Kymera Therapeutics, Inc. Q1 FY2023 Earnings Call

Good morning, and welcome to the Kymera Therapeutics First Quarter 2023 Earnings Conference Call. Please note that this event is being recorded today. I would now like to turn the conference over to the Chief Financial Officer, Bruce Jacobs. Please go ahead, sir.

Good morning, everyone, and welcome to the Kymera Therapeutics quarterly conference call. I'm Bruce Jacobs, Chief Financial Officer at Kymera, and I'll be joined today by Nello Mainolfi, Founder President and CEO; and Jared Gollob, our Chief Medical Officer. After our prepared remarks, we will open the call to your questions. Before I get started, I'd like to remind everyone that some of the comments that management may make on this call include forward-looking statements, as outlined in the press release. Actual events and results could differ materially from those expressed or implied by any forward-looking statements as a result of various risks, uncertainties and other factors, including those set forth in Kymera's most recent filings with the SEC and any other future filings that the company may make with the SEC. You are cautioned not to place any undue reliance on those forward-looking statements and Kymera disclaims any obligation to update such statements, except as required by law. With that said, I'll now hand the call over to Nello.

Thanks, Bruce, and thank you, everybody, for joining us today. This month marks the seven-year anniversary of our founding. As Kymera reached this milestone, I thought I would spend a few minutes reflecting on the progress we've made on our ambitious plans to build the best-in-class fully integrated global medicines company. Since our funding, we have focused on a target selection strategy that would allow us to use this novel drug modality in target areas that would uniquely benefit from it and on evolving the platform to reach novel therapeutic hypotheses. Over that time, we've continued to enhance our platform capabilities and advance programs in areas of significant patient needs that cannot be meaningfully addressed by conventional medicines, building a high-value pipeline and demonstrating our ability to design molecules that have the potential to transform disease treatment. Our first-in-class IRAK4 degrader program, KT-474, is a molecule we discovered and developed through Phase I and is planned to start Phase II trials conducted by our partner, Sanofi. In December of last year, we shared positive early data in both hidradenitis suppurativa in atopic dermatitis patients that demonstrated strong translation of our preclinical PK/PD and safety models into the clinic. With this program, we have seen, for the first time, clinical benefits of a hydro bifunctional degrader in inflammation and immunology indications for the first proof-of-concept of clinical differentiation of a degrader compared to a small molecule inhibitor. This is a substantial accomplishment for a company that is pioneering a new modality. Sanofi expects to initiate the first Phase II study of KT-474/nHS this year, followed by a study in AD. Our three oncology programs continue to make progress. Of note, we have initiated the Phase I clinical trial of our MDM2 degrader, KT-253. The clinical effect of stabilizing P53 and P53 wild-type tumor is a concept that has been pursued extensively in the biopharma industry. There are a handful of MDM2 small molecule inhibitors in the clinic with some activity in a variety of tumor types. Unfortunately, the activity has been limited given that inhibition of MDM2 leads to a transcriptional feedback loop, which creates more protein that makes it harder for occupancy-driven small molecule inhibitors to block, leading to reduced therapeutic indices. We believe KT-253, on the other hand, has the potential to overcome that feedback loop because it removes the protein and does so in a catalytic manner. This makes KT-253 a highly potent candidate that may be able to induce an irreversible acute apoptotic response with brief exposure while allowing time for the recovery of any normal cells that may be affected, creating an improved therapeutic index. With KT-253, we believe we have a degrader that can remove MDM2, stabilize P53, and overcome the feedback loop generated by MDM2 reduction, giving us the opportunity to explore the clinical potential of such a powerful mechanism fully. We look forward to sharing more updates as the trial advances, including safety and proof-of-mechanism data later in the year. Near term, we plan to present additional preclinical data on KT-253's pharmacological profile at the European Hematology Association Congress next month. Our IRAKIMiD program, KT-413, targets IRAK-4 and the image substrates, and has the potential to be the first precision medicine to treat a genetically defined subset of tumors. KTE-413 has been designed to target MYD88-mutant lymphoma, and we're currently in dose escalation of the Phase I trial in B-cell lymphomas, including DLBCL. We shared some initial data from the trial in December, showing that we engage the target without any dose-limiting toxicities. Our third oncology program, KT-333, targets STAT3, which has been linked to numerous cancers and inflammatory and autoimmune diseases, and is the first degrader against an on-track transcription factor to enter the clinic. We're currently in dose escalation of the Phase I trial in the broad subset of liquid and solid tumor patients, where we've also shown early proof of mechanism. Our focus in 2023 for both KT-413 and KT-333 will be the degradation profile and evaluating their biological and clinical impact in the appropriate target patient populations. As disclosed today, we plan to provide a clinical update focused on degradation and safety for KT-413 and KT-333 at the International Conference on Malignant Lymphoma, or ICML, in June. We intend to present data evaluating antitumor activity in the target patient populations for both programs later in the year. In addition, we continue to push the signs of TPD forward and identify best and first-in-class opportunities to transform the treatment of disease. We have several exciting programs in our preclinical pipeline that are designed to address well-validated immunology and oncology pathways in areas of significant patient need and commercial opportunity. These include developing tissue-selective restricted E3 ligase treatment programs as well as a new generation of molecular glues, exploiting newly identified avenues to expand the reach to high-value on-drug and non-regulatable targets. We hope to be able to share more on these efforts later this year or early next. Jared will now cover in more detail our recent progress for each of our disclosed programs before turning the call over to Bruce for a financial update. I will then finish with some concluding remarks before handing the call to the operator for a Q&A session in which Jared, Bruce, and I will be available. Jared?

