We just have two on the MDM2 program. I guess first on the dosing strategy. Is there potential in the study to evaluate alternative dosing intervals that could potentially optimize the clinical profile in 253 between solid versus liquid tumors, given possible differences in PKPD in those settings? Are you fairly comfortable with the every three weeks dosing across all tumor types? And then secondly, obviously, you're just starting monotherapy dose escalation, but how are you currently thinking about the strategy for 253 and combinations? It seems like you know, coming out of ASH amid a venetoclast combination might be on the table for AML, so just wanted to get your thoughts there. Thank you.

Thanks. That was a great question. Maybe, Jared, do you want to take them? Sure.

Yeah, maybe starting with the dosing schedule, you know, as we stated up front, you know, we are going in with a once every three-week IV infusion, which we think, you know, has the potential to be highly active based on our preclinical models, but also has the ability to mitigate myelosuppression. We do have flexibility based on our preclinical tox studies to dose less frequently, even every two weeks, if we thought that was necessary. Your question is an interesting one. Could we ever envision a situation where you might have one schedule for liquid tumors and one for solid tumors? That's always a possibility, and I think we do have that flexibility. Our plan, though, right now, our expectation, rather, is that every three-week dosing will be active in both liquid and solid tumors, but at least we do have that flexibility to dose less frequently if we think it's necessary from a pharmacodynamic standpoint and if we think that it would be tolerated from a safety standpoint. In terms of combinations, that's obviously a very good question as well, and you mentioned venetoclax. We've been doing some, I think, very interesting preclinical work looking at our drug in both venetoclax-resistant and sensitive AML models, and we can see activity of our MDF2-degrader as a monotherapy, even in venetoclax-resistant models, which is very encouraging for the possibility of our seeing activity with our drug in AML patients who have previously seen venetoclax. And as you know, more and more patients are getting venetoclax, either in the upfront setting or in the relapsed refractory setting. But I think we've also seen some very encouraging data with our drug combined with venetoclax, either in venetoclax-resistant or venetoclax-sensitive AML. So I think we will have the opportunity to look at that combination. I think that will be probably one of the combinations that we do prioritize once we're through with monotherapy dose escalation, have a good sense for the safety profile, and then start to look at combinations that we can use for development in the future. But I think I want to be clear that I think we do feel that the activity we're seeing preclinically is such that we believe that there's a substantial opportunity for MDM2 to greater as a monotherapy in both liquid tumors and solid tumors. But I think these combination approaches always give us even additional development opportunities that we want to take advantage of.

The next question comes from Mer Fromm with Cohen. Please go ahead.

Hi. Thanks for taking that question. Maybe just following up with MDM2, some of the same questions. What is the kind of target degradation profile you're aiming for in terms of kind of percent reduction? But I think, you know, given all you're saying about kind of this therapeutic window, just at least as important is, you know, the duration of that degradation?

Yes, Mark, thanks for the great question. So what we've seen preclinically is that the degradation above 80%, 80%, 90% for really a short period of time, even two to four hours, is enough to lead to this really profound apoptotic response. And that's why actually we designed this type of drug with this type of dosing paradigm where we dose it IV where we are able to reach this really high, quick, high C marks initially that leads to quick down regulation and then clearance of the drug relatively quickly so that we can optimize on degradation of the target in tissues that are, you know, highly sensitive so that we can capture maximal anti-tumor effect and then we can kind of take the time for healthy cells to recover before we dose again. Actually monitoring the MDM2 degradation and pathway engagement is a large piece of work that the team here has done, given actually the complexity of the pathway and also how to measure MDM2 levels, which are initially already relatively low. So it's actually also some really innovative science that we've done here at Chimera to monitor and to understand both engagement in terms of MDM2 degradation, but also downstream biomarker readout, which for us are just as critical, right? Seeing the right biomarker either increase or decrease downstream is what really drives that kind of anti-tumor effect. So I think as a part of that proof of mechanism data that Jared was mentioning that we'll share hopefully this year, at least obviously that's the goal and plan, will obviously have that type of information, you know, depth of target engagement, time of target engagement, and also safety that will go with that.

