Foghorn Abandons Uveal Melanoma Program after Subpar Phase I Results

Pictured: Doctor holding up hand to stop, courtesy of iStock

Pictured: Doctor holding up hand to stop, courtesy of iStock

Foghorn Therapeutics will no longer advance studies of a potential treatment for uveal melanoma—a rare and advanced form of cancer—after disappointing Phase I clinical results, the company announced Wednesday. Instead, it will advance the treatment for acute myeloid leukemia.

Foghorn was testing FHD-286, a selective and allosteric small molecule inhibitor of BRG1 and BRMtwo highly similar proteins that are the catalytic engines of the chromatin regulatory system. Research on uveal melanoma has pointed to inhibitors of this system having antiproliferative activity on the cancer. Preclinical studies showed FHD-286 had anti-tumor activity in a broad range of malignancies, including both hematologic and solid tumors.

Uvealor intraocularmelanoma is the most common form of eye cancer but a relatively rare cancer that forms from melanin-making cells. In the U.S., about 2,000 people are diagnosed each year and the cancer metastasizes in about 50% of cases, which results in a poor prognosis.

Foghorn was primarily testing the safety and tolerability of FHD-286, which the Phase I trial supported. The dose-escalation study evaluated 73 metastatic uveal melanoma patients, 47 of whom had target lesions for evaluation. Of those, only one had a durable partial response, nine had stable disease with the severity and extent of the cancer neither increasing nor decreasing and eight had tumor reductions in target lesions. Reductions in circular tumor DNA were also observed. 

While the results weren’t enough for Foghorn to push ahead with the treatment for uveal melanoma, the company is advancing studies of FHD-286 for acute myeloid leukemia (AML).

The compound is being tested in Phase I in combination with decitabine or cytarabine, which inhibit DNA methylation and slow or stop the growth of cancer cells, respectively. The study, which will test the effectiveness of the combination treatment in patients with relapsed or refractory AML, is expected to begin in the third quarter of 2023.

Wednesday's update is more bad news for Foghorn, which has had two of its clinical-stage programs paused by the FDA during the past two years.  

Earlier this year, the FDA placed a partial clinical hold on FHD-609, an investigational protein degrader, after a patient developed a grade 4 QTc prolongation—irregular heartbeat—event. The candidate compound is being investigated as a treatment for synovial sarcoma, a rare and aggressive soft tissue cancer.

In 2022, FHD-286 was put on hold in AML after a patient died due to differentiation syndrome, which is a group of severe drug reactions to treatments for this cancer. The FDA lifted the hold earlier this month. Foghorn said in a press release that it had established an “independent adjudication committee,” which found that of the six cases of differentiation syndrome in the study, one was definitively differentiation syndrome but did not contribute to the patient’s death.

Connor Lynch is a freelance writer based in Ottawa, Canada. Reach him at lynchjourno@gmail.com.

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