Study of BMF-219 in Healthy Adult Subjects and in Adult Subjects With Type 2 Diabetes Mellitus (T2D)

Biomea Fusion

Status and phase: Suspended; Phase 2; Phase 1

Conditions: Type 2 Diabetes Mellitus

Treatments: Drug: BMF-219

Study type: Interventional

Funder types: Industry

Identifiers

NCT05731544

COVALENT-111

Details and patient eligibility

About

A Phase 1/ 2 Randomized, Double-Blind, Placebo-Controlled Single and Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of BMF-219, an Oral Covalent Menin Inhibitor, in Healthy Adult Subjects and in Adult Subjects with Type 2 Diabetes Mellitus.

Full description

This is a Phase 1/ 2 study that will examine the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single and multiple dose levels of BMF-219, an orally bioavailable selective covalent inhibitor of menin, in healthy subjects and in subjects with T2D. This study will assess the effect of BMF-219 as single ascending dose (SAD) and multiple ascending dose (MAD).

Enrollment: 414 estimated patients

Sex: All

Ages: 18 to 65 years old

Volunteers: Accepts Healthy Volunteers

Inclusion criteria

Healthy Subject Inclusion Criteria:

1. Males or females, age ≥18 and ≤65 years.
2. BMI ≥18 and ≤35 kg/m2.
3. Subjects are healthy on the basis of their medical history, physical examination, ECG, and routine laboratory data.
4. Females are to be not pregnant, non-lactating. Females can be postmenopausal. Females of childbearing potential must have a negative pregnancy test at screening and be willing to have additional pregnancy tests during the study.
5. All subjects must be willing and able to provide written, signed informed consent and be willing and able to comply with all study procedures and tests.

Subjects with T2D: (MAD Cohorts) Inclusion Criteria:

1. Males or females, age ≥18 and ≤65 years.
2. Diagnosed with T2D within the last 15 years.
3. Treated with lifestyle management with or without at the most 3 anti-diabetic medications with a stable dose for at least 2 months prior to screening. If on metformin, the stable dose should be at least 500mg/day.
4. HbA1c ≥7.0% and ≤10.5%.
5. BMI ≥25 and ≤40 kg/m2.
6. Females are to be not pregnant, non-lactating. Females can be postmenopausal. Females of childbearing potential must have a negative pregnancy test at screening and be willing to have additional pregnancy tests during the study.
7. All Subjects must be willing and able to provide written, signed informed consent and be willing and able to comply with all study procedures and tests.

Subjects with T2D: (Expansion Cohort) Inclusion Criteria:

1. Males or females, age ≥18 and ≤65 years.
2. Diagnosed with T2D within the last 7 years.
3. Treated with lifestyle management with or without at the most 3 anti-diabetic medications with a stable dose for at least 2 months prior to screening. If on metformin, the stable dose should be at least 500mg/day.
4. HbA1c ≥7.0% and ≤10.5%.
5. BMI ≥25 and ≤40 kg/m2.
6. Females are to be not pregnant, non-lactating. Females can be postmenopausal. Females of childbearing potential must have a negative pregnancy test at screening and be willing to have additional pregnancy tests during the study.
7. All Subjects must be willing and able to provide written, signed informed consent and be willing and able to comply with all study procedures and tests.

Exclusion criteria

Healthy Subject Exclusion Criteria:

1. Evidence or history of any clinically significant disease or malignancy.
2. Mean QTcF ≥ 440 msec on triplicate ECGs. Use of medications known to significantly prolong the QT or QTcF interval.
3. History of hypertension or untreated hypertension (sitting systolic blood pressure (BP) ≥140 and diastolic BP ≥90 mm Hg).
4. Known self or family history (first-degree relative) of multiple endocrine neoplasia Type 1.
5. History of stomach or intestinal surgery or resection (except appendectomy, hernia repair, and/or cholecystectomy).
6. A history or evidence of human immunodeficiency virus (HIV), hepatitis C virus (HCV), or hepatitis B virus (HBV) infection at screening or active COVID-19 infection on screening. A COVID-19 infection requiring hospitalization within the past 30 days prior to the screening visit is not allowed.
7. Use of any live vaccines against infectious diseases within 30 days of initiation of investigational product.
8. Current smoker of more than 5 cigarettes per day.
9. Use of proton pump inhibitors is prohibited. Antacids are permitted but must be given a minimum of 2 hrs before or 2 hrs after administration of study drug. Subjects receiving PPIs who switch to H2receptor antagonists are eligible for enrollment in the study.
10. Excessive use (>8 cups/day) of coffee, tea, soda.
11. Receiving an investigational intervention or having participated in another clinical trial within 30 days.
12. Currently dieting (formal weight loss program) and/or are currently using or have used within 2 months of screening any drugs for weight management.
13. Received prior menin inhibitor treatment.

Subjects with T2D (MAD Cohorts) Exclusion Criteria:

1. Type 1 Diabetes Mellitus or a secondary form of diabetes or any prior history of diabetic ketoacidosis.
2. 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.
3. Known self or family history (first-degree relative) of multiple endocrine neoplasia Type 1.
4. Use of anti-diabetes medications (sulfonylureas, insulin, dipeptidyl peptidase-IV inhibitor [DPP-4I] [linagliptin and saxagliptin only] thiazolidinediones) within last 2 months prior to screening.
5. Fasting plasma glucose ≥255 mg/dL.
6. Fasting C-peptide <0.8 ng/ml.
7. Fasting insulin >55 μIU/mL.
8. Mean QTcF ≥450 ms. Use of medications known to significantly prolong the QT or QTc interval.
9. Fasting triglyceride ≥500 mg/dL.
10. Have an eGFR <60 mL/min/1.73 Equation at screening.
11. AST ALT > 1.5 × ULN, bilirubin > 1.5 × ULN. Isolated GGT elevation >2.5 ULN without > 1.5 x ULN AST, ALT and/or total bilirubin but with a history of abnormal LFTs in the last 6 months or a medical history of a liver disorder should be excluded.
12. History of acute or chronic pancreatitis.
13. Serum lipase and/or amylase above 1.5 x ULN.
14. Active hepatitis B virus (HBV) or active hepatitis C virus (HCV) at screening. Known positive test, if any, prior to screening or history of human immunodeficiency virus (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.
15. Use of any live vaccines against infectious diseases within 30 days of initiation of investigational product.
16. Subjects with positive drug screen (except marijuana [tetrahydrocannabinol (THC)] during screening.
17. TSH >6 mIU/L or <0.4 mIU/L (on stable thyroid replacement dose for 3 months prior to screening).
18. Severe uncontrolled treated or untreated hypertension (systolic blood pressure >150 mmHg or diastolic blood pressure >90 mmHg).
19. 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 (e.g., breast carcinoma, cervical cancer in situ, melanoma in situ) treated with potentially curative therapy.
20. History of stomach or intestinal surgery or resection and/or gastroparesis (except that appendectomy, hernia repair, and/or cholecystectomy will be allowed).
21. History of cirrhosis.
22. Current smokers of more than 3 cigarettes per day.
23. Currently dieting (formal weight loss program) and/or are currently using or have used within 2 months of screening any drugs for weight management.
24. Use of Proton pump inhibitors is prohibited. Subjects receiving PPIs who switch to H2-receptor antagonists are eligible for enrollment in the study.
25. History of any illness, underlying medical condition or unstable medical or psychological condition (including drug or alcohol abuse) that, in the opinion of the investigator, might confound the results of the study or pose additional risk in administering study drug to the subject.

Subjects with T2D (Expansion Cohort) Exclusion Criteria:

1. Type 1 Diabetes Mellitus or a secondary form of diabetes.
2. Prior history of diabetic ketoacidosis or hyperosmolar coma.
3. History 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.
4. Known self or family history (first-degree relative) of multiple endocrine neoplasia Type 1 (MEN1).
5. Use of any of the following anti-diabetes medications within 2 months prior to screening: sulfonylureas, insulin, and the dipeptidyl peptidase-4 inhibitors (DPP4i) linagliptin and saxagliptin (sitagliptin and other DPP4i allowed) thiazolidinones [TZD]) within last 2 months prior to screening.
6. Fasting plasma glucose ≥255 mg/dL.
7. Fasting C-peptide <0.8 ng/ml.
8. Fasting insulin >55 μIU/mL.
9. Mean QTcF interval >450 ms on triplicate ECGs. Use of prescription or over-the-counter medications known to significantly prolong the QT or QTc interval is excluded.
10. Fasting triglyceride ≥500 mg/dL.
11. eGFR<60 mL/min/1.73.
12. (AST) or (ALT) >1.5 × ULN, Total bilirubin >1.5 × ULN at screening.
13. History of acute or chronic pancreatitis.
14. Serum lipase and/or amylase above 1.5 x ULN.
15. Active hepatitis B (HBV) or active hepatitis C virus (HCV) at screening. Known positive test or history of human immunodeficiency virus (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.
16. Subjects with positive drug screen (except marijuana [tetrahydrocannabinol (THC)]) during screening.
17. TSH >6 mIU/L or <0.4 mIU/L (on stable thyroid replacement dose for 3 months prior to screening).
18. Severe uncontrolled treated or untreated hypertension (systolic blood pressure >150 mmHg or diastolic blood pressure >90 mmHg).
19. 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 (e.g., breast carcinoma, cervical cancer in situ, melanoma in situ) treated with potentially curative therapy.
20. History of stomach or intestinal surgery or resection and/or gastroparesis.
21. History of cirrhosis.
22. Current smokers of more than 5 cigarettes per day.
23. Currently dieting (formal weight loss program) and/or are currently using or have used within 2 months of screening any drugs for weight management.
24. Use of Proton pump inhibitors is prohibited. Subjects receiving PPIs who switch to H2-receptor antagonists are eligible for enrollment in the study.
25. Any known or suspected allergy to trial product, similar compounds or excipients. medical or psychological condition (including drug or alcohol abuse) or historical abnormal laboratory values that, in the opinion of the investigator, might confound the results of the study or pose additional risk in administering study drug to the subject.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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414 participants in 5 patient groups

Phase 1 SAD Cohorts

Experimental group

Description:

Phase 1 SAD Cohorts with healthy adults randomized 3:1 receiving BMF-219 or placebo.

Treatment:

Drug: BMF-219

Phase 1 single dose food effect sub-study

Experimental group

Description:

Phase 1 single dose food effect sub-study with healthy adults randomized 1:1:1:1:1:1 receiving BMF-219 or placebo fasted, with a low-fat meal, and with a high fat meal.

Treatment:

Drug: BMF-219

Phase 1 single dose tablet PK sub-study

Experimental group

Description:

Phase 1 single dose x3 PK tablet open-label sub-study with healthy adults randomized 1:1 receiving BMF-219 or placebo fasted, with a low-fat meal, and with a high-fat meal).

Treatment:

Drug: BMF-219

Phase 2 MAD Cohorts

Experimental group

Description:

Phase 2 MAD Cohorts with healthy adults (MAD1) or adults with T2D (MAD 2-8) randomized 3:1 receiving BMF-219 or placebo.

Treatment:

Drug: BMF-219

Phase 2 Expansion Cohort

Experimental group

Description:

Phase 2 Expansion Cohort adults with T2D randomized 3:1 ratio receiving BMF-219 or placebo.

Treatment:

Drug: BMF-219