Thanks, Nello. I'll provide a brief recap of where we stand with our clinical programs and what we expect in the coming months. Turning to our oncology pipeline. I want to update everyone on our disclosed programs, which include our Stat3, Aracamid, and MDM2 degraders. As Nello mentioned, KT-253, our MDM2 degrader, received IND clearance from the FDA at the end of last year. We initiated the Phase I trial in March and expect to dose our first patient shortly. MDM2 is the crucial regulator of the most common tumor suppressor p53, which remains intact in close to 50% of cancers. We believe KT-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. KT-253 has the potential to be effective in a wide range of hematological malignancies and solid tumors with functioning p53. We've shown preclinically that KT-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. Additionally, we presented data at the ASH Annual Meeting last year, supporting an intermittent dosing schedule of KT-253 in acute myeloid leukemia (AML), which has the potential for improved efficacy and safety using a degrader approach. The Phase I trial is evaluating the safety, tolerability, pharmacokinetics, pharmacodynamics, and clinical activity of KT-253 in patients with relapsed or refractory high-grade myeloid malignancies, acute lymphocytic leukemia (ALL), lymphomas, and solid tumors. Patients in the KT-253 Phase Ia dose escalation study will receive IV doses of KT-253 administered once every three weeks. The open-label study is intended to identify the recommended Phase II dose for KT-253 and will be comprised of two arms with ascending doses of KT-253 in each arm. The first arm will consist of patients with lymphomas and advanced solid tumors, and the second arm will consist of patients with high-grade myeloid malignancies in ALL. We plan to share initial safety and proof-of-mechanism data from the Phase I clinical trial later this year. Now turning to our other two oncology trials that are ongoing. STAT3 is a transcriptional regulator that has been linked to numerous cancers as well as inflammatory and autoimmune diseases. Our Phase I clinical trial is evaluating KT-333's potential in hematological malignancies and solid tumors. Specifically, the trial is evaluating the safety, tolerability, PK/PD, and clinical activity of KT-333 in adult patients with relapsed and/or refractory lymphomas and solid tumors. We reported on the first dose level in December, showing initial proof of mechanism for STAT3 degradation in PBMC and no dose-limiting toxicities with good translation of PK/PD from preclinical models to patients. The trial is continuing to enroll, and based on the PK/PD we showed in December, with robust target knockdown for 72 hours followed by recovery, we expect to be at pharmacologically active doses by DL3 or DL4, as previously announced. The trial's second stage will consist of Phase Ib expansion cohorts to further characterize the safety, tolerability, PK/PD and antitumor activity of KT-333 in relapsed and/or refractory STAT3-dependent T-cell malignancies, as well as in solid tumors. Our IRAKIMiD program, KT-413, is a novel heterobifunctional degrader that targets degradation of both IRAK4 and the image substrates. KT-413 was designed to address both the IL-1R, TLR, and the type 1 interferon pathway synergistically to broaden activity against MYD88 mutant B-cell malignancies. KT-413 is on a similar timeline as KT-333 and is currently in the dose escalation stage of the Phase I trial, evaluating the safety, tolerability, PK/PD, and clinical activity of KT-413 in patients with relapsed and/or refractory B-cell non-Hodgkin's lymphomas. We reported in December that the first two dose levels have been completed, showing initial proof of mechanism with IRAK-4, Ikaros, and Ailos degradation in PBMC and tumor and no safety signals with good translation of PK/PD for preclinical models to patients. We are continuing enrollment and similar to KT-333, we expect to be at pharmacologically active doses by DL3 or DL4 as previously announced. The trial's second stage will consist of Phase Ib expansion cohorts in DLBCL to further characterize the safety, tolerability, PK/PD, and antitumor activity of KT-413 in relapsed/refractory MYD88 mutant and MYD88 wild-type DLBCL. As Nello mentioned, we look forward to sharing updated degradation and safety data on these two programs at ICML in June. We'll present a poster on KT-333 at the conference, and an update on KT-413 will appear in the ICML abstract book. As we've said previously, we expect to assess the clinical impact of degradation in the respective target patient populations for both KT-333 and KT-413 and to share that data at a medical meeting later this year. I'll end with our IRAK4 program, KT-474. As Nello mentioned, Sanofi will be taking KT-474 into Phase II and initiating trials in HS and AD, the first of which in HS is planned to start this year. There is limited additional information I can share with you at this time other than to say the plans in place for starting Phase II are tracking with Sanofi's and our expectations. Finally, with respect to KT-474, we look forward to presenting the clinical data from the Phase I program at the EADV symposium in Sevilla later this month, which will mark our first time sharing these exciting data at a major scientific meeting.

