Kymera Therapeutics, Inc. Q1 FY2022 Earnings Call

Welcome to Kymera Therapeutics Quarterly Conference Call. Leading the call from management are Nello Mainolfi, Founder and CEO; Jared Gollob, Chief Medical Officer; and Bruce Jacobs, Chief Financial Officer. After management's prepared remarks, we will open the call to your questions. Before we get started, I would 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 these forward-looking statements and Kymera disclaims any obligation to update such statements. I will now hand the call over to Nello Mainolfi, Founder and CEO.

Thank you, operator, and thanks everybody for joining us on our first quarterly results conference call. We look forward to using this forum every quarter to update all our stakeholders on the progress we're making in building Kymera into a best-in-class, fully integrated, degrader medicine company. Before we transition into the program updates, I just wanted to take a moment to reflect on some of Kymera's achievements since we founded the Company just over five years ago, and also as we near almost our two-year anniversary since our 2020 IPO. When Kymera was founded in 2016, we had bold ambitions for the Company we wanted to build. As you'll likely know by now, the foundation of the Company was predicated really on leveraging what at the time was an emerging area of science, targeted protein degradation. While we weren't then, and certainly are not now, the only company engaged in TPD, I think it's fair to say that we've approached it in a very unique way. As a result, we believe there are several important points of differentiation with respect to our strategy and our approach that still holds true today. From a target selection standpoint, we've been guided by strict criteria, which we believe has led us to focus on unique, high-value targets, where there is a clear advantage to using a degrader versus small molecule inhibitors or another technology, several of which you know well and we will discuss today. We remain acutely focused on those targets that address high unmet needs, have biology that has been well validated, and, where possible, can be addressed with a precision medicine approach. We also embarked on this mission with the belief that to truly harness the full potential of TPD, we needed to invest thoughtfully, but aggressively in building our E3 ligase capabilities, and ultimately our industry-leading E3 ligase toolbox. We believe our efforts here represent an important competitive advantage that we can and will leverage. While we're building a strong pipeline of oncology-focused degraders, which happens to be the focus of also most of our peers, we believe that there is great potential in inflammatory conditions as evidenced by the IRAK4 program. But we have not stopped there, as we've engaged with partners who help us target other disease areas and in doing so, we're building a truly disease-agnostic TPD company. We have also recently unveiled our ongoing investment in targeting high-value, un-drugged, and non-ligandable proteins using small molecule molecular glues. I think it is fair to conclude that both our pipeline and diverse platform investments position Kymera in a very unique place in the landscape of highly innovative biotech companies. Looking now at the present, from that ambitious beginning, we have succeeded in building a company in which the targets that were on top of our listing early in '16 and '17 remain our lead programs today. We have entered the clinic with three programs, each of which simplifies meaningful first-in-TPD. With the IRAK4 degrader KT-474, which is the first heterobifunctional degrader for immune inflammatory indications. We launched the first randomized placebo control trial in healthy volunteers in the TPD industry. With KT-333, our STAT3 degrader, we're the first company to bring a heterobifunctional degrader against an undrugged transcription factor into the clinic and KT-413, our dual degrader, IRAK4 substrates has the potential to be the first therapy in diffuse, large B-cell lymphoma, targeting a genetically defined subset of patients. And last but certainly not least, we are excited to continue to progress our MDM2 degrader, KT-253, forward to IND submission later this year. While we have not disclosed much about all the work we're doing in our discovery pipeline, I hope you all appreciate that the fully disclosed pipeline programs represent only a fraction of what we hope to deliver from the significant investments we've made in our platform and pipeline over the years. As we highlighted in the press release this morning, 2022 is setting up to be a year rich in data, milestones, and scientific progress at Kymera. Jared will walk you through our recent progress and our goals for 2022 for each of our disclosed programs. Before turning the call to Bruce for a financial update, I will then finish with some concluding remarks before handing the call to the operator to facilitate a Q&A session in which Jared, Bruce, and myself would be available.

