This conference call transcript was computer generated and almost certianly contains errors. This transcript is provided for information purposes only.EarningsCall, LLC makes no representation about the accuracy of the aforementioned transcript, and you are cautioned not to place undue reliance on the information provided by the transcript.
spk08: Good day and welcome to the Chimera Therapeutics second quarter 2024 results 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 one on your telephone keypad. To withdraw your questions, please press star then two. Please note this event is being recorded. I would now like to turn the conference over to Justine Konigsberg, Head of Investor Relations. Please go ahead.
spk01: Good morning and welcome to Chimera's quarterly update call. Joining me this morning are Nella Manolfi, President and CEO, Jared Golub, our Chief Medical Officer, and Bruce Jacobs, our Chief Financial Officer. Following our prepared remarks, we will open the call to questions. In order to have enough time to address everyone's questions, please limit your questions to one and a relevant follow-up. Before we begin, I would like to remind you that today's discussion will include forward-looking statements about our future expectations, plans, and prospects. These statements are subject to risks and uncertainties that may cause actual results to differ materially from those projected. A description of these risks can be found in our most recent 10Q filed with the SEC. Any forward-looking statements speak only as of today's date, and we assume no obligation to update any forward-looking statements made on today's call. With that, I'll now turn the call over to Nello.
spk15: Thank you, Justine, and good morning. Every day we take important steps towards our goal of building a fully integrated global biotechnology company, demonstrating our ability to consistently deliver first-and-best-in-class programs that target validated pathways with the potential to address large underserved disease areas. The progress we've made over the past quarter highlights our novel approach to drug development that emphasizes innovative molecular design, fidelity of translation from preclinical settings to the clinic, data-driven development strategies, and the commitment to maximize the impact of our science to improve patients' lives. Our unique approach has led to the development of a pipeline of exciting degrader medicines with the potential to change treatment paradigms for multiple diseases, as evident in our recent updates and presentations at major medical congresses and publication in peer-reviewed journals over the past few months. Our STAT6 program, for example, was featured at both ATS and DDW, MDM2 at ASCO, and STAT3 at AACR and EHA. In addition, we published data from our non-interventional trial evaluating IREC4 expression in patients with HS in the Journal of Investigative Dermatology. The findings we've shared across these forums highlight the differentiated profiles of our programs. Before handing the call over to Jared for a more detailed overview, I wanted to highlight two important updates in our immunology pipelines. I will start with our IRAC4 program. As a reminder, KC474, our IRAC4 degrader partnered with Sanofi, the first hetero-bifunctional molecule to have been dosed in healthy volunteers and then HS and AD patients. We have shown in our phase one studies deep degradation of IRAC4 in blood and skin, resulting in impact on biomarkers of inflammation, both systemically and in the skin of HS and AD patients. This robust PD profile has resulted in clinical benefits measured by easy and prorated scores in AD and high score and pain in HS. KT474 has likely been the most studied degrader in a Phase I setting. Last month, we announced, after an interim review of safety and efficacy of the ongoing HS and AD Phase II trials, that Sanofi intends to expand both of these trials with a goal to accelerate the path to registrational Phase III studies for both HS and AD. The impact of these expansions effectively allows us to transition seamlessly into more expansive dose range-finding Phase II studies. As a result, while the modified Phase II trials will be larger and extended, the expectation is that this will enable a direct transition into Phase III more quickly than anticipated. Staying with immunology, we've been talking about the concept of oral degraders with biologics-like activity, a unique value proposition for Canera's platform in this attractive therapeutic area. Our STAT6 program best exemplifies this concept. Dupilumab is the drug that has transformed the lives of almost a million patients with Th2 diseases, and in doing so has become, with sales that are projected to reach $20 billion, a mega blockbuster and one of the largest drugs in this industry. At Canera, we've developed an oral degrader that, by targeting STAT6, the selective transcription factor of the IL-413 pathway, is able to block the pathway in a similar or superior way. In fact, we've shown in preclinical studies that an orally active picomolar STAT6 degrader, KT621, is more potent than dupilumab at blocking Th2 signaling in cell systems and equal or superior at blocking Th2 inflammation in preclinical disease models. Overall, the preclinical data generated to date demonstrate the opportunity for KT621 with best impact with potential given its dupilumab-like activity and the convenience of an oral pill. We believe that a paradigm-shifting oral drug with this profile has the potential to change how Th2 diseases such as AD, asthma, COPD, and others can be treated. Our mission is not only to target the patients that are currently on biologic that the more than 100 million patients that are not currently on biologics, and by doing so, we have the potential to change millions of lives around the globe. We're excited to start our KT621 Phase I trial soon. We usually don't comment on the status or results of ongoing IND enabling studies, but since one of the most frequently asked questions we receive is the current status of the program, I wanted to provide a brief update. Very happy to say that we have completed all of the IND enabling studies with no safety findings of any kind. Case in point, in our GLP toxicology studies, at all doses tested, we did not see any adverse events of any type. This is an important milestone for the program, for KMR, and hopefully for millions of patients in the future. With those activities behind us, the next update you should expect will be when we dose our first subject. And importantly, We look forward to sharing the Phase I results in the first half of 2025. I will let Jared share more details on our programs, and then I'll be happy to do questions. Jared?
