Hoping to have the first FDA-approved thrombolytic agent to treat acute peripheral arterial occlusion (PAO), Nuvelo Inc. began enrolling patients in a Phase III trial of alfimeprase, an enzyme produced by recombinant DNA technology and designed to dissolve blood clots.

The development of alfimeprase is a "high priority for our company," said Michael Levy, Nuvelo's vice president of research and development. "We feel this is a very medically important problem we're working on" that could change "the paradigm of therapy" for acute PAO - the blocking of blood flow to the lower limbs by a clot, also known as a "leg attack."

The trial also marks a significant milestone for Nuvelo as its first Phase III trial, which will help transform it into a late-stage development company, Levy added.

The trial, NAPA-2 (Novel Arterial Perfusion with Alfimeprase-2) is designed as a randomized, double-blind study comparing 0.3 mg/kg of alfimeprase vs. placebo in 300 patients slated for surgery to clear clogged leg arteries. The primary endpoint will be the avoidance of open vascular surgery within 30 days of treatment.

"Avoiding that surgery is a meaningful endpoint," Levy said, "because this is not a trivial surgery." Many PAO patients are considered poor surgical risks, he added, with estimates showing that about 20 percent to 25 percent die perioperatively as a result of those risks.

Investigators will measure the return of normal blood flow to a previously blocked artery as the trial's secondary endpoint, along with safety endpoints that include the incidence of bleeding.

There are no approved thrombolytic therapies to treat acute PAO, though plasminogen activators often are used off label. Those are designed to work by converting plasminogen into plasmin to dissolve the blood clots, but those treatments often take 24 to 36 hours to clear a clot because they act indirectly, Levy said. He added that plasminogen activators also carry the risk of causing a lytic state, with 5 percent to 16 percent of patients suffering a major incidence of bleeding and about 2 percent at risk for a vascular stroke.

Because it does not rely on the plasminogen system, alfimeprase, which Nuvelo licensed from Thousand Oaks, Calif.-based Amgen Inc., is the "only drug that acts directly to dissolve the blood clot, and it acts more quickly, about two to four hours," Levy told BioWorld Today. "Beyond that, alfimeprase immediately binds to a protein in the blood called alpha-2 macroglobulin and becomes inactivated, so it doesn't cause systemic bleeding."

Nuvelo previously announced results from the NAPA-1 Phase II trial that demonstrated the ability of alfimeprase to restore arterial blood flow within four hours of initiation of dosing and resulted in a minority of patients requiring open vascular surgery within 30 days of treatment.

The Sunnyvale, Calif.-based company also is gearing up to start a Phase III trial of alfimeprase in central venous catheter occlusion, which occurs when a clot forms within a catheter and hinders the flow of blood or solutions such as chemotherapy and nutrients. Levy said a Phase II study in catheter occlusion showed that alfimeprase cleared the clot "in as quickly as five minutes, and the majority within 15 minutes."

Although there is an existing product for the indication - South San Francisco-based Genentech Inc.'s Cathflo Activase (alteplase) - it typically requires two to four hours to clear a clot.

"We're interested in other indications," Levy said, adding that the company anticipates investigating alfimeprase in stroke patients. He said about 500,000 patients suffer an ischemic stroke per year, in which the blood vessel to the brain is blocked. Plasminogen activators can be used, but they can cause a hemorrhagic conversion in about 20 percent of patients.

If alfimeprase is approved for the first two indications, Nuvelo is estimating a market of more than $500 million annually. Acute PAO affects more than 100,000 people in the U.S. yearly, while catheter occlusion affects roughly 1.25 million.

Advancing the product into the stroke indication could expand alfimeprase's market into blockbuster territory, Levy said.

Along with the initiation of its first Phase III trial, Levy said it has been a "month of milestones" for Nuvelo, which was founded as Hyseq Pharmaceuticals in 1994 and built upon a genomics-based discovery technology.

Earlier this month, the company announced that the first drug candidate derived from its genomics research entered preclinical studies, NU206, yielded a development and commercialization collaboration with the pharmaceutical division of Kirin Brewery Co. Ltd. Under terms of the agreement, Nuvelo will receive $2 million in up-front fees and will take the lead in worldwide development, paying 60 percent of the costs and receiving 60 percent of the profits. (See BioWorld Today, April 5, 2005.)

Nuvelo's recombinant nematode anticoagulant protein, rNAPc2, which inhibits Factor VIIa/tissue factor, was licensed from Seattle-based Dendreon Corp. for $4 million in up-front fees, plus milestones and royalties. That product is completing a Phase IIa trial in acute coronary syndromes.

Last year, the company licensed ARC183, a direct thrombin inhibitor, from Cambridge, Mass.-based Archemix Corp., and has it in a Phase I program. With positive results there, Nuvelo expects initiating a program in coronary bypass surgery.

Nuvelo ended 2004 with about $50 million in cash, cash equivalents and short-term investments, and added about $68 million to that through a public offering in February.

The company's shares (NASDAQ:NUVO) lost 17 cents Monday to close at $6.45.