IRAK4

KT-474 is a potent, highly selective, orally bioavailable IRAK4 degrader, in development for the treatment of IL-1R/TLR-driven complex inflammatory diseases where there is an opportunity to significantly advance the standard of care in a broad variety of diseases. In the Phase 1 trial, KT-474 showed evidence of robust IRAK4 degradation in the blood and active skin lesions of HS and AD patients and was generally well tolerated. Treatment with KT-474 was associated with a systemic anti-inflammatory response and improvement in skin lesions and symptoms in both HS and AD patients, with internal consistency between the effect on inflammatory biomarkers and impact on clinical endpoints. KT-474 was generally safe and well-tolerated, with no serious adverse events, no drug-related infections, and no dose interruptions or discontinuations due to adverse events. Sanofi, which is collaborating with Kymera on the development of KT-474 (SAR444656) outside of the oncology and immuno-oncology fields, initiated two randomized, placebo-controlled Phase 2 trials evaluating KT-474 for the treatment of HS and AD, and the first patient was dosed in the HS trial in October 2023

More information on the Phase 2 studies in HS (NCT06028230) and AD (NCT06058156) can be found at www.clinicaltrials.gov.

STAT3

The Phase 1 clinical trial of KT-333 is designed to evaluate the safety, tolerability, PK/PD and clinical activity of KT-333 dosed weekly in adult patients with relapsed and/or refractory lymphomas, leukemias and solid tumors. In June at the International Conference on Malignant Lymphoma (ICML), with a data cutoff date of May 1, 2023, Kymera presented data on thirteen patients who received a mean of five doses across the first four dose levels (DL1-4) of the trial, including patients with solid tumors, cutaneous T-cell lymphoma and peripheral T-cell lymphoma. With DL4 still open to accrual at the time of the presentation, data reported from DL1-3 found plasma exposure increased with dose, reaching levels close to those predicted to be efficacious, and demonstrated dose-dependent STAT3 degradation with up to 88% mean maximum reduction in peripheral blood mononuclear cells and degradation profiles at DL3 near levels of knockdown that led to antitumor activity in preclinical models. We shared at ICML that there were no dose-limiting toxicities observed in the study. The Phase 1a dose escalation stage is ongoing, recruiting broadly across solid and liquid tumors. Additional data from the Phase 1 clinical trial will be shared at the American Society of Hematology Annual Meeting in December 2023. KT-333 has been granted Orphan Drug and Fast Track designations by the U.S. Food and Drug Administration for both the treatment of relapsed/refractory cutaneous T-cell lymphoma (CTCL) and relapsed/refractory peripheral T-cell lymphoma (PTCL).

More information on the Phase 1 study can be found at www.clinicaltrials.gov, identifier NCT05225584.

MDM2

KT-253 targets MDM2, the crucial regulator of the most common tumor suppressor, p53. p53 remains intact (wild type) in close to 50% of cancers, meaning that it retains its ability to modulate cancer cell growth. While small molecule inhibitors have been developed to stabilize and upregulate p53 expression, they induce a feedback loop that increases MDM2 protein levels, which can repress p53 and limit their efficacy. In preclinical studies, KT-253 has demonstrated the ability to overcome the MDM2 feedback loop and rapidly induce cancer cell death, even with brief exposures. This may also enable an improved therapeutic index, which could result in a superior efficacy/safety profile. The Phase 1 study began dosing patients in May and is designed to evaluate the safety, tolerability, pharmacokinetics/pharmacodynamics, and clinical activity of KT-253 in patients with relapsed or refractory high grade myeloid malignancies, including acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), lymphoma and solid tumors. Patients in the KT-253 Phase 1a dose escalation study are receiving IV doses of KT-253 administered once every 3 weeks. The open-label study is intended to identify the recommended Phase 2 dose for KT-253 and is comprised of two arms, with ascending doses of KT-253 in each arm. The first arm consists of patients with lymphomas and advanced solid tumors, and the second arm consists of patients with high grade myeloid malignancies and ALL. As shared in November 2023, with a data cutoff of October 20, 2023, KT-253 achieved clinical proof-of-mechanism in Phase 1 clinical trial and demonstrated anti-tumor activity in first solid tumor cohort without dose-limiting toxicities or hematologic adverse events. KT-253 has been granted orphan drug designation by the U.S. Food and Drug Administration for the treatment of AML.

More information on the Phase 1 study can be found at www.clinicaltrials.gov, identifier NCT05775406.

Discovery Programs

Kymera is leveraging the Company’s proprietary E3 Ligase Whole-Body Atlas, including the differential expression profile of known E3 ligases, to pursue targets and indications that may benefit from tissue-restricted or -selective degradation. Kymera has also expanded the Company’s platform to develop a new generation of molecular glue degraders for high value undrugged and non-ligandable targets, exploiting a newly identified degron motif. Multiple programs are approaching development stage in 2023.