spk05: Thanks, Nilo. Starting with KT474. As mentioned, last month we announced Sanofi's decision to expand the ongoing Phase II studies in HS and AD following an interim analysis of KT474 safety and efficacy by an independent data monitoring committee. This exciting development is a great outcome for Chimera and our IRAC4 program. Importantly, it not only reinforces Sanofi's strong commitment to the program, but also provides the potential to inform future registrational trials in a way that should accelerate overall timelines. Just a step back, the expansion effectively will allow a seamless transition into more expansive dose range-finding Phase II studies. The goal is really to structure the studies with the necessary regulatory perspective to enable dose selection for phase three. While it will take longer to complete phase two, these two expanded phase two trials in HS and AD will support moving directly to phase three. Therefore, the overall timelines to phase three, and ultimately to registration, should be meaningfully shorter. Since the update last month, Sanofi is undertaking activities to update the protocols, and once this work is complete, We expect the new details will be posted on clintrials.gov. Once that happens, we will be able to discuss updated timing related to trial completion and data releases. As a result, we expect the Phase II results, which will be shared in their entirety following this expansion, will be beyond our prior guidance of the first half of 2025. As Nella mentioned, KT621, our first-in-class STAT 6th grader, has the potential to be a once-daily oral medicine capable of delivering dupilumab-like activity and safety in highly prevalent allergic diseases. We recently presented additional data at the ATS conference that demonstrated activity of KT621 comparable to a saturating dose of the IL-4 alpha antibody dupilumab in an asthma efficacy model, including robust inhibition of all the tested cytokines, chemokines, and cell infiltrates involved in Th2 inflammation in asthma. The data also demonstrated reduced disease severity in the lungs after low daily oral doses of KT621 comparable to dupilumab. I should also note, as Noah mentioned, that KT621 was well-tolerated in our preclinical testing now in both non-GLP and GLP-TOC studies with no adverse events at any doses. We look forward to presenting additional KT621 preclinical data in a poster session next month at EADV. the largest international meeting in Europe for dermatology. We remain on track to commence a Phase I single and multiple ascending dose clinical study of KT621 in healthy subjects in the coming months, with data expected in the first half of 2025. We plan to share more details around our development plans for Phase I and beyond when we provide additional updates on the program later this year. Bounding out our immunology pipeline, we unveiled our first-in-class oral TIK2 degrader, KT294, at our R&D day. We have shown that small molecule inhibitors do not block all the scaffolding functions of TIK2 and therefore are not able to replicate the TIK2 loss of function profile. In addition, small molecule inhibitors cannot block the catalytic function fully at steady state. The opportunity for this program with depletion of TIK2 is not to just have a drug that is incrementally better than TIK2 small molecule inhibitors, but to bring to patients an oral, biologic-like pathway blocker and thereby deliver a best-in-class agent for conditions like IBD, psoriasis, psoriatic arthritis, and lupus, among others. For this program, we expect to initiate and complete Phase I testing in 2025. In summary, these timelines put us in a position to share Phase I data for our two new immunology programs, STAT6 and TIK2, in 2025, which is shaping up to be a very busy and exciting year for Chimera. Moving to oncology, this also has been a busy stretch for our two clinical programs, KT253 and KT333, targeting MDM2 and STAT3, respectively. We've recently shared updates demonstrating the disease-modifying impact of these degraders at ASCO and EHA, highlighted by major responses in liquid and solid tumors. In addition to the clinical activity that has been demonstrated, we have been particularly encouraged by tolerability, which has exceeded our expectations in both cases. That has resulted in our ability to escalate to higher dose levels than expected. As a reminder, MDM2 is an oncogenic protein that modulates the most common tumor suppressor, p53. While small molecule inhibitors have been developed to stabilize and upregulate p53 expression, they have been unable to show meaningful clinical benefits of p53 stabilization with acceptable safety margins. We believe this is likely due to their inability to overcome a feedback loop that increases MDM2 protein levels when P53 is upregulated. Due to its differentiated mechanism, KT253 has shown the ability to overcome the MDF2 feedback loop and rapidly induce apoptosis with brief exposures in preclinical studies. This provides an opportunity for improved efficacy and safety profile. We're encouraged by the data emerging from the KT253 Phase I dose escalation trial. In our ASCO poster in June, we provided a clinical update from 24 patients as of April 9th. That update included 16 patients in arm A with solid tumors and lymphomas up to dose level 5, and 8 patients in arm B with high-grade myeloid malignancies up to dose level 3. We demonstrated potent upregulation of P53 pathway biomarkers and signs of antitumor activity in multiple tumor types shown to be sensitive in preclinical models, including responses in one of two valuable patients with Merkel cell carcinoma and two of two patients with post-myeloproliferative neoplasm acute myeloid leukemia. at doses that were well-tolerated without the traditional hematological toxicity seen with small molecule inhibitors. Dose escalation in the Phase Ia clinical trial is ongoing, and we expect to complete enrollment in the second half of 2024, and subsequently to share the Phase Ia data set and guidance on next steps. Separately, we expect to present our biomarker-based patient selection strategy for the next phase of KT253 development