RP-3467: Our Polymerase Theta (Polθ) preclinical program.

We are developing a small molecule inhibitor of polymerase theta, or Polθ, a SL target associated with BRCA mutations and other genomic alterations. This program was added to our portfolio through a collaboration with our co-founder, Dr. Agnel Sfeir, now at Memorial Sloan Kettering Cancer Center, who initially published her observations on the SL between BRCA and Polθ in Nature in 2016.

Polθ is a DNA polymerase enzyme that participates in the repair of double-strand breaks in DNA. Mutations in genes such as BRCA1 and BRCA2 increase the frequency of these breaks, resulting in SL with Polθ. Preclinical studies have shown that inactivation of Polθ, both on its own and in combination with PARP inhibitors, reduces survival in BRCA-mutated cells, but not in BRCA wild-type cells. BRCA1 and BRCA2 mutations are routinely identified in multiple genetic profiling tests and observed in approximately 1% to 7% of patients with breast and ovarian cancer.

We reported comprehensive preclinical data for RP-3467 in November 2023, in which RP-3467 demonstrated complete, sustained regressions in combination with PARP inhibitors and compelling anti-tumor activity in combination with RLT and chemotherapy. In June 2024, we further presented our preclinical findings in a plenary session at the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities. We initiated the Phase 1 clinical trial of RP-3467 (POLAR) in the fourth quarter of 2024, as well as dosed the first patient in the POLAR trial with the combination of RP-3467 and olaparib. Upcoming expected milestones include topline safety, tolerability and early efficacy data from the POLAR trial in monotherapy and in combination with olaparib in the third quarter of 2025.