Study of BMF-219 in Healthy Adult Subjects and in Adult Subjects With Type 2 Diabetes Mellitus (T2DM)

Study Overview
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Brief Summary
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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
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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 T2DM. This study will assess the effect of BMF-219 as single ascending dose (SAD) and multiple ascending dose (MAD).

Official Title
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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 T2DM

Conditions
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Type 2 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: Healthy Subject: Males or females, age ≥18 and ≤65 years. BMI ≥18 and ≤35 kg/m2. Subjects are healthy on the basis of their medical history, physical examination, ECG, and routine laboratory data. Females are to be not pregnant, non-lactating, and can be postmenopausal (defined as amenorrheic for at least 1 year while not taking oral contraceptives [OCPs] without an alternative cause). Females of childbearing potential must have a negative pregnancy test at screening and be willing to have additional pregnancy tests during the study. They must also agree to commit to either continued abstinence from engaging in reproductive sexual activity or to use 2 adequate forms of contraception methods simultaneously from the time of giving informed consent until 90 days after the last dose of investigational product to avoid pregnancy. Adequate contraception is defined as oral, intravaginal, transdermal, implantable or injectable contraceptives, intrauterine devices, surgical sterilization (achieved through hysterectomy, oophorectomy, bilateral salpingectomy or tubal ligation) in addition to an intrauterine hormone-releasing system (IUS) and/or spermicide. Females must be willing to refrain from egg donation, and in vitro fertilization during treatment and until the end of contraception requirement. If needed, female subjects should be advised to seek advice about egg donation and cryopreservation of germs cells before treatment. Males with partners who are female with reproductive potential must agree to commit to either continued abstinence from sexual intercourse or that they or their partners will use at least 2 effective contraceptive methods when engaging in reproductive sexual activity throughout the study and will avoid conceiving for 90 days after the last dose of BMF-219. Males must be willing to refrain from sperm donation during treatment and until the end of contraception requirement. If needed, male subjects should be advised to seek advice about sperm donation and cryopreservation of germ cells before treatment 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 T2DM: (MAD) Males or females, age ≥18 and ≤65 years. Diagnosed with T2DM within the last 15 years. Treated with lifestyle management with or without at the most 3 anti-diabetic medications (metformin*, sodium-glucose cotransporter 2 [SGLT2] inhibitor, glucagon-like peptide1 receptor agonists [GLP-1Ra], dipeptidyl peptidase-IV inhibitor [DPP-4I] [alogliptin and sitagliptin only]) with a stable dose for at least 2 months prior to screening. * If on metformin, the subject must be on a minimum stable dose of ≥500mg/day prior to the screening visit. HbA1c ≥7.0% and ≤10% at screening. BMI ≥25 and ≤40 kg/m2. If treated with lipid-lowering therapy, the dose must be stable for at least 30 days prior to screening. Females are to be not pregnant, non-lactating, and can be postmenopausal (defined as amenorrheic for at least 1 year while not taking oral contraceptives [OCPs] without an alternative cause). Females of childbearing potential must have a negative pregnancy test at screening and be willing to have additional pregnancy tests during the study. They must also agree to commit to either continued abstinence from engaging in reproductive sexual activity or to use 2 adequate forms of contraception methods simultaneously from the time of giving informed consent until 90 days after the last dose of investigational product to avoid pregnancy. Adequate contraception is defined as oral, intravaginal, transdermal, implantable or injectable contraceptives, intrauterine devices, surgical sterilization (achieved through hysterectomy, oophorectomy, bilateral salpingectomy or tubal ligation) in addition to an intrauterine hormone-releasing system (IUS) and/or spermicide. Females must be willing to refrain from egg donation, and in