Following Patient Death, FDA Puts Foghorn Study on Partial Hold

FDA_Sarah Silbiger/Getty Images

Courtesy of Sarah Silbiger/Getty Images

The U.S. Food and Drug Administration has issued a partial clinical hold for Foghorn Therapeutics' Phase I clinical study, investigating the safety and efficacy of FHD-286 in patients with relapsed and/or refractory acute myelodysplastic leukemia (AML) and myelodysplastic syndromes (MDS). Currently, enrolled participants who are benefitting from the treatment will continue dosing, but no additional participants may be recruited during this hold. 

The hold follows a serious adverse event in which a study participant died after developing possible differentiation syndrome. This syndrome is commonly associated with AML and MDS treatments but remains deadly because leukemia cells release vast amounts of cytokines. Low blood pressure, breathing difficulties, fluid accumulation and fevers can present clinically. Differentiation syndrome is believed to be an on-target mechanism for FHD-286. 

Foghorn's CEO, Adrian Gottschalk, commented on the news. 

"Patient safety remains our top priority. 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," he said. 

Relapsing or refractory AML refers to recurring leukemia or leukemia that has not responded to treatment. Patients with AML suffer from cancer originating from the cells that form blood, beginning in the bone marrow. MDS is a collection of cancers that occur when the young blood cells in the bone marrow do not go on to mature. One of the most recognizable MDS manifestations is anemia, where bleeding is uncontrollable. Both AML and MDS can carry a fatal prognosis. 

FHD-286 was formulated as a small-molecule enzymatic inhibitory mechanism that allows BRG1 and BRM protein activity blockage. These proteins are responsible for the catalysis of the BAH complex. By inhibiting these proteins, FHD-286 inhibits the chromatin regulatory complex and transcription regulation, key components of cancer. The formulation was created using Foghorn's Gene Traffic Control platform. 

The study (NCT04891757) design is open-label, examining dose-escalation effects as patients receive the oral treatment. Primary outcome measurements include incidence of treatment-emergent adverse events and dose-limiting toxicities. Secondary endpoints are intended to evaluate event-free survival, overall survival and hematologic improvement, among other factors. The estimated enrollment is 50 participants. 

An additional study (NCT04879017) is still ongoing, evaluating the efficacy of FHD-286 in patients with metastatic uveal melanoma (mUM). The first patient was dosed in May of 2021, and the study design is similar to the previously mentioned study. Approximately 100 participants will be enrolled in this study. The estimated completion date is currently August of 2025, barring any FDA holds or other incidences. 

The FDA has requested extensive data and an explanation of clinical activities during the clinical hold, including all dosage schedules. Safety will need to be re-evaluated, along with the provision of a risk mitigation strategy. 

Prior to this hold, Foghorn anticipated releasing the first set of data in the second half of 2022. The timeline for FHD-286 is now uncertain. Preclinical data showed efficacy, as anti-tumor activities were seen in various cancer cell types, including AML and mUM. Doses of 1.5 mg/kg QA were well tolerated in mouse models. The therapeutic worked well with cytarabine chemotherapy and venetoclax targeted therapy. 

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