Phase 2 Trial of BMF-219 in Participants With Type 1 Diabetes Mellitus

Study Overview
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Brief Summary
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Phase 2 Trial of BMF-219 in Participants with Type 1 Diabetes Mellitus.

Detailed Description
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Study COVALENT-112 is a 52-week, Phase 2 trial designed to examine beta-cell function, insulin sensitivity, and both glucose and lipid metabolism in participants with T1D treated with BMF-219. BMF-219 is an orally bioavailable, covalent small-molecule menin inhibitor.

Official Title
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Phase 2 Randomized, Double-blind Trial of BMF-219 Compared to Placebo in Participants With Type 1 Diabetes Mellitus

Conditions
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Type 1 Diabetes Mellitus

Intervention / Treatment
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* Drug: BMF-219


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males or females, age ≥18 and ≤60 years. Diagnosed with stage 3 T1D within the following timeframes: Main study: participants diagnosed within 3 years prior to screening. Open-label substudy Cohort 1: participants diagnosed within 3 years prior to screening. Open-label stubstudy Cohort 2: participants diagnosed between 3 to 15 years prior to screening Treated with insulin only (no other diabetes medications) for at least 2 months prior to screening. HbA1c ≥6.5 and ≤10.0% at screening. BMI ≤40 kg/m2. Fasting or stimulated C-peptide Concentration as follow: Main study Participants with C-peptide concentration ≥0.2 nmol/L (0.60 μg/L). (If fasting C-peptide concentration is between 0.15 [0.45 μg/L] - 0.20 nmol/L [0.60 μg/L], stimulated C-peptide concentration [using MMTT] > 0.20 nmol/L [0.60 μg/L] is acceptable). Open-label substudy Cohort 1: Participants with C-peptide concentration ≥0.2 nmol/L (0.60 μg/L) if diagnosed within 3 years prior to screening (if fasting C-peptide concentration is between 0.15 [0.45 μg/L] - 0.20 nmol/L [0.60 μg/L], stimulated C-peptide concentration [using MMTT] > 0.20 nmol/L [0.60 μg/L] is acceptable) Open-label substudy Cohort 2: Participants with fasting C-peptide concentration ≥0.08 nmol/L (0.24 μg/L) if diagnosed between 3 and 15 years prior to screening (if fasting C-peptide concentration is <0.08 nmol/L (0.24 μg/L), stimulated C-peptide (using MMTT) ≥0.08 nmol/L (0.24 μg/L) is acceptable. Documented presence of at least 1 T1D1-related autoantibody (glutamic acid decarboxylases; insulin-associated tyrosine phosphatase antibody; insulin autoantibody; islet cell antibody; antibodies to ZnT8) within the past 3 years. Exclusion Criteria: Diagnosis of MODY, T2D or any other subtype of diabetes mellitus other than T1D. Have had recurrence (≥2 episodes) of severe hypoglycemia (defined by the occurrence of neuroglycopenic symptoms requiring the assistance of another person for recovery) within the last 6 months prior to screening or, has a history of hypoglycemia unawareness or poor recognition of hypoglycemic symptoms as judged by the investigator. Known self or family history (first-degree relative) of multiple endocrine neoplasia Type 1. Use of diabetes medications except insulin within 30 days or within 5 half lives of the drug prior to screening. Any of the following within the last 6 months prior to screening: MI, angina, coronary artery bypass graft, percutaneous coronary intervention (diagnostic angiograms are permitted), TIA, cerebrovascular accident or decompensated congestive heart failure, or currently have New York Health Association Class III or IV heart failure. Participants with fasting triglyceride ≥500 mg/dL. Have an eGFR <60 mL/min/1.73 m2 by the CKDEPI Creatinine Equation at screening. Impaired liver function, defined as screening AST or ALT >1.5 × ULN, Total bilirubin >1.5 × ULN. History of acute or chronic pancreatitis. Serum lipase and/or amylase above 1.5 x ULN. Active HBV or active HCV at screening. Known positive test or history of HIV. An active COVID-19 infection at screening. A COVID-19 infection requiring hospitalization (or release from the hospital) within the past 30 days prior to the screening