Small Biotech Companies Target CNS Disorders

Psychiatric TimesPsychiatric Times Vol 15 No 5
Volume 15
Issue 5

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.

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.

ABS and Nerve Growth Factor

American Biogenetic Sciences Inc. (ABS), a global biopharmaceutical and diagnostic company with facilities in New York, Boston, Europe, Israel and Russia, has recently been issued a patent on their ABS 200 series. Because of its nerve growth factor (NGF)-like activity, this class of drugs is in development for the potential treatment of neurodegenerative disorders including Alzheimer's disease, Parkinson's disease, and damage caused by stroke and head trauma.

NGF is one of a set of natural proteins, which also includes brain-derived growth factor, NT-3 and others. Evidence gathered from experiments suggests that increased levels of these neurotrophic proteins could protect endangered neural tissue, and might retard the progression of neurodegenerative disorders or improve recovery from neural trauma. Although these naturally occurring proteins cannot cross the blood brain barrier, the 200 series compounds readily cross the barrier and promote nerve cell growth. Like NGF, they induce the expression of NCAM, a member of the immunoglobulin supergene family of recognition molecules which is proposed to be critical to the orderly structure of the CNS and involved in memory, learning and neurodevelopment. Preliminary experiments suggest that the drugs protect against chemical-induced amnesia and help prevent age-associated loss of memory in animals.

In February, Ciaran Regan, Ph.D., professor of pharmacology, University College Dublin, Ireland, and Heinz Nau, Ph.D., professor and chairman of the department of food toxicology at the University of Hanover, Germany, presented promising preclinical results of their research on ABS 205 at an international conference on Alzheimer's disease held in Boston. Commenting on the research, Regan said, "The promising results with ABS 205...encourage[s] the pursuance of this compound as a novel therapeutic approach to neurodegenerative disorders." The research, ABS says, also provides a drug discovery platform on which other active molecules can be screened for the potential treatment of serious neurological conditions.

In another area, ABS is developing an orally active small molecule drug for epilepsy. The compounds in the ABS 100 series are valproate analogs believed to possess a broad spectrum of anticonvulsant activity, and in animal studies they controlled seizures without producing sedation or teratogenic side effects associated with valproate and other anticonvulsants. Kinetic studies suggested that the compound has a longer duration of action than valproate, a known reference compound for treatment of epilepsy, and thus might require less frequent dosing.

Neurogen's Development Programs

According to Harry Penner Jr., president and CEO of Neurogen Corp., most biotech companies have only one or two development programs. Neurogen, located in Branford, Conn., has more than 10 programs for anxiety, insomnia, cognition enhancement and obesity, as well as schizophrenia and epilepsy.

NGD 91-2, Neurogen's small molecule compound designed to reduce anxiety, completed Phase Ia studies conducted by Pfizer Inc. in November 1997. NGD 91-2 modulates the GABA receptor complex by targeting only those receptor subtypes linked to anxiety. This specificity may lessen the occurrence of side effects such as sedation, motor skill impairment and memory loss often associated with current therapies.

Neurogen's focus for the treatment of epilepsy is ADCI, a novel small molecule that works by antagonizing NMDA receptors and blocking voltage-dependent sodium channels. ADCI has been licensed to Wyeth-Ayerst Laboratories, which began Phase I human clinical testing of ADCI in mid-1997.

Neurogen is also investigating three areas of their research on cognitive enhancement. In partnership with Pfizer researchers, Neurogen has identified a class of small molecule compounds that acts through specific GABA receptor subtypes believed to enhance cognitive function. They expect human clinical studies of one of these compounds, NGD 97-1 to begin this year.

Localization of the D4 receptor subtype in areas of the brain associated with learning and memory may indicate that D4-specific compounds are effective cognition enhancers. In models of learning and memory, these compounds have shown enhancing effects, and Neurogen, along with its partner Schering-Plough, plans to study these compounds for the treatment of cognitive impairment and schizophrenia.

As part of its Accelerated Intelligent Drug Design program, Neurogen is also investigating the potential therapeutic benefit of drugs that have a high affinity for the galanin1 receptor subtype in treating Alzheimer's disease.

Galanin is a neuropeptide neurotransmitter whose receptors are found in areas of the brain responsible for feeding, as well as for learning and memory. Neurogen researchers theorize that a small molecule drug that blocks the effect of galanin might modulate acetylcholine, a neurotransmitter implicated in Alzheimer's disease.

The future success of these three companies and others delving into the secrets of the brain will lie in their ability to know which of increasingly large numbers of small-molecule compounds have promise as potential drug candidates, and to bring to this their knowledge of neurobiology, medicinal chemistry and molecular biology...and perhaps some canny partnering.

Related Videos
Erin Crown, PA-C, CAQ-Psychiatry, and John M. Kane, MD, experts on schizophrenia
nicotine use
brain schizophrenia
eating disorder brain
exciting, brain
© 2024 MJH Life Sciences

All rights reserved.