Hemorrhagic profile of the fibrinolytic alfimeprase after ischemia and reperfusion.

OBJECTIVE: Recanalization therapies for ischemic stroke have been slow to change clinical practice because of perceived and published risks of hemorrhage associated with lytic administration. We quantified alfimeprase in an acute ischemia-reperfusion model, as compared with recombinant tissue plasminogen activator, with hemorrhagic transformation as the primary endpoint and infarction volume and blood-brain barrier permeability as secondary endpoints. METHODS: Five groups were studied in a blinded fashion: alfimeprase at doses of 0.03 (n=8), 0.1 (n=11) and 0.3 mg/kg (n=8); recombinant tissue plasminogen activator at 1 mg/kg (n=9); carrier infused controls (n=9). The middle cerebral artery was occluded for 5 hours followed by removal of the suture for reperfusion. Drugs were infused immediately following reperfusion over a 10-minute period. Approximately 24 hours later, the animals were anesthetized and decapitated, and the brains were rapidly harvested and frozen. Serial brain sections were obtained and inspected for hemorrhages. Infarction and blood-brain barrier permeability were also evaluated in additional experiments in control, 0.1 mg/kg alfimeprase and 1 mg/kg recombinant tissue plasminogen activator-treated rats. RESULTS: The hemorrhagic transformation frequency, neurological deficit and the mortality rate of alfimeprase were significantly lower than for recombinant tissue plasminogen activator at the 0.03 mg/kg dose and not statistically different at the higher doses. Infarction and blood-brain barrier permeability were not significantly different among control, 0.1 mg/kg alfimeprase and recombinant tissue plasminogen activator. DISCUSSION: In this model, alfimeprase, a new fibrinolytic agent, exhibits a profile comparable to recombinant tissue plasminogen activator.

Continuous subcutaneous delivery of exenatide via ITCA 650 leads to sustained glycemic control and weight loss for 48 weeks in metformin-treated subjects with type 2 diabetes.

AIMS: Evaluate the efficacy and tolerability of ITCA 650 in subjects with type 2 diabetes treated for up to 48 weeks. METHODS: This was a 24-week extension to a randomized, 24-week, open-label, phase 2 study in subjects with type 2 diabetes inadequately controlled with metformin. Subjects received ITCA 650 mg (20, 40, 60 or 80 µg/day). Mean changes for HbA1c, weight, and fasting plasma glucose (FPG) were evaluated. RESULTS: Mean changes in HbA1c from baseline to week 48 ranged from -0.85% to -1.51%. At week 48, ≥64% of subjects with an HbA1c ≤7% at week 24 maintained an HbA1c ≤7%. The incidence of adverse events (AEs) was dose-related and ranged from 13.3% with 20 µg/day to 37.5% with 80 µg/day. Most AEs were mild and transient; the incidence of nausea declined from 12.9% to 9.5% over the 24-week extension. One subject on ITCA 650 80 µg/day experienced mild intermittent vomiting. Three (3.5%) subjects experienced severe AEs, but none were considered related to study drug. CONCLUSION: Significant changes in HbA1c, body weight, and FPG attained with ITCA 650 were maintained to 48 weeks. The incidence of AEs was lower in the 24-week extension than in the initial 24-week treatment phase.

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.