Thanks, Jared. I'll quickly cover the financials before turning the call back to Nello for some closing remarks. Before getting into the specific financial results for the quarter, I wanted to briefly address the events surrounding Silicon Valley Bank as it relates to Kymera. At the time of the receivership of SVB, we had very limited exposure to the bank. In response to the events in March, we removed all of our excess operating cash that was held there and moved the outstanding letter of credit that was also there that is held to support our new lease. At this time, we have modest cash at SVB to support our current operating needs. As a brief reminder, Kymera's investment policy prioritizes protection of principal and our liquidity needs above all and limits our investments to government securities and highly rated corporate bonds. This policy guides our investment approach, and it's been coupled with the recent expansion of our banking and asset management relationships to further diversify our financial risk. That said, back to the financials for the quarter, we recognized $9.5 million of revenue. This total reflects revenue recognized pursuant to our Sanofi and Vertex collaboration. At the end of the quarter, our deferred revenue total on the balance sheet was approximately $57 million. That reflects partnership revenue we expect to recognize over the next several years, excluding the receipt of any potential future milestones. With respect to operating expenses, R&D for the quarter was $42.2 million, of which $4.7 million represented non-cash stock-based compensation. The adjusted cash R&D spend of $37.5 million, including stock-based compensation, reflects about a 3% decrease from the comparable amount in the fourth quarter of '22. Our SG&A spending for the quarter was $12.6 million, of which $4.7 million was non-cash stock-based compensation. The adjusted cash G&A spend of $7.9 million, also excluding stock-based compensation, reflects a 10% increase from the comparable amount in the fourth quarter of 2022. Finally, we exited the first quarter with a cash and equivalents balance of approximately $516 million. As we shared earlier in the year, we believe our cash runway extends into the second half of 2025 projection, which includes milestones only related to the start of the first two Phase II trials for KT-474. I will now turn the call back to Nello.

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

We will now begin the question-and-answer session. Our first question will come from Vikram Purohit with Morgan Stanley.

This is Gospel on for Vikram. We have one question. For KT-413 and KT-333, you have mentioned that you expect those Level 3 and 4 in each program to demonstrate clinical activity. When this is available, what do you think is going to be the best way to interpret the data to gauge the strength of the clinical activity for each molecule? What is your benchmark for determining a good outcome versus a more mixed one?

