A patient died in a clinical trial testing Foghorn Therapeutics’ candidate for blood cancers, leading the FDA to suspend studies of new patients. The deaths are still under review, but early signs point to known side effects of the leukemia therapy.
this Partial clinical hold Patients currently enrolled in a Phase 1 dose-escalation study were allowed to continue receiving the experimental Foghorn drug FHD286, announced after the market close on Thursday. Meanwhile, the Cambridge, Mass.-based biotech company said it was working with the agency to resolve regulatory issues.
In leukemia, immature blast cells have a limited ability to differentiate into mature myeloid cells. These blast cells accumulate in the bone marrow, leading to cancer-related effects. Foghorn aims to treat cancer by modulating gene expression with drugs that selectively hit targets in the chromatin regulatory system, 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 reported that the drug inhibited the expression of BRG1, thereby suppressing the expression of genes associated with high cell proliferation, while also inducing the expression of genes associated with mature myeloid cells. Foghorn has advanced its drug to Phase 1 testing in patients with the blood cancers acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). A separate Phase 1 program for uveal melanoma is underway.
Leukemia drugs are designed to induce differentiation, turning immature blast cells into mature myeloid cells.But these drugs can also trigger an excessive immune response called differentiation syndrome, in which the drug-targeted bone marrow cells release inflammatory proteins called cytokines. Symptoms of the syndrome include fever, difficulty breathing, fluid buildup around the heart and lungs, low blood pressure, and kidney failure. Differentiation syndrome can be treated with steroids and supportive care, but the condition can be life-threatening.
The patient deaths reported Thursday occurred in a blood cancer study. According to Forghorn, the patient may have differentiation syndrome, an effect the company notes is consistent with FHD-286’s mechanism of action — it should differentiate cells. The FDA has requested a review of the trial’s safety database, along with mitigation strategies and a breakdown of clinical activity at all dose levels tested, Foghorn said.
“Patient safety remains our top priority,” Foghorn Chief Executive Adrian Gottschalk said in a prepared statement. “We appreciate the dialogue with the FDA and will work with the FDA to resolve the partial clinical hold for AML/MDS as soon as possible.”
Shares of Foghorn fell more than 24% in after-hours trading Thursday night to around $8.67 a share.
Differentiation syndrome has led to partial shelving of clinical trials in other blood cancers. last November, FDA partially shelved Kura oncology study after patient deaths suspected of being linked to the syndrome. The patient’s family did not consent to an autopsy, so Kula could not determine whether differentiation syndrome contributed to the death.but FDA lifts partial hold in January after companies agree to mitigation strategy This includes watching closely for signs of the syndrome.
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