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

• ClinicalTrials.gov Identifier: NCT05731544
• Recruitment Status: Recruiting
• First Posted: February 16, 2023
• Last Update Posted: February 13, 2024
• Sponsor: Biomea Fusion Inc.
• Information provided by (Responsible Party): Biomea Fusion Inc.

Tracking Information

• First Submitted Date: December 26, 2022
• First Posted Date: February 16, 2023
• Last Update Posted Date: February 13, 2024
• Actual Study Start Date: August 17, 2022
• Estimated Primary Completion Date: July 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 9, 2024)

• Safety Assessments [ Time Frame: 52 weeks ]
  Assessed by treatment emergent adverse events.(TEAEs), drug discontinuation due to TEAEs, serious adverse events, clinically significant laboratory, vital, and ECG evaluations.
• Pharmacokinetics Assessments [ Time Frame: 12 weeks ]
  Assessed by effect of fed conditions on serial and sparse pharmacokinetic data.
• Change in HbA1c [ Time Frame: 12 weeks. ]
  Assess the change in HbA1c from baseline to week 12.

Original Primary Outcome Measures (submitted: February 7, 2023)

• Treatment of emergent adverse events and observed in single and multiple ascending oral doses of BMF-219 in healthy subjects and subjects with T2DM. [ Time Frame: 14 months ]
  Descriptive summaries of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs).
• Effect of fed conditions on PK and TEAEs following a single and multiple doses of BMF-219 in healthy subjects. [ Time Frame: 14 months ]
  Pharmacokinetics will be determined using quantified differences in area under the plasma concentration vs time curve (AUC).
• Effect of fed conditions on PK and TEAEs following a single and multiple doses of BMF-219 in healthy subjects. [ Time Frame: 14 months ]
  Pharmacokinetics will be determined using quantified differences in peak plasma concentration (Cmax).
• Effect of fed conditions on PK and TEAEs following a single and multiple doses of BMF-219 in healthy subjects. [ Time Frame: 14 months ]
  Pharmacokinetics will be determined using quantified differences in time to peak plasma concentration (tmax).
• Effect of fed conditions on PK and TEAEs following a single and multiple doses of BMF-219 in healthy subjects. [ Time Frame: 14 months ]
  Pharmacokinetics will be determined using quantified differences in time to half peak plasma concentration (t1/2).
• Effect of fed conditions on PK and TEAEs following a single and multiple doses of BMF-219 in healthy subjects. [ Time Frame: 14 months ]
  Pharmacokinetics will be determined using quantified differences in TEAE between the fed conditions.

Current Secondary Outcome Measures (submitted: February 9, 2024)

• To determine the effects of BMF-219 on glycemic parameters in subjects with T2D. [ Time Frame: 18 months ]
  Assess changes in plasma glucose, c-peptide, and insulin at different timepoints both fasted and in response to OGTT.
• To determine the impact of multiple ascending doses of BMF-219 on beta-cell function in subjects with T2D. [ Time Frame: 18 months ]
  Descriptive summaries of homeostatic model assessment beta-cell function %beta and insulin resistance (HOMA-B and HOMA- IR).
• To assess the effect on HbA1c [ Time Frame: 12 Months ]
  Proportion of subjects achieving an HbA1c < 7% at Week 12.

Original Secondary Outcome Measures (submitted: February 7, 2023)