at a medical meeting later this year. In June, we provided a clinical update on our STAT-3 program at the European Hematology Association annual meeting. KT333 is a potent, highly selective degrader of STAT-3 and the first heterobi-functional degrader against a historically undrugged transcription factor to enter the clinic. The poster provided a clinical update as of June 3rd from 47 patients enrolled through seven dose levels with a mean of 9.1 doses. We are encouraged by the data generated to date, showing strong target knockdown in blood and tumor, induction of interfering gamma response in blood and tumor, and signs of preliminary clinical efficacy in lymphomas at tolerated doses. Preclinically, we've seen robust single-agent activity in T and NK cell lymphomas, as well as a strong genetic rationale for why stat-free targeting should be active in Hodgkin's lymphoma. This is translated well in the clinic in terms of the antitumor responses we have seen in Hodgkin's lymphoma CT, CL, and NK cell lymphoma. We believe the emerging data in Hodgkin's lymphoma patients is particularly intriguing with complete responses in two of three heavily pretreated patients who had progressed after prior checkpoint inhibitor therapy and anti-CD30 ADC, enabling subsequent potentially curative stem cell transplants. Because we did not see strong signals of preclinical activity as a single agent in solid tumors, it's not been surprising that we have observed only stable disease in a handful of solid tumor patients enrolled into the trial. However, we have seen activity in syngeneic mouse solid tumor models in combination with anti-PD-1 drugs. This is likely driven by STAT3's immunomodulatory mechanism, which we believe provides an opportunity for combination with anti-PD-1 in both solid tumor and Hodgkin's lymphoma patients. Given the activity we've observed in Hodgkin's lymphoma, which includes the two aforementioned complete responses, we are focused on enrollment of additional Hodgkin's lymphoma patients to further explore the very encouraging activity we've seen there. We believe there is also an opportunity for future expansion into solid tumors in combination with anti-PD-1 and other targeted therapies. We expect to complete enrollment of this study and share data in the second half of 2024. We look forward to keeping you updated on all our preclinical and clinical programs. Before we take questions, I'll hand the discussion to Bruce to review our second quarter financial results. Thank you, Jared. As I review our second quarter 2024 financial highlights, please reference the tables found in today's press release. Revenue in the second quarter of 2024 was $25.7 million. All of that was attributable to our Sanofi collaboration. With respect to operating expenses, R&D for the quarter was $59.2 million. Of that, approximately $7.3 million represented non-cash stock-based compensation. The adjusted cash R&D spend of $51.9 million, which excludes that stock-based comp, reflects a 22% increase from the comparable amount in the first quarter of 2024. On the G&A side, our spending for the quarter was $17.4 million, of which $7.1 million was non-cash stock-based comps. The adjusted cash G&A spent of $10.3 million, again, excluding stock-based comp, reflects a 21% increase from the comparable amount in the prior sequential quarter. Finishing up with our cash balance at the end of the quarter was $702 million. Our cash balance is expected to ride a runway into the first half of 2027 and will enable us to execute on multiple data readouts, including oncology proof-of-concept results in 2024 and KTE 474 Phase 2 data, and several clinical inflection points for our STAT 6 and TIC-2 programs expected in 2025. This concludes our prepared remarks, and we would be happy to now address any questions you may have. Operator?
spk08: We will now begin the question and answer session. To ask a question, you may press star then 1 on your telephone keypad. If you are using a speakerphone, please pick up your hands up 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 two. At this time, we will pause momentarily to assemble our roster.
spk07: Our first question comes from Eric Joseph with JP Morgan.
spk08: Please go ahead.
spk03: Oh, hi, good morning. Thanks for taking the question. Just wondering if you could elaborate a little bit further on the type of data you and Sanofi were able to review as part of their decision to expand the phase two program. I'm wondering whether safety, whether it was just based on safety or whether there was an efficacy component or some surrogate thereof. And I know that there's some moving parts to work through here, but I guess you have a loose sense of when there could be, when we might see data from the phase two trial, um, after it's expanded and whether there might be interim readouts within. Thanks.
spk15: Yes, thanks for the question, Eric. So there was an interim analysis of both safety and efficacy, as we said. And as we said, the companies, both Sanofi and Camaro, had access to the blinded data There was IDMC that had access to both blinded and unblinded data. I can't speak to, again, the content of the review or the questions that were asked, but obviously what we should conclude from this update that we provided a few weeks ago and now we're obviously highlighting again is that the review of the data was supportive of further investment into the program. Don't forget that this is... one of the few programs in the pipeline where Sanofi is running multiple phase 2 studies in parallel without having previously run a proof-of-concept study in a placebo-controlled manner. So it speaks, again, I think, to the level of enthusiasm that we both have for this program. With regards to timelines, we hopefully will be able to see an update on clinicaltribe.gov in the upcoming months. and that will include also expected completion dates. And at that time, we should be able, we will be able to comment on the timelines. As we said, Jared said earlier, it's going to be beyond the first half of 25 that was initially guided to, but at this point, we're not able to provide more accurate guidance.
