Relay Therapeutics has received Breakthrough Therapy Designation (BTD) from the U.S. Food and Drug Administration for zovegalisib (RLY-2608) in combination with fulvestrant for the treatment of adults with PIK3CA-mutant, hormone receptor–positive, HER2-negative (HR+/HER2–) locally advanced or metastatic breast cancer whose disease has recurred or progressed following treatment with a CDK4/6 inhibitor.
The designation is supported by robust clinical data from the ongoing Phase 1/2 ReDiscover trial, which is evaluating zovegalisib in combination with fulvestrant, as well as in combination with fulvestrant and CDK inhibitors. The FDA review included data across all PIK3CA mutations, both kinase and non-kinase, from two dosing regimens with comparable drug exposure: 600 mg twice daily (BID) fasted and 400 mg BID fed, the latter being the dose selected for the ongoing Phase 3 ReDiscover-2 trial.
Safety and efficacy data from the 600 mg BID fasted cohort were previously presented at the ASCO 2025 Annual Meeting, with additional subgroup analyses shared at the 2025 San Antonio Breast Cancer Symposium. Initial Phase 1/2 data from the 400 mg BID fed dose, including results in CDK4/6-experienced patients, are scheduled to be presented for the first time at the ESMO Targeted Anticancer Therapies Congress on March 16, 2026.
Breakthrough Therapy Designation is intended to expedite the development and regulatory review of therapies for serious conditions where early clinical evidence indicates substantial improvement over existing treatments. The designation provides access to all Fast Track features, along with enhanced FDA guidance and increased interaction with senior agency leadership.
Zovegalisib is Relay Therapeutics’ lead program and a next-generation PI3Kα inhibitor designed to selectively target mutant PI3Kα while sparing the wild-type enzyme. Unlike traditional orthosteric PI3Kα inhibitors, which are limited by toxicity and lack of mutant selectivity, zovegalisib is an allosteric, pan-mutant, isoform-selective PI3Kα inhibitor. It was discovered using Relay’s Dynamo® platform, enabled by solving the full-length cryo-EM structure of PI3Kα and applying long-timescale molecular dynamics simulations to distinguish mutant from wild-type conformations.
HR+/HER2– breast cancer is the most common subtype of the disease, with approximately 40% of patients harboring activating PIK3CA mutations. These patients often experience poorer outcomes following standard CDK4/6 inhibitor–based therapy and currently have limited treatment options.
If approved, zovegalisib has the potential to address a substantial portion of the estimated 140,000 HR+/HER2– breast cancer patients with PI3Kα mutations diagnosed annually in the United States, as well as patients with PI3Kα mutation-driven vascular anomalies, another active area of clinical development for the drug.
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