NEW YORK – Ideaya Biosciences said Tuesday that it has selected a lead candidate in its Pol theta synthetic lethality program as part of an ongoing collaboration with GlaxoSmithKline.
Ideaya's candidate is a small molecule inhibitor of the helicase domain of DNA polymerase theta. Under a 2020 collaboration agreement with GSK, South San Francisco, California-based Ideaya will evaluate the drug in combination with GSK's PARP inhibitor Zejula (niraparib) in tumors with homologous recombination deficiency, including patients harboring mutations in BRCA1/2 or other genes affecting DNA repair.
The deal covers three of Ideaya's synthetic lethality programs, involving Pol theta, MAT2A, and Werner syndrome helicase inhibitors. Under the terms of their arrangement, GSK paid Ideaya $100 million upfront and purchased $20 million worth of its common stock. GSK also has an option to pay $50 million and exercise rights to the MAT2A program. In April, Ideaya began a Phase I trial of its MAT2A inhibitor in tumors with MTAP deletions.
With regard to the Pol theta program, the companies are collaborating on investigational new drug application-enabling studies. They hope to file an IND and begin human studies in the first half of 2023. GSK will then lead clinical development efforts, and Ideaya will be eligible to receive up to $485 million in milestones payments, including $10 million for advancing the Pol theta asset through the IND phase.
According to Ideaya, Pol theta is significant in cancers with BRCA1/2 mutations because it promotes DNA repair through microhomology-mediated end-joining (MMEJ), which is active in cancer cells with homologous recombination deficiency. PARP1 is also involved in MMEJ DNA repair, suggesting that the combination of a Pol theta helicase inhibitor and a PARP inhibitor could be synergistic.
"The development candidate has demonstrated robust in vivo efficacy in combination with niraparib, with significant tumor regressions and durable responses in multiple cancer models," Benjamin Schwartz, head of GSK's oncology synthetic lethality research unit, said in a statement. "We believe the Pol theta helicase and niraparib combination has the opportunity to deliver meaningful patient benefit."