Kymera Therapeutics, Inc.

Hello, and welcome to the Chimera Therapeutics second quarter 2023 quarterly results call. I'd now like to turn the call over to Bruce Jacobs.

Mr. Jacobs, 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 Minalti, Founder, President, and CEO, Jared Gold, our Chief Medical Officer, and I'm also excited to welcome Justine Konigsberg, Chimera's new Head of Investor Relations, to her first Chimera Quarterly Call. After our prepared remarks, we'll open the call to your questions, as we always do, and 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 obligations to update such statements except as required by law. With that said, I'll now hand the call over to Nello.

Thanks, Bruce, and thank you, everyone, for joining us today. We're excited to review the progress we made over the last quarter and discuss how it contributes to achieving our mission of building a best-in-class, fully integrated global degrader medicines company. Over the past few months, we've shared updates on our clinical oncology pipeline and preclinical work, including multiple presentations at scientific meetings across the world relating to KT253, KT413, and KT333. I will provide an overview of this progress, and Jared will share more details during his remarks. Starting with the most recent addition to our clinical pipeline, we dosed the first patient in the phase one study of our MDM2 degrader, KT253, which addresses a critical and drug mechanism in cancer biology that has been pursued in the biopharma industry for many years. The data we presented at IHA in June showed that 253 has the potential to overcome the inherent limitations of small molecule MDM2 inhibitors against these well-validated targets. In preclinical models of ALL and AML, a single dose of KT253 drove durable tumor regressions and demonstrated differentiated pharmacology compared to a small molecule inhibitor. In June, 253 was also granted orphan drug designation by the FDA for the treatment of AML. This program exemplifies our unique approach of selecting targets with strong genetic validation in pathways where we believe targeted protein degradation offers the best or only option for an effective treatment. And we look forward to investigating it in a variety of cancers and sharing more on this program, including clinical proof of mechanism in patients later this year. With respect to KT413, which targets IRAC4 and IMID substrates, EGROS and ILOS, and KT333, which targets STAT3, both are continuing in the dose escalation stages of their Phase I studies. As a reminder, our focus this year for these programs is to evaluate the degradation and the safety profile of these first-in-class mechanisms and their biological and clinical impact in the appropriate patient populations. We recently shared encouraging data from the trials showing fidelity of PKPD translation from preclinical models to patients. At the ICML meeting in June, we shared data demonstrating that both molecules were approaching or were already at the target degradation levels we believe, based on preclinical models, are sufficient to achieve antitumor activity without any dose-limiting toxicities observed. Later this year, we intend to provide additional data evaluating anti-tumor activity in the target patient populations for these two programs. Our first-in-class ARAC4 degrader, KT474, is in development with our partner Sanofi for the treatment of TLR-IL1R-driven immune inflammatory diseases with higher medical needs, such as hydrothonitis suppurativa, atopic dermatitis, and potentially others. We're very excited about the potential of KT474 for patients with inflammatory diseases who currently lack an effective oral medicines with a good safety profile. And we expect the phase two studies in both HS and AD to initiate in the fourth quarter of 2023. This degrader is designed to block TLR-IL-1R-mediated inflammation more broadly compared to monoclonal antibodies targeting single cytokines and to enable pathway inhibition that is superior to RX4 kinase inhibitors by eliminating both the kinase scaffolding functions of RX4. Jared recently presented the Phase I data from this program at the EADP Symposium in Seville. which demonstrated that 474 administered to HS and AD patients had tolerability PK and PD similar to healthy volunteers, achieved robust IRAC4 degradation in blood and skin associated with the systemic anti-inflammatory effect, and showed promising clinical activity in both HS and AD. In parallel to our clinical programs, we continue to drive the science of targeted protein degradation and identify first- and best-in-class opportunities to transform the treatment of disease. We have several exciting programs in our preclinical pipeline that are designed to address well-validated pathways in areas of significant patient need with multibillion-dollar revenue potential. We look forward to sharing more details on these programs later this year, early next, in an R&D day. Along with our clinical and scientific progress, we work to ensure that we have the people and resources to build a sustainable, fully integrated company. To that end, we recently appointed Dr. Jeremy Chadwick as Chief Operating Officer, who will serve as a key member of our leadership team, help guide the development of our first-in-class programs, and scale our capabilities to support our growth. Jeremy joins us from Takeda, where he held leadership roles in global regulatory affairs, drug safety, global clinical supply chain, and development operations. As Bruce mentioned, we're also very happy to welcome Justine Konigsberg as Vice President and Head of Investor Relations. Justine has spent more than 25 years in the industry, and she'll be engaging with many of you on the call in the upcoming weeks. Let me pause here and turn the call over to Jared, who will now cover in more details recent progress from our clinical oncology programs before turning the call over to Bruce for a financial update.

