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

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.

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 and must agree to use adequate contraception during the study and for approximately 90 days following the last administration 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, or bilateral salpingectomy or tubal ligation) in addition to/or a combination of an intrauterine hormone-releasing system (IUS) and spermicide for at least 90 days. 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 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.Subjects with T2DM: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 and must agree to use adequate contraception during the study and for approximately 90 days following the last administration 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, or bilateral salpingectomy or tubal ligation) in addition to/or a combination of an intrauterine hormone-releasing system (IUS) and spermicide for at least 90 days. 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 performed within 5 min of each other. Use of prescription or over-the-counter medications known to significantly prolong the QT or QTcF interval. (As a guide to known drugs associated with QTc prolongation, please refer to the following Credible Meds web page for a list of drugs that prolong QT and/or cause Torsades de Pointes, https://crediblemeds.org/pdftemp/pdf/CombinedList.pdf)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 are 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 must be dosed at least 2 hrs before and approximately 10 hrs after 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 on Day 1.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 nontherapeutic 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.Subjects with T2DMType 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]) within last 2 months prior to screening.Fasting plasma glucose ≥270 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 performed within 5 min of each other. Use of prescription or over-the-counter medications known to significantly prolong the QT or QTc interval is excluded. (As a guide to known drugs associated with QTc prolongation, please refer to the following Credible Meds web page for a list of drugs that prolong QT and/or cause Torsades de Pointes, https://crediblemeds.org/pdftemp/pdf/CombinedList.pdf.)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 × ULNHistory of acute or chronic pancreatitis.Serum lipase and/or amylase above ULN.A history or evidence of HIV or active HCV, active HBV, or 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 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.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 (sitting systolic blood pressure >150 mmHg or diastolic blood pressure ≥95 mmHg). [If the blood pressure is ≥150/95, 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) of or more 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.Prior to entrance into the CRC in Phase 2 (including entry into the CRC for the PK blood testing at the Day 1, Week 1, and Week 4 Visit), the participants are not allowed to use excessive amounts (>8 cups/day of coffee, tea, soda, chocolate or seville oranges, grapefruit, grapefruit hybrids or grapefruit juice, pomelos, exotic citrus fruits or fruit juices 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), fruits and fruit juices mentioned above, and alcohol are not allowed within 12 hrs before entrance into the CRC and during the stay in the CRC.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 and approximately 10 hrs after 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.