| Outcome Measures: |
Primary: Safety and tolerability (as assessed by incidence and severity of adverse events (AEs), hypoglycemia and changes from baseline in vital signs, ECGs and safety laboratory parameters)., To evaluate the safety and tolerability (as assessed by incidence and severity of AEs, hypoglycemia and changes from baseline in vital signs, ECGs and safety laboratory parameters) of multiple ascending doses of PE0139 administered as once weekly injection for 6 weeks in adults with T2DM., AEs and hypoglycemia (Day -60 to 63), Vital signs (Days -60, -10, 0, 7, 14, 21, 28, 35, 42, 49 and 63), safety laboratory parameters (-60, -10, 14, 28, 42, 49 (as needed), and 63) ECGs (-60, -10, 14, 28, 42, 49 (as needed) and 63). | Secondary: Pharmacokinetic (PK) profile - Area under the curve over the dosing interval (AUC (0-t)), Characterize the PK profile of PE0139 following 6 weeks repeat, once-weekly dosing to explore dose response relationship., PK measured for Dose 1 (pre-dose, 1, 3, 6 hours post-dose, daily for 6 days), Doses 2-5 given on days 7, 14, 21 and 28, respectively, (pre-dose) and Dose 6 (pre-dose, 1, 3 and 6 hours post dose, daily for 10 days and 14 days post-dose).|Pharmacokinetic (PK) profile - Area under the curve concentration-time profile from 0 to Tmax [AUC (0-tmax)] and from Tmax to t [AUC(tmax-t], Characterize the PK profile of PE0139 following 6 weeks repeat, once-weekly dosing to explore dose response relationship., PK measured for Dose 1 (pre-dose, 1, 3, 6 hours post-dose, daily for 6 days), Doses 2-5 given on days 7, 14, 21 and 28, respectively, (pre-dose) and Dose 6 (pre-dose, 1, 3 and 6 hours post dose, daily for 10 days and 14 days post-dose).|Pharmacokinetic (PK) profile - Maximum serum concentration (Cmax), Characterize the PK profile of PE0139 following 6 weeks repeat, once-weekly dosing to explore dose response relationship., PK measured for Dose 1 (pre-dose, 1, 3, 6 hours post-dose, daily for 6 days), Doses 2-5 given on days 7, 14, 21 and 28, respectively, (pre-dose) and Dose 6 (pre-dose, 1, 3 and 6 hours post dose, daily for 10 days and 14 days post-dose).|Pharmacokinetic (PK) profile - Time to Cmax (Tmax), Characterize the PK profile of PE0139 following 6 weeks repeat, once-weekly dosing to explore dose response relationship., PK measured for Dose 1 (pre-dose, 1, 3, 6 hours post-dose, daily for 6 days), Doses 2-5 given on days 7, 14, 21 and 28, respectively, (pre-dose) and Dose 6 (pre-dose, 1, 3 and 6 hours post dose, daily for 10 days and 14 days post-dose).|Pharmacokinetic (PK) profile - Elimination Rate Constant (Lamda z), Characterize the PK profile of PE0139 following 6 weeks repeat, once-weekly dosing to explore dose response relationship., PK measured for Dose 1 (pre-dose, 1, 3, 6 hours post-dose, daily for 6 days), Doses 2-5 given on days 7, 14, 21 and 28, respectively, (pre-dose) and Dose 6 (pre-dose, 1, 3 and 6 hours post dose, daily for 10 days and 14 days post-dose).|Pharmacokinetic (PK) profile - Elimination half-life (t1/2), Characterize the PK profile of PE0139 following 6 weeks repeat, once-weekly dosing to explore dose response relationship., PK measured for Dose 1 (pre-dose, 1, 3, 6 hours post-dose, daily for 6 days), Doses 2-5 given on days 7, 14, 21 and 28, respectively, (pre-dose) and Dose 6 (pre-dose, 1, 3 and 6 hours post dose, daily for 10 days and 14 days post-dose).|Pharmacokinetic (PK) profile - Clearance (CL/F), uncorrected for bioavailability, Characterize the PK profile of PE0139 following 6 weeks repeat, once-weekly dosing to explore dose response relationship., PK measured for Dose 1 (pre-dose, 1, 3, 6 hours post-dose, daily for 6 days), Doses 2-5 given on days 7, 14, 21 and 28, respectively, (pre-dose) and Dose 6 (pre-dose, 1, 3 and 6 hours post dose, daily for 10 days and 14 days post-dose).|Pharmacokinetic (PK) profile - Volume of Distribution (Vz/F), uncorrected for bioavailability, Characterize the PK profile of PE0139 following 6 weeks repeat, once-weekly dosing to explore dose response relationship., PK measured for Dose 1 (pre-dose, 1, 3, 6 hours post-dose, daily for 6 days), Doses 2-5 given on days 7, 14, 21 and 28, respectively, (pre-dose) and Dose 6 (pre-dose, 1, 3 and 6 hours post dose, daily for 10 days and 14 days post-dose).|Pharmacodynamic (PD) Profile - Change from baseline in fasting plasma glucose, Characterize the PD response of various doses of PE0139 and glucose (as assessed by fasting and non-fasting plasma glucose), PD response measured as fasting plasma glucose (FPG) (daily by subject up to day 21 and Days -60, between days -10 and -7, 0, 1-7, 14, 21, 28, 35, 36-49 and 63 at CRU)|Pharmacodynamic (PD) Profile - Change from baseline in average glucose by CGM, Characterize the PD response of various doses of PE0139 and glucose (as assessed by CGM), PD response measured by continuous glucose monitoring (CGM) (baseline collected ≥7 days pre-dose daily after dose 3 for 4 weeks)|Fructosamine changes, Assess the effect of various doses of PE0139 on change in fructosamine following 6 weeks of repeat, once-weekly dosing., Measured at pre-dose and 7 days after last dose|Required dose adjustment to background therapy, Assess the incidence for required dose adjustment to background therapy across various doses of PE0139 and compared to placebo., All scheduled and unscheduled visits (Days -60 to 63)|Reported hypoglycemic events (% of subjects experiencing severe and non-severe hypoglycemic events), Describe incidence, severity, and duration of reported hypoglycemic events across various doses of PE0139 and compared to placebo. Reported as % of subjects experiencing a hypoglycemic event (severe (requiring medical assistance or ≤36 mg/dL glucose) or non-severe (not requiring medical assistance and \<70mg/dL glucose)), All scheduled and unscheduled visits (Days -60 to 63)|Binding anti-drug antibodies to PE0139 and insulin (as needed). If positive, neutralizing activity will also be assessed., Characterize the immunogenicity profile (binding drug antibodies to PE0139 and insulin (as needed) and neutralizing antibodies if noted to be positive) following 6 weeks of repeat, once-weekly dosing., Collected at Pre-dose, Days 7, 14, 21, 28, 35, 42, 49, 63 and 91.
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