Kymera Therapeutics, Inc.

conference call. Leading the call from management Arnello Mainolfi, founder and CEO, Jared Golub, chief medical officer, and Bruce Jacobs, chief financial officer. After management prepares remarks, we will open the call to your questions. To ask a question, please press star 1 on your telephone. 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 Chimera'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 can merit these claims any obligation to update such statements. I will now hand the call over to Nelo Minofi, 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 Chimera into a best-in-class, fully integrated, degraded medicine company. Before we transition into the program updates, I just wanted to take a moment to reflect on some of Chimera'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 Chemero was founded in 2016, we had both ambitions for the company we wanted to build. As you all 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, and as a result, we believe there are several important points of differentiation with respect to our strategy and our approach that still hold 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 inhibitor or another technology, several of which you know well and we will discuss today. We remain optimistic. Acutely focused on those targets that address high and met 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 E3LiGASE knowledge, capabilities, and ultimately, our industry-leading E3LiGASE 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 also of most of our peers, we believe that there is a great potential in inflammatory conditions, as evidenced by our RAC4 program. But we have not stopped there. as we've engaged with partners to 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 undrugged 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 Chimera in a very unique place in the landscape of highly innovative biotech companies. Looking now at the present, from the ambition beginning, we have succeeded in building a company in which the targets that were on top of our list in early 16 and 17 remain our lead programs today. We have entered the clinic with three programs, each of which exemplifies meaningful first in TPD. With our ARAC4 degrader, KT474, which is the first hetero-bifunctional degrader for immune inflammatory indications, we launched the first randomized placebo-controlled trial in healthy volunteers in the TPD industry. With KT333, our STAT3 degrader, we're the first company to bring a hetero-bifunctional degrader against an undrugged transcription factor into the clinic. And KT413, our dual degrader of IRAC4 and IMID 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, KT253, forward to IMD 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 four 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 Chimera. Jared will walk you through our recent progress and our goals of 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 will be available. Jared?

Thanks, Melo. Starting with our oncology programs, we are pleased to report that the three disclosed oncology programs, STAT3, Arachamid, and MDM2, are all tracking as expected. First, I will discuss our STAT3 programs. PT333, as mentioned, is our lead STAT3 degrader. As a 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 FDA in 4Q21. The first clinical site was activated in 1Q22, and the trial is actively recruiting patients. As a reminder, KT333 is being evaluated in adult patients with relapse, 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 Arachamid, KT413 is a novel hetero-bifunctional degrader that targets degradation of both IRAC4 and the imid substrates icorose and ilose with a single small molecule. KT413 was designed to address both the IL-1R TLR and the type 1 interferon pathways synergistically to broaden activity against mighty 88 mutant B-cell malignancies. KT413 is on a similar timeline as STAT3, having received IV clearance from FDA late last year. The first clinical site was activated in 1Q22, and patient recruitment is underway. As a reminder, the Phase I trial for KT413 is focused on adult patients with relapsed refractory B-cell lymphomas, including mighty 88-newton diffuse large B-cell lymphoma, or DLBCL. Our plans remain to present KT413'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 IRAC4 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, KT253, 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 KT253 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 KT253 that demonstrated extremely potent in vitro cell killing and in vivo anti-tumor 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, KT253 is currently in IND enabling activities to support an IND filing in the second half of 2022. Finally, I will cover our IRAC4 program and our lead candidate, KT474. As previously disclosed, late last year we completed dose escalation in the single ascending dose and multiple ascending dose portions of our phase one clinical trial, where we enrolled over 100 healthy adult volunteers. As reported, initial data demonstrated near complete IRAC4 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 we explored a range of doses from 25 to 200 milligrams, robust IRAC4 degradation was seen across all dose levels, with up to 98% reduction in PBMC at steady state between day 7 and 14, plateauing after 100 milligrams. In skin, IRAC4 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 IRAC4 levels at daily doses of 50 to 200 milligrams. Finally, ex vivo cytokine induction by TLR agonists showed greater than 50% inhibition of most cytokines, and maximum inhibition of 85% in the 100 milligram dose group. This robust inhibition was seen in conjunction with greater than 90% IRAC4 knockdown in monocytes. 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 milligrams 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-milligram dose is the level at which we have maximized the pharmacology of KT474 and which will drive robust IRAC4 degradation leading to TLR-IO1R 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 KT474 in the fed state versus fasted, we are enrolling an additional SAD cohort to determine the 100 milligram dose equivalent in the fed state. Once we have those results, we will then proceed to the patient cohort portion of the trial. With respect to the patient cohort, we have made a modification to the study design. Specifically, we will be extending the dosing duration from 14 to 28 days. This decision was made in conjunction with our partner, Sanofi, and we recently aligned with 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. But with this 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 hydradenitis separativa, 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 KT474 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 to 20 millisecond 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 milliseconds, and therefore the QTC prolongation did not qualify as a grade one adverse event. 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 KT474 through further clinical development. Before Neville concludes the call with some closing remarks, I will hand the call to Bruce Jacobs, our Chief Financial Officer, who will share some brief comments on our financial results for the first quarter. Bruce?