Thanks, Nello. I'll provide a brief recap of where we stand with our clinical programs and what to expect in the coming months. As Nello mentioned, we have begun dosing patients in the Phase I multicenter open-label dose escalation clinical trial in evaluating our investigational MDM2 degrader, KT253, and recruitment in the trial is going well. MDM2 is the crucial regulator of the most common tumor suppressor, P53. P53 remains intact or wild-type in close to 50% of cancers, meaning that it retains its ability to modulate cancer cell growth. We believe 253 has the potential to be a highly potent degrader that, unlike small molecule inhibitors, has been shown preclinically to have the ability to overcome the MDM2 feedback loop and rapidly induce apoptosis, even with brief exposures. 253 has the potential to be effective in a wide range of hematological malignancies in solid tumors with functioning p53. We've shown preclinically that 253 has superior activity compared to MDM2 small molecule inhibitors and demonstrated greater than 200-fold improvements in both in vitro cell growth, inhibition, and apoptosis. And additionally, we presented data at EHA in June demonstrating that a single high dose of 253 administered intravenously in preclinical models of AML and ALL led to greater than 90% MDM2 degradation in tumors within one hour of dosing, strong P53 upregulation and induction of apoptosis within the first 8 to 24 hours, and sustained tumor regressions. In contrast, lower doses of 253 administered more frequently or repeat dosing with an oral MDM2 small molecule inhibitor led only to relatively weak p33 activation and apoptosis induction and modest tumor growth inhibition. These preclinical results suggest that a pulse IV dosing regimen of 253 has the potential for an improved efficacy and safety profile over MDM2 small molecule inhibitors currently in the clinic. The Phase 1 trial is evaluating the safety, tolerability, PKPD, and clinical activity in patients with relapsed or refractory high-grade myeloid malignancies, ALL, lymphomas, and solid tumors. Patients in the Phase 1A dose escalation study are receiving IV doses of 253 administered once every three weeks. The open-label study is intended to identify the recommended Phase 2 dose and is comprised of two arms with ascending doses of 253 in each arm. Arm A consists of patients with lymphomas and advanced solid tumors, and arm B consists of patients with high-grade myeloid malignancies and ALL. Dosing in arm B will start once a pharmacologically active dose has been reached in arm A, at which time dose escalation will proceed in parallel across both arms and continue until the maximum tolerated dose is established for each arm. We plan to share initial safety and proof of mechanism data for the phase one clinical trial later this year. Now, turning to our other two ongoing oncology trials. STAT3 is a transcriptional regulator that has been linked to numerous cancers as well as to inflammatory and autoimmune diseases. KT333 is being developed for the treatment of STAT3-dependent hematological malignancies and solid tumors. The Phase I clinical trial of 333 is designed to evaluate the safety, tolerability, PKPD, and clinical activity of 333 dose weekly in adult patients with relapsed and or refractory lymphomas, leukemias, and solid tumors. In June, at ICML, with a data cutoff date of May 1st, 2023, Chimera shared that 13 patients received a mean of five doses across the first four dose levels of the trial, including patients with solid tumors as well as CTCL and PDCL. While the fourth dose level was still open for accrual at that time, data reported from DL1 through 3 found plasma exposure increased with dose, reaching levels close to those predicted to be efficacious, and demonstrated dose-dependent STAT3 degradation with up to 88% mean maximum reduction in peripheral blood mononuclear cells. with evidence of stat-free pathway inhibition and down-regulation of inflammatory biomarkers in peripheral blood. Degradation profiles at DL3 were near levels of knockdown that led to anti-tumor activity in preclinical models. We shared at ICML that there were no dose-limiting toxicities observed in the study. The Phase I dose escalation stage is ongoing, recruiting broadly across solid and liquid tumors. KT413 is a novel, hetero-bifunctional degrader that targets degradation of both IREC4 and the image substrate iclozomylose. 413 was designed to address both the IL-1R TLR and the type 1 interferon pathway synergistically to broaden activity against mighty 88 mutant B-cell malignancies. The phase 1 clinical trial is designed to evaluate the safety, tolerability, PKPD, and clinical activity of 413 administered as an IV infusion once every three weeks to adult patients with relapsed and or refractory B-cell non-Hodgkin's lymphomas. In conjunction with the ICML meeting, we shared that as of June 1st, the first three dose levels had been completed and the fourth was accruing patients. At that point, five patients were treated across DL1 through 4 and received a mean of 2.2 doses. including patients with transformed activated B-cell-like diffuse large B-cell lymphoma, follicular lymphoma, marginal zone lymphoma, and plasmablastic lymphoma, all of whom were MITEI 88 wild type, except for one who had a MITEI 88 gain-of-function mutation. Data reported across DL1 through 4 showed plasma exposure increased with dose, reaching levels close to those predicted to be efficacious. 413 achieved dose-dependent degradation of up to 70% IRAC4, and 96% to 100% Icarus and Ilos in peripheral blood mononuclear cells after a single dose. Degradation profiles at DL3 to 4 were consistent with knockdown levels associated with antitumor activity and preclinical models of MyD88 mutant lymphomas. We showed at ICML that there were no dose-limiting toxicities or drug-related neutropenia observed in the study. The Phase I dose escalation portion of the trial is ongoing, recruiting a broad population of B-cell lymphoma patients. We look forward to sharing data evaluating the anti-tumor activity of KT333 and KT413 in their respective target patient populations later this year. Finally, the KT474 Phase II studies in both HS and AD, which are being advanced by Sanofi, are expected to commence in 4Q23, first in HS and followed shortly thereafter in AD. We will share more details around the trials as we approach the dosing of the first patients. I will now hand the call to Bruce, who will share some brief comments on our financial results for the second quarter.

