Randomized trial of continuous subcutaneous delivery of exenatide by ITCA 650 versus twice-daily exenatide injections in metformin-treated type 2 diabetes.

OBJECTIVE: To evaluate ITCA 650, a continuous subcutaneous miniature osmotic pump delivery system of exenatide versus twice-daily exenatide injections (Ex-BID) in subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS: We conducted a randomized, two-stage, 24-week, open-label, phase 2 study in type 2 diabetes inadequately controlled with metformin. Stage I: 155 subjects were randomized to 20 or 40 µg/day of ITCA 650 or Ex-BID 5 → 10 µg. Stage II: 131 subjects were rerandomized to 20, 40, 60, or 80 µg/day of ITCA 650. Change from baseline for HbA1c, weight, and fasting plasma glucose were evaluated at weeks 12 and 24. RESULTS: HbA1c was significantly lower in all groups after 12 and 24 weeks. Stage I: mean change in HbA1c from a mean baseline of 7.9-8.0% was -0.98, -0.95, and -0.72% for the 20 and 40 µg/day ITCA 650 and Ex-BID groups, respectively, with 63, 65, and 50% of subjects achieving HbA1c levels ≤ 7% (P < 0.05). Stage II: significant (P < 0.05) reductions in HbA1c (≈ 1.4% from baseline) were achieved with 60 and 80 µg/day ITCA 650, and 86 and 78% of subjects achieved HbA1c ≤ 7% at 24 weeks; respectively. Weight was reduced by 2.8-3.7 kg (P < 0.05) at 24 weeks in all except the 20 → 20 µg/day group. ITCA 650 was well tolerated; nausea was lower and transient with 20 µg/day relative to Ex-BID; and 60 µg/day had the best profile of tolerability and HbA1c lowering. CONCLUSIONS: ITCA 650 significantly reduced HbA1c and weight and was well tolerated. The 20 → 60 µg/day regimen was considered the best dose for further examination in phase 3.

DUROS technology delivers peptides and proteins at consistent rate continuously for 3 to 12 months.

BACKGROUND: DUROS((R)) delivery technology consists of sterile, nonbiodegradable, single-use devices for continuous, subcutaneous administration of therapeutic molecules at steady rates. DUROS delivery technology is capable of delivering a wide range of therapeutic molecules for durations ranging from 3 to 12 months. Administration of therapy via DUROS devices may facilitate patient compliance with treatment since the DUROS device does not require self-injections. Consistent delivery of drug levels within a targeted therapeutic window achievable with DUROS delivery technology avoids exposure to high initial drug concentrations that can result from bolus injections and that may be associated with certain adverse drug effects. METHODS: Several approaches have been taken to assess the suitability of DUROS devices for delivery of the therapeutic molecules leuprolide acetate, glucagon-like peptide-1 (GLP-1), and omega interferon (omega IFN). Testing includes determining protein stability and measuring in vitro protein release rates. RESULTS: Three peptides or proteins were formulated into either a solution (leuprolide) or Intarcia's proprietary DUROS suspension formulation (GLP-1, omega IFN) and filled into DUROS devices. The devices demonstrated reliable start-up and continuous steady drug delivery in in vitro studies. Stability of the molecules was maintained for 3 years at 37 degrees C (leuprolide), 2 years at 30 degrees C (omega IFN), or 6 months at 37 degrees C (GLP-1). Patients in clinical studies of a 1-year DUROS device found the device to be comfortable and convenient. CONCLUSIONS: Multiple studies demonstrated that peptides or proteins remain stable in DUROS devices and that delivery at a steady rate can be achieved over a wide range of delivery rates.