Biomea Fusion, Inc. announced the presentation of new clinical data from the first two cohorts of patients with T2D enrolled in the Phase II portion of its ongoing Phase I/II clinical study (COVALENT-111) of BMF-219, the company’s investigational oral covalent menin inhibitor. Beta cell loss is a critical component of the etiology and pathogenesis of both type 2 and type 1 diabetes; menin is thought to function as a key regulator of beta cell mass and health in the pancreas. BMF-219, discovered and designed by Biomea using its FUSION™ platform to specifically inhibit menin, has shown in pre-clinical studies three modes of action: the regeneration, reactivation, and preservation of functional beta cells.

This is the first clinical observation of an investigational menin inhibitor dosed in patients with diabetes, showing continued improvements in glycemic control after cessation of therapy. Along with safety and efficacy, COVALENT-111 is evaluating BMF-219’s disease-modifying potential, which has now shown initial proof of concept for continued glycemic control even after treatment is stopped. Late Breaking Clinical Update for COVALENT-111 at ADA 2023: 40 patients were enrolled in the first three Multiple Ascending Dose (MAD) cohorts of COVALENT-111, with the first cohort (Cohort 1) comprising 16 healthy volunteers (HVs); 12 HVs received 100 mg of BMF-219 once daily (QD) and 4 HVs received placebo QD for two weeks and thereafter followed off treatment for an additional six weeks.

In Cohorts 2 and 3, T2D patients (n=12 per cohort with 10 patients treated with 100 mg BMF-219 QD and 2 placebo patients QD) were treated for four weeks with or without food, respectively, and then followed for 22 weeks after treatment. In these two treatment cohorts, enrolled patients had T2D diagnosed for <15 years, were between the ages of 18 to 65, had been treated with lifestyle management with or without up to three standard-of-care anti-diabetic medications, excluding sulfonylureas and insulin, with a stable dosing regimen for at least two months prior to screening, had a BMI =25 and =40 kg/m2, and had poorly controlled diabetes (HbA1c =7.0% and =10%). At baseline, diabetic patients in Cohorts 2 and 3, had a mean HbA1c of 8.0% and 8.1%, respectively.

At Week 12, eight weeks after the last dose of BMF-219: Patients who received BMF-219 in Cohort 2 and 3 had a mean HbA1c reduction of 0.1% and 1.0%, respectively. For Cohort 3 (100 mg BMF-219 QD without food for 4 weeks): 50% of patients (n=5/10) saw a continued improvement in HbA1c with a mean reduction in HbA1c of 1.49% at Week 12, compared to the mean reduction of 0.9% at the end of the dosing period at Week 4 (an additional 62% HbA1c reduction); 60% (n=6/10) of patients achieved an HbA1c of 7% or below at the end of Week 12, compared to 30% (n=3/10) at the end of dosing period (Week 4) and 10% (n=1/10) at the end of Week 1; The average C-peptide expression for patients in Cohort 3 increased through Week 8. A similar increase in HOMA-B was observed, stabilizing at Week 8; As measured by CGM, 7 of 10 (70%) of patients maintained or improved time in range while off treatment (between Week 4 and Week 12); For Cohort 2 (100 mg BMF-219 QD with food for 4 weeks): 50% of patients (n=5/10) showed a mean reduction in HbA1c of 0.94% at Week 12, an additional 114% HbA1c reduction compared to the mean reduction of 0.44% at the end of the dosing period at Week 4; 10% (n=1/10) of patients achieved an HbA1c of 7% or below at the end of Week 12, compared to 0% (n=0/10) at the end of the dosing period (Week 4) and 0% (n=0/10) at the end of Week 1; As measured by continuous glucose monitoring, 6 of 10 (60%) of patients maintained or improved time in range while off treatment (between Week 4 and Week 12); Placebo: 4 diabetic patients on placebo had a mean HbA1c increase of 0.10% at Week 12; Cohort 1 (Healthy Volunteers): Minimal mean change (-0.1% to 0.1%) was observed in HbA1c during 14 days of BMF-219 treatment and 6 weeks of follow-up. Safety Data: As reported in March 2023, during the 4-week dosing period BMF-219 was generally well tolerated; all patients completed the treatment, and all patients continue to be in follow-up to assess the durability of the treatment effect.

There were no dose reductions, dose discontinuations, or severe or serious adverse events. In the active treatment Cohorts 2 and 3 (100 mg QD, n=20; Placebo, n=4), 2 of 20 patients treated with BMF-219 showed mild (Grade 1) related treatment emergent adverse events (TEAEs) compared to no related TEAEs in 4 patients treated with placebo. No patients showed symptomatic hypoglycemia, significant changes in hemoglobin levels, or other TEAEs.

During the off-treatment period (Week 4 to Week 12), no severe or serious TEAEs were noted. Dosing of patients in the 200 mg without food cohort was recently completed and is now in the follow-up period. The 200 mg with food cohort led to an increase in mild to moderate nausea compared to 200 mg without food.

This cohort will be transitioned to 100 mg BID dosing. No other clinical symptoms or clinical concerns were observed in this dose level. In the HV Cohort 1 (100 mg QD, n=12; Placebo, n=4), 2 of 12 patients treated with BMF-219 and 1 of 4 patients treated with placebo showed mild (Grade 1) TEAEs.

No other TEAEs were observed. Next Steps and Updates with BMF-219: BMF-219 in Diabetes (COVALENT-111) - Complete dose escalation, identify optimal dose levels (expected by end of 2023); Initiate dose expansion for COVALENT -111 and explore longer durations of treatment (for up to 12 weeks) in two dose cohorts subject to FDA review/feedback (expected in first quarter of 2024); Explore potential utility of BMF-219 in type 1 diabetes and initiate clinical cohort (expected in first quarter of 2024); Further clinical updates to be determined (Encore abstract for the European Association of the Study of Diabetes in October was not accepted); BMF-219 in Oncology (COVALENT-101 /102); and Continue enrollment to establish optimal dose levels across seven liquid and solid tumors. Early clinical data for the AML/ALL cohort (expected in second half of 2023).