So first, I'd like just to be clear, we said in December that we expect those Level 3 and those levels 4 to be at clinically active exposures and levels of degradation. Obviously, the question will be at those doses, do we see clinical activity, just to be clear. So just to remind everybody, these are first-in-class mechanisms. And for both mechanisms for 413 and 333, we've shown some really compelling preclinical data. Remind you, for 413, we've shown that if you degrade IRAK4, Ikaros, and Ailos for about 72 hours, anywhere between 50% and 90% across the three proteins, we can drive MYD88 mutant tumors to complete remissions. For 333, we've shown that if you degrade that for about 90% for about 48 hours, we're able to drive some subsets of liquid tumors. We've talked about CTCL, PTCL, LGL, and leukemias to at least in some preclinical models that we were able to run to complete remission. So the question that we want to ask, we always look at clinical translation from two perspectives. The first one is the molecule's ability to translate what it was designed to do. And so we ask of these two molecules to replicate our preclinical degradation profile. As I mentioned, what we believe to be clinically relevant is this 50% to 90% degradation for 413 and 90% degradation for 333 for, as I said, 72 hours for one program and 48 hours for the second. As we continue to explore PK/PD and safety in the clinic, and in fact, what we said is that we're going to give an update on ICML on that. We want to make sure that our molecules are able to reach those degradation profiles at tolerated doses and exposures with a tolerated profile. The second part of the clinical translation derisking is whether that particular degradation profile, which we have shown in the preclinical studies, translates into an antitumor effect. That's going to be a question that we're going to try to answer and show data later this year, as we said. It's hard for us to set a bar because just to be clear, we're running relatively broad Phase I dose escalation studies in terms of patient population. We will have probably a handful of patients that fit the right criteria in terms of the disease and type of tumor types. What we would like to see in those patients is the translation of antitumor effect. We're staying away right now from comparing and setting a bar just because we're still early in the clinical development. Jared, anything you want to add to that?

No, I think that covers it all.

Our next question will come from Michael Schmidt with Guggenheim.

Just a follow-up on 333 and the 413. As you think about this upcoming update at the ICML conference, can you talk about a bit how far in you are in those two Phase I studies now beyond dose level one or two? How many patients do you have data for at this point, or how are you tracking towards identifying a recommended Phase II dose? And then on 413, I think you already had 95% to 100% knockdown of Ikaros and Ailos last December. I guess, how much higher do you need to go? And how confident are you in not seeing issues around potential on-target toxicities related to those two targets that you go much higher?

We really haven't been guiding externally in terms of where we are right now with regards to enrollment across both the studies. As we showed back in December, we presented data on DL1, the first dose level for KT-333, and the first two dose levels for KT-413. All we can really say is that we're continuing to enroll across both studies. When we do present updates at ICML, at that time, we'll be able to really update on numbers and where we are in terms of which dose levels. In terms of the knockdown question, yes, you're right that with regard to 413 and Ikaros and Ailos knockdown, we did show a very robust knockdown of greater than 90%, 95% in peripheral blood, in particular, with those first two dose levels is the data we shared back in December. For IRAK4, I think at that time, we had approximately 40% knockdown of IRAK4 in the blood. We had one serial set of tumor biopsies from the first dose level where we showed around 60% knockdown of Ikaros and Ailos in tumor and around 20%, 25% knockdown of IRAK4. I think what we want to be able to show in subsequent dose levels is continued strong knockdown levels of Ikaros and Ailos in the blood. We'd like to see further knockdown of IRAK4, getting up into that 50% to 70% range that Nello alluded to earlier, which is associated with antitumor activity in our preclinical models. And if it's possible, where we can get voluntary tumor biopsies, we also want to continue showing activity there as well.

I just want to add one thing, Michael, and probably for everyone's benefit. I think it's an exceptionally exciting time to be at Kymera. We have the luxury of witnessing what is first-class in mechanisms translating into patients. We've done it with direct mechanisms, and now we're doing it with three other mechanisms. So I don't think we're trying to deflect questions. It's really like we are observing new biology at play here.

Our next question will come from Brad Canino with Stifel.

I feel like I'm going to ask Michael's questions in a different way because I just want to check on the upcoming Lugano presentation. Will that include additional patient numbers and dose cohorts relative to last December's disclosure? And then a specific question on KT-413. As we watch these safety data evolve through the rest of the year, as you dose escalate, do you have a range of neutropenia across grades that you're going to be comfortable with, especially when you think about marching this drug eventually to earlier lines in the treatment paradigm, which will be in combination with the DLBCL standards of care?

Yes, I understand, and I appreciate your follow-up because perhaps we weren't clear enough. Yes, there will be additional data, obviously. If not, we wouldn't be presenting at ICML. We will have significantly more data on the programs we are discussing. On the neutropenia question, I’ll let Jared share his thoughts. I want to reiterate something we've mentioned before, which is that the opportunity with 413 lies in our ability to translate the synergistic biology between IRAK4, Ikaros, and Ailos. The crucial question is whether the synergistic biology we've observed preclinically can produce a significant antitumor effect through an immediate apoptotic response that requires just 72 hours of knockdown. If this translates to clinical settings, I believe we will manage the neutropenia concern better than other programs because of this apoptotic dosing, which helps us achieve an immediate apoptotic response in the initial days, while any potential on-target safety issues arising from the pharmacology can be addressed with the alternative dose in PARADIGM. Jared, do you want to add anything regarding the actual grade of neutropenia?

