A Study of LGD-6972 in Patients With Type 2 Diabetes Mellitus

This will be a 12-week, randomized, double-blind, placebo-controlled, 4-arm, parallel group,
multi-center study to evaluate the safety and efficacy of LGD-6972 in subjects with T2DM
inadequately controlled on metformin monotherapy (a stable [≥12 weeks], daily dose of ≥1000mg
at randomization). Subjects with T2DM will be treated with one of 3 dose levels of LGD-6972
(5 mg, 10 mg, or 15 mg) or placebo once daily (QD) for 12 weeks. Randomization will be
stratified by HbAlc ≤8.5% or >8.5% at the Placebo Lead-in Visit.

Qualified subjects who require adjustment or stabilization of their metformin dose will
participate in a run-in period of up to 12 additional weeks prior to randomization. Subjects
will have the option to participate in an oral glucose tolerance test (OGTT) at baseline and
end of treatment for assessment of exploratory endpoints.

Inclusion Criteria:

1. Female subjects must be surgically sterile (hysterectomy or bilateral oophorectomy or
bilateral tubal ligation), or naturally post-menopausal for at least 12 months and
with a follicle stimulating hormone (FSH) level in the post-menopausal range (if not
taking hormone replacement therapy)

2. Male subjects must either have a vasectomy or agree that they and any female partners
will use 2 acceptable forms of contraception, one of which must be a condom, until 30
days after the last dose of study drug. Other acceptable forms of contraception
include hormonal contraceptives that have been at stable dose for 12 weeks prior to
randomization, intrauterine device, Depo-Provera®, Norplant® System Implants,
bilateral tubal ligation, bilateral oophorectomy, hysterectomy, and contraceptive
sponge, foam, or jelly. Also, male subjects must not donate sperm during the study and
for 30 days after the last dose of study drug

3. Willing and able to provide written informed consent

4. Diagnosis of T2DM according to American Diabetes Association criteria

5. Currently on stable metformin or metformin extended-release therapy (unchanged dose
[minimum daily dose of 1000 mg] for ≥12 weeks prior to screening)

6. Subjects must have an HbA1c value of ≥7.0% to ≤10.5%

7. Subjects must have a fasting plasma glucose of ≤260 mg/dL

8. Subjects must have a body mass index (BMI) between 25 kg/m2 and 40 kg/m2, inclusive,
and must weigh more than 45 kg

Exclusion Criteria:

1. History of type 1 diabetes mellitus or history of diabetic ketoacidosis or persistent
hypoglycemia or hypoglycemia unawareness

2. Women of childbearing potential, lactating, or has a positive pregnancy test

3. History or presence of alcoholism or drug abuse within 2 years prior to screening

4. Unwilling to comply with study restrictions, including restrictions on strenuous
exercise

5. Presence of any of the following conditions: renal impairment (defined as history or
estimated glomerular filtration rate at screening of <45 mL/min using the Modification
of Diet in Renal Disease equation), diabetic proliferative retinopathy, severely
symptomatic diabetic neuropathy requiring treatment, diabetic gastroparesis, active
liver disease (other than asymptomatic nonalcoholic fatty liver disease), cirrhosis,
symptomatic gall bladder disease, or pancreatitis

6. Serum triglyceride level > 400 mg/dL at screening

7. Liver transaminase levels (AST or ALT) >150% ULN, total bilirubin >2 ULN, or creatine
kinase (CK) levels > 3 × ULN at screening

8. History or evidence of clinically significant cardiovascular, pulmonary, renal,
endocrine (other than T2DM), hepatic, neurologic, psychiatric, immunologic,
hematologic, gastrointestinal, or metabolic disease or surgical intervention (eg,
bariatric surgery) or allergic conditions (including drug allergies, but excluding
untreated, asymptomatic, seasonal allergies at time of dosing)

9. Myocardial infarction, unstable angina, arterial revascularization, stroke,
symptomatic peripheral artery disease, deep vein thrombosis, New York Heart
Association Functional Class III or IV heart failure, or transient ischemic attack
within 6 months prior to screening

10. History of malignant hypertension or a recent history of uncontrolled high blood
pressure or at screening has a seated systolic blood pressure >160 mmHg and/or
diastolic blood pressure >100 mmHg after at least a 5 minute rest. Blood pressure is
determined as the mean of triplicate measurements collected at 2- minute intervals
after the subject has been sitting quietly for at least 5 minutes. Therapy for
hypertension (beta blockers excluded) that has been stable for at least 8 weeks prior
to screening is permitted

11. Arm size in excess of the maximum limit of the largest cuff provided with the study
blood pressure monitor

12. History of malignancy (except adequately treated basal or squamous cell skin cancer or
cervical carcinoma in situ) within 5 years prior to screening

13. History or evidence of QT prolongation or clinically significant QT prolongation (QTcF
>450 msec) at screening, or other significant ECG findings at screening that may place
the subject at increased risk by participating in the study

14. Treatment with any type of insulin (injected or inhaled) for > 6 consecutive days
within 6 months prior to screening or any insulin therapy within 12 weeks prior to
screening

15. Treated with peroxisome proliferator-activated receptor-gamma agonists
(thiazolidinediones [TZDs]), incretin therapy (GLP-1 agonists). or amylin mimetics
within 12 weeks prior to screening

16. Taking any of the following prohibited medications

- Antidepressants, antipsychotics, anti-epileptics, hormone replacement therapies
(estrogen, progestin), testosterone therapies, and thyroid replacement
medications that are not at a stable dose for at least 12 weeks prior to
screening

- Lipid-modifying medications and anti-hypertensive medications that have not been
at a stable dose for at least 8 weeks prior to the Screening Visit (excluding
bile acid sequestrants, ezetimibe, and beta blockers, which are prohibited

- Over-the-counter herbal medications and supplement (aside from once daily
multivitamins)

17. Treatment with systemic corticosteroids, which must be discontinued at least 4 weeks
prior to screening. Note: Inhaled, intraarticular, intranasal and topical
corticosteroids are permitted

18. Currently treated with weight-loss medications. These must be discontinued ≥12 weeks
prior to screening

19. History or evidence of intravenous illicit drug use, active hepatitis B virus (HBV),
hepatitis C virus (HCV), and/or human immunodeficiency virus (HIV) infection

20. Known hypersensitivity or idiosyncratic reaction to glucagon receptor (GCGR)
antagonists or LGD-6972

21. Participation in another interventional clinical trial within 30 days prior to dosing
or treatment with an investigational product with 14 days or 5 half-lives of the
Screening Visit (whichever is longer)

22. Donated ≥ 450 mL of blood within 56 days of screening or has donated blood products
within 30 days of screening

23. Inability to comply with study procedures or to adhere to study-required restrictions