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.

BRCA1 and BRCA2 mutations have also been shown in clinical trials to be SL with PARP inhibitors in multiple tumors, such as breast and ovarian cancer. While PARP inhibitors have proven effective in BRCA-mutant tumors, no statistically significant overall survival benefit has been reported in breast or pancreatic cancer to date, highlighting the potential for other SL targets, such as Polθ, to demonstrate meaningful efficacy as a monotherapy or in combination with PARP inhibitors.

We anticipate advancing a development candidate into the clinic in 2024.