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

And our next question will come from Chris Shibutani with Goldman Sachs.

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

It's a great question, which I could spend a day on, but I'll try to do it in a couple of minutes. First, I'd like to recognize the path that we've taken from an early company that was sitting on a potentially transformative new drug modality and decided to commit to building a real company. I often use this definition of a real company, meaning committed to seeing programs through the different phases of development and eventually commercialization because we believe that in order to capitalize on the power of this really strong new modality, you have to commit to see it through. You cannot depend on other industry partners to do so because that's what history has taught us. New modalities have been developed in biotech companies and biotech companies only at best. So that's our commitment. Now the first seven years have been years full of execution, but also learning. We learned the type of targets that best benefit from this technology. We've shown we were fortunate enough that our early targets have played out extremely well into early clinical development, demonstrating the power of the technology. We've also learned, and maybe we haven't discussed broadly enough, the type of targets we don't work well with this technology. I think we've been focused and we've been really good at understanding early on the type of targets that aren't worth applying this technology again. Our first wave of targets, I think, are well positioned to demonstrate with a catalyst-rich sequence the power of degrading targets in human patients and the impact of that degradation on human disease and human condition. The next two years, we will see proof of concept across the four clinical programs that we have in our pipeline. We will see proof-of-concept of KT-474 in HS and AD. We will see proof of concept of KT-413 in lymphoma. We'll see proof of concept of KT-333 in several disease types or cancer types and potentially outside of oncology. We would see MDM2, I think, final realization of full potential. However, Kymera could not be the type of company we want to build if we stop there. Our investment has been in actually the learnings that we've taken from the first few years since our funding into applying this technology to a new generation of targets. We have decided for our new generation of pipeline to focus heavily on two areas that we believe will define the success of biotech going forward, which is an area where there is a larger clinical need and large commercial opportunities, with a maybe slightly higher focus in immunology, where we've learned ahead of everybody else. We were the first company to take a degrader into immunology. We've already shown meaningful clinical data. We haven't really talked about all the platform learnings that we have been able to amass through the development of that asset, and we are able to translate that to a series of novel immunology programs that we will be disclosing in the next few months. I think we're also not naive enough to believe that we can do all of that on our own. It would be impossible, just to be clear. For the type of indications and programs that we want to develop, it would be impossible to commercialize eight programs on our own in the next five years or seven years. The question is, how do we optimize the synergies that one can build in this biopharma ecosystem, which is, obviously, the best in the world in business terms. As we've done with Sanofi for 474, I suspect there will be other partnerships that will maximize value creation here. We're just not in a position to talk about them because I don't think we're quite there yet. We're focused on translating these programs in the clinic and advancing a new generation of program into the clinic. As we progress on this part, we will share more on what are the strategic choices that we have in front of us.

Our next question will come from Marc Frahm with TD Cowen.

Maybe just to start one right after ICML, the guidance for initial MDM2 data midyear. Can you just walk through again the target degradation profile there, both in terms of depth, but also kind of the timing of that degradation?

So this is MDM2, right? So MDM2, just to be clear, we won't be presenting at ICML. I misunderstood, but… What we are presenting in the short term on MDM2 is preclinical data at the EHA conference. Later in the year, we will be presenting early clinical data. What we call this proof of mechanism is how much degradation we see in early cohorts and what the safety profile is, which for this program is going to be meaningful because in a way, all MDM2 programs in the past have suffered from the ability to engage the target fully and managing the right safety profile. We haven't talked deeply about the degradation profile and the extent of degradation needed to achieve a biological response in preclinical species. I will say, in order for us to overcome this feedback loop of MDM2 transcription regulation, we need to have a deep MDM2 degradation that is actually limited in terms of hours, not even days. Once we are able to knock down MDM2 deeply for a short period of time, we see a profound commitment to apoptosis across a wide variety of tumor types. We've observed that this commitment to apoptosis is sufficient to not require another dose for weeks. We're going into the clinic with this program with once every three weeks dosing. What we're trying to demonstrate in the first innings of this program is that we see profound degradation in the early few hours. We're also witnessing a manageable safety profile, which, in preclinical species, we've characterized, and we feel really confident around.