vitro fertilization during treatment and until the end of contraception requirement. If needed, female subjects should be advised to seek guidance about egg donation and cryopreservation of germ cells before treatment. Males with partners who are female with reproductive potential must agree to commit to either continued abstinence from sexual intercourse or that they or their partners will use at least 2 effective contraceptive methods when engaging in reproductive sexual activity throughout the study and will avoid conceiving for 90 days after the last dose of BMF-219. Males must be willing to refrain from sperm donation during treatment and until the end of contraception requirement. If needed, male subjects should be advised to seek advice about sperm donation and cryopreservation of germ cells before treatment. 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 Subjects: Evidence or history of any clinically significant disease of the following systems: pulmonary, gastrointestinal (appendectomy, hernia repair, and cholecystectomy allowed), cardiovascular (including a history of arrhythmia or conduction delays on ECG), hepatic, neurologic, psychiatric, renal, genitourinary, endocrine, metabolic, dermatologic, or hematologic. Evidence or history of malignancy (excluding basal cell carcinoma of the skin, completely resected squamous cell carcinoma of the skin with no recurrence for 12 months). An ECG considered by the investigator indicative of active cardiac disease or with abnormalities that may interfere with the interpretation of changes in ECG intervals at screening. Mean QTcF (Fridericia [QTcF=QT/RR1/3]) interval greater than 440 msec on triplicate ECGs. Use of prescription or over-the-counter medications known to significantly prolong the QT or QTcF interval. History of hypertension or untreated hypertension (sitting systolic blood pressure (BP) ≥140 and diastolic BP ≥90 mm Hg). [If the blood pressure is ≥140/90, then 3 consecutive BP readings are allowed after resting for 5 min prior to each reading. The average of 3 BP readings will be recorded.] Known self or family history (first-degree relative) of multiple endocrine neoplasia Type 1. History of stomach or intestinal surgery or resection that would potentially alter absorption and/or excretion of orally administered drugs (except appendectomy, hernia repair, and/or cholecystectomy). 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. Use of any live vaccines against infectious diseases within 30 days of initiation of investigational product. Subjects with positive drug abuse screen (except marijuana [tetrahydrocannabinol (THC)]) and/or consumption of poppy seed-containing products (poppy seed cake, cookies, bagels) within 48 hours prior to dosing will be excluded. Any significant blood loss, donation of 1 unit (450 mL) or more of blood or received a transfusion of any blood or blood products within 2 months prior to dosing. Current smoker of more than 5 cigarettes per day. Any regular use of prescription or nonprescription drugs that cannot be stopped at screening (exceptions can be discussed with the Biomea Medical Monitor or designee). 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. In the study period, however, the study drug must be dosed at least 2 hrs before administration of an H2 blocker. Excessive use of methylxanthine-containing beverages (>8 cups/day of coffee, tea, soda, or chocolate). Prior to entrance into the CRC in Phase 1, the subjects are not allowed to use excessive amounts of coffee and/or a diet that deviates notably from the 'normal' diet (according to the Investigator's judgment). The use of methylxanthine-containing beverages or food (coffee, tea, cola, chocolate) and alcohol is not allowed within 12 hrs before entrance into the CRC and during the stay in the CRC. Seville oranges, grapefruit, grapefruit hybrids or grapefruit juice, pomelos, exotic citrus fruits or fruit juices ingestion or treatment with any CYP3A4 inhibitor, inducer, or substrate within a week prior to dosing. Receiving an investigational intervention or having participated in another clinical trial within 30 days or within 5 half-lives of the investigational drug, whichever is shorter, prior to screening. Exception may be made if the individual is enrolled in a non-therapeutic observational study (registry) or the observational portion of a therapeutic study where the sponsoring authority authorizes enrollment. Any known or suspected allergy to the trial product, similar compounds, or excipients. History of atopy (severe or multiple allergic manifestations) or clinically significant multiple or severe drug allergies. 