London, UK- AstraZeneca has announced that it will not pursue further development of an investigational drug, NXY-059, known as Cerovive, after results of a phase 3 trial showed no significant reduction in stroke-related disability with treatment vs placebo [1].

In a statement, the company notes that full results from the Stroke Acute Ischemic NXY-059 Trial (SAINT II) will be reported at the upcoming International Stroke Conference in February 2007 in San Francisco.

SAINT II was a randomized, double-blind placebo-controlled trial of the drug in 3200 patients with ischemic stroke, enrolled from 350 participating centers in 31 countries. Principal investigator was Dr Ashfaq Shuaib (University of Alberta, Edmonton). The primary outcome was reduction in stroke-related disability assessed by the modified Rankin scale.

However, the trial ultimately fell short of achieving statistical significance with NXY-059 compared with placebo on this primary end point, with an odds ratio of 0.94 (p=0.33), the company release said.

NXY-059 is a free-radical trapping agent that had been shown to be neuroprotective in animal models of stroke. The results of SAINT II are disappointing in light of positive results seen the with agent in SAINT I, published earlier this year in the New England Journal of Medicine, showing that treatment with NXY-059 within 6 hours of ischemic stroke significantly improved the primary outcome of reduced disability at 90 days, although treatment did not have a significant effect on other outcomes, including neurologic function on the National Institutes of Health Stroke Scale (NIHSS) [2].

An intriguing finding from a post hoc analysis of SAINT I was that, in patients who received tPA, treatment with NXY-059 was associated with a lower incidence of hemorrhagic transformation (p=0.001) and of symptomatic intracranial hemorrhage (p=0.036).

The SAINT I trial marked the first time that a neuroprotective strategy had shown benefit in a large clinical trial, despite excellent results with many such agents in animal models of stroke. After SAINT I, the enrollment in SAINT II was increased to 3200 from 1700 to increase its statistical power.

"AstraZeneca plans no further development of NXY-059 in acute ischemic stroke," Tomas Odergren, vice president and global product director for the agent, said in the company statement. However, it does plan a pooled analysis of SAINT I and SAINT II data to see what further information might be gleaned, the release notes.

The result from SAINT II "is obviously disappointing but not entirely unexpected," Dr Larry B Goldstein, director of the Duke Center for Cerebrovascular Disease at Duke University Medical Center and current chair of the American Heart Association Stroke Council, said. "It also points out that post hoc subgroup analyses—ie, reduction of tPA-related hemorrhages in the prior study—can be misleading, and findings from a single trial of a putative new therapy need to be confirmed in a second trial."

Dr Ralph L Sacco (Columbia University, New York), also characterized the news as disappointing, both for the field of acute stroke therapy and in particular the concept of neuroprotection. "We were cautiously optimistic after SAINT I but knew that a larger trial was required to substantiate the findings," he said. "I still remain optimistic that the right drug, in the right stroke patient, using a sensitive outcome, will show benefits in a neuroprotection trial, but the stakes remain high."

Dow Jones Newswires reported yesterday that AstraZeneca's share price dipped on the news. "AstraZeneca is now left with a very thin pipeline after the recent expensive failures in late-stage testing of drugs such as blood-thinner Exanta (ximelagatran), lung cancer drug Iressa, and Galida for diabetes," the newswire report notes.

It adds that analysts at Deutsche Bank AG had previously forecast sales of around $750 million for NXY-059 and quotes Deutsche Bank analysts as saying in a note to investors that "the setback is likely to prompt investors to question the breadth and risk profile of the late-stage pipeline" at the company.

Third-quarter results, though, also released yesterday by AstraZeneca, showed sales up 11% and earnings per share up 34%.