visit. Use of any live vaccines against infectious diseases within 30 days of initiation of investigational product. Diagnosis of, or treatment for, any cancer within the last 2 years with the exception of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ, melanoma in situ) treated with potentially curative therapy. Prior diagnosis of celiac disease. History of stomach or intestinal surgery or resection and/or gastroparesis that would potentially alter absorption and/or excretion of orally administered drugs (appendectomy, hernia repair, and/or cholecystectomy will be allowed). History of cirrhosis. Current smokers of more than 5 cigarettes per day. Use of Proton pump inhibitors (PPIs) is prohibited. Antacids are permitted but must be given a minimum of 2 hours before or 2 hours after administration of trial intervention. Participants receiving PPIs who switch to H2-receptor antagonists are eligible for enrollment in the trial.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Main Study<br>The Main Study will enroll randomized participants with T1D diagnosed within 3 years and with C-peptide concentration ≥0.2 nmol/L (0.60 μg/L). The main study uses a randomized, double-blind, placebo-controlled design with parallel assignment among 3 treatment arms . The trial begins with a screening period of up to 35 days. Eligible participants will be randomly assigned to 1 of 3 arms using a 1:1:1 ratio: Arm A: BMF-219 100 mg QD for 12 weeks Arm B: BMF-219 200 mg QD for 12 weeks Arm C: Matching placebo. | Drug: BMF-219<br>* BMF-219 is an orally bioavailable, covalent small-molecule menin inhibitor.<br>|
| Experimental: Open Label Substudy<br>The open-label substudy will enroll participants with T1D into 2 cohorts: participants with T1D diagnosed within 3 years with C-peptide concentration ≥0.2 nmol/L (0.60 μg/L) and participants with T1D diagnosed between 3 to 15 years with C-peptide concentration ≥0.08 nmol/L (0.24 μg/L). The substudy uses a randomized, open-label design with parallel assignment between 2 treatment arms in each cohort. The substudy begins with a screening period of up to 35 days. Eligible participants will be randomly assigned by cohort to 1 of 2 treatment arms: Cohort 1: Participants with T1D diagnosed within 3 years with C-peptide concentration ≥0.2 nmol/L (0.60 μg/L) Arm A: BMF-219 100 mg QD for 12 weeks Arm B: BMF-219 200 mg QD for 12 weeks Cohort 2: Participants with T1D diagnosed between 3 to 15 years with C-peptide concentration ≥0.08 nmol/L (0.24 μg/L). Arm A: BMF-219 100 mg QD for 12 weeks Arm B: BMF-219 200 mg QD for 12 weeks | Drug: BMF-219<br>* BMF-219 is an orally bioavailable, covalent small-molecule menin inhibitor.<br>|
| Placebo Comparator: Main Study Double Blind Arm C<br>Matching placebo. | Drug: BMF-219<br>* BMF-219 is an orally bioavailable, covalent small-molecule menin inhibitor.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess the effect on endogenous insulin secretion | Mean change from baseline in stimulated C-peptide AUC. | 12 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess the effect on endogenous insulin secretion | Maximum stimulated C-peptide: the highest value at any time point during the 4-hour MMTT. | 12 Weeks | 
| To assess the effect on additional glycemic parameters | Mean change from baseline in HbA1c. | 12 Weeks of treatment | 
| To assess the effect on additional glycemic parameters | Mean change from baseline in FPG. | 12 Weeks | 
| To assess hypoglycemia events | Percentage of participants with hypoglycemic episodes (with confirmed self-plasma glucose monitoring) including level 2 hypoglycemic events (<54 mg/dL regardless of symptoms) and level 3 (severe) hypoglycemia across different timepoints. | 12 weeks | 
| To assess the effect on insulin doses | Change from baseline in mean daily insulin dosing. | 12 Weeks | 
| Rate of symptomatic hypoglycemic episodes | Evaluation and comparison of the number of symptomatic (both minor and severe) hypoglycemic episodes with BMF-219 vs placebo during the study. | 12 Weeks and during study duration | 
| Incidence of adverse events | Evaluation and comparison of the number of adverse events with BMF-219 vs placebo during the study. | 12 Weeks and during study duration |