spk03: Okay, great. Thanks for taking the question, and I'll hop back in queue.
spk18: Thanks.
spk07: Our next question comes from Jeff Jones with Oppenheimer.
spk08: Please go ahead.
spk04: Good morning, guys, and thanks for taking the question. Just a quick one on the R&D and G&A trends, obviously picked up significantly from the prior quarter with the extensive work you have going on. Just how should we think about the trends there And then in follow-up as well on the jump in collaboration revenues from Sanofi, how should we think about that moving forward? Thank you.
spk05: Yeah, sure. This is Bruce. Jeff, thanks for the call. So in terms of the trends, there's nothing unusual there in terms of the growth quarter of a quarter versus what we had expected. As the year progresses, as obviously we get closer to the start of the studies for STAT6, you know, you'll see that come through in the R&D line. G&A is just, you know, modest growth in the organization. You know, we haven't guided towards annual burn, typically don't, but, you know, last I looked at this read, they're generally in the right ballpark. But definitely for this year, a little more back-end loaded than front-end loaded. And that's typically how our years have gone and representative of what you'll see this year. In terms of the revenue, there was just a catch-up in revenue related to the Santa Fe Alliance. All the revenue is a result of that. So that resulted in a higher level this year. this quarter, but I think it will be a little unusually high vis-a-vis the rest of the year. And you can do some calculations based on the deferred revenue balances on our balance sheet for how it might look over the coming year or so. So hopefully that helps a little bit. Happy to take more offline as well if you'd like.
spk04: Appreciate that, Bruce. I'll jump back in here.
spk08: Our next question comes from Kelly Shee with Jefferies. Please go ahead.
spk09: Congrats on the progress, and thank you for taking my questions. Maybe I'll start a sixth program. Based on the multiple preclinical studies you have presented findings with, could you comment on more specific plans for the phase one? Would it be like a single indication or multiple indications, or the decision has been made on the discoveries from preclinical studies? Which one to prioritize? Thank you.
spk15: Yeah, thanks. Maybe I'll let Jared comment on the Phase 1 plans. We haven't described the details of our plans before the Healthy Volunteers. I think maybe just to remind, the update that we're giving today on the program is really on the fact that we were able actually to accelerate our path to Phase 1, and we're able to conclude and complete our IND enabling studies. We are on track, if not earlier, compared to what we had said to start the Phase I study. Maybe, Jared, you can provide some high-level description of our Healthy Volunteer Study.
spk05: Yes, so the Phase I Healthy Volunteer Study, being in Healthy Volunteers, we expect to be able to move through it quickly. It will be a traditional single ascending dose and multiple ascending dose Phase I study. The MAD portion will consist of 14 daily doses. Within that study, as we did for the IRAC IV Phase I study, We'll have a number of different pharmacodynamic measures, which will be critical to that study in addition to looking at safety. And those measures will include looking at, you know, STAT6, for example, in blood and skin. And also, importantly, we'll have an opportunity to look at several different Th2 biomarkers in the circulation, in particular, to be able to look at IgE and TARC, you know, giving us an opportunity to show impact on the biology of the IL-4, IL-13 pathway, even in healthy volunteers.
spk07: Thank you.
spk08: Our next question comes from Vikram Perot with Morgan Stanley. Please go ahead.
spk14: Hi, good morning. Thank you for taking our questions. We had two on the INI pipeline. First on 474, just wanted to get your latest thoughts on when we could learn more from yourself and Sanofi on indication expansion beyond HS and AD and what might be flowing into those decisions. And then secondly for the TIC-2 program. Just wanted to see how you're thinking about indication selection. How broad do you think the development program could be, and what will you be looking for in the initial Phase I data to help make those decisions? Thanks.
spk15: Yeah, thanks, Vikram. So on 474, as we said in the past, we believe this pathway has relevance in a broad variety of diseases. Our initial foray is in skin and derm, so with HS and AD, you know, again, based on pathway agents with existing proof of concept, you know, we expect this pathway and this target to be relevant in respiratory, in both asthma and COPD, in GI inflammation, IBD, as well as traditional, let's say, rheumatology, both RA and lupus. So the opportunities are vast. As we've communicated in the past, there is a process that has been ongoing within the collaboration to prioritize a series of indications that the team has done. Again, I cannot speak for Sanofi, who will have the final decision-making on this, but all I can say is that the recent update and what we have seen, I think, continues to support the enthusiasm around the program. the potential eventual expansion. I'll leave it to Sanofi to speak to the timing of that, but I will say that at least we're getting closer to hopefully that decision. With regard to TIK2, again, as Jared said earlier, this program is really for us an opportunity to provide an oral molecule with biologics-like profile and actually unique biologics-like profile. If you think about you know, this pathway is involved in I23L12 and type 1 interferon, and being able to block those three pathways fully with a single oral small molecule should provide highly differentiated profile. So there's lots of potential diseases that one could go after. The ones that, you know, others have gone after, psoriasis, psoriatic arthritis, IBD, lupus, obviously are up there. There are potentially others that could be interesting. I think our goal will be in phase one study to demonstrate that our mechanism of action is able to show a full blockade of these pathways, unlike any other agents that has been tested so far. And then our plan would be to do a proof of concept in an indication that will actually demonstrate that differentiated profile. But we'll speak with more details about that once we're closer to our phase one study.