Thanks, Jared. I will quickly cover the financials before turning the call back to Nello for some concluding remarks. For the quarter, we recognized $16.5 million of collaboration revenue, and at the end of the quarter, our deferred revenue total on the balance sheet was approximately $45 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 $45.8 million. Of that, approximately $5.7 million represented non-cash stock-based compensation. The adjusted cash R&D spend of $40.1 million, which excludes that stock-based comp, reflects a 7% increase from the comparable amount in the first quarter of 2023. On the G&A side, our spending for the quarter was $14.1 million, of which $5.5 million represented non-cash stock-based comp, The adjusted cash G&A spend of $8.6 million, again, excluding stock-based compensation, reflects a 9% increase from the comparable amount in the first quarter of 2023. We exited the first quarter with a cash and equivalence balance of approximately $472 million. As we shared earlier in the year, we believe that our cash runway extends into the second half of 2025 and projection that includes milestones only related to the start of the first two Phase II trials for KT474, both of which we stated today are expected to occur in 2023. I'll now turn the call back to Noah. Thanks, Bruce.

As said, we're very excited to be soon in Phase II with KT474 in two indications, as well as by the progress we've made on our oncology clinical program. Our rapid progress in building our pipeline, generating clinical momentum, and advancing the science of TPD gives us confidence that Chimera will be able to capitalize on the untapped potential of this powerful modality to enhance the treatment of disease and improving patients' lives. We look forward to sharing exciting updates on our clinical programs, platform, and company in the second half of the year. I will now hand the microphone to the operator so 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 anytime you would like to withdraw from the queue, please press star 1. Please also be reminded that you may only ask one question and one follow-up question. That being said, we will now take a moment to review our queue.

Thank you for waiting.

Your first question comes from the line of Mark Fram from TD Catlin. Sir, your line is open.

Thanks for taking my questions. Let me start off with KT333. Monotherapy clinical responses are expected to be only relevant for maybe a fraction of the opportunity, and that segment is a bit of a different hypothesis than the rest of the population. Can you work through how you plan to approach dose selection as you get this larger data set later this year?

Thanks, Mark. So maybe I'll just take the first part of the question, and then I'll pass it to Jared. So just to remind everybody, so our SAT-3 program, which encompasses a liquid tumor opportunity, a solid tumor opportunity, and opportunities outside of of oncology has started with our first clinical endeavor with KT333. So obviously it's a broader opportunity across several potential indications. And we have clear hypotheses that we're pursuing in the clinic. The first one, which is in our mind the earliest one that could lead to proof of concept is single-agent activity in a subset of T-cell lymphoma leukemias that we've discussed in the past, PTCL, CTCL, LGL leukemias, which obviously also have subsets. The reason why we have focused on those indications as single-agent opportunities is because we've seen preclinically that when we dose our degrader, KT333, once a week or even once every two weeks, we're able to achieve profound antitumor effects. And we can actually rationalize it translationally by the fact that many patients in those particular subsets have either STAT3 mutation or pathway activation. So we have a biomarker activity as well as biomarker sensitivity in those opportunities. The phase one dose escalation includes those particular subtypes as well as solid tumors. As I've said in the past, we've said in the past, in solid tumors, the opportunity are based on our preclinical data in combination. We've talked about combination with immune therapy. We've mentioned combination with targeted agents that we haven't discussed externally yet. And so now circling back to your question, just so that it's all clear, so in terms of single agent activity, in terms of responses, anti-tumor activity that we expect to be able to talk about later in the year will come from a subset of patients from this phase one dose escalation. And we've said in the past a handful of patients that might include CTCL, PTCL, LGL. With regards to how we think about selecting, I assume you meant the phase two dose. Maybe I'll let Jared comment on that.

Sure. So, Mark, we've always sort of stated that our dose selection will be based on a combination of PD and safety. We've looked at our preclinical data, especially in these stat-free dependent T-cell malignancies where we found that, you know, 90% or greater, you know, knockdown of stat-free for 48 to 72 hours is associated with anti-tumor activity. So our aim is to be able to, you know, get to a dose that gives us at least that sort of a profile, you know, 90% or greater knockdown, you know, in peripheral blood and or in tumor where we can get tumor biopsies that's lasting 48 to 72 hours in that, you know, associated with favorable safety profile. That's the sort of you know, a PD profile that we want to be able to then take into the phase 1B expansion. So our recommended phase 2 dose would likely be a combination of being able to see that level of PD along with safety, you know, if possible, you know, as Nella mentioned, if in a handful of patients, you know, in the target patient population with these stat 3 dependent T cell malignancies, we can see a few responses at those doses that are giving us that sort of PD and safety that would give us even more confidence in bringing that dose into the next phase, which are these phase 1B expansions, which right now are slated to be in these T-cell malignancies like CTCL, PTCL, and LGL, as well as in solid tumors.

Okay, that's very helpful. Maybe a similar type of question, but for MDM2, just you kind of walk through the depth of degradation you want to get and with that postal dosing, but how long do you think you need to be at 90%? What's the minimum there?