Thanks, Nello. Starting with our oncology programs, we are pleased to report that the three disclosed oncology programs STAT3, IRAK4-MiD, and MDM2 are all tracking as expected. First, I will discuss our STAT3 program. KT-333, as mentioned, is our lead STAT3 degrader. As brief background, STAT3 is a transcriptional regulator that has been linked to numerous cancers and other inflammatory and autoimmune diseases, and it is a target that has long been considered undruggable. Our focus here is on developing selective STAT3 degraders for the treatment of hematological malignancies and solid tumors, as well as autoimmune and fibrotic diseases. We believe our STAT3 degraders have the potential to provide a transformative solution to address multiple STAT3-dependent pathologies. In terms of a clinical update, recall that we received IND clearance from the FDA in 4Q '21. The first clinical site was activated in 1Q '22, and the trial is actively recruiting patients. As a reminder, KT-333 is being evaluated in adult patients with relapsed refractory liquid and solid tumors, including aggressive lymphomas. Dose escalation is expected to proceed throughout 2022, and we look forward to presenting the first patient data, including preliminary safety and proof-of-mechanism clinical data in the second half of 2022. Moving now to IRAK4-MiD, KT-413 is a novel heterobifunctional degrader that targets degradation of both IRAK4 and the IMiD substrates, Ikaros and Aiolos, with a single small molecule. KT-413 was designed to address both the IL-1R, TLR, and the Type 1 interferon pathways synergistically to broaden activity against MYD88 mutant B-cell malignancies. KT-413 is on a similar timeline in STAT3, having received IND clearance from the FDA late last year. The first clinical site was activated in 1Q '22, and patient recruitment is underway. As a reminder, the Phase I trial for KT-413 is focused on adult patients with relapsed refractory B-cell lymphomas, including MYD88 mutant diffuse large B-cell lymphoma or DLBCL. Our plans remain to present KT-413's first patient data, including preliminary safety and proof-of-mechanism clinical data, in the second half of 2022. Before concluding with an update on our IRAK4 program, I wanted to touch briefly on MDM2, a program we announced for the first time at our R&D day late last year. As we have shared, we are very excited about the potential of this program. MDM2 is the crucial regulator of the most common tumor suppressor p53, which remains intact or wild type in more than 50% of cancers. Based on preclinical data, we believe our highly potent MDM2 degrader KT-253 has the ability, unlike small molecule inhibitors, to suppress the MDM2 feedback loop and thus the potential to rapidly induce apoptosis even with brief exposures. We believe KT-253 has the potential to be effective in a wide range of hematological malignancies and solid tumors with functioning p53. Just a few weeks ago, we shared preclinical data at AACR highlighting the biological superiority of MDM2 degradation over inhibition. Specifically, we presented preclinical data for KT-253 that demonstrated extremely potent in-vitro cell killing and in-vivo antitumor activity with intermittent dosing that is superior to data reported for existing small molecule inhibitors and indicates the potential for improved efficacy and safety with degradation versus inhibition. You can find that poster along with all other publications in the scientific resources section of our website. As planned, KT-253 is currently in IND enabling activities to support an IND filing in the second half of 2022. Finally, I will cover our IRAK4 program and our lead candidate, KT-474. As previously disclosed, late last year, we completed dose escalation in the single ascending dose and multiple ascending dose portions of our Phase I clinical trial, where we enrolled over 100 healthy adult volunteers. As reported, initial data demonstrated near complete IRAK4 knockdown in PBMC and skin, as well as robust ex-vivo inhibition of multiple disease-relevant cytokines with a favorable safety profile. Specifically in the