A Safety Study of ARRY-403 in Patients With Type 2 Diabetes

• Characterize the safety profile of the study drug in terms of adverse events, clinical laboratory tests, vital signs and electrocardiograms. [ Time Frame: Duration of study ] [ Designated as safety issue: Yes ]
• Characterize the pharmacokinetics (PK) of the study drug and metabolites in terms of plasma concentrations. [ Time Frame: 10 days ] [ Designated as safety issue: No ]

• The safety of once-daily (QD) and twice-daily (BID) oral administration of ARRY-403 in patients with type 2 diabetes [ Time Frame: 10 days ] [ Designated as safety issue: Yes ]
• The PK properties of ARRY-403 and metabolites during QD and BID oral administration of ARRY-403 [ Time Frame: 10 days ] [ Designated as safety issue: No ]

• Assess the effect of study drug on glycemic control as determined by an oral glucose tolerance test (OGTT). [ Time Frame: 10 days ] [ Designated as safety issue: No ]
• Characterize the pharmacodynamic (PD) activity of the study drug on biomarkers. [ Time Frame: 10 days ] [ Designated as safety issue: No ]

• The effect of 10 days of QD and BID oral administration of ARRY-403 on glycemic control [ Time Frame: 10 days ] [ Designated as safety issue: No ]
• The PD effects of ARRY-403 during 10 days of QD and BID oral administration on biomarkers, but not limited to, glucose, insulin, C-peptide, glucagon and non-esterified fatty acids [ Time Frame: 10 days ] [ Designated as safety issue: No ]

This is a Phase 1 study, involving a 10-day dosing period, designed to test the safety of investigational study drug ARRY-403 (as monotherapy or in addition to stable metformin therapy) in patients with Type 2 diabetes. Approximately 128 patients from the US will be enrolled in this study.

• Drug: ARRY-403, glucokinase activator; oral
  multiple dose, escalating
• Drug: Placebo; oral
  matching placebo

• Experimental: ARRY-403
  Intervention: Drug: ARRY-403, glucokinase activator; oral
• Placebo Comparator: Placebo
  Intervention: Drug: Placebo; oral

Key Inclusion Criteria:

• Male or female (females must be of non-childbearing potential), between the ages of 18 and 70 years, inclusive.
• Diagnosis of Type 2 diabetes.
• Fasted C-peptide value ≥ 0.8 ng/mL.
• HbA1c ≥ 6.5% and ≤ 10.0% for monotherapy cohorts (study drug only) or HbA1c ≥ 7.5% and ≤ 10.0% for combination cohorts (study drug and on a stable regimen of metformin monotherapy that includes a morning dose for ≥ 8 weeks prior to first dose of study drug).
• BMI ≥ 25.0 kg/m2 and ≤ 40.0 kg/m2
• Additional criteria exist.

Key Exclusion Criteria:

• Recent history (i.e. less than 6 months) or concomitant/ongoing clinically significant hematologic, renal, pulmonary, gastrointestinal, hepatic, psychiatric, neurologic, dermatologic or allergic disease (including drug allergies that are clinically significant and not remote, but excluding untreated, asymptomatic, seasonal allergies at the time of dosing), or other conditions at the discretion of the investigator.
• Significant cardiac disease, myocardial infarction within 6 months of study start, unstable angina, congestive heart failure, known arrhythmias of ventricular etiology, unexplained syncope or syncope/seizures related to arrhythmia.
• History of gastric surgery, vagotomy, bowel resection or any surgical procedure that might interfere with gastrointestinal motility, pH, or absorption.
• A positive test for drugs or alcohol.
• Active infectious diseases including hepatitis B, hepatitis C, or human immunodeficiency virus (HIV). Past history and inactive hepatitis B and C, as confirmed by serological testing, are allowed.
• Women who are pregnant or breastfeeding.
• Donation or loss of ≥ 550 mL of blood (including plasmapheresis) or receipt of a transfusion of any blood product within 8 weeks prior to first dose of study drug.
• Additional criteria exist.