Foghorn®Therapeutics Inc. announced that the U.S. Food and Drug Administration (FDA) has lifted the clinical hold on the Phase 1 monotherapy dose escalation study of FHD-286 in acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS). Foghorn plans to commence a Phase 1 study of FHD-286 in combination with decitabine or cytarabine in relapsed and/or refractory AML patients in the third quarter of 2023. On August 23, 2022, Foghorn announced a full clinical hold in the AML/MDS Phase 1 study due to suspected cases of fatal differentiation syndrome believed to be associated with FHD-286 treatment.

Differentiation syndrome is associated with AML/MDS therapeutics that induce differentiation, causing undifferentiated cancer cells to mature, and is an effect that has been seen with, and is believed to be on-target for, the proposed mechanism of action for FHD-286. The clinical hold was lifted as of June 1, 2023. Foghorn has amended the protocol and plans to commence a Phase 1 study of FHD-286 in combination with decitabine or low-dose cytarabine (LDAC) in relapsed and/or refractory AML patients.

The decision to advance to the Phase 1 combination study is based on clinical data demonstrating FHD-286's effect as a broad-based differentiation agent, its safety profile, as well as supportive pre-clinical combination data, including robust efficacy data in multiple CDX and PDX models. FHD-286 Phase 1 Monotherapy Dose Escalation Study Data in AML/MDS. The Phase 1 dose escalation study of FHD-286 in relapsed and/or refractory AML and MDS enrolled 40 patients who had exhausted all other treatment options and was designed to assess safety and tolerability.

The patients' baseline characteristics in the study included: 36 relapsed and/or refractory AML patients and four relapsed and/or refractory MDS patients The majority of patients in the study had an abnormal karyotype (82.5%) and poor genetic risk factors (65% with adverse genetic status). Patients in the study had a broad range of mutations. 67.5% of patients in the study had received three or more prior lines of therapy.

In the Phase 1 dose escalation study, FHD-286 had an adverse event profile generally consistent with a highly relapsed and/or refractory AML patient population. The doses tested were 2.5 mg, 5.0 mg, 7.5 mg, and 10.0 mg taken orally once daily. The most common treatment-related adverse events were dry mouth, increased blood bilirubin, increased alanine transaminase (ALT), and rash.

The most common grade 3 or higher treatment-related adverse events included increased blood bilirubin, hypocalcemia, differentiation syndrome, stomatitis, and increased ALT. In response to the FDA clinical hold, Foghorn established an independent adjudication committee of leading AML experts, chaired by Martin Tallman, M.D., Northwestern Memorial Hospital. The committee concluded the rate of differentiation syndrome was 15% (six patients out of 40) and classified one case as definitive for differentiation syndrome but not contributing to the patient's death.

The adjudication committee classified five cases as indeterminate for differentiation syndrome. In the Phase 1 dose escalation study, reductions in both peripheral and bone marrow blast counts, as well as recoveries in absolute neutrophil count (ANC), were observed in a subset of heavily pre-treated relapsed and/or refractory patients, irrespective of mutational status. Across a broad range of patients, differentiation was observed both morphologically and/or through biomarkers.

Additionally, patients with evaluable paired bone marrow biopsies demonstrated differentiation as measured by changes in CD11b+ cells, CD34+ cells, and other associated biomarkers. FHD-286 Phase 1 Combination Study Details: Foghorn plans to commence the Phase 1 combination study of FHD-286 in relapsed and/or refractory AML patients in the third quarter of 2023. Study details include: FHD-286 will be dose escalated in combination with either fixed dose decitabine or fixed dose cytarabine in a standard 3+3 dose escalation design.

The study will enroll relapsed and/or refractory AML patients and the protocol allows for first-line relapsed and/or refractory AML patients. The study will assess safety, tolerability, and efficacy of the combination regimens. The combination of FHD-286 with decitabine or cytarabine may mitigate the risk for differentiation syndrome given the cytoreductive properties of these agents.

Please refer to the corporate deck on Foghorn's website here for additional detail. FHD-286 is a highly potent, selective, allosteric and orally available, small-molecule, enzymatic inhibitor of BRG1 (SMARCA4) and BRM (SMARCA2), two highly similar proteins that are the ATPases, or the catalytic engines of the BAF complex, one of the key regulators within the chromatin regulatory system. In preclinical studies, FHD-286 has shown anti-tumor activity across a broad range of malignancies including both hematologic and solid tumors.