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After Restructuring, C4 Turns the Page on Its Targeted Protein Degrader Pipeline

A proteasome breaking down a protein molecule

NEW YORK – C4 Therapeutics hopes to end 2024 on a high note by sharing positive data from ongoing trials of its protein degrader candidates, including the BRAF V600-targeted CFT1946, following its restructuring and downsizing in January.

C4 Chief Medical Officer Len Reyno said that the financial landscape in 2023 was a "very challenging ride for many companies," but that C4 has "turned over some of our clinical leaves" and expects to win the confidence of clinicians and investors with early clinical data later this year.

The company announced a restructuring and reduction in force in January alongside a sharpened focus on its most promising protein degrader programs. While the company is continuing development of its BRAF V600-, IKZF1-, and EGFR-targeted protein degrader programs, it has discontinued development of the BRD9-targeted protein degrader CFT8634 as a treatment for patients with SMARCB1-null tumors. Reyno said that while CFT8634 is no longer in clinical development, the company views it as a "success story," in that it demonstrated degradation of the target. "What we didn't see was that degradation of that target was associated with robust clinical responses," Reyno said. "So we curtailed development."

C4's drug discovery and development program is centered around targeted protein degradation. Unlike drugs that inhibit the activity of an enzyme or a receptor, a targeted protein degrader makes use of the ubiquitin proteasome system which disposes of disease-causing proteins in the cell. This system is activated when E3 ligase attaches multiple ubiquitin molecules to the target protein. The resulting ubiquitinated protein is then shuttled to the proteasome where it is broken down into its component amino acids. Protein degrader drugs temporarily links the target protein with E3 ligase, enabling its degradation by the proteasome. The degrader can repeatedly catalyze this reaction to permanently destroy many copies of the target protein.

In choosing targets to pursue with this strategy, Watertown, Massachusetts-based C4 is focusing on targets where there's a specific rationale to justify the use of a degrader. In the case of BRAF V600-mutated cancers, when BRAF is inhibited, the RAF protein remains available for dimerization, which causes a feedback loop leading to paradoxical activation of the pathway the drug is supposed to inhibit. C4 reasoned that if a drug can remove the protein altogether so that it's no longer available for dimerization, it could address one of the primary drivers of resistance to BRAF inhibitors.

"The rationale is really strong, and so is the opportunity," Reyno said. He added that although there are approved BRAF inhibitors that have high response rates, there is still unmet need due to the inadequate progression-free survival associated with those drugs. In C4's view, patients who initially responded to a BRAF inhibitor, but subsequently progress, represent an opportunity to add a second precision therapeutic to target that resistance mechanism.

BRAF V600E mutations are present in about 8 percent of all cancers, including 60 percent of melanomas, up to 12 percent of colorectal cancers, and 4 percent of non-small cell lung cancers. Most patients with BRAF V600-altered cancers respond to BRAF inhibitors, which are typically given in combination with a MEK inhibitor, but the treatment benefit tends to be limited by resistance, which is often mediated by the formation of those RAF dimers.

The US Food and Drug Administration granted tumor-agnostic approval to Novartis' BRAF inhibitor Tafinlar (dabrafenib) with the MEK inhibitor Mekinist (trametinib) in June 2022 for patients with advanced, refractory solid tumors harboring a BRAF V600E mutation based on data from the Phase II ROAR and NCI-MATCH trials. Approximately 80 percent of patients in those studies with BRAF V600E-mutated tumors responded. However, in the ROAR trial, in which researchers studied the drug combo in patients with BRAF V600E-mutated rare cancers, median progression-free survival ranged from just 5.5 months to 9.5 months for the various cancer types. And in NCI-MATCH, among 35 patients with solid tumors, lymphomas, or multiple myelomas with a BRAF V600E mutation who were treated with the drug combo, the median progression-free survival was 11.4 months.

