Since 2021, biotechnology company Foghorn Therapeutics (“Foghorn”) has been developing its therapeutic candidate FHD-286 for a number of malignancies. In one Phase 1 study, researchers are testing the pharmacokinetics, pharmacodynamics, safety, efficacy, and tolerability of the drug for people with relapsed or refractory acute myeloid leukemia (AML) or relapsed or refractory myelodysplastic syndromes (MDS). The company has also been evaluating FHD-286 for metastatic uveal melanoma, a rare cancer that forms in melanocytes (melanin-producing cells) in the eyes. At the end of June 2023, Foghorn shared an update on this clinical program via a news release.

Evaluating FHD-286

First, let’s talk about what FHD-286 is. This investigational, selective, allosteric, small-molecule BRG1/BRM inhibitor works to prevent tumor growth. It blocks BRG1 and BRM, which have both been shown to contribute to increasing tumor size and spread. Taken orally, FHD-286 has been shown in preclinical and clinical studies to have promising anti-tumor and immunomodulatory properties.

The company’s update centered around data from the Phase 1 dose escalation study, which sought to understand the highest dose of FHD-286 that can safely be used to treat metastatic uveal melanoma. Doses evaluated included 2.5mg, 5mg, 7.5mg, or 10mg FHD-286 daily, or 10mg, 15mg, 20mg, or 22.5mg FHD-286 on a week on/week off basis. Research also explored how safe the drug was.

Altogether, 73 patients enrolled. Patients had received (on average) two treatments before FHD-286. FHD-286 shrunk tumor sizes in eight participants, contributed to disease stability in nine, and had one patient experience a durable partial response. Similarly to the AML study, this trial found FHD-286 to be relatively safe and well-tolerated. Some adverse reactions did occur, however. These included rashes, muscle weakness, nausea and vomiting, fatigue, low red blood cell counts, low blood potassium levels, dry mouth, and altered taste.

Though these results show promise, Foghorn has chosen not to move forward in developing FHD-286 for metastatic uveal melanoma. Instead, the company will pursue FHD-286 development for AML. In the future, Foghorn plans to hold a Phase 1 study to evaluate whether using FHD-286 in conjunction with cytarabine or decitabine increases its efficacy.

Uveal Melanoma

Ocular melanoma, which forms in the eye, can be broken down into three categories. A significant majority of ocular melanoma is uveal melanoma, forming in the uvea (iris, choroid layer, ciliary body). About 15% of ocular melanomas differ, forming in other sites or in the conjunctiva. Doctors don’t know exactly what causes uveal melanoma, though they have identified risk factors such as older age, inherited skin disorders or genetic mutations, being white, and UV light exposure.

Uveal melanoma often begins as a small tumor before progressing. In some cases, it causes no symptoms; this can make it difficult to diagnose and treat in earlier stages. Unfortunately, an estimated 50% of people with uveal melanoma experience metastasis (when the cancer spreads to another part of the body). Despite available treatments such as radiation, photodynamic therapy, and surgery, prognosis associated with the metastatic form of this cancer is still relatively poor.

If symptoms occur, they may include:

• Dark spots on the iris that may grow in size
• Blurred vision
• Pupil shape alterations
• Vision loss
• Glaucoma (complication)