Abstract 2777: Alfimeprase, a Novel Direct-Acting Fibrinolytic Agent in Acute Peripheral Arterial Occlusion: Report of a Phase 2, Multi-Center, Open-Label, Dose-Defining Study (NAPA-1)
Alfimeprase is a recombinant direct-acting fibrinolytic that rapidly clears thromboses without generation of the systemic lytic state that has been associated with major bleeding, including intracerebral hemorrhage, following plasminogen activator infusion. We evaluated the safety and activity of three doses (0.1, 0.3, and 0.6 mg/kg) of catheter-directed, intra-thrombus alfimeprase delivered as two manual pulsed boluses for acute peripheral arterial occlusion (PAO) of the leg (Rutherford Class I or IIa). All subjects received aspirin and heparin. Seven of 113 (6.2%) subjects developed local arterial puncture site hematomas classified as major bleeds. Two of the major bleeds were reported as possibly related to study drug. No systemic, distant bleeds related to alfimeprase administration were reported. Transient hypotension (SBP ≤ 90 mmHg) developed in 16 subjects. Mean levels of plasma α2-macroglobulin, responsible for the rapid and irreversible inactivation of circulating alfimeprase, decreased by 38%, 53%, and 63% in the 0.1, 0.3, and 0.6 mg/kg dose groups, respectively, from baseline and returned to baseline within 14 days. There were no deaths and no cases of intracerebral hemorrhage during the 30 day follow-up. In the intent-to-treat population, restoration of arterial flow by 4 hours after study drug infusion, based on blinded angiographic core lab evaluation, was observed in 60% of subjects in the 0.6 mg/kg dose group, 55% in the 0.3 mg/kg dose group, and 31% in the 0.1 mg/kg dose group. Partial or complete thrombolysis was observed in 73% of subjects in the 0.6 mg/kg dose group, 76% in the 0.3 mg/kg dose group, and 50% in the 0.1 mg/kg dose group. Overall, 58% of subjects avoided open vascular surgery and were able to be managed solely using endovascular techniques at 30 days. The ability of alfimeprase 0.3 mg/kg to rapidly restore arterial blood flow and facilitate the avoidance of open vascular surgery with its associated cardiac morbidity and mortality is the focus of ongoing Phase 3 trials.