Assistant

Nuvelo Inc. presented detailed results from its failed study of alfimeprase in peripheral arterial occlusion, initially reported in late 2006, and told investors it planned to move forward with the thrombolytic agent in ischemic stroke and catheter occlusion.

A direct-acting fibrinolytic candidate, alfimeprase has proven to be a difficult drug to get through the development process. In December 2006, alfimeprase hit a stumbling block after the product missed its endpoints in two Phase III studies - failing to avoid open vascular surgery within 30 days of treatment in a statistically significant percentage of patients with peripheral arterial occlusion (PAO) in one trial and failing to restore function at 15 minutes in a catheter occlusion in a second study. Those data prompted the firm to suspend treatment in another PAO study, as well as in a separate CO trial though Nuvelo re-initiated enrollment in that study last year. (See BioWorld Today, Dec. 12, 2006, and Aug. 23, 2007.)

The company reported PAO data late Thursday at the International Symposium on Endovascular Therapy in Hollywood, Fla., stemming from the missed Phase III study, designated the NAPA (Novel Arterial Perfusion with Alfimeprase)-2 study and the suspended NAPA-3 study. Both trials were designed to evaluate avoidance of open vascular surgery within 30 days of treatment as the primary endpoint.

Results from the 300-patient NAPA-2 study showed that 34.9 percent of patients receiving alfimeprase met the endpoint vs. 37.2 percent of patients receiving intrathrombus placebo and 18.4 percent of patients receiving perithrombus placebo. Data from the perithrombus arm was particularly interesting, since they suggested that "delivery may have been a key factor" in alfimeprase's failure in the trial, Susan Begelman, associate director for medical sciences for the San Carlos, Calif.-based firm, said during a conference call.

Interim data from NAPA-3, which had enrolled 102 patients at the time it halted, were better. In that study, 29.4 percent of patients getting alfimeprase achieved 30-day open vascular surgery avoidance compared to 17.6 percent in the intrathrombus placebo arm. NAPA-3 did not include a perithrombus placebo arm.

But, "while the magnitude of the difference between the two groups is greater [in NAPA-3], we still did not see the efficacy that we had expected among patients treated with alfimeprase," Begelman said.

Alfimeprase is designed to work by directly degrading fibrin, the "scaffolding that holds blood clots together," Begelman said.

Data did, however, indicate that in patients with longer clots or smaller drops in alpha-2 macroglobulin, a naturally occurring blood protein that inactivates the thrombolytic activity of alfimeprase, the drug tended to yield poorer efficacy, suggesting that a delivery method designed to improve the retention of alfimeprase at the clot site might improve lysis, Begelman said.

In terms of safety, overall adverse events, including hypotension and peripheral embolism, were higher in the alfimeprase treatment groups in both studies, though NAPA-2 also produced "two unexpected events," with regard to serious adverse events, Begelman said. She reported that patients receiving Nuvelo's drug had a 16.2 percent rate of cardiac disorders compared to 1.8 percent in the intrathrombus placebo group and 13.2 percent in the perithrombus placebo group.

Those cardiac disorders "ran the gamut," she said, and "cannot be explained by a single mechanism."

The NAPA-2 study also showed a 17.6 percent infection rate among patients in the alfimeprase arm vs. 8.1 percent and 7.9 percent in the intrathrombus placebo and perithrombus placebo arms, respectively.

That "imbalance was not seen in NAPA-3," Begelman said, the results of which showed that both cardiac disorder and infection rates were higher in the placebo arm.

No intracranial hemorrhages were reported in either study.

Given those PAO data, Nuvelo has "considered various delivery technologies," she told investors, and has "decided to focus our efforts and resources" to develop alfimeprase in ischemic stroke and catheter occlusion.

The restarted SONOMA-3 (Speedy Opening of Non-functional and Occluded catheters with Mini-dose Alfimeprase) study is expected to include up to 100 patients to receive a single, 10-mg dose of the drug at a concentration of 5 mg/mL. Data from that study are expected in the first half of this year.

Last month, Nuvelo dosed the first patient in a Phase II study of alfimeprase in acute ischemic stroke. That 100-patient study is designed to assess efficacy as the recanalization of the primary arterial occlusive lesion within 120 minutes of treatment. Alfimeprase has been granted fast-track status in that indication.

Nuvelo regained all rights to alfimeprase in mid-2007 after partner Bayer Healthcare AG pulled out of the companies' potential $385 million deal signed in early 2006, though Bayer retains a one-time option to get back into the collaboration upon Nuvelo initiating a pivotal Phase III trial of alfimeprase in stroke. (See BioWorld Today, June 28, 2007.)

Nuvelo, which has not yet reported its fourth quarter earnings, posted a net loss of $14.4 million, or 27 cents per share for the third quarter of 2007. As of Sept. 30, the firm had $117.3 million in cash and investments.

Shares of Nuvelo (NASDAQ:NUVO) closed at $1.59 Friday, down 1 cent.