Washington Editor

Bad news for Nuvelo Inc.: Its partnered thrombolytic drug alfimeprase failed two Phase III studies, one in acute peripheral arterial occlusion (PAO) and the other in catheter occlusion (CO).

As a result, shares in San Carlos, Calif.-based company (NASDAQ:NUVO) took a beating Monday, plunging 79.3 percent, or $15.50, to close at $4.05.

Nuvelo Chairman and CEO Ted Love expressed disappointment during a conference call with investors, though he also noted that the drug "definitely" produced thrombolytic effects.

Alfimeprase missed its primary endpoint in avoiding open vascular surgery within 30 days of treatment in the PAO setting, and failed to hit its primary endpoint of restoring function at 15 minutes in CO, relative to placebo. In addition, both trials did not meet key secondary endpoints. The drug is designed to directly degrade fibrin when delivered through a catheter at the site of a blood clot.

The failure of the two studies, NAPA-2 (Novel Arterial Perfusion with Alfimeprase-2) and SONOMA-2 (Speedy Opening of Non-functional and Occluded Catheters with Mini-dose Alfimeprase-2), prompted Nuvelo and Bayer HealthCare AG to temporarily suspend enrollment in two ongoing Phase III trials, NAPA-3 and SONOMA-3, until further analyses and discussions with outside experts and regulatory agencies are completed.

"We need to analyze these data to really understand what occurred," Nicole Foderaro, Nuvelo's associate director of corporate communications and investor relations, told BioWorld Today. "We are going to do a full analysis to further understand what happened here in terms of efficacy and safety, and also investigate if this was a delivery or dosing issue."

Specific data from the NAPA-2 and SONOMA-2 studies weren't released - those findings will be submitted for presentation at a future medical meeting - but Love provided hints of the underlying problems.

In NAPA-2, he said the mechanical manipulation of the delivery catheters "possibly" could have complicated data. Potentially, the devices produced a placebo effect in creating a channel to dissolve a number of the clots, or they obviated alfimeprase's thrombolytic effects because the channel allowed the drug to move away from the clots, where it was rapidly inactivated by the naturally occurring protein alpha-2 macroglobulin, per its design. In SONOMA-2, he said the drug restored function at 15 minutes at a rate that was statistically significant relative to placebo and "well below" the typical FDA standard of p=0.05, but not as low as a prespecified level for this trial, p=0.00125.

In addition, Love indicated that neither drug manufacturing nor geographic study locations could be blamed for the missed endpoints.

Both were randomized, double-blind trials that enrolled about 300 patients. NAPA-2 tested a 0.3 mg/kg dose of alfimeprase, while SONOMA-2 looked at 3 mg. NAPA-2's secondary endpoints included restoration of arterial blood flow, safety endpoints such as the incidence of bleeding, and pharmacoeconomic endpoints such as length of hospital and intensive care unit stay. SONOMA-2's secondary endpoints examined vessel opening rates at later points in time.

In terms of safety, patients who received the investigational drug had more bleeding incidents, though there were no cases of intracerebral hemorrhage in any of the trials. But until those various efficacy questions get solved, the partners also will hold up plans to test alfimeprase in strokes in deep-vein thrombosis in addition to suspending NAPA-3 and SONOMA-3 for now. The former had enrolled about 100 patients to date, and about 250 had entered the latter.

In a Phase II PAO study, alfimeprase showed potential for thrombolysis with rates of up to 76 percent and restoration of arterial flow with rates of up to 60 percent within four hours of initiation of dosing. Also, up to 69 percent of study patients were able to avoid open vascular surgical intervention in the 30 days following treatment with alfimeprase.

A Phase II trial in the CO setting showed that alfimeprase restored flow to 40 percent and 50 percent of clotted catheters five and 15 minutes after the first dose, respectively, while a comparator product, Cathflo Activase (alteplase, Genentech Inc.), failed to restore flow to any catheters after either time point. In addition, alfimeprase restored flow to 60 percent of occluded catheters two hours after the first dose and to 80 percent of occluded catheters two hours after the second dose, compared with 46 percent and 62 percent with Cathflo Activase.

Under Nuvelo's global collaboration with Bayer, the Leverkusen, Germany-based pharmaceutical firm would commercialize alfimeprase in all territories outside the U.S. and pay Nuvelo tiered royalties. Nuvelo retains stateside commercialization rights, and will remain the lead entity for designing and conducting the global development programs.

Though Love noted that both companies remain "committed to the drug," he added that the findings would accelerate Nuvelo's interest in further in-licensing opportunities. He said that the company is "well positioned financially" to continue forward with other programs in its portfolio, given its $157 million in cash reserves at the end of last quarter and access to another $50 million through a loan facility.

Foderaro said it would take several months to fully analyze the alfimeprase findings.