BRD9

Merck KGaA is now the fourth Big Pharma to sign on to a collaboration with C4 Therapeutics. Apparently, C4 Therapeutics' protein degradation tech brings all the Mercks to the yard. The Massachusetts biotech has signed on Merck KGaA in a $740 million biobucks partnership to find two degraders for cancer.  Merck KGaA is offering $16 million upfront and $740 million in biobucks for the two degraders aimed at proteins that drive cancer growth. Merck will pay for C4’s discovery work and be responsible for future clinical development, according to Monday's announcement. C4 also stands to make mid single- to low double-digit royalties should any of the targets turn into marketed drugs.  Paul Lyne, head of Merck KGaA’s oncology research unit, said the deal adds more depth to the company’s protein degradation investments.  The deal comes less than three months after Merck & Co. inked a research partnership with C4 of its own, paying $10 million upfront and more than $600 million in biobucks for the smaller company to develop an exclusive degrader-antibody conjugate (DAC). The New Jersey Merck has the option to license three additional DACs, which would push the value of the deal to $2.5 billion.  C4 has now inked collaborations with four Big Pharmas, with Biogen and Roche also tied up in collaborations with the company.  But despite the business development momentum, C4 has had a bumpy few months. The company announced layoffs to 30% of the team in January, impacting some 45 employees. That move came two months after C4 halted development on CFT8634, a small molecule for which degrading the BRD9 protein did not seem to translate to efficacy in patients with cancer.  Instead, C4 is prioritizing two other clinical stage assets: CFT7455 and CFT1946. The former is an IKZF1/3 degrader being tested in patients with multiple myeloma and non-Hodgkin lymphoma, while CFT1946 is aimed at patients with BRAF V600-mutated solid tumors.  C4 spent virtually the exact amount on R&D in 2023 as it did in 2022, according to the company's fourth-quarter earnings report, citing lower preclinical costs but higher clinical-stage costs. The biotech still reported a sizable $282 million in cash on hand as of the end of the year. 

C4 Therapeutics has inked a potentially lucrative deal with Merck KGaA to discover two targeted protein degraders against undisclosed oncogenic proteins. The collaboration adds to Merck's growing portfolio of protein degradation projects as it expands its presence in the space.Under the agreement, C4 will receive an upfront payment of $16 million from Merck, which will help cover the costs of discovery research efforts for the two programmes. In turn, Merck will be responsible for developing and commercialising any drug candidates emerging from the partnership.C4 is eligible to receive up to approximately $740 million in combined discovery, development, and commercial milestones across the two programmes. It will also be able to pocket mid-single to low-double digit tiered royalties on potential future sales of any approved products.Merck's protein powerplayThe deal marks Merck's fourth collaboration in the protein degradation space, following agreements inked in 2022 with Amphista potentially worth over €932 million ($1 billion), Proxygen for up to €495 million ($537 million), and Celeris Tx. The German pharma giant has been actively pursuing partnerships to bolster its pipeline of targeted protein degraders, a modality that has drawn interest from a number of other major players, including Novo Nordisk (for more, see – Spotlight On: Targeted protein degradation grows up).For the collaboration, C4T will leverage its proprietary TORPEDO platform. According to the company, the platform allows it to create both molecular glue degraders, or so-called MonoDACs, and heterobifunctional degraders, referred to as BiDACs, providing the capability to target "almost any disease-causing protein."CEO Andrew Hirsch said the deal "highlights [our] differentiated approach to targeted protein degradation science and our strong track record of designing novel targeted protein degrader medicines with desirable drug-like properties."C4 is also partnered with Merck & Co. to develop degrader-antibody conjugates in a deal potentially worth $600 million.However, Monday’s alliance comes on the heels of a corporate restructuring at C4, which recently cut 30% of its workforce, or about 45 positions, to extend its cash runway into 2027. The layoffs followed the company's decision to discontinue development of its BRD9-targeted degrader, CFT8634, due to insufficient efficacy in a Phase I trial.

A total of 45 positions will be impacted, with the changes likely to be completed by the end of the quarter. Two months after C4 Therapeutics discontinued one of its cancer assets, the small molecule medicines biotech has revealed that this narrowing of focus will come at the cost of a 30% reduction in headcount. C4 announced on Nov. 1 that it was halting work on an oral BRD9 degrader called CFT8634 in synovial sarcoma and SMARCB-1 null tumors after the high levels of BRD9 degradation identified in a phase 1/2 trial didn’t result in sufficient efficacy for heavily pre-treated patients receiving CFT8634 by itself. Instead, the Massachusetts-based biotech said at the time that it would prioritize its two other candidates in phase 1/2 trials. The company’s lead candidate, dubbed CFT7455, is an IKZF1/3 degrader being studied in combination with corticosteroid dexamethasone for patients with relapsed or refractory multiple myeloma (R/R MM), as well as a monotherapy for patients with advanced non-Hodgkin’s lymphoma.  The other asset being prioritized is CFT1946, a BRAF V600 degrader taking aim at solid tumors including non-small cell lung cancer (NSCLC), colorectal cancer and melanoma. The asset is currently being evaluated in a dose escalation phase 1/2 trial to treat solid tumors with BRAF V600 mutations. The company confirmed in a post-market release yesterday that it would also continue to support the phase 1 development of CFT8919—an oral degrader designed to treat EGFR L858R mutations present in patients with NSCLC—by its China-based partner Betta Pharmaceuticals, as well as “delivering on three discovery collaborations and progressing a streamlined internal discovery effort.” In the release, C4 explained that restructuring its operations in this way would result in around 30% of its employees being laid off. A total of 45 positions will be impacted, with the changes likely to be completed by the end of the quarter, it added in a related SEC filing. The biotech entered the new year with $330 million in cash and equivalents. This had been recently topped up by selling off $72 million in shares, as well as a $10 million upfront payment as part of a degrader-antibody conjugate collaboration with Merck & Co. in December and a $25 million equity investment from a subsidiary of Betta as part of the CFT8919 licensing deal. Combined with savings from the layoffs and restructured operations, C4 said it now expects its cash runway to extend into 2027. The decision to restructure the company “was not a decision we made lightly,” CEO Andrew Hirsch said in the Jan. 9 release. “Our sharpened focus on progressing CFT7455 and CFT1946 to critical clinical milestones, along with advancing targeted protein degradation research through our discovery collaborations with Roche, Biogen and Merck and our internal research efforts, will help C4T deliver breakthrough therapies for patients with cancer and other diseases,” Hirsch added. “Our strengthened balance sheet, coupled with cost savings from our restructuring, provide sufficient runway to execute through and beyond critical milestones across the portfolio.” Those milestones include updated data from the ongoing phase 1 dose escalation trial of CFT7455 in R/R MM, which is due in the second half of 2024 along with data from a trial in non-Hodgkin’s lymphomas. The second half of this year is also likely to see a readout from a phase 1 dose escalation trial of CFT1946 in melanoma, colorectal cancer, non-small cell lung cancer and other cancers with BRAF V600X mutations.