I mean, so I'll start this, and then if needed, Jared can add. So the nice thing about the MDM2 program and how we're developing it is really trying to replicate What we've seen in cancer genetics, which is ablation of the gene, in this case MDM2, leads to a rapid and complete reliance on this gene from a wide variety of cancer cells that have p53 wild type. And what we've then observed experimentally, obviously the gene deletion is irreversible. Protein degradation, as we all know, is reversible. So then the question that you're asking is how long do you need to deplete the target to see activity? So what we've seen in our models preclinically, that as as little as four to eight hours of exposure to a degrader that leads to robust degradation is sufficient to drive profound commitment to apoptotic cell death. And so actually, in a way, it you know, as you know, with those once every three weeks, and in white for other programs, that degradation needs to be sustained either for 48 hours or 72 hours. In this particular program, we only need a few hours, single-digit hours, in order to drive the strong apoptotic response.

Thank you.

The next question comes from the line of Brad Panetta from Stifle.

Sir, your line is open. Good morning. For KT333, now that you're getting a handle on the clinical PKPD, should we expect you to open a healthy volunteer study to dial in the STAT3 degradation degree in kinetics that you need based on your I&I models in order to prepare for a potential phase 1, 2 I&I study? Or is this going to be pursued by a separate asset altogether?

Brad, thanks. This is a great question that I'm going to answer high level now, and then hopefully I think when we meet in an R&D day, as I said, most likely late this year, but most likely early next, I think we will cover hopefully with more details that question. But I can say right now that we're evaluating opportunities both for a potential 3-3-3 transition into immunology as well as other particular assets and other formulations. So maybe I'll leave it at that. This is where we're investigating. But I think what we take from this phase one study, which is not to be underestimated, is the really good translation that we've seen not only in PK and PD, which to be honest with this company has been a constant now for multiple programs, but more importantly on safety. So we feel now we're in a place where we can much more comfortably plan outside of oncology clinical study for a first-in-class target that has obviously very broad biological application. So sorry if I can't answer with details, but hopefully this gives you an idea about what we're thinking about.

That's all right. I look forward to that update. Let me also ask on MDM2, when you think about the safety data from the prior small molecule inhibitors, and particularly knowing that your target population is AML, where the blood count recovery is going to be important for those patients, what are you looking to see in terms of platelet impact, thrombocytopenia rates, in this first look to gain confidence in the profile for continued development. Thank you.

Yeah, thanks, Fred. I'll actually let Jared comment specifically on your question, but I do want to take the opportunity to add something to your question, which is, so, you know, our clinical development team has designed, I think, a, you know, I would say elegant, people don't like this word, but I still use it, an elegant plan to evaluate the PKPD safety and activity in both solid tumors, liquid tumors, and these myeloid malignancies. And the idea was to split the AML, ALL type of dose escalation from the other indications because, as you know, and as you mentioned, the context is quite different. And so the plan is right now we're escalating in solid tumor and other liquid tumors and until we feel we've reached a clinically active dose and then enter the AML space only when we're clinically active already so that, you know, the safety does not unnecessarily, or sometimes the more challenging safety assessment doesn't influence the readout on the clinical activity. One other thing that I will say is that the way that these molecules work, which is, as we said, a rapid degradation with the recovery within the first three weeks, should allow us to build a therapeutic index that should allow us to evaluate the clinical activity of MDM2 degradation in MDM2 P53-sensitive tumor types. And as with all the other programs in Chimera's pipeline, we believe we can answer this question in early clinical development, meaning in Phase I or late Phase I clinical investigation. Our ability to build a therapeutic index is really the goal of our Phase I study. If we're able to show that and demonstrate that to ourselves, I think that will hugely de-risk this program and will allow us to be confident in investing, you know, a lot of money to develop this program. And if not, we obviously will be willing to make decisions. And that's what the philosophy is around all of our programs. But, Jared, maybe you can comment specifically on, you know, how we're looking at thrombocytopenia and other – possibly, you know, related events that one might expect from P53 upregulation?

Sure. Well, I think, you know, as you just alluded to, you know, with this hit-and-run approach of dosing once every three weeks, you know, and based on our GLP-TOX data, our expectation is that, you know, our sort of depth of myelosuppression and or the duration of myelosuppression, you know, will be less than what is seen with the small molecule MDM2 inhibitors, which, as Neldo just said, should give us a superior therapeutic index. With that being said, in AML, of course, the tolerability of myelosuppression is much higher. In fact, one does expect to see a certain degree of myelosuppression as you're clearing blasts and having an effect on the bone marrow that usually would then lead to clinical responses, hopefully complete responses. And so that's why we separated out these two arms, the high-grade myeloid malignancies and ALL, separate from the arm looking at solid tumors and lymphomas because there is a different level of tolerability in terms of how clinicians view myelosuppression. And so we may see myelosuppression in AML patients, which would be a good thing because that would be telling us that we're seeing a response to MDM2 inhibition. But again, we do expect the depth and duration of that myelosuppression to be less and to give us a better therapeutic index. And likewise, in solid tumors, we do expect to see less myelosuppression in that particular population, which could allow us more attraction in developing the drug in patients with lymphoma and solid tumors compared to the small molecule inhibitors that have been limited in their dosing by the dose-limiting toxicities of GI tox as well as myelosuppression.

