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The tweaked protocol in Neurobiological Technologies Inc.'s latest Phase III program with Viprinex (ancrod) for stroke could strengthen NTI, despite skeptics who might point to earlier adverse-event problems that caused one study to halt.

A defibrinogenating thrombin-like enzyme derived from the venom of the Malayan pit viper, Viprinex's Phase III campaign so far has yielded one success and a failure, due to the early quit.

"I think there's no question whatsoever that the compound itself is effective as a defibrogenating agent and a clot-buster," Russell McAllister, analyst with Merriman Curhan Ford & Co., told BioWorld Financial Watch. The question involves safety, but Genentech Inc.'s Activase (tissue-type plasminogen activator), the standard of care, "has issues with [the risk of] hemorrhages as well" - and the alternatives to getting no treatment are grim, he noted.

Even based on results from the second Phase III trial (the failed one), "I'd elect to take the drug myself," McAllister said. "But you don't get to make that decision. The FDA makes it for you."

The road to the $3 billion stroke market is paved with casualties. Headliner blow-ups include Renovis Inc.'s Cerovive, also known as NXY-059, which failed in a Phase III trial last fall, knocking down investor hopes and Renovis' shares. They closed more than 70 percent lighter on the news, and partner AstraZeneca plc pulled out of its deal with Renovis after Cerovive missed its primary and secondary endpoints in the study. (See BioWorld Financial Watch, May 16, 2005.)

This month, Renovis cut staff by 40 percent to reduce costs and work on projects such as the nearest-term clinical program, which comes from the collaboration with Pfizer Inc., focused on vanilloid receptors. Pfizer plans to put the program into the clinic this year, targeting pain and urinary incontinence. Renovis also has P2X7 and P2X3, antagonists of purinergic receptors, scheduled to enter the clinic next year, and there's a deal with Genentech Inc. on another preclinical program.

Another high-profile thrombolytic fizzle was Nuvelo Inc.'s alfimeprase, partnered with Bayer HealthCare AG, which in December failed two Phase III studies, one in acute peripheral arterial occlusion (PAO) and the other in catheter occlusion (CO). Nuvelo shares plunged almost 80 percent on the news.

Designed to directly degrade fibrin when delivered through a catheter at the site of a blood clot, 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. Neither trial met secondary endpoints.

The outcome 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 to suspend enrollment in two ongoing Phase III trials, NAPA-3 and SONOMA-3, until scientists do further analyses and company officials talk with outside experts as well as regulators.

NTI has been hurt somewhat by other failures, but interim results from the Viprinex Phase III push are expected in the second half of this year. If the compound can be conclusively proven to work in ischemic stroke - especially without problems such as intracranial hemorrhages - the drug could take away at least part of about $50 billion in costs associated with the third leading cause of death (and the leading cause of disability) in the U.S.

Genentech's Activase must be administered within three hours of stroke onset, which means that fewer than 4 percent of stroke victims get help fast enough. NTI thinks Viprinex might do the job as long as six hours after onset.

"Six hours is a pretty good amount of time to figure out that something's wrong and get to the hospital," McAllister pointed out. He added that he has heard "the number 25 percent to 30 percent thrown around," as experts estimate the portion of stroke victims who might get treatment inside the Viprinex time window.

NTI's bottom line gets some help from royalties on Namenda (memantine), approved in October 2003 for Alzheimer's disease. The NMDA receptor antagonist was developed by Forest Laboratories Inc. and NTI, which last week said Merz Pharmaceuticals GmbH (which co-markets Namenda in German-speaking countries) paid about $1.7 million in quarterly royalties.

The strategic research and marketing cooperation agreement with Merz was entered in the spring of 1998, and Merz signed a development and marketing agreement with Forest two years later. Given Namenda's success, should NTI have bargained for a better deal? "In hindsight, absolutely," McAllister said, but the drug's prospects were just becoming known.

In the fall of 2005, NTI sold rights to its Phase III product Xerecept to a subsidiary of Celtic Pharma Holdings LP for up to $48 million. Xerecept is a synthetic preparation of the natural human peptide, corticotropin-releasing factor, designed to reduce peritumoral edema, which can lead to brain ischemia, herniation and death. This month, NTI got the final non-contingent payment from Celtic - $4 million - which brings guaranteed fees to a total of $33 million. The rest of the potential money would come as regulatory milestones are met.

Viprinex's march goes on. Last month, NTI opened a state-of-the-art snake facility owned and operated by the firm's German partner, Nordmark Arzneimittel GmbH & Co. KG, to provide the compound's active ingredient. Located in Moorrege, Germany, the plant is one of the world's few GMP facilities for reptiles. NTI and Nordmark shared the $5.8 million cost of building the facility, which can house more than 1,500 vipers. Snakes are milked once a month.

Most of the handful of firms using venom for drugs make synthetic versions. Elan Corp. plc sells Prialt (ziconotide intrathecal infusion), the equivalent of a conopeptide found in a marine snail, for the management of severe chronic pain. Eisai Co. Ltd. bought the European rights to Prialt early last year in a deal worth up to $100 million. Amylin Pharmaceuticals Inc. markets Byetta (exenatide) for diabetes, which contains versions of elements found in Gila monster saliva. Byetta is partnered with Eli Lilly & Co.

In development is TM-601 from TransMolecular Inc., undergoing Phase II trials for glioma. The compound contains an engineered form of chlorotoxin peptide found in Giant Yellow Israeli scorpion venom. Forest Labs has desmoteplase, a form of protein found in bat saliva, which is in Phase IIb/III trials for stroke. (At the end of October, Forest and partner Paion AG said the independent data safety monitoring committee lifted the clinical hold on desmoteplase following a review of cumulative data from 170 randomized subjects. The committee recommended that patient enrollment in the study resume with no modification to the protocol. The trial had been put on hold due to undisclosed safety concerns.)

A natural Cobra venom drug from ReceptoPharm Inc., RPI-78M, has reached Phase II trials in adrenomyeloneuropathy and will soon begin Phase II trials in multiple sclerosis.

Synthetics outnumber natural venom drugs "in the big spectrum, yes, but I would say it's an area that's being revisited," McAllister said, particularly since some apparently strong compounds such as Viprinex can't be made in the laboratory.