• Pharmacokinetics of BMF-219 single and multiple ascending doses of BMF-219 in healthy subjects and subjects with T2DM. [ Time Frame: 18 months ]
  Pharmacokinetics will be determined using area under the plasma concentration vs time curve (AUC).
• Pharmacokinetics of BMF-219 single and multiple ascending doses of BMF-219 in healthy subjects and subjects with T2DM. [ Time Frame: 18 months ]
  Pharmacokinetics will be determined using peak plasma concentration (Cmax).
• Pharmacokinetics of BMF-219 single and multiple ascending doses of BMF-219 in healthy subjects and subjects with T2DM. [ Time Frame: 18 months ]
  Pharmacokinetics will be determined using time to peak plasma concentration (tmax).
• Pharmacokinetics of BMF-219 single and multiple ascending doses of BMF-219 in healthy subjects and subjects with T2DM. [ Time Frame: 18 months ]
  Pharmacokinetics will be determined using time to half peak plasma concentration (t1/2).
• Pharmacokinetics of BMF-219 single and multiple ascending doses of BMF-219 in healthy subjects and subjects with T2DM. [ Time Frame: 18 months ]
  Pharmacokinetics will be determined using accumulation ratio.
• Pharmacokinetics of BMF-219 single and multiple ascending doses of BMF-219 in healthy subjects and subjects with T2DM. [ Time Frame: 18 months ]
  Pharmacokinetics will be determined using dose proportionality ratio.
• To determine the impact of multiple ascending doses of BMF-219 on glycemic parameters in subjects with T2DM. [ Time Frame: 18 months ]
  Estimation of plasma glucose (PG) and change in PG across study follow-up.
• To determine the impact of multiple ascending doses of BMF-219 on glycemic parameters in subjects with T2DM. [ Time Frame: 18 months ]
  Proportion of subjects achieving glycated hemoglobin (HbA1c) less than 7%.
• To determine the impact of multiple ascending doses of BMF-219 on glycemic parameters in subjects with T2DM. [ Time Frame: 18 months ]
  Estimation of 6-hour plasma glucose profiles and change in profiles across study follow-up.
• To determine the impact of multiple ascending doses of BMF-219 on glycemic parameters in subjects with T2DM. [ Time Frame: 18 months ]
  Estimation of continuous glucose monitoring (CGM) profiles and change in profiles across study follow-up.
• To determine the impact of multiple ascending doses of BMF-219 on beta-cell function in subjects with T2DM. [ Time Frame: 18 months ]
  Descriptive summaries of fasting insulin and C-peptide.
• To determine the impact of multiple ascending doses of BMF-219 on beta-cell function in subjects with T2DM. [ Time Frame: 18 months ]
  Descriptive summaries of C-peptide and insulin responses to OGTT.
• To determine the impact of multiple ascending doses of BMF-219 on beta-cell function in subjects with T2DM. [ Time Frame: 18 months ]
  Descriptive summaries of proinsulin.
• To determine the impact of multiple ascending doses of BMF-219 on beta-cell function in subjects with T2DM. [ Time Frame: 18 months ]
  Descriptive summaries of homeostatic model assessment beta-cell function (HOMA-B).
• To determine the impact of multiple ascending doses of BMF-219 on beta-cell function in subjects with T2DM. [ Time Frame: 18 months ]
  Descriptive summaries of homeostatic model assessment insulin resistance (HOMA-IR).
• To determine the impact of multiple ascending doses of BMF-219 on beta-cell function in subjects with T2DM. [ Time Frame: 18 months ]
  Descriptive summaries of proinsulin-to-insulin ratio.
• To determine the impact of multiple ascending doses of BMF-219 on lipid parameters in subjects with T2DM. [ Time Frame: 18 months ]
  Descriptive summaries of fasting total cholesterol (TC).
• To determine the impact of multiple ascending doses of BMF-219 on lipid parameters in subjects with T2DM. [ Time Frame: 18 months ]
  Descriptive summaries of density of lipoprotein cholesterol: low (LDLC), very low (VLDLC), or high (HDLC).
• To determine the impact of multiple ascending doses of BMF-219 on lipid parameters in subjects with T2DM. [ Time Frame: 18 months ]
  Descriptive summaries of triglyceride (TG).
• To determine the impact of multiple ascending doses of BMF-219 on lipid parameters in subjects with T2DM. [ Time Frame: 18 months ]
  Descriptive summaries of free fatty acid (FFA).
• To assess the effect of multiple ascending doses of BMF-219 on body composition in subjects with T2DM. [ Time Frame: 18 months ]
  Outcome will be measured by body weight.
• To assess the effect of multiple ascending doses of BMF-219 on body composition in subjects with T2DM. [ Time Frame: 18 months ]
  Outcome will be measured by waist-to-hip ratio.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study of BMF-219 in Healthy Adult Subjects and in Adult Subjects With Type 2 Diabetes Mellitus (T2D)
• Official Title: A Phase 1/2 Randomized, Double-Blind, Placebo-Controlled Single and Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, PK, and PD of BMF-219, an Oral Covalent Menin Inhibitor, in Healthy Adults and Adults With T2D
• Brief Summary: 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.
• Detailed 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).
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Masking Description:

The subject and the investigator involved in the treatment or clinical evaluation of the subjects will be unaware of the group assignments. Specific personnel (e.g., PK assay specialist, Medical Monitor or designee, Biostatistician, Safety scientist) will be unblinded to subject treatments to permit real-time interpretation of the safety and PK data.

Primary Purpose: Treatment

• Condition: Type 2 Diabetes Mellitus

Intervention

Drug: BMF-219

Investigational Product

Study Arms

• Experimental: Phase 1 SAD Cohorts
  Phase 1 SAD Cohorts with healthy adults randomized 3:1 receiving BMF-219 or placebo.
  Intervention: Drug: BMF-219
• Experimental: Phase 1 single dose food effect sub-study
  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.
  Intervention: Drug: BMF-219
• Experimental: Phase 1 single dose tablet PK sub-study
  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).
  Intervention: Drug: BMF-219
• Experimental: Phase 2 MAD Cohorts
  Phase 2 MAD Cohorts with healthy adults (MAD1) or adults with T2D (MAD 2-8) randomized 3:1 receiving BMF-219 or placebo.
  Intervention: Drug: BMF-219
• Experimental: Phase 2 Expansion Cohort
  Phase 2 Expansion Cohort adults with T2D randomized 3:1 ratio receiving BMF-219 or placebo.
  Intervention: Drug: BMF-219

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: February 9, 2024): 414
• Original Estimated Enrollment (submitted: February 7, 2023): 188
• Estimated Study Completion Date: May 2025
• Estimated Primary Completion Date: July 2024 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 65 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Contacts

Contact: Rima Sakhapara; 1-844-245-0490; clinicaltrials@biomeafusion.com

Contact: Sanchita Mourya, MD; 1-844-245-0490; clinicaltrials@biomeafusion.com

• Listed Location Countries: Canada, United States

Administrative Information

• NCT Number: NCT05731544
• Other Study ID Numbers: COVALENT-111
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Biomea Fusion Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: Biomea Fusion Inc.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Biomea Fusion Inc.
• Verification Date: February 2024