Thank you. Your next question comes from the line of Chris Shibutani from Goldman Sachs. Sir, your line is open.

Great. Thank you very much. Good morning. Two questions. So on KT474, it certainly is sounding reassuring that Sanofi has formally committed, if I understand, the conversation that we've had in June with you guys. It seemed as if AD was a trial that was going to start in 23, perhaps a little bit less clarity and possibly to follow an in HS. Perhaps I've gotten that mixed, but to be clear, I think the update today is that both trials will commence by the end of this year. Is that the case? And then, Bruce, what kind of additional sort of timeline should we think about in terms of milestone payments as this program progresses? And are you guys advancing 474 or any of the other tool compounds through phase one type work potentially to look at additional indications. I know, Nella, you've highlighted mechanistically, biologically rationales to go into other broader categories, RA, lupus, et cetera. Thank you.

Yeah, thanks, Chris. So I'll answer some of these, and I think you had like three, four questions in there that was very elegant. And then I'll let Bruce answer the milestone question. So first one, yeah, just to clarify further, so what we've said for the past nine months since December, seven months, we've said that... Sanofi was going to take over clinical development of KT474, and that there was commitment to initiate at least one phase 2 study in 2023 that was named to be DHS phase 2 study. They did commit also to initiate an AD phase 2 study, but we were not, as collaborators, as collaborations, we did not participate. point to the exact time of phase to start. It was not clear that it would have been in 2023. So what we're updating today was finally that also the phase to start of AD will happen in 2023. So HS will be first and AD will be second. Both of them will start in fourth quarter of 2023. And so we want to thank Sanofi for allowing us to share more details and also to accelerating the initiation of the second Phase II study. With regards to other indications before I let Bruce comment on the milestones, I mean, we as collaborators continue to discuss other opportunities, and I think we both feel, I can probably speak for both, we both feel that there are other opportunities that are both mechanistically and clinically that fit the profile of an Rx4 degrader. We're just not at this moment able to share more details, but rest assured that as things progress, we will be updating on those strategies.

Yeah, and thanks, Chris. This is Bruce. Just to clarify on the milestones, so what we've said in the past is that the first phase two patient dose generate milestones by indication up to a certain number, and we've said at least two and hadn't commented before that. Beyond that, I should say the first two milestones for HS and AD are included in our runway guidance. but no other milestones. And then I think I heard you ask about the additional program or the additional molecules that we might generate targeting IRAC4. That was contemplated in the initial collaboration agreement, and so the work that is ongoing there has potential to generate milestones as well. We just haven't said specifically what those critical events are and the timing, but I think that's something you'll hear updates from us on over time as well.

Right, and you said initial collaboration agreement. There was an update to that collaboration agreement in November of 2022, so that's still contemplated in this most recent active agreement, correct?

Yeah, exactly. When we discussed the amendment, we made the comment at the time that, you know, the aggregate milestones remain unchanged, and that includes with respect to the follow-on, you know, compounds, molecules that may be generated as well. So the aggregate total remains unchanged. Thanks.

Confirmation reassuring progress. Appreciate it.

Thank you. Your next question comes from the line of Michael Schmidt from Guggenheim. Hey, guys.

Good morning. Thanks for taking my questions. I had one on KT413. where we've seen the updated phase one data at ICML recently where it looks like you're achieving target degradation already at dose level three or four. Can you talk a bit about how the neutrophil recovery and neutropenia has tracked with your expectations based on the cyclic dosing and also perhaps talk about the scope of the clinical update later this year and expectations for that. Thank you so much.

Thanks, Michael. So maybe I'll start with the second part of your question, and then I'll let Jared address the first part of your question with regards to expectations. So for both programs, as we said, the goal is really to continue and evaluate PKPD safety and potentially, you know, complete the dose escalation portion of the Phase Ia study. And as you know, the goal of those escalations was to establish safety, in this case also PKPD. But as you know, in clinical development, especially in oncology, it is important to assess early signs of antitumor activity to solidify the hypotheses of these oncology programs providing benefits to patients. So as part of the dose escalation for both programs, we expect that we'll have a handful of patients for 413 to be myD88 mutant and out of the old B-cell lymphoma that we're recruiting and for 333, CTCL, LGL, and PTCL out of the whole liquid and solid tumor cohort in order for us to, again, establish early signs of antitumor activity. So, again, in terms of expectation, we hope to being able to report on a complete data set on the PKPD and safety as part of the dose escalation study and then hope to have, let's say, a handful of patients from each of the studies that fit the sensitive patient population where we would be able to evaluate the anti-tumor activity of these first-in-class mechanisms. What we're now going to be able to discuss is obviously extent of response rates and and metrics just because we believe that those are more scientifically sound in a better design study to evaluate the clinical activity, which we believe is expansion cohorts and beyond. But again, anti-tumor activity, validation of these mechanisms, ability to correlate degradation to impact on tumors is what we hope to be able to share later in the year. So maybe, Jared, you can talk about the neutropenia question.