spk14: Understood. Thanks for the context.
spk08: Our next question comes from Brad Canino with Stiefel. Please go ahead.
spk02: Thank you. Two for me. First, and Nellie just talked about this a little bit, but given the recent external news, can you discuss the confidence of TIK2 as a tractable target for IBD? And then second, maybe a bit of a strategy question, but years ago before this named pipeline really evolved to the shape it is today, I mean, you naturally highlighted a lot of the discovery efforts at Chimera. And I just want to pull back and ask, how would you characterize the degree of discovery efforts now? What are some of the areas of focus, and how do you maintain that while also asking a lot of questions individually and collectively across the clinical pipeline today? Thank you. Thank you.
spk15: Jared, do you want to take the first question? I'll take the second one.
spk05: Sure. Yeah, in terms of your question around, you know, our approach to starting in TIK2 and our expectations for activity in IBD, You know, I mean, there have been some challenges with the TIK2 small molecule inhibitors to show activity in IBD. You know, with Ducra, for example, part of that might be due to the fact that while it's hitting, say, IL-12, IL-23, because it's also not selective just for TIK2, it's also hitting JAK. It's also probably affecting IL-10, which can be a real problem in IBD, because if you block IL-10, you're going to interfere with mucosal healing, which is going to be an important component of any sort of therapeutic where you don't interfere with that. So we think one of the real advantages of our picture degrader is that we can maximally block the key inflammatory pathways, IL-12, IL-23, and type 1 interferon, while at the same time completely sparing IL-10 signaling. And we think that that will be a distinct advantage for our approach in this disease, and that's why we anticipate being able to show activity in IBD as well as in the other indications that Nello was discussing earlier, including the durum indications like psoriasis and room indications like lupus.
spk15: Yeah, and just maybe to add a small statement on the recent data, I think it's important to look at the profile of the molecules tested and their activity at blocking the relevant pathways. And so it's difficult, as you know well, Brad, to compare or to use the other trials as a testament to the value of that biology in that particular disease, you know, without taking into the context of the actual molecule profile. With regards to the discovery efforts, I think one thing that we've been consistent with at Chimera has been the focus on pathways that have high degree of validation and within those pathways going after targets that have not been drugged or drugged well. And I think if you look at the type of targets that we've gone after, what really rises to the top are two main classes, transcription factors, and we have, you know, STAT3 and STAT6 as an example, or scaffolding protein, IRAC4, TIK2. And I believe that the general philosophy will continue to be the same. As we mentioned early in the year, we have increased substantially our effort in immunology. Again, we've talked about STAT6 with an amazing profile so far. We've talked about TIK2 with great potential. We've talked about IREC4 for years now. You'll hear about new programs, hopefully as early as as next year, again, in the context of, you know, difficult to drug or impossible to drug targets with other modalities within, you know, the same immunology landscape. I think our goal and our vision and I have the highest degree of confidence where I sit today is that we will have the best in industry oral immunology pipeline if we don't already have that. And I think that's what, you know, the world should expect for us. in the next few months and years.
spk18: Next question.
spk08: Our next question comes from Mark Brown with TD Cohen. Please go ahead.
spk12: Thanks for taking my questions. Maybe one quick one on oncology, just the 253 update. Can you clarify if the data presentation this year just the biomarker approach, or should we also expect the kind of full clinical update this year to happen this year, or is that going to be a next year event? And then maybe a broader question kind of on the INI portfolio and just kind of Chimera's approach. Do you view the oral convenience of your molecules as, you know, so important that it's acceptable to develop molecules? tools that end up having clinical profiles are maybe not quite as good as the leading injectables? Or is the idea here that you really have to show every bit as much efficacy, if not more, than anything that's out there?
