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Small Biotech Companies Target CNS Disorders

Small Biotech Companies Target CNS Disorders

The concept of a barrier between the blood and the brain arose in the late 19th century when the German bacteriologist Paul Ehrlich observed that certain dyes administered intravenously to small animals stained all of the organs except the brain. Ehrlich interpreted this to mean that the brain had a lower affinity for the dye than the other tissues. In subsequent experiments, one of Ehrlich's students injected a blue dye directly into the cerebrospinal fluid of rabbits and dogs. The dye readily stained the entire brain, but did not enter the bloodstream to stain the other internal organs.

These experiments demonstrated that the central nervous system is separated from the blood by a barrier of some kind. Today scientists know that large molecules cannot permeate the barrier, but that small fat-soluble (lipophilic) molecules can dissolve through capillary cell membranes and become absorbed by the brain.
Joann Data, M.D., Ph.D., executive vice president of product development and regulatory affairs at CoCensys Inc. biopharmaceuticals in Irvine, Calif., explained about small molecule absorption, saying, "The issue about small molecule compounds is that they can be taken orally and absorbed in the body without being destroyed in the stomach. They don't have to be injected; you don't have to give them by vein. They are very similar in structure to the natural hormones in our body."

Many of today's drugs designed for CNS disorders--although small molecule compounds--affect numerous receptor types, producing unwanted side effects such as anxiety, sedation, impaired memory and learning, delirium and hallucinations. The goal of a number of biopharmaceutical companies is to develop drugs that target specific receptors, eliminating these unpleasant side effects. Three of these companies are profiled in this article. They and others like them promise to have a big impact on how CNS disorders will be treated in the future.

CoCensys' Epalon Program

CoCensys has a number of new entities focusing on several therapeutic categories, said F. Richard Nichol, Ph.D., president and CEO of CoCensys, during an interview with Psychiatric Times. One of these entities, said Nichol, is epalons.

It has been known since 1940 that certain steroids, called epiallopregnanolone (epalons), produce rapid anticonvulsant, sedative and anesthetic effects. According to a study by Nancy C. Lan, Ph.D., vice president of scientific affairs and intellectual property at CoCensys, and Kelvin W. Gee, Ph.D., professor of pharmacology at the University of California, Irvine, the rapid action was thought to be mediated by membrane perturbation. Accumulated evidence now strongly supports the existence of a unique binding site on the GABAA receptor, a major inhibitory or calming complex in the brain, through which these steroids mediate their action in a specific manner.

CoCensys has been able to develop synthetic versions of endogenous epalons, one of which is ganaxolone (CCD 1042), now in Phase II trials for the treatment of epilepsy and migraine. Ganaxolone was found to have a pharmacological profile similar to the endogenous epalon 3?,5?-P in that it maintains potency as a positive allosteric modulator of the GABAA receptor and exhibits anticonvulsant activity against chemically induced seizures.

Lan and Gee also demonstrated that ganaxolone exhibited anticonvulsant activity against maximal electroshock seizures in an animal model of generalized tonic-clonic convulsion. The most interesting observation, they noted in study results published in Drug News and Perspectives (December 1997; 10 [10]), was that during experiments, ganaxolone exhibited anticonvulsant activity against fully kindled seizures in rats. This suggested the potential utility of ganaxolone in the treatment of complex partial epilepsy.

Preclinical studies are also underway in determining the efficacy of epalons for the treatment of anxiety. According to CoCensys, the lead epalon for this indication, Co 2-6749, seems to have a better efficacy/safety profile than do benzodiazepines, the current class of drugs used to treat anxiety. Co 2-6749, now in preclinical trails, has been outlicensed to Wyeth-Ayerst, which will do all subsequent research, licensing and marketing.

CoCensys is also doing research on glutamate antagonists, which block the activity of glutamate, the major excitatory neurotransmitter in the brain. When overproduced, glutamate can damage nerve cells and cause stroke and neurodegenerative disorders. The firm has completed a number of Phase I safety studies on ACEA 1021, a glutamate antagonist for the treatment of stroke. The results have shown no evidence of dose-limiting CNS side effectshallucinations, delirium, agitation and cardiovascular effectshowever, some preliminary results have shown traces of ACEA 1021 in the urine of some subjects, a potentially dose-limiting effect. CoCensys is also developing other drugs that selectively block only one of the NMDA receptor subtypes and may have applicability as a therapeutic for a number of neurodegenerative disorders such as Parkinson's disease.

Nichol said that CoCensys has also been conducting research on sodium channel blockers. "The group we are working on may have some applicability for neuropathic pain. Pain disorder covers diabetes and selective forms of cancer, areas where morphine may no longer be useful and the patient is in dire pain," Nichol told Psychiatric Times.

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