multiple ascending dose portion of the trial where subjects received 14 daily doses and explored a range of doses from 25 mg to 200 mg, robust IRAK4 degradation was seen across all dose levels with up to 98% reduction in PBMC at steady state between day seven and 14, plateauing after 100 mg. In skin, IRAK4 levels were also reduced to near the lower limit of detection by day 14 at the top dose, but had not yet reached steady state, suggesting that continued dosing beyond 14 days would likely result in further declines in IRAK4 levels at daily doses of 50 mg to 200 mg. Finally, ex-vivo cytokine induction by TLR agonists showed greater than 50% inhibition of most cytokines and maximum inhibition of 85% in the 100 mg dose group. This robust inhibition was seen in conjunction with greater than 90% IRAK4 knockdown in monocytes. With that previously disclosed data as context, I will now comment on our plans for 2022, including a few recent developments. We have selected the dose equivalent of 100 mg in the fed state to take into Part C, the patient portion of the Phase I trial. Based on our clinical experience to date, we believe that the 100 mg dose is the level at which we have maximized the pharmacology of KT-474, and which will drive robust IRAK4 degradation leading to TLR INR pathway inhibition in multiple different disease-relevant cell types that can impact inflammation and result in disease-modifying clinical activity. Having observed in SAD, an increase in exposure with KT-474 in the fed state versus fasted, we are enrolling an additional SAD cohort to determine the 100 mg dose equivalent in the fed state. Once we have those results, we will then proceed to the patient cohort portion of the trial. In respect to the patient cohort, we have made a modification to the study design. Specifically, we will be extending the dosing duration from 14 days to 28 days. This decision was made in conjunction with our partner, Sanofi, and we recently aligned with the FDA on this protocol modification. Many of you have asked about our ability to track clinical endpoints in this portion of the trial, which we had not planned to do with just 14 days of dosing. With the change to 28 days of dosing and 14 days of follow-up, we have now added several exploratory clinical endpoints, including the eczema area and severity index, or EASI for atopic dermatitis, total abscess, and inflammatory nodule count for hidradenitis suppurativa, as well as additional measures of symptoms and physician or investigator global assessments for both diseases. We plan to share the results of the patient cohort in the second half of this year, as previously guided. Finally, prior to selecting the dose for the patient cohort, we undertook a comprehensive analysis of all safety data from the SAD and MAD portions of Phase I, which recently included unblinded results. Consistent with what we have previously disclosed, the unblinded safety analysis showed KT-474 to be safe and well tolerated with no serious adverse events and no treatment discontinuations. A full analysis of 24-hour Holter ECGs, as well as safety ECGs that were part of the Phase I study, did not show any arrhythmias or other ECG adverse events. We did identify a modest non-adverse, non-dose-dependent, 10 msec to 20 msec prolongation of QTc relative to baseline only after multi-dosing in the MAD portion of the trial. This modest effect plateaued by day seven and completely reversed after day 14, following the completion of dosing. Importantly, the QTc interval itself remained less than 450 msec and, therefore, the QTc prolongation did not qualify as a grade 1 adverse event. The FDA was informed of the full safety data set, including the comprehensive QTc analysis, and did not object to the proposed dose selection, as well as the protocol adjustments to Part C that include 28 days of dosing, both to enable evaluation of exploratory clinical endpoints and to extend safety monitoring. Our broader clinical plans, aside from this adjustment to the patient cohort, remain unchanged and we are excited to advance KT-474 through further clinical development.