The next question is from Mike Kratke with SVB Securities. Please go ahead.

Hi, everyone. Thanks for taking our questions. For KT413, can you talk a little bit about the potential next steps from a clinical development standpoint and how you could aim to pursue a potential accelerated regular path forward here? And just beyond that, I mean, how should investors think about the potential sequencing of indications you're going to be pursuing? Thanks.

Thanks, Mike. Jared, do you want to take that one?

Yeah, sure. Yeah, thanks for that question. I mean, clearly for us with 413, you know, the mighty 88 mutated B-sub malignancies are front and center in terms of development. And there, I think we see, you know, three, at least three potential opportunities. DLBCL, of course, where the mutation is seen in about 25 to 30 percent of patients, which represents a substantial opportunity. We're talking about, you know, prevalence numbers that are in the thousands. We think also, you know, Waldenstrom's macroglobulinemia is another very interesting opportunity since about 90, 95% of those patients have this mutation and is their high IMET need, you know, both in the relapsed refractory setting after BTK inhibitors, but even up front, you know, to find novel therapies that can achieve complete responses rather than just partial responses. And then finally, you know, primary CNS lymphoma, where this mutation is seen in about 80% of patients, also a very, very high IMET need for that population, albeit a smaller population than DLBCL. I think when we think about this drug, we have to think about the unique positioning here especially within DLBCL. You know, in DLBCL, there really is no therapeutic that is aimed at a genetically defined subset of DLBCL. And as one knows, you know, in this disease, you know, the genetics of the disease now is really more important than the histology. And more and more, the trend is really defining, you know, genetic populations based on their outcome, their survival to frontline ARCHOP or other frontline therapies and really trying to hone in on genetic subtypes, what the prognosis is of those subtypes, and then finding new drugs, you know, that can take advantage of vulnerabilities in patients with those different genetic abnormalities. And I think 4 and 3 has the potential to be the first drug, you know, for my D88-mutated lymphoma. This mutation confers actually a worse survival outcome after frontline RCHOP, so there really is a high-end need for these patients, and having a drug that really, for the first time, would be going after a genetically-defined subset of DLBCL we think positions this uniquely, not just therapeutically, but also from a regulatory standpoint. We know there are precedents, you know, from FDA for granting accelerated approval for drugs that are active, especially in genetically defined subsets within oncology. And so we do think that there is a real accelerated approval opportunity here in relapsed refractory mighty 88 mutated DLBCL with a potential rapid development path, you know, following phase 1B that could even just consist of an open-label phase 2 study that could lead to accelerated approval. So that is a possibility, we think, for DLBCL. So that, I think, is really the first near-term opportunity for developing this drug in my D88 mutated malignancies. But with that being said, we think there could be also rapid accelerated approval opportunities in second-line Waldenstroms if we have transformative activity in patients who have progressed after prior BTK inhibitors. That could also lead to a rapid development path. And certainly in primary CNS lymphoma, where there's a very high in that need and very few drugs at all being developed in that space, I think there, too, we see another potential rapid development opportunity.

The next question comes from Derek Archilla with Wells Fargo. Please go ahead.

Hi. This is for Derek. Thanks for taking our questions. Two quick ones from us. First, on the program, what kind of data update can we expect this year? And the second question, from a TPD perspective, given you are developing glutes, heterobifunctional degraders, and tissue-specific ligases, is there any plan to look at extracellular proteins?