And then maybe back to the 333 and 413 trials. As you mentioned earlier, the enrollment criteria is pretty broad and not necessarily in the early parts focused entirely on the patient population who might have the most robust signification activity. But are you seeing a real bias kind of in the enrollment just given that there is some testing, particularly from MYD88, out there toward the target populations, or should we think the epidemiology is really what we'll see?

I think, as you've noted, the 413 study is broadly enrolling B-cell non-Hodgkin's lymphoma on Phase Ia. We do have sites that are enrolling patients, and these are sites that have the ability to identify MYD88 mutant patients as well, either with DLBCL or Waldenstrom's. As we get into higher doses, those sites know that those are patients of interest. And as Nello alluded to earlier, we'd like to be able to have some of the targeted indications enrolled onto the study as we get into those higher doses to give us an opportunity to show initial antitumor activity. Likewise, for the STAT3 program, we're broadly enrolling solid tumors as well as B and T-cell lymphomas on Phase Ia. Likewise, we also have a number of sites that do have CTCL, PTCL, and LGL patients, and those sites are capable of putting those patients onto the trial, especially as we get into those higher pharmacologically active doses. Once again, we would have an opportunity to show antitumor activity in those target indications.

And our next question will come from Mike Kratky with SVB.

Regarding the KT-474 data to be presented at EADV, will there be any new analysis included in these results, and what incremental new info could we expect to get?

No. In our oral presentation, I think it will be a summary of data that we've already shared. What I will say is that we're working on a manuscript that will have more insights into the data. For the presentation, I would expect it to be what we've shared in the past, given that it's also a relatively short presentation.

And our next question will come from Eric Joseph from JPMorgan.

This is Hannah for Eric. Just wondering how many dose levels you're planning to evaluate in the KT-253 dose escalation study. Based on that, at which level would you expect to be as pharmacologically active doses? And are you commenting on the specific doses that are being evaluated in that study? Secondly, can you comment at this time on the expected biomarkers that are being used to evaluate MDM2 degradation? How quickly do you expect these to begin to change in response to degradation?

We haven't really commented publicly on how many dose levels are in that study or the doses that we're actually planning to prosecute. Whenever we bring a dose into our Phase I studies, it's based on our preclinical data on our GLP toxicity studies, and we usually expect that even the lower dose levels will have the potential ability to result in some downregulation of the target. However, we really haven't provided specifics on that. With regard to measuring pharmacology in addition to looking at MDM2 regulation, we do have other biomarkers included in the study that help us look at p53 pathway activation because as you know, if we're hitting MDM2 the way we want to, we should see upregulation of p53 pathway and the various biomarkers associated with that activation. We've built this into our Phase I study that we'll be able to measure these different biomarkers in the blood as we proceed with dose escalation.

The only thing to add is that if you look at all the programs we've disclosed, the first dose has always been dosed with measurable levels of degradation. We expect that to be in line, but we have to run the study to see.

And our next question will come from Zhiqiang Shu with Berenberg.

This is Andy on for Zhiqiang. The first question is, for your STAT3 program, I think you communicated the knockdown or the degradation window. I am just wondering what's the ideal therapeutic window that you're targeting, and if there's any clinical rationale for that? The other question is your STAT3 and IRAKIMiD program, what's your ability or willingness to make them orally available?

The first question is about our STAT3 program. We've previously demonstrated through extensive preclinical research that our degradation profile shows approximately two days or 48 hours of significant degradation around 90% or more, followed by a recovery of that degradation over the course of a week or even two weeks. This pattern is effective in producing strong antitumor effects across various tumor types and is highly tolerated. This is the hypothesis we are bringing into the clinical setting. While we could potentially dose every two weeks, we have chosen to start with a weekly regimen to ensure substantial degradation in the initial 48 hours of the program. This approach has proven to be both effective and tolerable in preclinical tests. In terms of oral administration, we usually initiate the program with the therapeutic product profile based on the mechanism. If the male is unknown, we typically adjust according to what we learn throughout the process. For both of these programs, our biological and translational hypothesis focuses on frequent dosing to effectively manage both the activity and recovery of the target, as well as to build the therapeutic index. We have leveraged the distribution and pharmacokinetics of this compound to achieve degradation over multiple days from a single dose. This profile allows for infrequent dosing, which is more manageable via parenteral administration. These two programs are not intravenous because we began with the 413 as an oral drug, administering daily in preclinical models early in development. We later altered the dosing approach to manage both activity and safety.

And our next question will come from Ellie Merle with UBS.