Thanks, Jared. I will keep my comments brief. For the quarter, we recognized $9.6 million of revenue. This total reflects revenue recognized pursuant to our Sanofi and Vertex collaborations. At the end of the quarter, our deferred revenue total on the balance sheet was approximately $93 million. That reflects partnership revenue that we expect to recognize over the next several years. With respect to operating expenses, R&D for the quarter was $35.9 million of which about $3.9 million represented non-cash, stock-based compensation. The adjusted cash R&D spend of $32 million, which again, excludes the stock-based compensation, reflects about a 5% decrease from the comparable amount in the December quarter. Our G&A spending for the quarter was $10.6 million, $4 million of which was non-cash stock-based comp. The adjusted cash G&A spend of about $6.6 million, again, excluding stock-based compensation, reflects a 2% decrease from the comparable amount in the December quarter. And finally, for my part, we exited the first quarter with cash and equivalents of approximately $523 million. That provides a runway based on our current anticipated spending levels into 2025. And please recall, we do not include in our cash runway any payments for milestones that we have not yet received. I'll now turn the call back to Nello for some concluding remarks.

Thanks, Bruce and Jared. In conclusion, I think I can clearly say that we're very excited about where Kymera is at the moment. We have an exciting first-in-class pipeline that is progressing through the clinic; a best-in-class platform and discovery engine of which we'll continue to hear about as we disclose more programs and data; productive partnerships with Vertex and Sanofi that allow us to expand across multiple disease areas; and as you've heard from Bruce, a very strong cash position that enables us to continue to invest in high-value programs and generate several important data sets in the next few years. In 2022, we're looking forward to generating key proof-of-mechanism data in two oncology clinical programs, KT-413 and KT-333 against two undrugged targets and pathways, IRAK4-MiD and STAT3, both with broad franchise potentials. We're also very excited to add our fourth clinical program later in the year with our MDM2 degrader, KT-253, which we believe will have large clinical potential. With regards to KT-474, as you've heard from Jared, after consultation with the FDA, we've extended our Phase I patient studies to 28 days to generate even more potentially de-risking data, including the possibility of early clinical proof of concept. We strongly believe that this mechanism has the potential to be the best-in-class small molecule anti-inflammatory drug, and we're excited to explore clinical activity in HS, AD, and eventually in a wide variety of additional indications. I'd like to thank, first of all, the Kymera team for every day pushing boundaries in a completely new drug modality, and for continuing to execute on our very ambitious goals. I would like to thank our collaborators for enabling us to operate efficiently in a globally challenging landscape; our partners for the rich contributions; and last but not least, all the healthy volunteers and patients that allow us to advance the development of our potentially transformative therapies. Finally, I would like to thank all of you that have taken time this morning for our first quarterly call and looking forward to a rich Q&A. I'll now hand the microphone back to the operator so that we can take your questions. Thank you.

The first question comes from Eliana Merle with UBS. Please go ahead.

Congrats on all the progress. Maybe just first on the 28-day patient cohort, I guess, do you still anticipate enrolling 20 patients or, given the sort of lengthening of the study, do you anticipate perhaps enrolling more patients as well? And then if you could just comment on the anticipated mix between atopic derm and HS patients within that cohort? And then second, just on the QT prolongation, can you give us just a little bit more color on what was seen, sort of, like the number of patients, which dose levels, and I think you said it wasn't considered grade 1, even... I mean, just any more color would be helpful? And I guess also when you did the unblinding of the safety data, just maybe what dose levels the mild heart palpitations were seen at?

Cool. Thanks, Ellie. This is Nello here. So maybe I'll just give a brief overview and then I'll let Jared here comment on the specifics. So as we said, the extension of the study to 28 days was mostly driven by our desire to pursue an opportunity to understand even further the pharmacodynamics and potential clinical profile of the molecule, given the competitive space, and to be honest, given the profound pharmacology that we've observed so far. Also after unblinding the study, we wanted to take the opportunity to extend the duration of dosing to further our understanding of the safety, which so far has been actually quite promising. Maybe Jared, you can comment a bit on the unblinding, what we've learned as well as I think Ellie's question was also about this modest finding that we have with QTc, which doses and how it was detected.

Sure. Yes. As we described on the call, we were always planning to unblind and really have a comprehensive look at all the safety data once we decided that we wanted to dose escalate further and when we were going to then choose our dose to bring it to Part C. The unblinding really showed that the adverse events that we saw with the blinded analysis still remained the primary adverse event that we saw in a relatively small proportion of patients, including headache that was predominant; mild palpitations that were also predominantly mild and self-limited, as well as several subjects with nausea. It turned out that the adverse events, these in particular, we're seeing in the drug arm, not in the placebo arm, and that was not unexpected. And again, just to note that these were relatively few in number, they were self-limited, and they were predominantly mild. In terms of the QTc finding, as we described, this was not seen in the SAD portion of the study, and it was not seen following the first dose of the MAD, it was only seen after multi-dosing. This was a modest effect. This 10 msec to 20 msec increase is a modest effect. This change in QTc is well below the 60 msec threshold that is associated with risk of arrhythmia. And also importantly, the QTc interval itself remain less than 450 msec, which is essentially within the normal range, which is also well below the 500 msec threshold which confers risk of arrhythmia. So, we note this modest change in QTc, but it's important to note that this is well away from the threshold associated with any sort of possibility of clinical adverse events such as arrhythmia.

Okay, thanks. Maybe I will just add one thing as we go, Bruce, if we go to the next question here. So, why are we sharing a non-adverse event in this call today, as obviously, never made to the table of adverse event, and actually we only learned it afterward, and the reason that we're doing so is just because we want to keep our style of communication transparent and continue to maintain a high level of rigor and credibility. Obviously, we can discuss over the next half an hour, this particular finding but hopefully we get to talk about the other things as well.

Thank you. Your next question is from Brad Canino with Stifel. Please go ahead.