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. Currently dieting (formal weight loss program) and/or are currently using or have used within 2 months of screening any drugs for weight management (Bupropion-naltrexone [Contrave], orlistat [Xenical], lorcaserin [Belviq], phentermine, phentermine-topiramate [Qsymia], mazindol, pramlintide, zonisamide, or any other, either by prescription or as part of a clinical study) or diet attempts using herbal supplements or over-the-counter medications. Received prior menin inhibitor treatment. Subjects with T2DM (MAD) Type 1 Diabetes Mellitus or a secondary form of diabetes or any prior history of diabetic ketoacidosis. 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 anti-diabetes medications (sulfonylureas, insulin, dipeptidyl peptidase-IV inhibitor [DPP-4I] [linagliptin and saxagliptin only] thiazolidinediones) within last 2 months prior to screening. Fasting plasma glucose ≥240 mg/dL. Fasting C-peptide <0.8 ng/ml. Any of the following within the last 6 months prior to screening: myocardial infarction (MI), angina, coronary artery bypass graft, percutaneous coronary intervention (diagnostic angiograms are permitted), transient ischemic attack (TIA), cerebrovascular accident or decompensated congestive heart failure, or currently have New York Health Association Class III or IV heart failure. An ECG considered by the investigator indicative of active cardiac disease or with abnormalities that may interfere with the interpretation of changes in ECG intervals at screening. Mean QTcF (Fridericia [QTcF=QT/RR1/3]) interval greater than 450 ms on triplicate ECGs. Use of prescription or over-the-counter medications known to significantly prolong the QT or QTc interval is excluded. Subjects with fasting triglyceride ≥ 500 mg/dL. Have an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 by the CKD-EPI Creatinine Equation at screening. Impaired liver function, defined as screening aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 1.5 × ULN, bilirubin > 1.5 × ULN History of acute or chronic pancreatitis. Serum lipase and/or amylase above 1.5 x ULN. Active hepatitis B virus (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. Use of any live vaccines against infectious diseases within 30 days of initiation of investigational product. Subjects with positive drug screen during screening and/or consumption of poppy seed-containing products (poppy seed cake, cookies, bagels) within 48 hours prior to dosing will be excluded. Untreated or uncontrolled hypothyroidism/hyperthyroidism defined as thyroid stimulating hormone (TSH) >6 mIU/L or <0.4 mIU/L (on stable thyroid replacement dose for 3 months prior to screening). Severe uncontrolled treated or untreated hypertension (systolic blood pressure >150 mmHg or diastolic blood pressure > 90 mmHg). [If the blood pressure is ≥150/90, then 3 consecutive BP readings are allowed after resting for 5 min prior to each reading. The average of 3 BP readings will be recorded.] Active or history of proliferative retinopathy or maculopathy requiring treatment. Known significant diabetic neuropathy and autonomic neuropathy as evidenced by urinary retention, resting tachycardia (heart rate ≥120/min), or diabetic diarrhea. 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. History of stomach or intestinal surgery or resection and/or gastroparesis that would potentially alter absorption and/or excretion of orally administered drugs (except that appendectomy, hernia repair, and/or cholecystectomy will be allowed). History of cirrhosis. Any significant blood loss, donation of 1 unit (450 mL) or more of blood or received a transfusion of any blood or blood products within 2 months prior to dosing. Current smokers of more than 3 cigarettes per day. Participants should agree to refrain from seville oranges, grapefruit, grapefruit hybrids or grapefruit juice, pomelos, exotic citrus fruits or fruit juices a week prior to dosing and during the study. Treatment with systemic corticosteroids (>10 mg prednisone or equivalent daily) within 60 days of first dose which in the Investigator's opinion could interfere with the glucose level. Topical steroids, steroid containing inhalers, and nasal sprays are permitted in the study. Currently dieting (formal weight loss program) and/or are currently using or have used within 2 months of screening any drugs for weight management (Bupropion-naltrexone [Contrave], orlistat [Xenical], lorcaserin [Belviq], phentermine, phentermine-topiramate [Qsymia], mazindol, pramlintide, zonisamide, or any other, either by prescription or as part of a clinical study) or diet attempts using herbal supplements or over-the-counter medications. 