The FDA has also approved two BRAF V600-targeted therapies in pediatric low-grade glioma: Tafinlar-Mekinist and Day One Biopharmaceuticals' RAF inhibitor Ojemda (tovorafenib). Children with low-grade glioma harboring BRAF V600E mutations on Tafinlar-Mekinist in the Phase II/III TADPOLE trial survived for a median 20.1 months without cancer progression, compared with 7.4 months for patients on standard-of-care chemotherapy. And in the Phase II FIRELY-1 trial, among 76 patients treated with Ojemda, the overall response rate was 51 percent and the median progression-free survival was 13.8 months.

Reyno sees room to improve patient survival in those numbers. Although C4 is evaluating its BRAF V600-targeted CFT1946 as a monotherapy in its ongoing Phase I trial, in later stages of the study, the company plans to move on to testing the drug in combination with other therapies. "CFT1946 is not a me-too drug; it's a me-next drug," Reyno said, because they expect it to be an option that is second-line or potentially added on for patients who have stopped responding to front-line BRAF V600-targeted therapy.

In that Phase I trial, C4 is enrolling 206 patients with unresectable locally advanced or metastatic solid tumors that have tested positive for a BRAF V600 alteration via tumor tissue or liquid biopsy who have received one or more prior standard-of-care therapies. The trial will eventually include six arms with 20 to 40 participants in each with patients receiving CFT1946 alone or CFT1946 in combination with either Mekinist or Eli Lilly's EGFR inhibitor Erbitux (cetuximab). The investigators will track outcomes including adverse events, toxicities, overall response rate, disease control rate, and duration of response, and progression-free survival to assess the safety and efficacy of the therapy.

C4 is conducting the study in the US and Europe and expects to share data from the monotherapy cohorts in the second half of this year. Reyno said most patients will come from the three common indications where BRAF inhibitors are used — melanoma, colorectal cancer, and lung cancer — and in the early stages of the trial, the company will not attempt any further refinement of the patient group beyond selecting for BRAF V600 alterations.

Reyno said the priority in terms of biomarker strategy is to make sure the physician can identify patients that will benefit from the drug safely, and for CFT1946, that means identifying patients with BRAF V600 alterations that are no longer benefiting from treatment with a BRAF inhibitor. Beyond that, the company will assess whether additional biomarkers could be needed to refine the use of the drug and optimize screening for patients most likely to benefit from the treatment. To do that, C4 will make use of archival patient specimens from the initial diagnosis, or fresh biopsies taken at the time of trial enrollment to test for additional predictive biomarkers.

Looking ahead to a potential regulatory submission, Reyno said that it's "not a crazy concept" for C4 to seek a tumor agnostic approval, given that the company has begun its clinical program in solid tumors broadly. However, C4 will aim for the fastest path to make the drug available to patients, which might involve a narrower indication. That will mean exploring monotherapy treatment as well as combinations such as with an EGFR antibody for colorectal cancer or with Mekinist in lung cancer and melanoma.

C4 is also advancing two other protein degrader programs. The IKZF1 degrader cemsidomide (CFT7455) is in a Phase I/II all-comers trial as a treatment for relapsed and refractory multiple myeloma and non-Hodgkin lymphoma. And it has an EGFR L858R-targeted protein degrader, CFT8919, in preclinical development for non-small cell lung cancer. The FDA cleared an investigational new drug application for CFT8919, and C4 is developing it in partnership with Zhejiang, China-based Betta Pharmaceuticals. Under an agreement signed in May 2023, Betta will have exclusive rights to develop and commercialize the drug in greater China, including in Hong Kong, Macau, and Taiwan.

Reyno said Betta has an "impressive track record" of pursuing targets related to EGFR and lung cancer and noted that the prevalence of EGFR-mutated lung cancer is higher in China, so Betta will carry out early development of the drug, "and then we can make a decision [about] where it might fit in our clinical portfolio."

C4 boosted its balance sheet early in the year with a $25 million equity investment from a subsidiary of Betta, a $10 million upfront payment from Merck for a degrader-antibody conjugate collaboration, and about $72 million in net proceeds from an at-the-market financing facility. The company ended the first quarter of 2024 with $299.2 million in cash, cash equivalents, and marketable securities, which it believes will provide sufficient runway to accomplish its post-restructuring agenda.