On the newly added clinical endpoints for KT-474, I've seen data with the TNFs and IL-1 agents in HS, particularly where improvements don't max out until about eight weeks. So do you have any HS benchmarks in mind when you're thinking about the four-week time point? I'm especially asking in consideration of Pfizer's announcement to discontinue their IRAK4 small molecule this morning? And then looking forward to the other development opportunities for 474, I'd like to ask about your takeaways from the recent Nature publication, they implicated TLR7 as the central signaling pathway in lupus, and whether that might change your disease development prioritization at all?

Thank you, Brad. Those are excellent questions. I’ll address part of it, and then Jared can discuss the more specific aspects. I want to emphasize the 28 days. We're not conducting a 28-day study to provide conclusive proof-of-concept data. As we've previously mentioned, based on our preclinical studies, we have the opportunity to extend the duration of these studies to 28 days to strengthen our understanding of pharmacokinetics, pharmacodynamics, early clinical efficacy, and the safety profile, allowing us to better assess the risk-reward profile of the molecule. While I won’t comment specifically on other drugs in a four-week study, it’s reasonable to state that in both AD and HS, active treatments typically begin to differentiate from placebo in well-controlled studies within four weeks. Therefore, it would be shortsighted not to track clinical endpoints. We are not expecting to establish clinical proof-of-concept, as this is an open-label study, but we aim to further develop our relationship with RPD and explore early potential clinical endpoints. This effort is part of our ongoing commitment since the early stages of this program. Now, I'll let Jared talk about the comparisons he's monitoring. Regarding the Pfizer issue and other indications, we just learned a bit more about their studies. It's important to clarify that their HS study seems to have been halted, while the RA trials are still proceeding. I don’t want to speculate on this call, but it appears that there isn’t a safety concern given that other studies are still ongoing. We still lack data comparing HS with the three-arm study involving the JAK inhibitor and TYK2. It's uncertain if there has been a prioritization in their pipeline, and we’ll need to observe that. On the topic of opportunities, our presentation outlines several prospects relating to TH1, TH17, and TH2 biology. We have taken note of recent human genetic data on TLR7, which shows a strong correlation with lupus. Lupus is one of the diseases we're actively investigating with our partner Sanofi, and we'll strive to fully leverage the potential of this mechanism as we advance the program. Jared, do you have any comments on the comparisons?

Yes, maybe just to touch on this in terms of why extending also the 28 days. I think one of the main drivers for our decision to extend the 28 days of dosing came from our review with the pharmacodynamic data, where we saw that while knockdown in peripheral blood really reached steady state after seven days of dosing. In skin, we had not reached steady state after 14 days of dosing. Therefore, being able to extend dosing to 28 days would give us the opportunity to dose long enough to reach steady-state knockdown in skin. And since in Part C, what's very important to us is it now obtains skin biopsies of active, inflamed skin lesions, and being able to show not just knockdown of IRAK4 in the skin, but also impact on disease-relevant inflammatory biomarkers in the skin. We thought it was important to extend the 28 days to give us the best chance of really showing that sort of pharmacology in diseased skin. Now in terms of the comps, at 28 days, we know, for example, in the Humira pivotal studies in HS and the Dupixent pivotal studies in AD, if you look at the curves for their various primary endpoints or even their secondary endpoints, you can see that at 28 days, as Nello was saying, you can start to see separation clearly from placebo. So we think that there is potential opportunity to detect an initial sort of exploratory signal of clinical efficacy. What would be nice for us is to be able to connect a signal of efficacy with pharmacodynamic effect with proof of biology showing impact of IRAK4 and inflammatory biomarkers in both the skin and the blood. So being able to make that connection of Part C, we think would really help to further de-risk the program.

Thank you. And your next question comes from Michael Schmidt with Guggenheim. Please go ahead.

This is Paul on for Michael. I have one on your IRAKIMiD. There's been some renewed focus recently on tolerability with the next generation of IRAK4 inhibitors, particularly on neutropenia. So just wanted to get a sense of your expectations around digital safety for 413, given how you designed the molecule and any read-through, if any, from the competitive landscape. And then secondly, you mentioned STAT3 has some potential in inflammatory and fibrotic diseases. Just wondering if there are any gating factors that you're thinking about the potentially initiating development outside of oncology and if there's something we can expect if the pharmacodynamics and safety data from the Phase I look good?