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 H2-receptor antagonists are eligible for enrollment in the study. In the study period, however, the study drug should be dosed at least 2 hrs before administration of an H2 blocker. Treatment with any CYP3A4 inhibitor, inducer, or substrate within a week prior to dosing on Day 1. Receiving an investigational intervention or having participated in another clinical trial within 30 days or within 5 half-lives of the drug prior to screening. Exception may be made if the individual is enrolled in a non-therapeutic observational study (registry) or the observational portion of a therapeutic study where the sponsoring authority authorizes enrollment. Any known or suspected allergy to trial product, similar compounds or excipients. Have a history of atopy (severe or multiple allergic manifestations) or clinically significant multiple or severe drug allergies. 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1 (SAD Cohorts)<br>Phase 1 comprises of randomized healthy adult subjects in 4 cohorts. 10 subjects will be randomized at 7:3 (active and placebo) in sequential order in 4 dose escalating cohorts. Each cohort is composed of 2 sentinel subjects randomized at 1:1 (active and placebo), followed by 8 additional subjects randomized at 3:1 (active and placebo). | Drug: BMF-219<br>* BMF-219 is an orally bioavailable, covalent small-molecule menin inhibitor.<br>|
| Experimental: Phase 1 single dose, 3-period crossover, food effect substudy in 2 cohorts.<br>Each cohort comprises of 12 healthy adult subjects randomized at 1:1:1:1:1:1 in a 3-period crossover study with 6 treatment sequences. | Drug: BMF-219<br>* BMF-219 is an orally bioavailable, covalent small-molecule menin inhibitor.<br>|
| Experimental: Phase 2 (MAD Cohorts)<br>Phase 2 comprises of 1 cohort of 16 healthy adult subjects randomized at 3:1 (active and placebo) and 7 cohorts of T2DM adult subjects randomized at 5:1 (active and placebo) to obtain further safety and efficacy data to identify the potential optimal biological dose (OBD)/recommended Phase 2 dose (RP2D). | Drug: BMF-219<br>* BMF-219 is an orally bioavailable, covalent small-molecule menin inhibitor.<br>|
| Experimental: Phase 2 Expansion Cohort<br>Phase 2 comprises of 216 adult subjects (72 in each arm [54 active; 18 placebo]) with T2D treated with lifestyle management with at most 3 antidiabetic medication(s). Subjects will be randomized to 1 of 3 treatment arms using a 3:1 ratio. | 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 |
| --- | --- | --- |
| Treatment of emergent adverse events and observed in single and multiple ascending oral doses of BMF-219 in healthy subjects and subjects with T2DM. | Descriptive summaries of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs). | 14 months | 
| Effect of fed conditions on PK and TEAEs following a single and multiple doses of BMF-219 in healthy subjects. | Pharmacokinetics will be determined using quantified differences in area under the plasma concentration vs time curve (AUC). | 14 months | 
| Effect of fed conditions on PK and TEAEs following a single and multiple doses of BMF-219 in healthy subjects. | Pharmacokinetics will be determined using quantified differences in peak plasma concentration (Cmax). | 14 months | 
| Effect of fed conditions on PK and TEAEs following a single and multiple doses of BMF-219 in healthy subjects. | Pharmacokinetics will be determined using quantified differences in time to peak plasma concentration (tmax). | 14 months | 
| Effect of fed conditions on PK and TEAEs following a single and multiple doses of BMF-219 in healthy subjects. | Pharmacokinetics will be determined using quantified differences in time to half peak plasma concentration (t1/2). | 14 months | 
| Effect of fed conditions on PK and TEAEs following a single and multiple doses of BMF-219 in healthy subjects. | Pharmacokinetics will be determined using quantified differences in TEAE between the fed conditions. | 14 months | 
| Expansion: To assess the effect on HbA1c | Change in HbA1c from baseline at Week 12 | 12 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics of BMF-219 single and multiple ascending doses of BMF-219 in healthy subjects and subjects with T2DM. | Pharmacokinetics will be determined using area under the plasma concentration vs time curve (AUC). | 18 months | 
