In a deal potentially worth $3 billion, privately held Repare Therapeutics Inc., of Cambridge, Mass., and Montreal, entered a research collaboration with Bristol Myers Squibb Co. (BMS) to identify synthetic lethal precision oncology targets for drug candidates.

In the deal, Repare is eligible to receive about $3 billion in license fees, discovery, development, regulatory and sales-based milestones. The company is also set to receive from BMS an up-front payment of $65 million, including a $15 million equity investment. Royalty payments on net sales of all products that BMS commercializes in the deal could also go to Repare. In exchange, BMS received exclusive worldwide rights for developing and commercializing selected oncology targets discovered in in the collaboration.

Repare will use its genome-wide CRISPR/Cas9-based screening platform, SNIPRx, to identify the targets. The platform uses isogenic cell lines to identify genomic alterations, including DNA damage repair, and then matches the patients with a therapy based on the tumor’s genetic profile.

Preclinical pipeline

Repare has three programs it is developing independently from the BMS collaboration, including preclinical-stage lead candidate RP-3500, an ATR inhibitor.

Repare’s second program, Manchester, targets an undisclosed targeted mutation that is synthetically lethal when paired with mutations in CCNE1-SL, which encodes the cell cycle protein cyclin E1. Manchester is in the lead optimization phase, poised to soon go into preclinical research.

The company’s third program is a Polθ inhibitor program that is in the lead generation phase targeting the cancer risk gene BRCA. Repare is collaborating with Ono Pharmaceutical Co. Ltd., of Osaka, Japan.

In June 2017, a series A worth $68 million helped Repare launch its R&D into ATR. Last September, Repare raised $82.5 million in a series B with help from a syndicate led by Cowen Healthcare Investments. Other participants included Orbimed, Redmile, BVF Partners LP and Logos Capital, as well as founding investors Versant Ventures and other existing investors MPM Capital, Fonds de Solidarité FTQ and BDC Capital.

Targeting ATR

Repare and others are targeting ataxia-telangiectasia and Rad3-related (ATR), a master DNA damage response regulator that works in concert with a second kinase, ataxia-telangiectasia mutated (ATM), to maintain genomic stability in response to DNA damage. Both Leverkusen, Germany-based Bayer AG and Cambridge, U.K.-based Astrazeneca plc are in the clinic, testing ATR inhibitors in combination with PARP inhibitors.

Bayer’s ATR inhibitor, BAY-1895344, is in a phase Ib study to determine how patients with advanced solid tumors, excluding prostate cancer, and ovarian cancer respond to treatment in a combination therapy with niraparib. The study is also designed to determine the optimal dose of the combination, how well it is tolerated, and how the body absorbs, distributes and discharges the drug. The open-label, interventional trial of about 56 participants began in late February and has an estimated primary completion date of June 2020.

Astrazeneca, along with Cancer Research UK, has a combination therapy clinical trial underway. The phase II study of ATR inhibitor AZD-6738 and PARP inhibitor olaparib is for patients with relapsed gynecological cancers. The study is designed to assess the response in groups of patients selected based on their cancer cell subtype and the presence of an abnormality in ARID1A gene. The non-randomized, parallel assignment study of about 40 patients began in November and has a primary completion date of March 2023.

Repare’s CEO, Lloyd Segal, said his company’s platform has an edge over the competition because it can select patients based on criteria beyond just ATM deletions. Segal also said more than 15% of the patient population is not eligible for PARP inhibitor therapy.

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