Kymera Therapeutics announces results from Phase 1 trial of KT-474

Kymera Therapeutics (KYMR) announced positive clinical results from the patient cohort portion of its KT-474 Phase 1 clinical trial, as well as updates on its three oncology programs: KT-413, KT-333 and KT-253. IRAK4 Degrader: Part C of Kymera’s KT-474 Phase 1 clinical trial was designed to confirm that the PK/PD and safety data previously demonstrated in healthy volunteers would translate into patients with hidradenitis suppurativa and atopic dermatitis. Sanofi (SNY), which is collaborating with Kymera on the development of KT-474 outside of the oncology and immune-oncology fields, has notified Kymera of its commitment to advance KT-474 into Phase 2 clinical studies. Initial Phase 2 clinical trial of KT-474 will investigate its potential in HS and AD with the first study initiating in 2023. Pharmacokinetics/IRAK4 Pharmacodynamics: In patients with HS and AD, KT-474 demonstrated plasma PK in Part C that was comparable to healthy volunteers in MAD3. Baseline IRAK4 level in skin lesions of HS and AD patients was approximately two-fold higher compared to healthy volunteers. KT-474 demonstrated IRAK4 knockdown in both blood and skin that was comparable to MAD3, with maximum degradation exceeding 90%. Target degradation was similar across HS and AD patients in both blood and skin. Safety: 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. Adverse events, which included headache, fatigue and diarrhea, were predominantly mild, and all fully resolved. Oncology Degraders: KT-333, KT-413, KT-253: STAT3 degrader program: The Phase 1a dose escalation portion of the trial is ongoing; dose level 1 has been completed with a total of four patients enrolled. Plasma PK and PD translated as expected in humans with mean maximum STAT3 degradation in PBMC following the first 2 doses averaging 66%, with maximum STAT3 knockdown of up to 86% as measured by mass spectrometry. There were no DLTs or treatment-related SAEs observed in DL1. DL2 [0.10 mg/kg] is currently enrolling. Kymera plans to share additional STAT3 clinical data in 2023. IRAKIMiD degrader program: 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. The Phase 1a dose escalation portion of the trial is ongoing; dose level 1 and dose level 2 have been completed. Plasma PK and PD translated as expected in humans with DL1 and DL2 showing dose-dependent degradation of IRAK4, Ikaros and Aiolos in PBMC, with up to 95/100% knockdown of Ikaros/Aiolos and 40% knockdown of IRAK4 in DL2. Serial tumor biopsies at Cycle 3/Day 4 in the patient treated at DL1 showed comparable knockdown of Ikaros/Aiolos and IRAK4 as in plasma. There were no DLTs or treatment-related SAEs and no neutropenia observed in DL1 and DL2 patient cohorts. Kymera plans to share additional IRAKIMiD clinical data in 2023. MDM2 degrader program: Kymera is currently preparing to initiate a Phase 1 clinical trial evaluating the safety, tolerability, PK/PD and clinical activity of KT-253 in adult patients with liquid and solid tumors in 2023. Kymera plans to share more details around the trial design and timelines in early 2023.