FDA sounds caution on Foghorn cancer drug with a partial hold after patient death


A patient has died in a clinical trial testing a Foghorn Therapeutics drug candidate for blood cancer, leading the FDA to pause enrollment of new patients in the study. Circumstances of the death are still under review, but early signs are pointing to a known side effect of leukemia therapies.

The partial clinical hold announced after the market close Thursday permits patients currently enrolled in the Phase 1 dose-escalation study to continue receiving the experimental Foghorn drug, FHD286. Meanwhile, the Cambridge, Massachusetts-based biotech said it is working with the agency to resolve the regulatory hold.

In leukemia, immature blast cells have a limited ability to differentiate into mature myeloid cells. These blast cells build up in the bone marrow, leading to the effects associated with the cancer. Foghorn aims to treat cancer by modulating gene expression with drugs that selectively hit targets in the chromatin regulatory system, which is a system that turns genes on or off. FHD-286 is a small molecule designed to block BRG1 and BRM, two key proteins of this regulatory system.

In preclinical testing, Foghorn has reported that the drug knocked down expression of BRG1, which in turn inhibited expression of genes associated with high cell proliferation while also inducing expression of genes associated with mature myeloid cells. Foghorn has advanced its drug to Phase 1 testing in patients with the blood cancers acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS). A separate Phase 1 program is underway in uveal melanoma.

Leukemia drugs are intended to induce differentiation, prompting the immature blasts to become mature myeloid cells. But these drugs can also spark an excessive immune response called differentiation syndrome, in which the myeloid cells targeted by the drug release inflammatory proteins called cytokines. Symptoms of the syndrome include fever, breathing difficulty, fluid buildup around the heart and lungs, low blood pressure, and kidney failure. Differentiation syndrome is treatable with steroids and supportive care, but the condition can become life-threatening.

The patient death reported Thursday occurred in the blood cancer study. According to Forghorn, that patient may have had differentiation syndrome, which the company noted is an effect that is consistent with FHD-286’s mechanism of action—it’s supposed to get cells to differentiate. Foghorn said that the FDA has requested a review of the trial’s safety database, as well as mitigation strategies and a breakdown of clinical activity across all of the dose levels tested.

“Patient safety remains our top priority,” Foghorn CEO Adrian Gottschalk said in a prepared statement. “We appreciate the dialogue with the FDA and will work diligently with the Agency to resolve the partial clinical hold in AML/MDS as soon as possible.”

Foghorn’s stock price sank more than 24% in after-hours trading Thursday evening to around $8.67 per share.

Differentiation syndrome has led to partial holds on other blood cancer clinical trials. Last November, the FDA placed a partial hold on a Kura Oncology study after a patient death was suspected to be associated with the syndrome. That patient’s family did not consent to an autopsy so Kura could not definitively determine whether differentiation syndrome caused the death. But the FDA lifted the partial hold in January after the company agreed to mitigation strategies that include watching closely for signs of the syndrome.

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