spk15: So on your first question, what we've said is, you know, we've been talking for a while about our commitment to share a biomarker-based strategy for, you know, forward-looking recruitment strategy for 253 and MDM2 based on sensitive biomarker. And so we will hopefully be able to share that this year at a medical meeting. What we said about our, you know, clinical data is, our plan or our expectations are that we should be able to complete those escalations this year. As you know, that doesn't depend only on us, but it depends on but also the safety profile of our drug and how many doses would be required to reach MTD. As you've seen for STAT3, we actually ended up escalating probably more than we had anticipated because the safety profile was better than we had anticipated based on our preclinical data. And so for MDM2, again, our desire to share the totality of de-escalation data, and so the reason why we're saying we'll share the data after we complete de-escalation and it all depends on when we complete de-escalation. We expect that we should be able to do that by the end of the year, but it will depend, again, on the safety profile and the timing to reach MTD. The trial is recruiting extremely fast, and so that recruitment of patients is definitely not on critical path. It's really the profile of the drug. With regards to the immunology pipeline, I mean, I think we've said it early in the year, we have selected targets that are able to be superior to equal, actually I should say, or superior at blocking those pathways than upstream biologics. That is actually true for IARC-IV. which should be superior to individual upstream IL-1 biologics, given that it should be able to block the pathway fully. And so, I have a clinical activity of the combined IL-1 family cytokine blockers. It is true for STAT6 and dupilumab. We've shown that we can block the pathway the same way. We'll hopefully also be able to show that in the clinic for TIK2, for the TIK2 program. So I think what we are trying to do, which is unprecedented in the history of immunology development, is to have an oral drug that does not compromise on efficacy. That is our goal. Again, compared to on-pathway biologics. And so again, I think STAT6 is the easiest example to outline. We believe, based on the biology that we have experimented and have shown so far, that we can block the pathway just as well as dupilumab, which is the I4 receptor alpha blocker. And so we expect the clinical profile in terms of pathway blockade that result in clinical activity to be, you know, at least as good as dupilumab. So, you know, I think we've historically had to compromise on efficacy with an oral drug. We are trying to say... here for the past few months that our ambition is that that will not be the case anymore. And that's really that when we say paradigm shift, which is a concept that has been embraced also by the broader community with our programs, it's just about that. It's the ability to actually change how we think about what should patients take as a drug that suffer from these diseases.
spk18: And I think that our programs can change that paradigm. Great. Thank you.
spk08: Our next question comes from Kalpit Patel with B. Riley. Please go ahead.
spk17: Yeah. Hey. Good morning. Thanks for taking the questions. You mentioned the expansion of the IREC-IV trials also includes testing of additional doses. Maybe help us understand the decision-making for that specifically and why more doses need to be tested now. And as a follow-up, if you can share, can you give us any additional color if the new doses are outside of the 50 to 200 milligram daily dose range?
spk15: Thank you. Yeah, great question, Khalid. So as you know, in order to initiate a phase three, registration of phase three study, it is expected from a sponsor to have a degree of dose ranging to establish the relationship between efficacy and safety. And so if you looked at the existing, let's use HS phase two study that is actually still now on clinicaltrials.gov, that actually had one dose and one placebo. It would have been extremely difficult, if not impossible, to go from that type of study into a phase three registrational study without exploring multiple doses. So that's what's driving the addition of other doses is the acceleration of getting into, after this study, into a phase three study. With regards to the type of doses, again, we're not in liberty to actually comment. I would also point to that actually in Europe, actually the doses are are revealed much sooner than in the U.S. So, you know, if you do some investigative work, it's not that hard to figure out what the existing dose versus the new doses will be. But maybe I'll stop here. What I will say is that the doses will be within the range that you said. Unfortunately, I can't comment more on where they will be.
spk18: Okay. Great. Thank you.
spk08: Our next question comes from Michael Schmidt with Guggenheim. Please go ahead.
spk13: Hi, thanks for taking our question. This is Paul, on for Michael. Just following up on a prior question on STAT6, can you talk about how we should interpret that early biomarker data coming out of the Healthy Volunteers next year? For instance, is there a certain threshold of serum IgE or TARC reduction that you're hoping to see, or is any directional and dose-dependent reduction sufficient to give you confidence in that program? And then just as a follow-up, is the goal here just to establish proof of concept, or could the PD data actually guide your thinking on target indication prioritization? Thank you.
spk15: Yeah, no, great question, Paul. So let me start with, so obviously we built a really robust preclinical package, right? We've shown in vitro, first that we degrade this target fully with picomolar concentrations in all relevant cell types. When I say relevant, I mean cell types, human cell types that are relevant to all these Th2 diseases, whether it's respiratory, derm, GI. We've shown that if you look at pathway inhibition, so IL-413 biology downstream of the receptor, we're able to block that pathway actually more potently than dupilumab. If we go in vivo, we've shown either in a in a topic term model, or more translationally, in the asthma model, that's a 30-day HDM model, we've shown that with 90% degradation of STAT6, we have an ability to block a plethora of CTH2 biomarker, as well as disease endpoints, either equally or better than the PIXN. So we've shown preclinically in terms of pharmacology, that this drug behaves like a very, very robust, probably best-in-class pathway inhibitor. We've also shown the safety profile to be, so far, absolutely pristine, which we talked about early in the year, in January, that we hadn't seen any adverse events in our non-GLP talks, today we're seeing as an update that even going through GLP talks, we haven't seen any adverse events in any doses that we've tested. So also the safety profile is quite compelling. So the goal of the phase one study is to demonstrate that everything that we've done so far in preclinical species, or at least most of the things that we've done in preclinical species, replicated humans. And importantly, the PK that leads to a dose-dependent and robust degradation in blood and skin. And then we're using the biomarker that depicts it as modulated to just confirm, to be honest, it's totally expected. but confirm in humans that blocking STAT6 will lead to downstream biomarker changes, which, again, we've shown extensively in all sorts of preclinical models. If you look at the data that the pictures have shown, and I encourage everybody to kind of study that so they were aligned on expectation, you've seen that with DUPI you can reduce TARC and also IgE in 28 days. And so if you look at that data, somewhere between 20 and 40 percent, depending on the biomarker that you use, again, it shows that there is a pathway in addition even in healthy volunteers that don't have ongoing inflammation. And so it's a confirmation of target engagement. I don't believe we will use that data for any decision-making with regards to indication, given that those are, again, qualitative biomarker in a healthy volunteer population. Our goal will be to go in patients soon thereafter to establish a more robust both proof of mechanism and proof of concept.
