Kymera Therapeutics, Inc.

Welcome to the Chimera Therapeutics quarterly conference call. Leading the call from management are Nello Manolfi, founder and CEO, Jared Golub, chief medical officer, and Bruce Jacobs, chief financial officer. After management's prepared remarks, we will open the call to your questions. To ask a question, you may press star then one on your telephone keypad. To withdraw your question, please press star then two. And please note, this event is being recorded. 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 Chimera disclaims any obligation to update such statements. I will now hand the call to Melo Manolfi, founder and CEO. Please go ahead.

Thank you, operator, and thank you, everyone, for joining us on our second quarter results conference call. We're excited to share with you today the continued progress we're making towards building Chimera into a best-in-class, fully integrated degrader medicines company. As we reach our two-year anniversary as a publicly listed company later this month, we can be really proud of a period of brilliant, outstanding growth and achievement at Chimera. I want to start by saying that the second quarter has been significant for us, particularly in terms of substantial clinical progress we've made by advancing our three lead programs into important stages of their development. Specifically, we dosed the first patients in our three first-in-class clinical programs, including commencing patient dosing in our Part C of our Phase I trial of KT474. This achievement ushers in a new phase for the company as we look forward to demonstrating how targeted protein degradation and these molecules in particular can impact disease and patients' lives. This is just the start of our journey toward treating patients in many disease areas such as adrethronitis separativa, atopic dermatitis through degradation of IRAC4 with KT474, hematological malignancies in solid tumors with KT333, our selective STAT3 degrader, and mighty 88-newton B-cell lymphomas with our arachnid degrader KT413, which has the potential to be the first precision medicine for these conditions. At Chimera, as evidenced by our initial programs, we have the ambitions and capabilities to really broadly apply our platform by expanding the draggable proteome to address inadequately dragged or undragged targets, creating the potential for us to transform the lives of patients, which is really what the company was founded upon and is going towards. We ended the second quarter in a very solid financial position with approximately $482 million in cash, three first-in-class TPD assets in clinical studies, one program KT253, our MD and 2D grader, close to IND filing, and multiple preclinical candidates expected to drive us to our goal of at least one new IND per year, and productive collaborations with our partners Sanofi and Vertec. We have multiple patient data sets expected by year-end, including the Part C data for KT474, our patient cohort. Our plan is to share this data later this year with the medical and investor communities, as well as with our partner Sanofi, to enable their decision around advancing KT474 into Phase II studies. Now, Jared will walk you through our recent progress and goals for 2022 for each of our disclosed programs before turning the call over to Bruce for then a financial update. I will then finish with some concluding remarks before handing the call back to the operator for a Q&A session in which Jared, Bruce, and myself will be available. Jared? Thanks, Nello.

