Benzinga | Dec 10, 2021 07:35AM EST

Relay Therapeutics Reports Preclinical Data Showing Support For Clinical Development Of RLY-2608 As Both Single, In Combo Agent

RLY-2608 combines with standard of care therapies to drive regressions in ER+/HER2- breast cancer models

CAMBRIDGE, Mass., Dec. 10, 2021 (GLOBE NEWSWIRE) -- Relay Therapeutics, Inc. (NASDAQ:RLAY), a clinical-stage precision medicine company transforming the drug discovery process by combining leading-edge computational and experimental technologies, today shared additional preclinical data at the 2021 San Antonio Breast Cancer Symposium for RLY-2608, the first known allosteric, pan-mutant and isoform-selective PI3K? inhibitor. The data presented in the poster help support the clinical development of RLY-2608 both in single agent and combination clinical trials for patients with PIK3CA (PI3K?) mutant tumors, including PI3K?-mutant, HR+/HER2- breast cancer.

The data indicate RLY-2608 synergizes with fulvestrant and the CDK4/6 inhibitor abemaciclib in cell viability assays in PIK3CAmut/ER+/HER2- cell lines. Oral administration of RLY-2608 in combination with fulvestrant or abemaciclib led to improved efficacy compared to either agent alone in ER+/HER2- xenograft models representing the most commonly observed PIK3CA mutations in breast cancer (H1047R, E542K, E545K). The triple combination of all three agents resulted in deep regressions across all models. Additionally, the combination arms had similar tolerability to monotherapy arms.

"We continue to validate our novel allosteric approach for PI3K? inhibition and believe that RLY-2608 has the potential to overcome many of the toxicity limitations seen with non-selective orthosteric inhibition of PI3K that lead to frequent discontinuations and challenges combining with standard of care inhibitors," said Don Bergstrom, M.D., Ph.D., executive vice president of R&D at Relay Therapeutics. "This preclinical profile supports the clinical development of RLY-2608 as what we believe is a truly differentiated molecule that can be safe and effective both as a single agent and in combination, and has the potential to address a major unmet medical need for patients with PI3K? mutant tumors, PI3K?-mutant, HR+/HER2- breast cancer."

The data presented at the conference also include previously presented preclinical data, showing RLY-2608 preferentially binds to the mutant protein, and binding occurs in a novel allosteric pocket and thus is not abrogated by buparlisib, an orthosteric site inhibitor. The data show that RLY-2608 binds faster to the mutant protein and demonstrates biochemical selectivity for mutant PI3K? over wild type (WT) and other family member isoforms in addition to exquisite selectivity over the rest of the kinome. RLY-2608 is shown to inhibit phosphorylated AKT (pAKT) in PI3K? mutant cancer cell lines independent of the hotspot mutation and inhibit proliferation. Finally, the data show that RLY-2608 demonstrates potent tumor growth inhibition in a dose-dependent manner leading to full regressions at doses associated with minimal impact on insulin levels, in contrast to non-selective orthosteric inhibitors.

These results support clinical investigation of RLY-2608 as a differentiated mechanism of mutant PI3K? inhibition with the first-in-human study anticipated to start in the first half of 2022.

The poster presentation from the 2021 San Antonio Breast Cancer Symposium is available on the Relay Therapeutics website at https://relaytx.com/publications.