| Pharmacokinetics of BMF-219 single and multiple ascending doses of BMF-219 in healthy subjects and subjects with T2DM. | Pharmacokinetics will be determined using peak plasma concentration (Cmax). | 18 months | 
| Pharmacokinetics of BMF-219 single and multiple ascending doses of BMF-219 in healthy subjects and subjects with T2DM. | Pharmacokinetics will be determined using time to peak plasma concentration (tmax). | 18 months | 
| Pharmacokinetics of BMF-219 single and multiple ascending doses of BMF-219 in healthy subjects and subjects with T2DM. | Pharmacokinetics will be determined using time to half peak plasma concentration (t1/2). | 18 months | 
| Pharmacokinetics of BMF-219 single and multiple ascending doses of BMF-219 in healthy subjects and subjects with T2DM. | Pharmacokinetics will be determined using accumulation ratio. | 18 months | 
| Pharmacokinetics of BMF-219 single and multiple ascending doses of BMF-219 in healthy subjects and subjects with T2DM. | Pharmacokinetics will be determined using dose proportionality ratio. | 18 months | 
| To determine the impact of multiple ascending doses of BMF-219 on glycemic parameters in subjects with T2DM. | Estimation of plasma glucose (PG) and change in PG across study follow-up. | 18 months | 
| To determine the impact of multiple ascending doses of BMF-219 on glycemic parameters in subjects with T2DM. | Proportion of subjects achieving glycated hemoglobin (HbA1c) less than 7%. | 18 months | 
| To determine the impact of multiple ascending doses of BMF-219 on glycemic parameters in subjects with T2DM. | Estimation of 6-hour plasma glucose profiles and change in profiles across study follow-up. | 18 months | 
| To determine the impact of multiple ascending doses of BMF-219 on glycemic parameters in subjects with T2DM. | Estimation of continuous glucose monitoring (CGM) profiles and change in profiles across study follow-up. | 18 months | 
| To determine the impact of multiple ascending doses of BMF-219 on beta-cell function in subjects with T2DM. | Descriptive summaries of fasting insulin and C-peptide. | 18 months | 
| To determine the impact of multiple ascending doses of BMF-219 on beta-cell function in subjects with T2DM. | Descriptive summaries of C-peptide and insulin responses to OGTT. | 18 months | 
| To determine the impact of multiple ascending doses of BMF-219 on beta-cell function in subjects with T2DM. | Descriptive summaries of proinsulin. | 18 months | 
| To determine the impact of multiple ascending doses of BMF-219 on beta-cell function in subjects with T2DM. | Descriptive summaries of homeostatic model assessment beta-cell function (HOMA-B). | 18 months | 
| To determine the impact of multiple ascending doses of BMF-219 on beta-cell function in subjects with T2DM. | Descriptive summaries of homeostatic model assessment insulin resistance (HOMA-IR). | 18 months | 
| To determine the impact of multiple ascending doses of BMF-219 on beta-cell function in subjects with T2DM. | Descriptive summaries of proinsulin-to-insulin ratio. | 18 months | 
| To determine the impact of multiple ascending doses of BMF-219 on lipid parameters in subjects with T2DM. | Descriptive summaries of fasting total cholesterol (TC). | 18 months | 
| To determine the impact of multiple ascending doses of BMF-219 on lipid parameters in subjects with T2DM. | Descriptive summaries of density of lipoprotein cholesterol: low (LDLC), very low (VLDLC), or high (HDLC). | 18 months | 
| To determine the impact of multiple ascending doses of BMF-219 on lipid parameters in subjects with T2DM. | Descriptive summaries of triglyceride (TG). | 18 months | 
| To determine the impact of multiple ascending doses of BMF-219 on lipid parameters in subjects with T2DM. | Descriptive summaries of free fatty acid (FFA). | 18 months | 
| To assess the effect of multiple ascending doses of BMF-219 on body composition in subjects with T2DM. | Outcome will be measured by body weight. | 18 months | 
| To assess the effect of multiple ascending doses of BMF-219 on body composition in subjects with T2DM. | Outcome will be measured by waist-to-hip ratio. | 18 months | 
| Expansion: To assess the effect on HbA1c | Proportion of subjects achieving an HbA1c < 7% at Week 12. | 12 Months | 
| Expansion: To assess the effect on blood glucose. | Change from baseline in fasting plasma glucose at Week 12. | 12 months | 
| Expansion: To assess safety and tolerability. | TEAEs and SAEs, safety laboratory tests, results of physical examinations, including vital signs, and 12-lead ECGs. | 12 Months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetes, Type 2 Diabetes Mellitus, Healthy Volunteers