We've made substantial progress with our clinical programs this quarter, which I am excited to share. I'll start with our IRAC4 program and our lead candidate, KT474, an orally available potential first-in-class degrader of IRAC4, a key protein involved in inflammation mediated by the activation of Toll-like receptors and IL-1 receptors. A barren deactivation of these pathways is the underlying cause of multiple immune inflammatory conditions. KT474 is being developed for the treatment of TLR, IL-1R-driven immune inflammatory diseases with high unmet medical need, such as hydradenitis seborrheiciva, atopic dermatitis, rheumatoid arthritis, lupus, GI inflammation, and potentially others. AT474 is designed to block TLR-IO1R-mediated inflammation more broadly compared to monoclonal antibodies targeting single cytokines, and to enable pathway inhibition that is superior to IRAC4 kinase inhibitors by abolishing both the kinase and scaffolding functions of IRAC4. We are collaborating with Sanofi on the development of the greater candidates targeting IRAC4, including KT474, outside of the oncology and immuno-oncology fields. Late last year, we completed dose escalation in over 100 healthy volunteers in the single ascending dose and multiple ascending dose portions of the KT474 phase 1 trial, the first randomized placebo-controlled trial for a hetero-by-functional degrader. The data demonstrated near complete IRAC4 degradation in peripheral blood, mononuclear cells, and skin, robust inhibition of multiple ex vivo stimulated disease-relevant cytokines, and a favorable safety profile. At the SID annual meeting in May, we disclosed that KT474 degrades IRAC4 and inhibits cytokine production in different immune and skin cell types, highlighting the broad impact of KT474 across multiple disease-relevant cell types and supporting the continued development of IRAC4 degraders in patients with HS, AD, and other IONR, TLR-driven autoimmune diseases of the skin, where IRAC4 plays a central role in the pathogenesis of inflammation. You can find that poster along with all our other publications in the scientific resources section of our website. Most recently, as Nello just mentioned, we are excited to share that we commenced dosing patients in the patient cohort part C of the phase one clinical trial. Part C is an open-label study of KT474 that is expected to enroll up to a total of 20 patients with moderate to severe hydradenitis suppurativa or atopic dermatitis to examine the safety, PK, PD, and exploratory biomarker and clinical activity of this first-in-class to greater therapeutic. While we are in the early stages of the patient cohort, we expect enrollment to progress as planned for us to disclose the data before year F. KT474 is being administered daily on an outpatient basis for 28 days, with patients followed through day 42. Patients will receive a daily dose of 75 milligrams of KT474 with food. This dose is expected to provide a plasma exposure that is approximately equal to that achieved with the 100 milligram per day dose in the fasted state in healthy volunteers in the MAD portion of the trial. which showed maximal or close to maximal degradation in blood and skin and broad disease-relevant cytokine inhibition ex vivo. The goal for this study is to confirm that our PD and safety profile in patients is in line with what we have seen in healthy volunteers. PDM points include the impact of KT474 on IRAC4 levels in PBMC and in active HS and AD skin lesions, as well as on the expression of pro-inflammatory gene transcripts in skin lesions and on both whole blood ex vivo cytokine induction and plasma biomarkers of inflammation. We are also undertaking an exploratory assessment of early impact on clinical endpoints, including eczema area and severity index, or EASI for AD, total abscess and inflammatory nodule count for HS, as well as symptom scores and global assessments of disease severity for both AD and HS. However, recall that this is an open-label study without placebo in a small number of patients, and we do not expect to reach steady-state IRAC-4 degradation in skin until the second half of the four-week dosing period. The objective of Part C, therefore, is to confirm PK, PD, and safety with the additional information on early signs of clinical activity. With regard to safety and tolerability, which so far has been quite favorable with no serious adverse events and with only few mild to moderate adverse events, we will continue to monitor the safety profile, including whether the modest non-adverse QTC prolongation that we observed with multi-dosing and healthy volunteers that plateaued after seven days continues to show evidence that it is self-limited, but in this case out to 28 days. We look forward to sharing the data from the patient cohort before year end. With respect to Sanofi and their decision to advance KT474 into phase two, We plan to share these patient data with them as soon as they are available and expect a decision on their plans within the timeframe set forth in our collaboration. Moving on to our oncology programs, we are pleased to report that the three disclosed oncology programs, STAT3, Arachamid, and MDF2, are all progressing well. First, I will discuss our STAT3 program. A target long considered undruggable, STAT3 is a transcriptional regulator that has been linked to numerous cancers and other inflammatory and autoimmune diseases. 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. AT333 is a potent and selective heterobifunctional small molecule protein degrader of the STAT3 protein in development for the treatment of liquid and solid tumors. Patient enrollment and dosing are ongoing in our phase one trial, which is evaluating the safety, tolerability, PKPD, and clinical activity of KT333 in adult patients with relapse and or refractory lymphomas and solid tumors. The first stage of the study is exploring escalating doses of KT333. It is important to highlight that in order to expedite dose escalation, we have been recruiting broadly in Phase 1A across solid and liquid tumors in order to reach pharmacologically active doses as soon as possible, before then focusing on patient populations where we expect to see clinical activity, either as a monotherapy or in combination with other agents. The second stage will consist of four Phase 1B expansion cohorts to further characterize safety, tolerability, PKPD, and antitumor activity, of KT333 in relapsed and or refractory peripheral T cell lymphoma, cutaneous T cell lymphoma, large granular lymphocytic leukemia, and solid tumors. This escalation is expected to proceed throughout 2022, and we look forward to sharing preliminary safety and proof of mechanism data before year end, with the goal, based on the broad population of liquid and solid tumors in phase 1a, of showing that we can attain levels of target degradation associated with anti-tumor activity disease-relevant animal models at doses that are safe and well-tolerated. Recall that we are also exploring STAT3 degradation in immune inflammatory indications using other STAT3 degraders. To that end, at the ULAR Congress in June, we presented data showing that KTX115, a tool STAT3 degrader, selectively and potently degraded STAT3 in human peripheral blood mononuclear cells and whole blood, aggregated stat-free phosphorylation and MCP CCL2 released by human monocytes more potently than JAK inhibition, and inhibited CD4-positive Th17 development and related cytokine production in vitro and prevented collagen-induced arthritis in mice. You can find those posters in the scientific resources section of our website. Moving now to our arachnid program, KT413 is a novel heterolife functional degrader that targets degradation of both IRAC4 and the imid substrates, the carotid myelos, with a single small molecule. KT413 was designed to address both the IONR, TLR, and the type 1 interferon pathways synergistically to broaden activity against mighty 88 mutant B-cell malignancies. KT413 is on a similar timeframe as STAT3, with patient enrollment and dosing ongoing in our phase 1 trial evaluating the safety, tolerability, and PKPD of KT413 in patients with relapsed and or refractory B-cell non-Hodgkin's lymphomas. The first stage is exploring escalating doses of single-agent KT413. Using a similar strategy as I just described for the KT333 Phase I, we are expediting dose escalation of Phase Ia by enrolling a broad population of B-cell lymphoma patients before then focusing on patients in whom we expect to see the most substantial clinical activity. Specifically, the second stage will consist of two Phase 1b expansion cohorts in DLBCL to further characterize the safety, tolerability, PKPD, and antitumor activity of KT413 in relapsed refractory MiD88 mutant and MiD88 wild-type DLBCL. Dose escalation is expected to proceed throughout 2022, and we look forward to sharing preliminary safety and proof-of-mechanism data before year-end. with the goal, based on the broad population of B-cell lymphoma patients in Phase 1a, of showing we can attain levels of target degradation associated with anti-tumor activity and disease-relevant animal models at doses that are safe and well-tolerated. I want 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. Our highly potent MDM2 degrader, KT253, unlike small molecule inhibitors, is able to suppress the MDM2 feedback loop and thereby rapidly induce apoptosis in susceptible P53 wild-type tumors with brief exposure. We believe KT253 has the potential to be effective in a wide range of hematological malignancies and solid tumors with functioning P53. Specifically, our use of biomarkers for an acute episodic response to MDM2 degradation has enabled the identification of several indications where we expect to see robust activity and a favorable safety profile with intermittent IV dosing, such as AML, lymphomas, and multiple different solid tumor types, including but not limited to uveal melanoma, mesothelioma, colorectal, and breast cancer. These all represent potential development opportunities for KT253, with patient selection to be further guided by ongoing work focused on mutation and or gene expression profiles. As planned, KT253 is currently in IND enabling activities to support an IND filing in the second half of 2022. Before Nello wraps up 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.