spk08: Our next question comes from Ellie Merle with UBS. Please go ahead.
spk06: Hi, this is Jasmine on for Ellie. Thanks so much for taking our question. We have two on oncology. So for stop three, could you give a little more color and talk about your view on the potential opportunity in Hodgkin's lymphoma? And then secondly, on your MDM2 strategy, specifically in solid tumors, are we going to hear an update on this when you give your biomarker patient selection update this year? And just based on the mechanism of action, what can you say about what you see as the most applicable set of solid tumors?
spk18: Thank you.
spk05: Yeah, maybe starting with your question on STAT3 and Hodgkin's, we've reported that we've seen complete responses in Hodgkin's lymphoma in patients who have then gone on to hopefully curative transplants. So that, you know, very encouraging data in Hodgkin's is consistent with what is known about the genetics of Hodgkin's disease where there's amplification of PD-L1 as well as JAK amplification, both of which, you know, would render those tumors potentially responsive to stat-free targeting. So as we've guided previously, you know, with the phase one study, we've now completed dose escalation and enrollment now is really focused on enrolling additional Hodgkin's patients. We see there being several different development opportunities for the drug, and we continue to see the sort of activity that we've seen to date. Those include opportunities for the drug as a monotherapy in third line and beyond, so for patients who have had prior anti-PD-1 drugs or prior anti-CD30 ADCs, and also a potential opportunity upline and second line in combination with anti-PD-1 So I think it'll be very interesting in terms of what we see for the remainder of the study this year. We plan on reporting data later this year once we've completed enrollment of those additional Hodgkin's patients that can provide, you know, both efficacy and safety update at that time. With regard to MDM2 and patient selection, I think Nella referred to this earlier, you know, we have had an ongoing extensive effort pre-clinically to identify different solid tumor types that are specifically sensitive to the greater mechanism of action. And we've been in the process of developing a biomarker signature of sensitivity using various, you know, solid tumor models. And our plan, you know, is to present later this year at a medical meeting an update so that people can see sort of what those preclinical data are showing and how those are potentially guiding how we plan to further enrich for certain solid tumor types for the MDM2 degraded program. So stay tuned for that presentation hopefully later this year where we can provide more details on what that biomarker strategy is going to look like.
spk07: Great, thank you. Our next question comes from Andy Chen with Wolf Research.
spk08: Please go ahead.
spk11: Hey, this is Brendan for Andy. Congrats on the progress thus far. Would you mind, can you please discuss some of the challenges in creating the STAT6 to greater? What were the hurdles you were first developing it? And if another to greater company puts their mind to it, how quickly could they discover or go from discovery stage to IND and how difficult would that process be?
spk15: Great question. So first I would say that StatFix has been a target that has been on the priority list of the biopharma industry that I can at least remember for the past 10 years since the early proof of concept of to pilumab and this pathway relevance to TH2 inflammation. And I believe that most pharma companies have had an effort in this space. We have spent years working on this program. We're not going to talk about details. At some point, we will. And the depth and breadth of work that we've done in STAT6 and our ambition to own this target completely from all points of view of pharmacological blockade of SAD6, you know, I think it's what's fundamentally driving all the effort that we've had so far. This is one of the best molecules we've made at Chimera in the past eight years, and I think it's going to be difficult to compete both timing and quality with Canera given everything that we've shown so far, but I can't speak to what it will take others. I don't know the capabilities that other companies have. I know that there is nobody, there is no company that is, you know, clinical stage or almost clinical stage as we are. And I haven't seen any data from any other company. So it's hard for me to comment on the competition.
spk08: Our next question comes from Kripa Devakonda with Truist. Please go ahead.
spk10: Hey guys, thank you so much for taking my question. Just following up on the previous question regarding Static's Degrader, one of your peers is developing, it's not like you said, Nello, it's not anywhere close to the clinic, but they're developing a Static's Degrader in collaboration with Sanopi. So from a big point of perspective, obviously they're trying to cast a wide net, but what Can you help us understand how Sanofi's collaboration can develop, potentially develop a static de-grader might or might not impact your collaboration for IRAC4 de-grader? Do you think there could be any overlap? And then just a clarification on the KT for STEM4 dose expansion that you announced. You're adding more patients, you know, expanding the doses. It seems like, you know, you've talked about there being an acceleration towards phase three study. Can you just clarify whether this has been discussed with the FDA already? Thank you.