This is Jasmine on for Ellie. On the MDM2 program, we know that RR AML has been disclosed as a particularly sensitive tumor type to MDM2 degradation. When thinking about other tumor types that could also potentially be sensitive in this mechanism, can you give any color that would help us understand the characteristics of the kinds of tumors you might be considering?

Jared, do you want to take this? I think the question was around probably AML.

I think the question was about AML. We assume that to be a sensitive tumor in our model systems; what are we doing on solid tumors? Even though we haven't presented as much data on solid tumors, we can say we've been doing a lot of work preclinically to identify those solid tumor types that have the same kind of exclusive sensitivity to MDM2 degradation that AML has, where we can dose intermittently, as we can with AML once every three weeks in tumor models and see profound tumor regressions. We have identified various solid tumor cell lines, and perhaps will later this year, be able to reveal what some of those are at presentations. We've been looking at those different solid tumor types to determine which are very sensitive to this mechanism. We've also had an active effort in trying to nail down potential biomarkers associated with the most responsive subsets of those different solid tumor types that could allow us to then use that to select patients moving forward as we go beyond Phase 1. This is an active area of research for us and is very important that, for us, it's not just going where other MDM2 have found before in terms of solid tumors; it's really forging our own path based on our preclinical data, making sure this is a data-driven decision for the solid tumor types we end up exploring as we get beyond Phase I.

I would also add that I encourage everybody to follow along as we disclose more preclinical data. For both KT-333 and MDM2 with KT-253, these are both applicable mechanisms in a wide variety of systems. We're covering some really, really fascinating, what I would call almost new biology — both alone and in combination with interesting agents where you can see meaningful patient impact when you have this new modality combined with existing mechanisms. So stay tuned, and you'll see much more of those in upcoming medical meetings.

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

And our next question will come from Timur Ivannikov with Raymond James.

So I just wanted to come back to QTc prolongation for a moment. Recently, one of the players in TPD reported a grade four prolongation event in our study of synovial sarcoma. Could you just remind us in your preclinical testing for the newest assets like 413, 333, and 253, did you see an interaction with ion channels preclinically? In the past, you've talked about a potential saturation effect on interaction with the ion channels. Do you still believe that's the case?

I would say that we can see with confidence that QT prolongation is not a class effect. As you know, QT prolongation or QTC prolongation is something that we've seen in the industry for the past 20 years since we discovered — and actually, we understood more since we discovered the ion channel, and it's impacted many small molecules. I think this is a molecule-specific phenomenon that we have seen in the industry, and I suspect we will continue to see. I want to remind you that several degraders are in the clinic, and the example you bring up is just one out of several examples where we have not seen QTC prolongation. Regarding KT-474 and Kymera, we've seen something that is unique, which is a time-limited effect where we see the appearance of subclinical QT that resolves spontaneously with continued dosing. That's an atypical phenomenon. We believe it's driven by a compound distribution that requires some time to reach steady state, and it might initially have higher exposures around the intracellular compartment of cardiomyocytes that express the ion channel. That's just a hypothesis. This is not the typical QT prolongation, which is often dose-responsive and concentration-responsive, which is what you see with most molecules. I don't know enough about what happened in the other company with that particular drug. I suspect that it's a different mechanism, given that they've seen it all at the high dose. I remind you that we've seen the same subclinical finding, obviously not a grade four. It was subclinical across all the four doses in our MAD study.

And our next question will come from Kelly Shi with Jefferies.

This is Sean on for Kelly. We have a question on HS with a rapidly evolving landscape. Can you share how your thoughts and positioning of KT-474 have evolved in light of the recent development in the space? Specifically, has any of the recent competitor data been factored into the Phase II trial design, the selection of efficacy endpoints, et cetera?

It's a great question talking about patients also. HS is a higher unmet need, we all know. I don't believe that HS is driven by a single cytokine. So I'm pleased to see that IL-17 agents work. I don't believe that IL-17 is the solution to HS, but it is going to be a great tool in the arsenal of tools that doctors and patients will have. I think it's great to see this evolving class of antibodies and the likes being developed in the space. This is a broad inflammatory disease, both local and systemic, that we believe requires a broad anti-inflammatory agent. We believe that IRAK4 is uniquely positioned to be both active and well tolerated and have — and obviously, be an oral agent. Our view of the unmet need and the opportunity for an oral active agent has not changed. There is still a high unmet need, and we believe we have an opportunity to have a broad impact in this disease. In terms of how we think about trial design, I don't believe we have learned from the elegant studies that have been run that has validated what are the key primary and secondary endpoints that one wants to see to confirm activity of drugs. I don't believe we've learned anything that has changed our view on how we want to design our clinical study, which we've obviously done in collaboration with Sanofi on Phase II. I think it's great to see other agents being active. The opportunity is totally still there for an oral active drug in that space that is, again, active and well tolerated.

