Preliminary data from Biomea Fusion's Phase I COVALENT-103 trial of BMF-500 in relapsed/refractory acute leukemia demonstrates encouraging clinical activity and safety profile, according to results selected for presentation at the upcoming European Hematology Association (EHA) 2025 Congress in Milan, Italy.
The poster presentation, scheduled for June 14, will highlight the emerging safety data, pharmacokinetics/pharmacodynamics, and clinical activity of BMF-500, a covalent FLT3 inhibitor, in patients with relapsed or refractory (R/R) acute leukemia (AL), including those with FLT3 mutations who previously received FLT3 inhibitors such as gilteritinib.
"While we have strategically shifted our internal focus to metabolic disease, the preliminary results from the COVALENT-103 study underscore the strong potential of BMF-500 in relapsed or refractory acute leukemia," said Mick Hitchcock, Ph.D., Interim Chief Executive Officer of Biomea Fusion. "Despite having received and failed multiple prior lines of therapy, the majority of treated patients experienced reductions in bone marrow blasts. Early signs of overall survival already exceed historical benchmarks, even at non-optimized dose levels."
Trial Design and Patient Population
The COVALENT-103 study is an open-label, non-randomized Phase I trial evaluating escalating doses of BMF-500 in adults with R/R acute leukemia with or without FLT3 mutations. The study includes two arms: patients not taking (Arm A) or taking (Arm B) CYP3A4 inhibitors.
As of February 3, 2025, 24 patients with R/R acute leukemia were enrolled, with four remaining on treatment. The patient population was heavily pretreated, with a median of four prior therapies (range 1-10), and 41.7% had previously undergone hematopoietic stem cell transplantation. All patients had prior exposure to venetoclax, and 15 (62.5%) had FLT3 mutations with prior exposure to FLT3 inhibitors including gilteritinib.
Safety and Efficacy Results
BMF-500 demonstrated a favorable safety profile with no dose-limiting toxicities or discontinuations due to treatment-related adverse events. Common treatment-emergent adverse events included febrile neutropenia, nausea, peripheral edema, hypokalemia, and hypocalcemia. Treatment-related adverse events were predominantly Grade 1-2, with only three Grade 3-4 events (leukocytosis, low white blood cell count, and ALT elevation) each occurring in 4.3% of patients.
Among the 11 efficacy-evaluable patients, nine (81.8%) showed clinical activity:
- 77.8% experienced decreased bone marrow blasts
- 33.3% showed decreased peripheral blasts
- Four patients had decreased hydroxyurea use
- Four patients required fewer transfusions
At the 100 mg twice-daily dose level (Arm A), one of two patients with FLT3 mutations achieved a complete remission with incomplete hematologic recovery (CRi) and completed six treatment cycles, while the other patient achieved more than 60% reduction in bone marrow blasts.
The median overall survival for the 23 patients in the safety population was 3.48 months, exceeding the historical median overall survival of 2.1 months for patients resistant to gilteritinib and venetoclax. Notably, the median overall survival for the seven efficacy-evaluable patients with FLT3 mutations has not yet been reached.
Pharmacokinetics and Pharmacodynamics
The study demonstrated that BMF-500 achieved near-complete FLT3 inhibition at steady state. Pharmacokinetic/pharmacodynamic analysis showed an EC90 of 500 ng/mL, with most patients at the 100 mg twice-daily (Arm A) and 25 mg twice-daily (Arm B) dose levels surpassing this threshold. Importantly, BMF-500 and its metabolites showed similar concentrations in bone marrow and plasma.
Dose escalation is continuing at 150 mg twice daily (Arm A) and 75 mg twice daily (Arm B) to identify the optimal biological dose and recommended Phase II dose.
Future Development Plans
Despite the promising results, Biomea Fusion plans to conclude its internal development of BMF-500 in oncology following completion of the dose escalation phase. The company is actively exploring strategic partnerships to advance the program.
"We are actively advancing partnership discussions for this very selective and active covalent binding molecule which was developed in-house for patients with very limited treatment options," Hitchcock noted.
About BMF-500
BMF-500 is an investigational, orally bioavailable, covalent small molecule inhibitor of FLT3, discovered and developed in-house at Biomea using the company's proprietary FUSION™ System. The drug is designed to be highly potent and selective against FLT3 mutations, including ITD, TKD, and resistance mutations like the gatekeeper F691. Unlike some other FLT3 inhibitors, BMF-500 lacks cKIT inhibition, which may contribute to its favorable safety profile.
The drug's covalent binding mechanism results in sustained target inhibition, with preclinical studies showing cytotoxicity even after washout and improved survival in FLT3-mutated acute myeloid leukemia xenografts.
Clinical Implications
The preliminary results from the COVALENT-103 trial are particularly significant given the poor prognosis for patients with relapsed or refractory FLT3-mutated acute leukemia who have failed prior FLT3 inhibitor therapy. The observed clinical activity, including one patient achieving CRi and the majority showing reductions in bone marrow blasts, suggests BMF-500 may offer a new treatment option for this difficult-to-treat patient population.
The favorable safety profile, combined with signs of efficacy even in heavily pretreated patients, positions BMF-500 as a potentially valuable addition to the treatment armamentarium for acute leukemia, particularly for those with FLT3 mutations who have exhausted other options.
Dr. Farhad Ravandi-Kashani from the University of Texas MD Anderson Cancer Center will present the detailed findings at the EHA 2025 Congress, providing the hematology community with a comprehensive look at this promising investigational therapy.
