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, plans to initiate Phase 2 clinical trials of KT-474 in both HS and AD in 4Q23.

More information on the Phase 2 study in HS can be found at www.clinicaltrials.gov, identifier NCT06028230.

IRAKIMiD

KT-413 is a novel heterobifunctional degrader targeting both IRAK4 and the IMiD substrates Ikaros and Aiolos. Designed to address both the IL-1R/TLR and Type 1 IFN pathways synergistically with a single molecule, KT-413 is in development for the treatment of MYD88-mutant B cell malignancies. The Phase 1 clinical trial of KT-413 is designed to evaluate the safety, tolerability, PK/PD and clinical activity of KT-413 administered as an IV infusion once every 3 weeks to adult patients with relapsed and/or refractory B-cell non-Hodgkin's lymphomas. In June 2023, Kymera shared that the first three dose levels (DL1-3) of the trial had been completed, with DL4 remaining open to accrual. Five patients had been treated across DL1-4, receiving a mean of 2.2 doses, including patients with transformed activated B-cell-like (ABC)-diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, marginal zone lymphoma, and plasmablastic lymphoma, all of whom were MYD88 wild-type except for one who had a MYD88 gain-of-function mutation. Data reported from DL1-4 found plasma exposure increased with dose, reaching levels close to those predicted to be efficacious, and demonstrated dose-dependent degradation of up to 70% IRAK4 and 96-100% Ikaros and Aiolos in PBMC after a single dose, with degradation profiles at DL3-4 consistent with knockdown levels associated with antitumor activity in preclinical models of MYD88 mutant lymphomas. There were no dose-limiting toxicities or drug-related neutropenia observed in study. The Phase 1a dose escalation portion of the trial is ongoing, recruiting a broad population of B-cell lymphoma patients.

More information on the Phase 1 study can be found at www.clinicaltrials.gov, identifier NCT05233033.

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. 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. 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.