And we have time for one more question, which will come from Rich Law with Credit Suisse.

This is Grace on for Rich. The first one is what's the development path and timelines for the STAT3 program in combo with PD-1, and do you see any other combo regimens that will make sense?

So yes, the answer to the second question is yes, we see several combo opportunities here. This is a bit what I was referring to earlier. We have the beauty of working with the new mechanisms; we learn also with some of our academic collaborators that have published and will continue to publish on this. What STAT3 biology can be combined with to drive synergistic antitumor effects. With regards to timing, so we're now focused, as you know, on dose escalation as a single agent, and we're obviously learning also when we can, when patients allow for biopsies, what's happening in the tumor microenvironment, that's one of the goals we have. Any combo will be part of the laser expansion cohort, which will happen after we conclude Phase Ia.

Operator, we probably can take one or two more. If you want to go to the queue, that would be great.

Our next question here will come from Geoffrey Meacham with Bank of America.

This is Hao calling in for Jeff Meacham, and thank you so much for accepting the question. I think you touched on this, so just a follow-up for KT-413. Could you talk about the choice of the Q3W? We see recovery across Ailos and to some extent, IRAK4. If it's helpful for the neutral opinion, could you talk about data and maybe some implication on the efficacy side that you have seen?

We've shown in our preclinical models and we've run multiple preclinical xenograft models of both CDx and PDX models of MYD88 mutated DLBCL. Very consistently, in those models, we've shown that a once every three week IV infusion results in complete responses that are durable. I think we're feeling fairly confident in the ability of a once every three week regimen to elicit activity in the target patient population. This comes back to what we've learned even in vitro and washout experiments, but we know that these MYD88 mutant cell lines, if you knock these targets down for about 72 hours, it commits these cells to apoptosis. That's why we think we're seeing these profound antitumor responses in the xenograft models. With regard to the every three week dosing and safety, we've learned from our GLP toxicity studies that when we do see a drop in neutrophil accounts, which is driven by the mid-activity of the drug. We can see a nice recovery of those accounts prior to the next dose three weeks later. We think that we anticipate having an acceptable therapeutic index with an every three week dosing regimen, while at the same time, still being able to maximize clinical activity even with that sort of intermittent dosing schedule.

And our last question here will come from Kalpit Patel with B. Riley.

Maybe one for IRAK for the greater the landscape. There have been other recent collaborations in the industry for developing IRAK4 degraders. I guess from the available information for these other molecules, are there any specific points of differentiation that you want to highlight? What early metrics do you think it might be crucial to focus on when making comparisons?

I would say we're very proud of having initiated a new field here with IRAK4, and I'm being serious. It's good to see that the mechanism has been finally recognized once you have the right approach, in this case, with a degrader approach. We have a drug that is quite exceptional. We can degrade the target 95% plus. We can degrade in the skin and in the blood. We've seen some really exciting early data in both HS and AD; it's a profile that's going to be hard to match. I don't know which molecules others are advancing. I know that there is a collaboration in which a molecule was, I think, optioned at DC. Clearly, a couple of them are at least a couple of years behind. There are also other molecules, but we just don't know what those molecules look like. It's hard for me to point to something besides saying we have a really, really good molecule that would be hard to match in terms of PK/PD activity and safety. We're also further ahead in competition.

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

Well, thanks. I want to thank everybody for joining our call today. It's been an exciting first quarter for 2023, starting from early in the year when we announced some of the strategic choices that we've made in terms of where we're taking our discovery engine and platform with some fees on the new programs. We've been talking about where and when we would be disclosing our oncology data across our pipeline, both preclinical and clinical. We'll have in the next seven weeks, actually presentations across the whole clinical pipeline, 474 at the ATB, then we'll have MDM2 preclinical in this case at the EHA. Then we have both KT-413 and 333 at ICML. We have more data in the second half of the year. This is really what this company will continue to be producing clinical data in first-in-class mechanisms with broad clinical potential. I expect that in the next two to three years, we'll have a large pipeline with continued cadence of clinical readouts. It's an exciting time. The first seven years of Kymera has been a fun ride, but the more exciting will be the next seven. Thank you very much for being on the call and looking forward to more interactions in the next few weeks.

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