Sure, Mike. So in terms of your question about neutropenia, you know, when we provided our update back in June around the ICML meeting, you know, we indicated that we had not seen any of those toxicities or any drug-related neutropenia, which was very encouraging to us, as you mentioned, because we were seeing a strong IMID activity with, you know, greater than 90% knockdown of iculose and ilose. but we're not seeing neutropenia. Yes, we're expecting to see some decrease in neutrophil count. We have seen some decrease in neutrophils followed by recovery, but it hasn't risen to the level of being neutropenia, which is in line with our preclinical data, our GLP-TOX data, where we did see some decline in neutrophils, but then we saw recovery prior to the next dose three weeks later. So the use of this every three-week dosing schedule, at least so far in the clinic, you know, has been successful from a safety standpoint in helping us to mitigate any sort of dose-limiting neutropenia, which we think is important because we do have this, you know, potent IMID activity as part of KT413, of course, along with the strong IRAC4-lowering activity that our ability to dose escalate without being limited by myelosuppression, especially neutropenia, or by GITOX is something which we see as being very encouraging so far.

Thank you.

Thank you. Your next question comes from the line of Kaulvit Patel from B Reilly Securities. So your line's open. Yeah, hey.

Yeah, hey, good morning and thanks for taking the question. For the planned phase two study in HS, can you give us any color on the expected trial design and maybe what types of patients you're planning to include in that trial? Would you allow the prior use of Humira in that study? And then I have to follow up.

Thanks for the question. It's a great question. Unfortunately, we're not in the position to comment on it. But I think soon enough, I believe, there will be updates on clinicaltrial.gov. At that point, we might be able to add some color around what's been disclosed. That's what we've agreed with our partner at this point.

Okay, got it. And what are you looking in terms of expectations for that trial in NHS? Are you looking to beat or match what Humira has performed historically? Or do you think there's a slight, you know, wiggle room here that you don't need as much efficacy because you have an oral option?

Another great question. I'm glad we're starting now setting expectations. So let's start with, you know, what we've seen so far. We've seen some really encouraging activity, I would say, in both HS and AD. Obviously, your question was focused on HS, which is okay, but I would say on both indications. In both indications, lack at this point a well-tolerated potent oral option that can help patients manage these really difficult diseases, especially, obviously, the moderate to severe cases. And our goal is to have an oral option that is well-tolerated and that works and helps patients and that we believe can be competitive with other agents that have been approved in those patient populations. I think once we complete the study and we have a dataset that is placebo-controlled and solid, I mean, we can then start to discuss If that type of data set is repeated in a phase three study, where is the commercial strategic placement of this particular drug? But I think right now it's premature to discuss the commercial option. All I can say in terms of clinical and patient impact, we are planning to develop this drug, and to be honest, others that you'll hear about in the future, to fill a need, which is an oral option for patients that don't have one that is both well-tolerated and active. And our limited experience, I would say limited again, in both HS and AD running studies in patients has been that regardless of the activity of existing options, Patients are looking for well-tolerated, easy-to-take oral drugs. And that's what Chimera is going to be focused on in the next few years.

Thank you. Your next question comes from the line of Vikram Purohit from Morgan Stanley.

So your line is open. Hi, good morning. Thanks for taking our questions.

So one follow-up, and apologies if this was discussed and we missed it, but on the topic of additional potential indications for 474 beyond HS and AD, what is your and Sanofi's cadence of decision-making there? Is that going to be dependent on data from the planned phase two studies in these two indications, or is that a separate decision-making process that you're going through with Sanofi at this time? And then secondly, I'm not sure to the extent You can talk about this, Nello, just given your recent remarks on the other question around HS, but has your insanity thinking around the design for the HS study and the patients you might enroll been impacted at all by recent competitive developments in that indication? Thanks.

Yeah, thanks Vikram. Both great questions and I think I can address both. So the first one, you know, I can't speak for Sanofi unfortunately. So what I can say though that we are, as any responsible drug development organization, and in this case partnership, are discussing what potential other opportunities are for an asset like this. And as you know, Chimera on our own have been doing this for now a few years. So obviously we don't have to reinvent the wheel that many times. But the conversations are around, you know, what are the other potential opportunities beyond HSNAD? I can't speak to the decision-making process, but maybe from my perspective what I can say is, that obviously generating exciting data in HSNAD might influence some other indications that are very close mechanistically and biologically to HSNAD. But it will not, in my mind, again, influence indications that are biologically close. and pathologically differentiated from HS and AD. And if you look at the list of potential indications that even we have on our website, you can imagine that there are, you know, numerous opportunities that fit the first packet and the second packet. So maybe I'll leave it at that at this point. For the second question, which was around have other studies impacted our clinical trial design. The short answer is no. The way that we and Sanofi had designed the Facebook study is to evaluate the, obviously, safety, as you know, safety and the clinical activity of an Rx40 grader in HS and in AD, And we believe that our design is going to be able to answer that question. The question is whether the drug is superior or inferior clinically to other drugs. That's not the goal of our phase two study. I put it out there already, as you can imagine. Again, and this goes back to we believe there is a clear need. in HS, in AD, I would argue in asthma, in COPD, in IBD, of well-tolerated, and this again, these are my words, of oral well-tolerated active drugs, and that's what we're trying to develop here.

