Study to Evaluate Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of LGD-6972 in Healthy Subjects and Subjects With Type 2 Diabetes Mellitus

Exclusion Criteria

• •1. Presence or history of cancer within 5 years prior to the Screening Visit (other than basal cell skin cancer without active lesions and adequately treated carcinoma in situ of cervix);
• •2. Presence or history of gastrointestinal (GI), hepatic, or renal disease or any other condition (including surgery) known to interfere with the absorption, distribution, metabolism or excretion of medicines. History of appendectomy and cholecystectomy is permitted;
• •3. Presence or history of significant cardiovascular, pulmonary (including asthma), hepatic, renal, gastrointestinal (including GI bleeding), hematologic (including coagulation disorders), immunologic, endocrine, psychiatric, or neurologic disease that, in the opinion of the Investigator, may cause an increase risk during the study or compromise interpretation of study data.
• •4. History of uncontrolled high blood pressure, or systolic blood pressure outside the range of 90 mmHg to 140 mmHg, inclusive, and diastolic blood pressure outside the range of 60 mmHg to 90 mmHg, inclusive, at the Screening Visit or at Day -1, confirmed by at least 2 repeat measurements. Repeat blood pressure measurements are permitted within 24 hours at the discretion of the Investigator;
• •5. History of Gilbert's disease or bilirubin \>1.5 X ULN at the Screening Visit or at Day -1;
• •6. History of clinically significant drug allergies (including LGD 6972, PEG 400, or Captisol®) and/or clinically significant food allergies as determined by the Principal Investigator;
• •7. Use of any alcohol or methylxanthine-containing beverages or food (eg, coffee, tea, cola, chocolate, and "power drinks") from 72 h prior to the first dose of study drug until after the last protocol specified blood sample;
• •8. Use of any tobacco products, nicotine-containing products, or pharmacologic smoking cessation therapy during the 3 months immediately prior to the first dose of study drug, and/or not willing or able to refrain from use of any of these products for the duration of the study until after the last protocol specified blood sample;
• •9. History of alcohol abuse within 2 years of the Screening Visit, in the judgment of the Investigator, or average weekly alcohol consumption of \>14 alcoholic drinks. One drink is defined as 1 glass of beer (approximately 10 oz to 12 oz) or 1 can (12 oz) of beer, 1 glass of wine (approximately 4 oz to 5 oz), or 1 glass of distilled spirits (hard liquor) containing 1 oz of the liquor (1 oz of liquid is approximately 30 mL);
• •10. Plasma triglycerides \>400 mg/dL at the Screening Visit or at Day -1;
• •11. History of drug abuse within 2 years of the Screening Visit, in the judgment of the Investigator;
• •12. Positive urine test for drugs of abuse (opiates, methadone, cocaine, amphetamines, cannabinoids, barbiturates, benzodiazepines) or cotinine at the Screening Visit or at Day -1;
• •13. Positive breath test for alcohol at the Screening Visit or at Day -1;
• •14. Not willing to abstain from strenuous exercise (eg, heavy lifting, weight training, calisthenics, aerobics) for at least 48 hours prior to admission to the investigational site until after the last protocol specified blood sample;
• •15. Use of substances known to be strong inhibitors or inducers of cytochrome P450 enzymes (eg, ritonavir, ketoconazole, nefazodone, grapefruit juice) within 14 days prior to the first dose of study drug through the last study visit. Chronic exposure to enzyme inducers such as paint solvents or pesticides, other investigational drug use, or illicit drug use within 30 days prior to study drug administration;
• •16. Use of prescription or non-prescription drugs, vitamins, herbal, and dietary supplements, within 14 days or 5 half-lives (whichever is longer) prior to the first dose of study drug, and willingness to refrain from taking any such medication until after the last protocol specified blood sample. The use of acetaminophen, not to exceed a total daily dose of 1 g, is permitted up to 24 hours prior to admission to the investigational site and then prohibited until after the last protocol specified blood sample. The use of stable hormone replacement medication by women, topical steroids, and stable thyroid medication is permitted. Medication regimens are considered stable if the dose and schedule of administration has not changed within the prior 3 months and is not expected to change for the duration of the study;
• •17. Recent significant changes in body weight, based on Investigator judgment, within 3 months prior to the Screening Visit or at Day -1;
• •18. Any abnormal diet or participation in a weight loss program that is not in the maintenance phase, or treatment with a weight loss medication within 8 months immediately prior to the Screening Visit, or prior weight loss surgery;
• •19. Donation of whole blood \>450 mL or blood products within 56 days prior to admission to the investigational site;
• •20. Hemoglobin \<12.0 g/dL in males or \<11.5 g/mL in females;
• •21. Use of any investigational drug within 30 days or 5 half-lives of the previous investigational drug prior to the first dose of study drug in this study, whichever is longer;
• •22. Positive screen for human immunodeficiency virus (HIV), hepatitis B, and/or hepatitis C at the Screening Visit;
• •23. Acute illness accompanied by temperature ≥101F within 5 days prior to study drug administration;
• •For participants with T2DM:
• •24. Diabetic complications (eg, proliferative retinopathy, peripheral neuropathy requiring treatment, or history or presence of neuropathic or vascular skin ulcers).
• •25. History of hypoglycemia unawareness or hypoglycemic episodes requiring assistance.
• •26. Impaired renal function defined as estimated glomerular filtration rate (eGFR by Modification of Diet in Renal Disease Study \[MDRD\] formula) \<60 mL/min at the Screening Visit or at Day -1.
• •27. History of Type 1 diabetes mellitus.
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