Great question. So maybe I'll start with the second one. You know, we always look at what is the...

what is the unmet need and the problem that we're trying to solve? And I personally feel that, you know, 80% of the proteome, roughly, hopefully I don't have the number wrong, is intracellular. We have really great tools today to drug extracellular proteins. So the real opportunity for extracellular proteins, if you have if you're able to compete with biologics by, you know, developing molecules that you can be kind of as infrequently dosing as the antibodies do or more, or if you have an oral degrader or extracellular protein. I think there are clearly opportunities there. At this stage of the company, I don't think that's an area where there is the highest opportunity and risk-reward scenario at this stage. But as we continue to grow the company, there might be opportunities also to go into that space. We actually looked at that a couple of years ago and decided not to go into that particular space. With regards to your first question on STAT3, as we said in the press release and also in the remarks that we made earlier, the goal this year is to dose patients at exposures and degradation profiles that we expect to be therapeutically relevant, and we also hope and expect and are driving towards recruiting patients at those doses where we expect to see clinical activity, meaning these are tumor types that we've seen preclinically to be sensitive to STAT3 degradation. And so what we expect to hopefully share this year is are we seeing anti-tumor response in patients that are, again, theoretically sensitive to STAT3 degradation at the right dose and at the right, again, length of dosing. And so it will be what we call an initial proof of concept. It will be, does STAT3 degradation in the right patients elicit an antitumor response?

As a reminder, please limit yourself to one question in the interest of time. The next question comes from Kalpit Patel with B. Riley. Please go ahead.

Good morning. This is Andy. I'm for Kalpit. Thank you for taking questions. Some from us on KT413. First, I understand that you're looking for meaningful clinical activity in those levels three and four, but have you observed any evidence of anti-tumor activity so far, even if it's just stable disease? And then second, You noted needing to maintain target knockdown for 72 hours, and we're seeing robust target knockdown in plasma of the target proteins, Icaros and Iolos, but they're rebounding to or above the baseline levels near the end of the dosing interval. Do you anticipate tweaking the dosing frequency, perhaps from every three weeks to every two weeks, to ensure adequate depletion of target proteins at all times? and is sustained depletion actually needed based on your preclinical models for meaningful anti-tumor activity?

Great.

I think these were three questions, but okay, let's do the first one was, I forgot already. Tumor activity, that's fine. Yeah, so obviously what we said, we expect to share data at a scientific meeting or in an event in which we decide to share data, and we decided not to give kind of updates along the way. So I guess I'm not going to answer that question. On the second one, which is second and third, are good questions. So first I want to remind everybody that, and there are slides on our website, that actually the degradation profile that we believe at least we know preclinically and we believe will translate clinically into anti-tumor effect and good safety is the one where we degrade these proteins for about 72 hours. And then we need to see full rebound of those proteins before we dose again. So actually the fact that by week three we see full recovery of these proteins not only is good, but it's necessary at least based on preclinical data to avoid, seeing neutropenia and other safety events that come with IMID. We do have flexibility to change those in paradigm if we need to, but right now we're really asking the biological question of is the degradation profile that we've seen preclinically to be the most active in MyD88 mutant tumors out of all the other agents that we've tested. Does that translate in similar levels of anti-tumor activities in the clinic. I think only after we kind of answer this question, we can start talking about is there an opportunity to tweak the dosing one way or the other.

The next question is from Zi Xu with Berenberg. Please go ahead.

Good morning. Thanks for taking the question. I have a quick one. On your updated corporate deck, you disclosed some of the discovery programs will be around IL-4, IL-13 pathway. I thought that's interesting. Can you talk about the potential advantage for using approach and degradation approach versus biologic approach and also talk about the medical need associated in those diseases?