Thank you. Your next question comes from the line of Eric Joseph from J.P. Morgan. Your line is open.

Thanks for taking the questions, and Just a couple from us on 253. And just this point of differentiation where you expect to be bypassing the feedback regulation of MDM2. Can you just remind us the mechanics of that feedback and is looking at sort of degradation after cycle one enough to support having a differentiated degradation profile, or would you perhaps need to look at degradation with subsequent cycles to get a better understanding of the max degradation profile and use that to optimize the schedule selection?

Yeah, another great question. We're very fortunate here to have great, great questions today. So the 253 What is the kinetics of the feedback loop and where does the overcoming of the feedback loop impact the biology of P53? I might add a kind of a follow-up point to your first point. What we have experimentally demonstrated that the feedback loop needs to be overcome by which means we need to retain high level of MDM2 degradation only for the first few hours. Actually, beyond the first few hours, it doesn't matter anymore whether you're degrading MDM2 or not, because once you degrade it for the first few hours, cells have an irreversible commitment to death. And so that's the hypothesis here. Small molecules, it actually doesn't really depend on the dose. I had a really hard time overcoming that just because it's you know, it's limited by how much compound you can give and the pace of that resynthesis of P53, of MDM2. We, being a catalytic, it doesn't really matter exactly what the dose is. We're able to degrade a large amount of MDM2 every minute that the compound is on board. So we should be able to evaluate mechanistically our ability to suppress MDM2 and to lead to cell death on cycle one. Now, multiple cycles might be needed to have maximal anti-tumor effect, but that, as you know, is just standard oncology drug development. And importantly, for us, the hypothesis is MDM2 degradation leads to apoptosis, leads to cancer cell death, leads to antitumor activity before we hit those limiting toxicity, which does not happen with small molecule inhibitors. And that's why I said earlier, we should be able to show that in a phase one study. Again, we're not going to be able to talk about what is the response rate in population X, Y, and Z with big numbers just because it's a dose escalation study. But we should be able to demonstrate that In patients and tumor types that are sensitive to this mechanism, at the right dose, we should be able to see anti-tumor activity before we hit dose-limiting toxicity. And that will be the definition of success, at least early success, for this program that other MDM2 inhibitor programs haven't been able to demonstrate convincingly, at least in our eyes.

Thank you. Your next question comes from the line of Ellie Merrill from UBS Financial. Your line is open.

Hey, guys. This is Jasmine on for Ellie. Thanks so much for taking our question. We saw from the update in June that the majority so far with 413 have been ID88 file type and not mutant. How should that inform our expectations for any potential anti-tumor effects you're expecting to see? Do you expect that proportion to change as enrollment continues? And then I have a follow-up.

So I didn't hear it very well, but I think you asked, I think I'm going to answer anyway, and you'll tell me if I understood your question. So it's true that as of as of the ICML update, which I want to remind everybody, the cutoff date, I believe, was June 1st. All the patients but one were MyD88Y type, and actually the only patient that was MyD88 mutant was the first patient in dose level 4, which in a way, you know, I think it was a bit of coincidence, but it was a fortunate coincidence, meaning that the only or the first patient with MyD88Y mutant or mutation was at a cohort that we believe should be or could be clinically active. we do expect to see activity only in mighty 88 mutant patients. That's based on our preclinical data where really strong activity was seen only in mighty 88 mutant patients. So our ability to demonstrate anti-tumor activity, as I said earlier in this program, will be driven by our ability to have patients multiple MyD88 mutant patients, as I said, a handful, as part of the dose escalation to evaluate the clinical activity, while the rest of the patients, I assume, will be mostly generating PK, PD, and safety data, which is, again, really the official goal of the Phase I study. But hopefully that answers your question.

Yeah, thank you. And then on the 333 program, How should we think about the discontinuation rate you expect going forward and then of the adverse events classified as related to the registry that you showed in the ICML poster? Do you see those as like related to the mechanism? Do you expect to see any of those going forward?

Well, I think actually Jared answered this one. Jared, hopefully you heard it well.

Yeah, I sort of heard part of it. A little bit of it wasn't entirely clear.

So maybe, Jared, I'll summarize the potential discontinuation rates in 333 and then what did we see in terms of relatedness of adverse events in the 333 study up to the ICML disclosure. That's my addition.

Yes. Yeah, I mean, we really haven't seen much in the way of discontinuation due to adverse events. We have had people, you know, who eventually have come off the study, but not due to adverse events. So in terms of what do we expect in terms of future discontinuation rate, hopefully it will be low in terms of adverse events. Patients may come off for other reasons, like disease progression, for example, but hopefully not for adverse events. You know, if we look preclinically at what we saw in In terms of safety, as we push to higher doses in preclinical studies, we did see GI side effects there and relatively modest effect on platelets. So far, we've seen relatively little of that as we've been dose escalating. And we have had adverse events, many of which have been related to disease as opposed to being related to the drug itself. But as we continue to dose escalate, we'll be watching carefully for you know, any adverse events that are thought to be related to treatment and see how those line up with what we saw preclinically. But I think that's the whole point really of phase one really is as we dose escalate to really see how well, you know, the level of stat three knockdown that we're seeing, you know, is tolerated by these patients. You know, it is difficult sometimes, you know, in these early phase one studies when you have very heavily pretreated patients, to be able to sort out events that you're seeing that are related to the disease itself versus those that are related to the drug, and the investigators at the sites ultimately have to make the call there. But so far, the safety profile has been encouraging, and we'll just continue to watch as we continue to enroll patients onto the trial.