Thanks, Paul. Those are great questions. To start, I think everyone is familiar with the pharmacology of IMiD and the strategies that Celgene, now Bristol, has implemented to develop those drugs. So, I’m not surprised to see the pharmacology of IMiD manifest in various clinical studies based on the compound's potency. Our objective has always been to enhance the synergistic pharmacology between IRAK4 degradation and IMiD degradation to maximize activity while ensuring safety. Based on the potency, pharmacokinetics, and distribution profile of our molecules, we’ve optimized this molecule for dosing every three weeks, which is quite different from the typical IMiD dosing schedules. We are confident going into the study that we will effectively explore how the preclinical study translates into clinical results concerning safety and activity. We will provide updates on the evolving data before the end of the year. Regarding STAT3, we have made significant investments in that program and recently there was a comprehensive review of other efforts in this area. It's fair to say that our selective degrader represents the most de-risked method for targeting STAT3 specifically and selectively. For a couple of years, we’ve focused on understanding the pharmacology and safety of STAT3 degradation, conducting multiple efficacy and safety studies across various disease states. We have separated oncology from non-oncology indications because we believe the degradation profiles required in oncology are quite different from those needed outside of oncology. The development of molecules outside of oncology is slightly behind as we are ensuring the pharmacokinetics, pharmacodynamics, and safety are firm before advancing to the clinic. I hope that provides some clarity on the STAT3 program.

Thank you. Your next question comes from Vikram Purohit with Morgan Stanley. Please go ahead.

This is Gospel on for Vikram. We have two questions. So, the first one pertains to Sanofi. I mean, could you walk us through the mechanics of how your decision-making process with Sanofi will unfold, following the release of the KT-474 data in the second half of 2022? Specifically, I mean, how long does Sanofi have to review the package and how will you be working with them to prioritize the indication to evaluate in Phase II? When do you think this disclosure could be provided to the Street? And how are you thinking about the timing and process for your opt-in decision?

Thank you. To start, we maintain close communication with all of our partners. They are fully aware of and involved in key regulatory interactions and internal decision-making. Once we complete the patient cohort to gather additional data, which we hope will provide important de-risking information, we will promptly present Sanofi with a comprehensive data package that includes all preclinical and Phase I data. This document is substantial, and while we haven't specified the exact timeframe, it will definitely take less than six months for them to decide whether to move KT-474 into Phase II. Our aim is to provide this complete dataset to Sanofi before the year's end, and we anticipate a swift decision since they are updated on the program's progress. Regarding Kymera's opt-in, if Sanofi chooses to proceed with KT-474 in a randomized placebo-controlled Phase II study, Kymera will then have the option to co-develop and commercialize in the U.S., sharing profits and losses equally. This decision will need to be finalized before the start of Phase III to ensure our operational and financial involvement in that study.

Thank you. Your next question comes from Kalpit Patel with B. Riley. Please go ahead.

One, just one question on your IRAKIMiD program, I think another drug developer Curis had a clinical hold placed recently on their IRAK4 inhibitor on safety concerns for rhabdo. I guess, does that in any sense impact your thinking about how you're advancing this IRAKIMiD program? From my understanding that Curis drug is more of a dirty kinase inhibitor that might have been responsible for the safety concerns, but do you have any evidence of elevated CK levels in your preclinical studies with the IRAKIMiD program?

Yes. Thanks for the question. No, I think it's a good question. I think as you mentioned, the Curis compound is a multi-kinase inhibitor in addition to IRAK4. One, its key target is FLT3. There have certainly been published reports of rhabdomyolysis occurring with other FLT3 inhibitors. So we think it's highly likely that the rhabdomyolysis that they're seeing and that's problematic and potentially dose-limiting for them is because of the FLT3 targeting. With regard to IRAK4 targeting, we, and others, have not seen any rhabdomyolysis with either IRAK4 targeting or the use of IRAKIMiD in our preclinical studies. As you know, in our IRAK4 Phase 1, we are engaging the target quite robustly and knocking out the target by 98%. We have not seen any rhabdomyolysis. We are not aware of any reports of rhabdomyolysis from Pfizer with their IRAK4 kinase inhibitor in their various clinical trials. Also, there are IRAK4 no individuals who, as adults, really have no clinical phenotype and certainly have no muscle pathology. Therefore, we don't think that there's a connection between IRAK4 targeting and rhabdomyolysis, and what Curis is seeing is probably due to off-target effects and most likely FLT3 targeting.