Yeah, so thanks, Z. That's a great question. We only have a couple of minutes. I could spend a couple of hours on this. But just very quickly, we built the company with working in pathways where there is high validation, where we believe protein degradation can unlock the biology better, fully, or for sure with a better technology. And so I think I'm not going to reveal anything new that you know, an antibody for that particular pathway is probably going to be the largest drug in the market in the next few years. And it's been approved in AD and in other, I believe, four other indications. And we believe that there is both an opportunity to develop an oral drug in that pathway, and actually we believe there is an opportunity to develop a better drug in that pathway, meaning a drug with a better efficacy profile. And so, you know, I don't have to do the math on the opportunities, but obviously if you look at the pixels in AD and the penetration and how much money that drug makes a year, you can imagine an oral small molecule that can serve that patient population in a better way, what are the opportunities there? So that's really what we're trying to solve for, have patients be treated with the best drugs, which we believe is what we're working on.

The next question comes from Timur Ivanikov with Raymond James. Please go ahead.

Yeah, thank you for the question. So just for KT474, just trying to understand the strategy for the studies a little better, I think HS study is starting first. So do you think there will be an overlap in time between those two studies? Just want to make sure that there's no gatekeeping factors in HS study like safety or efficacy data that Santa Fe may want to see before starting the AD study.

That's a great question. I mean, I'll answer short because we're kind of out of time. From our understanding, there will be a high likelihood that there will be an overlap between the studies. I don't believe there are data expectations that will inform necessarily, you know, when and how the second study will start. But again, this is We will talk more about the specifics as the studies initiate. Those are questions that Sanofi will have a better answer for.

The next question comes from Jeff Meacham with Bank of America. Please go ahead.

Thanks for taking the question. This is Joe on for Jeff. So we've talked a bit about the collaboration with Sanofi so far. I was wondering, how are you thinking about additional partnerships and collaborations in the near term? Because you called them out in your press releases as a strategic objective for the year. Can you provide a little bit of color on what types of partnerships you may be pursuing?

Yeah, it's a great question. So again, I'll try to be brief. There is two ways to think about strategic partnerships. One is, what are technologies, even assets, or early tools that will enable Chimera to grow better, faster? And then are there instead companies that we can partner some of our programs or our technology to create more value together versus independently developing or commercialized drugs? And I will say that those both areas are areas that we always think about and I don't have any specifics to update right now, but obviously a company like Chimera with the expertise that we built, there is way more that we could do than what we're doing. And then the question is, how do you get that, how do you solve that right?

And I think at this point, I don't have any specific update on it.

The last question today comes from Kelly Shee with Jefferies. Please go ahead.

Okay, congrats. This is John Tan on for Kelly. Thanks for taking our questions. So I have a question on K74. Can you provide more color on how you will work with Sanofi going forward? Do you anticipate continuing to engage with them over the course of Phase II initiation and maybe expanding the collaboration to other of your immunology programs that's coming up? Thank you.

So, I mean, we had the fortune to have a really good partner with Sanofi along the way. I will continue to say that because it's true. And we've worked very closely with them when we were running our program, the program, and we already are working very closely as now they are operationally and financially responsible for the program. I would also remind everybody we have an opt-in mechanism before phase three, so we're fully vested in the success of the program. Not only we have committees in place to obviously follow progress, but we actually have almost you know, weekly or biweekly interactions with them to make sure that we both give our best for the success of this drug. So I have no doubt that that will continue to be the case. I think there was a second question about other collaborations maybe. I can't really comment on that. For now, the rest of our pipeline that we've talked about is our own, and that's for now what we're doing and continuing to do. to generate value. We're well financed, as you see, to continue to advance these programs and create values, and that's our goal at this point.

This concludes the question and answer session. I would like to turn the conference back over to Nello for any closing remarks.

First, I would like to thank everybody for listening to our call, for the engaging Q&A. You all had great questions. Hopefully, we did our best to answer them in the most comprehensive way possible. We're excited about what we've done, but we've always aspired to do better year by year. We hope and expect that 2023 would be even more exciting than 2022. Encourage everybody to follow us and reach out to us if you have further questions. And, you know, we always wait for amazing data to speak for us. So we're excited to see how all these programs unfold and help patients in a wide variety of indications. So thanks again for the time. Apologies for being a bit late. And have a good rest of the day.

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