Renovis Inc. said regulatory filing for its neuroprotectant drug, Cerovive, could be delayed for as long as a year, following a decision to nearly double the number of patients enrolled in SAINT II, the second of two Phase III studies in ischemic stroke.
Cerovive, which is licensed for development to London-based AstraZeneca plc, was the first neuroprotective product to reach statistical significance in a Phase III trial. In early May, Renovis and AstraZeneca reported top-line data from the 1,700-patient SAINT (Stroke-Acute Ischemic-NXY Treatment) I study, showing that the drug met its primary endpoint of reducing disability after an acute ischemic stroke. (See BioWorld Today, May 5, 2005.)
"Following SAINT I, stroke experts agreed that those results were both clinically and statistically significant," said John Doyle, chief financial officer for Renovis, "but the effect levels were slightly smaller than we assumed in the original powering of the study."
The SAINT I data were used to calculate the powering for SAINT II, and it "suggested that an increase in patients would be required to have statistical powering of greater than 80 percent," Doyle told BioWorld Today.
Patient enrollment in the SAINT II study was increased from 1,700 to about 3,200. Based on the enrollment trends to date, that change will push back the anticipated filing date for a new drug application from the second half of 2006 to the second half of 2007, though Doyle said AstraZeneca is hoping to increase the enrollment rate by adding clinical sites in at least 10 countries that had participated in the earlier trial.
"They're trying to minimize the delay," Doyle said, adding that the companies expect to provide an update on rate of enrollment once those additional sites are up and running.
Shares of Renovis (NASDAQ:RNVS) lost 44 cents Thursday to close at $15.44, after trading as low as $14.92.
"Our feeling is that the ultimate objective here is to meet a pretty desperate need on the part of stroke patients," Doyle said. "There's really not much that can be done for them now. These steps that we've announced significantly increase the probability that Cerovive will become broadly available to them."
Cerovive is one of the few neuroprotective products for ischemic stroke in late-stage development. Ono Pharmaceutical Co. Ltd., of Osaka, Japan, is in Phase II testing with ONO-2506, a stroke agent partnered with Whitehouse Station, N.J.-based Merck & Co. Inc., while Aachen, Germany-based Paion Deutschland GmbH recently entered the clinic with its sodium and calcium channel blocker, Enecadin, in acute ischemic stroke patients. A New Zealand company, Neuren Pharmaceuticals Ltd. is in preclinical development with its neuroprotectant, NNZ-2566, for traumatic brain injury.
In addition to increasing enrollment, Renovis and AstraZeneca also met with regulators to modify the parameters of a secondary endpoint, which is designed to measure the drug's effect on neurological impairment following a stroke, according to the National Institutes of Health Stroke Scale. Cerovive missed the secondary endpoint in the earlier SAINT I trial, despite meeting the primary endpoint of reduced disability as determined by a Modified Rankin Scale.
AstraZeneca, which gained the rights to Cerovive in exchange for milestone and royalty payments, said a separate Cerovive trial, called CHANT, will continue as planned, following a recommendation from the Independent Data and Safety Monitoring Board. That Phase IIb study is enrolling 600 patients and aims to assess the safety and tolerability of 72 hours intravenous infusion of Cerovive in patients with acute intracerebral hemorrhage. Positive results from the CHANT study mean that, if approved, Cerovive could safely be administered to all stroke patients without requiring a CT scan.
Renovis is working to develop other products in its pipeline. The South San Francisco-based company has an ongoing Phase II study of REN-1654, an orally administered TNF-alpha release inhibitor, in patients with sciatica. An early study of REN-1654 failed to meet statistical significance in patients suffering post-herpetic neuralgia.
The company recently announced it was ending development of its leukocyte-traffic inhibitor, REN-850, in multiple sclerosis, after reporting unexpected pharmacokinetics in a Phase Ia trial. (See BioWorld Today, June 14, 2005.)