Thank you. Your next question comes from Divya Rao with Cowen and Company.

Divya on for Mark. First one is, could you talk about what constitutes meaningful degradation for IRAK4 in the AD/HS population? And then, do you think the levels of IRAK4 needed to drive this meaningful clinical benefit is different between the two? And then just like a little bit more broadly, are you willing to comment on the venues you plan to present the updates on all three clinical updates coming later this year? Would it be like a medical meeting or possibly another R&D day?

Great. So you broke up to the point, so I'm going to repeat the question. Hopefully I got it right. So the first part was, do you expect the degradation profile needed to be different between HS and AD? I'll let Jared take that one. And then I want to answer the presentation venues. So, we have always said that we like to present scientific data at scientific medical meetings. We've also said that our commitment to timeline and, again, going back to the point that I made about transparency and credibility, is paramount. So if we said that we're going to present the data before the end of the year, which is true for all three programs, we're going to try our best to do it in a medical meeting. If not, if for timeline reasons or abstract submission, etc., we won't be able to do, then we'll find another venue, whether it's an R&D Day or it's a focus meeting. It's not our preference by far, but, again, I just want to say that as a company, we like to commit to the timelines that we give, unless, obviously, some operational issue arises and we can't deliver on the timelines, which is not the philosophy we have at Kymera. Jared, do you want to comment on the degradation profile?

Yes. Yes, I think it's a really important question. I think that we anticipate that the degradation that we need for clinical impact should be similar for AD and HS. We've learned from our preclinical mechanistic models of inflammation that 85% or greater degradation really has an impact on inflammation and the induction of various inflammatory cytokines that drive inflammation. We've also learned from our Phase I healthy volunteer study so far that a similar threshold, 85% or greater degradation is associated with an impact on ex-vivo cytokine induction. So, we think that really what's important is how much degradation is needed to impact the function of the TLR IL-1R pathway, and importantly, the particular function that we're interested in is the induction of pro-inflammatory cytokines and chemokines. And so, we anticipate a similar threshold of knockdown, at least 85% or greater, in blood and in skin for us to really be able to impact inflammation in both of these diseases. We feel from what we've seen so far in the healthy volunteer study, with the dose that we plan on taking into Part C, that we should be able to readily attain those levels of IRAK4 degradation.

Thank you. Your next question comes from Eric Joseph with JPMorgan. Please go ahead.

I wanted to revisit the first question on QT, specifically the dose levels where you observed the extension or the prolongation and how it resolved. I guess, did it resolve on consistent dosing or was dosing modified in any way? And do you anticipate having to conduct a thorough QT study as part of the Phase I package prior to...?

Thanks, Eric. Great question. I think it's created an opportunity to clarify this point. So, I'll just want to clarify one thing and then I'll pass it to Jared. So, I think what we've said is that this is a non-dose-responsive, self-limiting, modest finding that never became an adverse event, not even a grade 1 for QTc. Again, I repeat, the reason why we're sharing it is for being transparent as a company. Maybe Jared, you can comment on those adjustments, resolution and all that stuff.

Yes, during the SAD and MAD, there were no ECG adverse events, and no changes in the QTc interval that qualified as an adverse event. It was only after completing those stages and conducting a more detailed analysis of ECGs before selecting the dose for Part C that we observed a small QT prolongation, which was not adverse. To maintain transparency with the FDA, we shared this data with them. We have received approval to proceed into Part C with a robust dose of 100 mg, which should enhance pharmacology. We are continuing daily dosing, extending it to 28 days, and incorporating clinical endpoints. Regarding the need for a thorough QT study, it's common for companies to conduct these studies. In some cases, they can be skipped if there is sufficient ECG data from the Phase I study to evaluate any QT effect. A thorough QT study might be considered depending on the findings in Part C. Currently, we understand that the QT effect observed is very modest and has not approached the threshold for being classified as adverse, not even close.

Thank you. Your next question comes from Richard Low with Credit Suisse. Please go ahead.

