Over the past year and a half Neurobiological Technologies Inc. kicked off two Phase III stroke trials with Viprinex (ancrod). So far, the trials have enrolled between 100 and 200 patients out of an anticipated 1,300 total, according to NTI's vice president and chief financial officer Craig Carlson. The Emeryville, Calif.-based company anticipates enrolling half of the patients in the first trial, or 325 out of 650 patients, by the end of the year.
To fulfill the needs of these trials and prepare for an eventual commercial launch, NTI announced last month the opening of a state-of-the-art snake facility owned and operated by NTI's partner, Nordmark Arzneimittel GmbH & Co. KG of Uetersen, Germany. The facility will provide the active ingredient in Viprinex: a defibrinogenating thrombin-like enzyme derived from the venom of the Malayan pit viper.
"The venom does three things: it limits the ongoing growth of a clot, thins the blood, and acts as a clot buster," Carlson explained.
In stroke, which strikes one American every 45 seconds, a blood vessel carrying oxygen to the brain is blocked by a clot or ruptured. The only drug approved for stroke is Genentech Inc.'s Activase (tissue-plasminogen activator, t-PA). More than sixty stroke related products have failed in the past decade, including NXY-059 from Renovis Inc. and AstraZeneca plc. (See BioWorld Today, Oct. 27, 2006).
Like t-PA, Viprinex is a reprofusion agent. But while t-PA must be administered within three hours, Viprinex is designed to be given up to six hours after a stroke. It essentially depletes fibrinogen, resulting in anticoagulation, improved blood viscosity and clot-lysing action. When its enzymes are injected through the long fangs of a Malayan pit viper, hemotoxicities result, but Viprinex is "highly diluted," Carlson said.
NTI's new snake facility, in Moorrege, Germany, 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 upwards of 1,500 vipers. Snakes are milked once a month by handlers who grasp them behind the head and allow them to bite into a sterile membrane. Between milkings, they live in separate rooms with individual air handling systems to prevent colony infection, as well as temperature and humidity controls. Handlers pass through negative pressure rooms prior to entering the snake facilities to further protect the reptiles from disease. Lighting, temperature and humidity are designed to mimic the snakes' natural jungle environment.
NTI is not the only biotech developing drugs based on animal venom, although they are one of the few using live animal by-product rather than a synthetic version.
Elan Corp. plc markets Prialt (ziconotide intrathecal infusion), the synthetic equivalent of a naturally occurring conopeptide found in a marine snail, for the management of severe chronic pain. Amylin Pharmaceuticals Inc. also markets a venom drug: Byetta (exenatide) for diabetes contains synthetic versions of elements found in Gila monster spit. Additional venom drugs in development include TM-601 from TransMolecular Inc., which is in Phase II trials for glioma and contains a synthetic version of the chlorotoxin peptide found in Giant Yellow Israeli scorpion venom, and desmoteplase from Forest Laboratories Inc., which is in Phase IIb/III for stroke and contains an engineered version of a protein found in vampire bat saliva.
One company using actual animal-derived venom rather than a synthetic version is ReceptoPharm Inc., a subsidiary of Boca Raton, Fla.-based Nutra Pharma Corp. ReceptoPharm is conducting Phase II trials in adrenomyeloneuropathy and will soon begin Phase II trials in multiple sclerosis with RPI-78M, which is derived from Cobra venom.
Using animal product rather than synthetic is a matter of economics, according to ReceptoPharm spokesperson David Schmidt. "When you only need small quantities, it is economical to use the actual venom. But if you need a tremendous amount of material, it becomes more cost-effective to use recombinant expression," Schmidt said.
Although ReceptoPharm uses live snake venom now, the company "would definitely need recombinant expression" prior to launching its drug, Schmidt said.
NTI, on the other hand, has no immediate plans to explore a synthetic version of Viprinex.
"This facility shows we are committed to the biological approach," Carlson said. He added that NTI has sufficient stored venom to "launch with very little or no new drug," although the company would need to bring a new purification machine online to handle the quantity of product needed for launch.
Carlson also noted that breeding programs are in place at the snake facility and that very little venom actually goes into each batch of drug. "We don't anticipate supply being an issue," he said.