spk15: Yeah, so thanks for the question. So in the first one, you know, we, Chimera and Sanofi have obviously different goals and different strategies to accomplish their goals. And we come together around IREC-IV. But, you know, everything else that we do as independent companies is, you know, obviously independent of each other. We know, obviously, we're aware that Sanofi is highly interested in Stat6. In fact, Sanofi is our only competitor in the Stat6 world. You know, they have licensed all the Stat6 agents that are available out there, even if ours isn't. And so that, I think, you know, from one point of view, if we need it, personally, I don't think we do, but validates how important this target is and how valuable this target is for any company, again, given that Sanofi has had two collaborations with two modalities for the same target, right? A small molecule inhibitor and a degrader. But we have a very strong relationship. We... We have an amazing team that works on 474 on both ends, and we don't believe, don't expect that our, let's say, our Stat6 competition will have any impact on 474. With regards to the doses that you've asked about, So the goal for the expansion, as we said, is in order to accelerate entry into a registrational study. And I think the, I don't know if the, what was the specific question? Ah, yeah. So with regards to, yeah, thank you, Jared. With regards to the FDA, I can't comment on that. Obviously, whenever there is a protocol amendment, there is a process, but given that Sanofi is the official sponsor, they're in charge of that particular path.
spk10: Great, thank you.
spk08: Our next question comes from Chris Shibutani with Goldman Sachs. Please go ahead.
spk16: Great, thank you very much. Many questions have been asked, perhaps two on the bigger picture side. One, thinking about additional immunology indications from your R&D day that started the year you had a slide that included, you know, the end market opportunities being very vast in some of the traditional indications like MS and rheumatoid arthritis. It would seem that there's a lot of existing therapies, combinations tend to be the playbook, and the industry is also looking to figure out how to better identify patients, patient selection strategies. And my questions are twofold. One is, How are you feeling about the potential to expand into CNS-type indications, noting that degraders are small molecules but larger? And number two, how are you starting to thread in patient selection strategies in terms of thinking about how you can enhance probabilities of success? I know that Santa Fe is in control of the advanced clinical development, but is there any scientific work, biomarker data that is helping inform what you think might be a way to chisel out a better sort of patient population to study to enhance your success there. Thanks.
spk15: Yeah, no, thanks, Chris. So, I mean, this is front and center of what we do here at Chimera. I think our work with STAT6 and the ability to select patients with Th2 inflammation, that in a way, although it's obviously something that comes with the mechanism, it's one of the few examples of targeted therapy in immunology. As you know, the example with Dupixen in eosinophilic asthma and COPD are just an example of how you can actually now prospectively select patients for these populations. I'll address one more, and then I'll let Jared comment also on what we do in terms of patient selection. But on the brain, on the CNS, I think we and others, I would say, have demonstrated extensively that degraders can access the CNS compartment. We have internal examples, several internal examples that we've shown that preclinically. So I don't, we, the choice of going into CNS indications would be driven by the mechanism, the opportunity, the, again, the unmet need and less by the capability or the ability of the technology. Jared, do you want to comment a bit generally on target selection?
spk05: Maybe in terms of on the patient selection sort of question, and this applies to IRAC4 and to STAT6 and I think to TIK2 as well, I think it's a very important question, but I think it's also important to emphasize that our expectations regarding the activity of these oral degraders is that we should not have to narrow the patient population up front in order to be competitive. If we are as active as upstream biologics, we believe that these drugs could be approved and used up front for very broad populations of patients across the very large indications for STAT6 and IRAC4 and TIK2. With that being said, we are building in to our studies. We did this with IRAC4, and certainly we're doing this with STAT6 and TIK2, extensive pharmacodynamic assays in Phase I and Phase II that include proteomics and transcriptomics on blood, and also, for example, on skin lesions, you know, for patients with skin diseases when they come onto our study, whether it be AD for STAT6 or psoriasis potentially for TIK2, that will allow us to retrospectively look at these various proteomic and transcriptomic profiles to then help us understand whether there are, you know, patient subsets that might be benefiting even to a greater extent than the broader population, and that might be important in helping us differentiate from other therapeutics.
spk07: This concludes our question and answer session.
spk08: I would like to turn the conference back over to Nello Manofoli for any closing remarks.
spk15: Thank you. So I just want to thank everybody. Actually, we made it almost to 9.30. So maybe just to highlight the key news of today, one which we had shared, you know, a few weeks ago on the expansion of the 474 Phase II program, Zimbote, HS, and AD were very excited and thankful to Sanofi for their increased investment and confidence in the program. And then more recently, the news of today was We're really, really close to initiating our phase one study with KT621 and especially showing that we've completed all the IND-enabled studies with great safety profile. And so we're really excited about updating you all next time on our progress towards our first inhuman dose that should happen soon. So thanks again.
spk18: We're available with any follow-ups today.
spk07: The conference is now concluded. Thank you for attending today's presentation. You may now disconnect.
Disclaimer