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Synthetic lethality-focused oncology biopharma Ideaya Biosciences announced earlier this week that is has selected the a potential-first-in-class Pol Theta Helicase development candidate (DC) for its collaboration with GlaxoSmithKline (GSK) to evaluate it as a combination therapy with GSK’s PARP inhibitor niraparib. Sold under the trade name Zejula, niraparib is indicated for treatment of patients with having tumors with BRCA or other homologous recombination (HR) mutations or homologous recombination deficiency (HRD).

The collaboration has the potential to generate $960 million in aggregate milestones from GSK, including up to $485 million in aggregate development and regulatory milestones and up to $475 million in commercial milestones and tiered royalties on global net sales by GSK.

“We are excited about potential clinical development opportunities for this potential first-in-class Pol Theta Helicase inhibitor,” said Michael White, SVP and chief scientific officer of Ideaya in a press release. “Pol Theta promotes DNA repair by microhomology-mediated end-joining (MMEJ), an error-prone mutagenic DNA repair pathway, which is active in BRCA mutant and other HRD cancer cells.  PARP1 is also involved in MMEJ DNA repair, supporting a hypothesis for synergistic combination of our Pol Theta Helicase DC with niraparib.”

The companies said that subject to successfully completing their ongoing preclinical and IND-enabling studies, they are planning an IND submission to the FDA with first-in-human studies to commence next year.

The selection of the development candidate comes about two years since the two companies first announced a collaboration on three of Ideaya’s synthetic lethality programs: Pol Theta, which yielded the current development candidate, as well as its MAT2A, and Werner Helicase programs. The collaboration came as Ideaya had solved the crystalline structure for each of the three programs which enabled a structure-based design approach to potential new therapies. The focus of the program was to explore potential combinations between Ideaya’s and GSK’s programs.

The 2020 collaboration provided an upfront payment to Ideaya of $100 million from GSK, along with a $20 million equity purchase of Ideaya stock.

Synthetic lethality is one of four core research focus areas for GSK in oncology. In synthetic lethality, cells tolerate the loss of single genes in isolation but not together in combination. When tumor suppressor genes are functionally lost in cancer, this mode of action can be used to exploit tumor-specific vulnerabilities through new medicines for patients with cancer.

“GSK is the ideal strategic partner for IDEAYA, as this partnership enables compelling potential combinations and the opportunity to build the industry leading Synthetic Lethality pipeline that targets molecularly defined populations in several major solid tumors, including potentially lung, prostate, breast, colorectal, and ovarian cancer,” said Yujiro S. Hata, CEO and president, IDEAYA Biosciences at the time of the June 2020 announcement.

The latest development deal exhibits the progress the two companies have made in leveraging the synergies of their two synthetic lethality development programs.

“The development candidate has demonstrated robust in vivo efficacy in combination with niraparib, with significant tumor regressions and durable responses in multiple cancer models.  We believe the Pol Theta helicase and niraparib combination has the opportunity to deliver meaningful patient benefit,” said Benjamin Schwartz, Ph.D., vice president, Head of Oncology Synthetic Lethality Research Unit at GSK.

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