Alfimeprase is an enzyme produced by recombinant DNA technology. It is a thrombolytic agent or blood clot dissolver that is intended to directly degrade fibrin when delivered through a catheter at the site of a blood clot.
Full analysis of the multi-center, multi-national, open-label, dose-escalation study, NAPA-1 (Novel Arterial Perfusion with alfimeprase-1), revealed that alfimeprase showed potential for thrombolysis (breaking up of a blood clot) with rates of up to 76% and restoration of arterial flow with rates of up to 60% based on intention to treat analysis. Furthermore, all thrombolytic activity and restoration of flow was recorded within four hours of initiation of dosing. Most plasminogen activator type thrombolytic agents may require a prolonged infusion of 24 to 36 hours in patients with acute PAO.
“Based on these data, I believe alfimeprase presents an opportunity to shift the paradigm of treatment for this very sick patient population,” stated Dr Ken Ouriel, Chairman of the Division of Surgery at the Cleveland Clinic and Principal Investigator for Nuvelo’s Phase I and II alfimeprase trials in PAO. “This is reflected in alfimeprase’s potential to offer significant advances in the rapid resolution of a clot while minimizing systemic side-effects such as intracerebral hemorrhage and other bleeding complications. I therefore believe alfimeprase warrants further study in acute PAO.”
“The opportunity to restore arterial blood flow within four hours of initiation of dosing with alfimeprase is remarkable,” said Dr Steven Deitcher, Vice President Clinical and Regulatory Affairs for Nuvelo. “As in heart attack, rapid restoration of blood flow is critical to reducing morbidity and mortality in leg attack. There is a real unmet medical need to address leg attack. While avoidance of open-vascular surgery with the use of currently available thrombolytics can reduce the risk of peri-operative morbidity and mortality, use of these plasminogen activator-based therapies presents unavoidable risks of major bleeding and intracerebral hemorrhage. Unlike these thrombolytics, alfimeprase shows the potential to avoid a systemic lytic state as its suggested lytic activity is localized to the site of drug delivery.”
Nuvelo is scheduled to meet with the Food and Drug Administration (FDA) to discuss the initiation of a Phase III trial that will be designed to further assess the efficacy and safety of alfimeprase in acute PAO patients.
About the study
The 24-center, open-label, dose-escalation study conducted in the United States, Europe, Hungary, Russia and South Africa evaluated the safety and activity of alfimeprase in acute PAO patients. The study was led by Dr Ken Ouriel and Dr Jacob Cynamon, Professor of Clinical Radiology and Director of the Division of Vascular and Interventional Radiology at the Montefiore Medical Center.
Patients were randomized to receive one of three doses of alfimeprase, 0.1 mg/kg, 0.3 mg/kg or 0.6 mg/kg. Doses were administered via a side-hole catheter in two separate, five to fifteen minute pulsed infusions, giving two-thirds of the dose up front, followed by the remaining one-third of the dose after two hours. Angiograms were taken at baseline (time zero), one hour and two hours with the final and conclusive angiogram taken at four hours after initial dosing.
Primary endpoints included: adverse event (AE) rate, serious adverse event (SAE) rate and major bleeding, including intracerebral hemorrhage (ICH), up to 30 days after dosing. Secondary endpoints included determination of alfimeprase activity; open-surgery free survival at 14 and 30 days; patency, as defined by restoration of flow; increase in ankle-brachial index (ABI) by greater than or equal to 0.15; and reduction in severity of planned surgical interventions.
Full analysis of the 113 subjects revealed that there were no ICHs or deaths. Hypotension rates in the lower doses (0.1 mg/kg and 0.3 mg/kg) were approximately 3% or 2 patients, one of whom was categorized by the investigator as not related to alfimeprase. AE, SAE, major hemorrhage and hypotension rates were dose-related and hypotensive episodes were not associated with any clinical sequelae. Of the 16 SAE level bleeding events reported, seven were major bleeds and nine were minor bleeds. Of the seven major bleeds, six were unrelated to alfimeprase and only one was categorized by the investigator as possibly related (a groin hematoma). Of the nine minor bleeds, three were categorized as possibly related to alfimeprase and six were unrelated or unlikely to be related to alfimeprase as determined by investigators. From 52% to 69% of study patients were able to avoid surgical intervention.
