West Coast Editor

With an FDA agreement in hand for the Phase III trial testing its thrombin-like enzyme against acute ischemic stroke, Neurobiological Technologies Inc. said patients will start enrolling in the next few weeks.

NTI's stock (NASDAQ:NTII) closed Monday at $3.05, down 3 cents.

The trial is expected to last "about 18 months," said Paul Freiman, president and CEO of Emeryville, Calif.-based NTI.

The defibrinogenating thrombin-like enzyme, Viprinex (ancrod), is derived from the venom of the Malayan pit viper, and NTI acquired it more than a year ago in the buyout of Empire Pharmaceuticals Inc., of Greenville, N.Y. (See BioWorld Today, July 16, 2004.)

By depleting plasma fibrinogen, Viprinex brings about anticoagulation and improved blood viscosity, along with a secondary fibrinolytic or clot-lysing action. The combined effects make for a perfusion strategy that in trials so far appears to restore and enhance oxygen flow to the stroke-affected area of the brain.

Empire acquired exclusive worldwide rights to the product in March 2002 from Abbott Park, Ill.-based Abbott Laboratories, which acquired it through the 2001 purchase of Knoll AG, of Ludwigshafen, Germany. Knoll had invested about $150 million in the product, which has proved its mettle in Phase III experiments.

A study in 1998 showed Viprinex was effective in preserving neurological function. The trial tested 500 patients with acute ischemic stroke. Treated within six hours of onset, patients won a reduction in blood viscosity of 20 percent to 30 percent and, when they stopped getting Viprinex, viscosity within 10 days returned to pretreatment levels.

Another U.S. trial also yielded positive results, Freiman said, but the picture hasn't been as bright overseas.

A Phase III trial in Europe that finished in 2000 enrolled patients to be treated within six hours of stroke onset, and the study failed when a planned interim analysis indicated lack of efficacy and increased incidence of intracranial hemorrhage - apparently because of higher dosing levels given over five days, and trial subjects with a higher risk of hemorrhage.

"There have been over 1,900 patients on the drug already," Freiman told BioWorld Today. "We spent the last year going through every patient's file and trying to figure out where the dots connected."

It turns out that "you only need a one-time infusion at a high dose, which lowers fibrinogen rapidly, and allows them to restore themselves to normal within 24 hours," he said.

Previous trials were giving the venom-based drug once per day for five days - doing "essentially what the snake is doing to its victim [over that longer period]," Freiman pointed out. "Even with that, they had two very successful trials."

Stroke affects more than 600,000 U.S. patients every year. Viprinex's main competitor would be Activase (tissue-plasminogen activator, t-PA), from South San Francisco-based Genentech Inc. Cleared for acute ischemic stroke in 1996, Activase must be given within three hours of the episode.

The treatment program for stroke hardly is adequate, Freiman said. "We believe we have a six-hour window at least, and we feel the rate of bleeding will be far less."

Another would-be competitor is the plasminogen activator Desmoteplase, a Phase II product in-licensed by New York-based Forest Laboratories Inc. from Aachen, Germany-based Paion GmbH. Forest considered in-licensing Viprinex, and NTI considered Desmoteplase. But the latter had been tested in far fewer patients than Viprinex.

Desmoteplase made news last month when Paion entered a potential €65 million (US$78.5 million) deal that would allow H. Lundbeck A/S, of Copenhagen, Denmark, marketing rights to Desmoteplase for stroke patients in Europe and Asia. (See BioWorld Today, July 12, 2005.)

In June, NTI signed agreements with Nordmark Arzneimittel GmbH & Co. KG, of Uetersen, Germany, and Baxter Pharmaceutical Solutions (part of Baxter Healthcare Corp., of Deerfield, Ill.) to manufacture, fill and package Viprinex for the Phase III trials.

NTI's money situation is "not good," Freiman acknowledged. The company has about $8.5 million in cash, with a burn rate estimated at $21 million to $22 million per year.

"We need to raise funds, obviously," he said, promising more news about that shortly. "We feel we're capable of raising a lot of cash, either through strategic alliances or the usual banking suspects. We have our irons in a couple of fires."

Also in pivotal Phase III trials is NTI's Xerecept, a synthetic preparation of the natural human peptide hormone corticorelin acetate or human corticotropin-releasing factor, for swelling around brain cancers. Freiman said a partner might be sought for that product in the near term.

"I'd like to hold on to Viprinex for as long as we can," he said.