Safety and Tolerability Study of Oral LGD-6972 for Type 2 Diabetes Mellitus
Safety and Tolerability Study of Oral LGD-6972 for Type 2 Diabetes Mellitus
Ligand Pharmaceuticals Incorporated is developing LGD-6972, a novel, orally-bioavailable
 addition to diet and exercise to improve glycemic control in adults with type 2 diabetes
 mellitus. The mechanism of action of LGD-6972 is to reduce the excess liver glucose
 production characteristic of type 2 diabetes mellitus that is a major contributor to
 hyperglycemia. This clinical trial will evaluate the safety and tolerability of escalating
 doses LGD-6972 administered daily over 2 weeks in both healthy subjects and subjects with
 type 2 diabetes mellitus.
This is to be a randomized, double-blind, placebo-controlled, sequential, multiple oral dose
 study conducted in normoglycemic healthy subjects (NHS) (Part 1) and subjects with type 2
 diabetes mellitus (T2DM) who are treated with monotherapy metformin (a stable dose at
 randomization) along with diet and exercise (Part 2). Subjects with T2DM who are not on a
 stable dose of metformin but meet all other entry criteria may be enrolled in the study at
 the discretion of the Investigator, but must undergo a stabilization period of at least 12
 weeks before determining eligibility for the study. In Part 1, a single group of healthy
 subjects will be dosed with repeated oral doses of 15 mg of LGD-6972 or placebo once daily
 (QD) for 14 days. In Part 2, a maximum of 3 groups of subjects with T2DM will be dosed with 3
 sequential, increasing doses of LGD-6972 (5 mg, 10 mg or 15 mg) or placebo QD for 14 days.
INCLUSION CRITERIA:

 Part 1

 1. Healthy, adult man or woman, 21 to 65 years of age. If the subject is a woman, she
 must be surgically sterile or naturally post-menopausal to be considered for
 enrollment.

 2. Willing and able to provide written informed consent.

 3. Not diabetic and has a fasting plasma glucose (FPG) between 70 mg/dL and 105 mg/dL,
 inclusive.

 4. Good health with no significant concomitant pathology based on medical history,
 physical examination, electrocardiogram (ECG), routine laboratory tests (chemistry,
 hematology, lipid profile, international normalized ratio, and urinalysis), and vital
 signs.

 Part 2

 1. Healthy, adult man or woman, 21 to 65 years of age. If the subject is a woman, she
 must be surgically sterile or naturally post-menopausal to be considered for
 enrollment.

 2. Willing and able to provide written informed consent.

 3. Has T2DM according to American Diabetes Association criteria.

 4. Currently on stable metformin therapy (unchanged dose for greater than or equal to 12
 weeks prior to screening). At the discretion of the investigator, subjects who are
 drug naïve or whose metformin dose has not been stable for at least 12 weeks at
 screening, may be started on metformin or have their metformin dose stabilized.
 Following 12 weeks of stable metformin, they may undergo re screening including
 assessment of HbA1c and FPG (inclusion criteria 5 and 6).

 5. Has an HbA1c level between 6.5% and 10.5% at screening. One retest is permitted.

 6. Venous FPG is 125 mg/dL and 260 mg/dL at screening and either the Day -1 venous FPG or
 the Day 1 capillary blood glucose (CBG) is 115 mg/dL and 260 mg/dL. One retest is
 permitted.

 7. Has a body mass index between 20 and 45 kg/m2, inclusive.

 EXCLUSION CRITERIA:

 Part 1

 1. Has a recent history of drug and/or alcohol abuse.

 2. Unwilling to comply with tobacco, nicotine, alcohol, and caffeine restrictions as
 specified in the protocol.

 3. Unwilling to comply with restrictions on strenuous exercise as specified in the
 protocol.

 4. Has history of clinically significant cardiovascular, pulmonary, renal, endocrine,
 hepatic, neurologic, psychiatric, immunologic, hematologic, gastrointestinal
 (including pancreatitis), or metabolic disease requiring medical treatment or has any
 medical problems that pose an increased risk during the study or that may compromise
 the integrity of the study data.

 5. Has liver transaminase levels (aspartate transaminase [AST] or alanine transaminase
 [ALT]) >10% of the upper limit of normal (ULN), or has creatine kinase (CK) levels >2
 × ULN at screening or admission to clinic (Day -1).

 6. Has a plasma triglyceride level >400 mg/dL. If triglyceride level is between 400 mg/dL
 and 500 mg/dL.

 7. Has a recent history of uncontrolled high blood pressure or has systolic blood
 pressure <90 mmHg or >140 mmHg or diastolic blood pressure <60 mmHg or >90 mmHg at
 screening.

 8. Is taking 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, or is unwilling 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.

 Part 2

 1. Has a history of hypoglycemic unawareness or recurrent hypoglycemia requiring
 assistance.

 2. Has liver transaminase levels (AST or ALT) >10% × ULN, or has CK levels >1.5 × ULN at
 screening or admission to clinic (Day -1).

 3. Has history of clinically significant cardiovascular, pulmonary, renal, endocrine
 (other than T2DM), hepatic, neurologic, psychiatric, immunologic, hematologic,
 gastrointestinal (including pancreatitis), or metabolic disease requiring medical
 treatment or has any medical problems that pose an increased risk during the study or
 that may compromise the integrity of the study data.

 4. Has a recent history of uncontrolled high blood pressure or has systolic blood
 pressure <90 mmHg or >140 mmHg or diastolic blood pressure <60 mmHg or >90 mmHg at
 screening. One retest of blood pressure within 24 hours is permissible at the
 discretion of the Investigator. Therapy for hypertension (beta blockers excluded) that
 has been stable for at least one month prior to screening is permitted. At the
 Investigator's discretion, one anti-hypertensive medication (angiotensin converting
 enzyme inhibitor, angiotensin receptor blocker, hydrochlorothiazide, or
 dihydropyridine calcium-channel blocker) may be initiated, or the dosage of a current
 antihypertensive medication up titrated, in a subject with blood pressure slightly
 above the eligibility criterion at screening. After at least 4 weeks of stable blood
 pressure treatment, if the subject's blood pressure has decreased to within the 140/90
 mmHg limit, the subject will be fully reassessed for eligibility.

 5. Has received insulin for more than 6 consecutive days within 6 months prior to
 screening or has received insulin within 3 months prior to screening.

 6. Has been treated with peroxisome proliferator-activated receptor gamma agonist,
 incretin therapy, amylin mimetics, or sodium-glucose linked transporter-2 inhibitor
 therapy within 12 weeks prior to screening; treatment with other diabetic medications
 (excluding metformin) within 3 weeks prior to screening.

 7. Is taking concomitant medications. At least 3 months of stable therapy for thyroid
 replacement and hypercholesterolemia (gemfibrozil, Welchol, and cholestyramine are not
 permitted) and at least 4 weeks of stable hypertension medications (as described
 above) and low dose aspirin are permitted.