Operator, in the interest of time, can we ask the questioners just to keep to one question so we can try to get through the rest of the queue? Understood.

Thank you. Now, your next question comes from the line of Kripa Devarakonda from Truist Securities. Your line is open.

Good morning. Thank you so much for taking my question. I know a lot of them have been answered with respect to Sanofi initiating programs in HS and AD. But given Sanofi's footprint in that space and also the evolution of the competitive landscape in HS as well as in AD, would be great to get your thoughts on potential for combos that could be synergistic. For instance, would an antibody targeting a downstream cytokine in the pathway be a potential combo partner? Thank you.

Yeah, no, great question. So, I mean, I would start with, again, saying what I said earlier, which is in both indications and others, patients still need effective therapies. If you look at even Dupixent, which is, you know, one of the most successful drugs in immune inflammatory diseases, has a really limited penetration rate. And so I think there is still a need for effective therapy that are simple to use and that are well-tolerated. If I want to indulge your question on the scientific merit, yeah, sure, there are opportunities to synergize across these multiple immune mechanisms. And I can't speak to those plans because, to be honest, have not been discussed. But one would say, let's say an observer of how the understanding of immune inflammatory diseases is evolving with time, that yes, there could be potential synergies across more than one mechanism. But that's just a scientific observation at this point from my standpoint.

Thank you. Your next question comes from the line of Derek Archo from Wells Fargo. Your line is open.

Hey, good morning, and thanks for taking my questions. Just a follow-up to an earlier question on KT333 or potentially another stat, three to greater, you might develop for I&I indications. Is this something that you would explore yourself, or is this purely for something that you would look to partner KT474? Thanks.

No, I mean, our strategy is not to partner immunology programs. We did partner KT, or I should say IREC4, in 2020, and that at the time was the right thing to do for the company, but that is not what our base case strategy is. So you should not expect that. the next immunology program is going to be partnered. I think it will depend on many factors, but I think you should not expect that we are based cases to partner these programs before they reach key inflection points in general.

Thank you. Your next question comes from the line of Kelly Shi from Jeffries. Your line is open.

Hi, this is Sean Pan on for Kelly. Thanks for taking our question. So one of your one point three objectives is to deliver two new IMDs. Can you provide more colors in terms of the indication and targets and how the learning from the current clinical programs have instructed your plan? Thank you.

Yeah, no, it's a great question. I'm not going to go into the specifics of the numbers there, but just generally what I said earlier is that we've learned a lot from the first seven years of this company. I think it's fair to say we're pioneering protein degradation, and for sure we're pioneering protein degradation in immune inflammatory diseases. Lots of learnings on how to develop at least early, to discover an early development of immune inflammatory degraders that have the potential to be best-in-class oral options. And so I think the expectation to have is that, you know, there will be a lot of focus on those particular type of programs. Large opportunities are met need oral immune inflammatory drugs and other indications. But I would say that the expectation is a lot of focus in that particular area.

Thank you. Your next question comes from the line of Rich Law from Credit Suisse. Your line is open.

Morning. This is Grace on for Rich. Thank you for taking our question. Just wondering for the 47, sorry, just wondering for the program 404, how are you thinking about positioning that in lines of therapy in the phase two study? Are you trying to stay broad, or will you narrow to a more specific patient population in a study? Thank you.

So thanks. I kind of addressed this earlier. At this point, we're developing a drug that we believe has the potential to be safe, active, and access a broader population of patients that right now are not served by existing therapies. Again, when we talk about labels and commercial positioning, that will happen further in clinical development. Right now, we don't have any reason to believe that we will be limited by any factors at this point.

Thank you. The last question on the queue comes from the line of Geoff Macon from Bank of America.

The line is open. Good morning, this is Haosheng calling in for Jeff Meechan. Thank you for the question. So just to follow up on BD, you know, other than immunology, are you looking for BDs for assessing your other therapeutic areas? And if so, what may be some of the things top of your mind when you're making these type of decisions?

The question is on BD.

Did you say BD, like business development, or AD?

Yes, BD, like KT474 type of collaboration.

Yeah, yeah. So, I mean, we've commented on this particular topic at length in the past, so I'll try and keep this short. I mean, a company with a broad pipeline that is an enabling platform that can deliver sustained innovation will continue to entertain potential synergistic partnerships I would say that's a broad concept. I don't think right now we're in the position to discuss specifics about indications area programs, but I think that statement probably will apply always for a company like Chimera that has such an effective engine to deliver potentially innovative therapies.

Thank you. Showing no further questions in the queue, I'll now hand the call over to Justine for closing remarks.

Thank you, Dustin, and thank you, everyone, for participating on today's call. I am very excited to join the Chimera team and look forward to working with many of you going forward. In the meantime, please don't hesitate to reach out to me or Bruce if you have any follow-up questions. Thank you, and this concludes today's call.

This concludes today's conference. You may now disconnect.