I have two questions. So regarding the QTc observation, did the FDA ask for any mitigation plans if that reoccurs again? And at what point would that trigger some sort of intervention? And then the second question I have is on KT-474. Can you share with us any updated changes to the timeline or preliminary discussions you had with Sanofi regarding the Phase II plans, like in terms of what type of patients will you be exploring? And also you mentioned the RCT trials. Would that be any head-to-head studies with biologics?

Yes. No, thanks. I just want to clarify again, the first point. We actually did not have to share this QTc finding with the FDA, but we decided to do so. We have a really strong relationship with our regulatory group. We've had close to four MD submissions and several other follow-ups, so we try to be as transparent and collaborative as we can with the FDA. We obviously had to engage them to amend the protocol. When we did, we also submitted all the safety, PK, and PT data that we generated. We really didn't receive much in the way of comments regarding how we're proposing to continue to explore the safety of the drug. I think they generally align with our proposed plans, and there was no particular mitigation plan that was discussed. This was our study design protocol. There was a general alignment in the big picture. With regards to Sanofi, again, we are very close to the team, to the development team. I think where we are today is that, as we have always said, we have some really high priority indications. There are several, but what we've discussed often is atopic dermatitis, hidradenitis suppurativa, rheumatoid arthritis. We talked last week a lot about lupus, for example. I think what we agree makes sense is to continue to see how the data emerge from this patient study. Obviously, now this patient study is much more powered in terms of data that we generate. I think with that data in hand, we will refine the strategy and the selection for the right priorities that we'll have for Phase II and beyond.

Thank you. Your next question comes from Zhiqiang Shu with Berenberg.

I have two questions. First, regarding the STAT3 program. Over the past year, you mentioned the possibility of accelerated approval based on the clinical data. Do you still maintain that perspective? Additionally, I noticed that you have updated the protocol to include a combination study. Could you elaborate on your plans for that combination study?

Yes, it was a bit noisy, but I think Jared, the question was: What is the path to potential accelerated approval that we're planning with STAT3? And then the combo, what is the plan on how to develop the combo?

Yes, I think with STAT3, we see the rapid development opportunity in STAT3 dependent key malignancies, especially certain T-cell malignancies like peripheral T-cell lymphoma, cutaneous T-cell lymphoma, and LGL leukemia, where you tend to see activating mutations in STAT3 or in JAKS or even just hyperactivation of the pathway. Our preclinical animal model data where we've seen very robust tumor activity with STAT3 degraders in monotherapy lead us to believe there are rapid approval or accelerated approval opportunities with our STAT3 degrader, KT-333 as a monotherapy. In terms of combination, we tend to think more about combination in solid tumors where we have shared very interesting data where the immunomodulatory properties of STAT3 synergize with anti-PD-1 drugs to show synergistic anti-tumor activity and various solid tumor models, syngeneic tumor models, such as colorectal cancer. Therefore, we think there could be an even larger opportunity for combination development with checkpoint inhibitors and solid tumors. Those paths may not be as accelerated because those are combination studies as the monotherapy path, but we think that those are also very attractive and represent even larger opportunities for the degrader.

Yes, I'm going to ask about your IRAKIMiD program. Have you seen any QTc findings in those programs, although I know it's still early?

Yes, so far, we're early in - we just opened our Phase I. So, we were not in possession of any human safety data. Generally, what I would say is that QTc prolongation is not a signal that we've had to deal with, within our pipeline. So, it's not something that is present in our portfolio molecules broadly.

Thank you. And I'm not showing any further questions in the queue. I would like to turn the call back to Nello Mainolfi for his final remarks.

Yes. So thank you. First, I want to thank everybody for tuning in today. I realize it was a very busy day in the biopharma space in terms of calls. So thanks for calling in. I just want to reiterate that we're a company that is almost six years in. We have a rich pipeline of programs across a variety of indications. Again, we've talked about HS, AD, T-cell lymphoma, T-cell leukemia, solid tumor, diffuse rash B-cell lymphoma, and then soon, with MDM2, other indications. You see that we're obviously a company that is trying to build into a fully integrated business that takes protein degradation into the space where it should be, which is really changing people's lives. We're here for any follow-up for any questions that others might have during the day or in the next few days. I want to thank the team here, Bruce and Jared, and the team at Kymera for continuing to generate really best-in-class data every quarter and wish everybody a good day.

Thank you, ladies and gentlemen, for participating in today's call. You may now disconnect. Have a wonderful day.