Alkermes sets sights on blood-brain barrier Alkermes, a small biotech company devoted to developing systems for transporting drugs across the bloodbrain barrier, has recently discovered an agent that reversibly increases brain capillary permeability, according to company founder Michael A. Wall. The agent may provide Alkermes with a general solution to drug delivery across the blood-brain barrier. Alkermes, which was founded in 1988 and is based in Cambridge, Mass., has been pursuing a number of approaches for breaching the blood-brain barrier, a formidable obstacle to many pharmaceuticals designed to act in the brain. According to Wall, that effort has now been narrowed to two approaches: the permeability enhancer and an antibody-based carrier that will transport a drug molecule across the barrier. The blood-brain barrier exists to protect the brain from fluctuating levels of chemicals in the blood. Capillaries in the brains of vertebrates have a structure that is different from capillaries in other parts of the body. The endothelial cells that form the walls of capillaries in nonneural tissues are loosely joined to each other, leaving pores called fenestrations through which pass molecules smaller than large proteins. Thus, blood plasma and extracellular fluid have essentially the same composition outside the central nervous system. The extracellular fluid of the central nervous system (CNS), however, has a different composition than blood plasma, and the bloodbrain barrier maintains that difference. The junctions between endothelial cells of capillaries in the CNS are tightly sealed, and most water-soluble molecules can cross these capillary walls only through selective, active transport systems. Such a system, for instance, carries glucose across the barrier. That's fine for the normal brain. But it poses a major problem for physicians who want to treat an infection of the brain or deliver a drug to correct abnormal brain func-
tion. The human immunodeficiency virus (HIV), for instance, infects the brain as well as a variety of immune system cells, and successful therapies for AIDS will have to be able to reach these virus particles. Drugs to treat Alzheimer's disease and Parkinson's disease, both neurodegenerative diseases whose incidence is expected to increase dramatically as the U.S. population ages, also must be able to cross the bloodbrain barrier. Not surprisingly, in a search that has gone on for more than two decades, a number of companies are working on ways to get drugs across the blood-brain barrier. Wall, who is an incurable entrepreneur—he has been involved in the creation of 11 companies in his career—sees the blood-brain barrier as the "angle" needed by a small company to break into the neuroscience market. With about $13 million in venture capital backing and, now, 28 employees, Alkermes may be close to achieving its goal. Company scientists have shown that the permeability enhancer permits three drugs—an opiate, an anticancer drug, and dopamine—to cross the blood-brain barrier in rats. Preliminary studies indicate that the compound has no negative side effects. "We are really excited about this," Wall says. About two thirds of Alkermes employees, he says, are now working on the permeability enhancer project. The permeability enhancer is a protein that apparently binds to a specific receptor on the endothelial cells of brain capillaries. Binding triggers a reversible increase in the permeability of the endothelial cell membranes. An attractive feature of such a molecule is that it is a general approach for transporting drugs across the blood-brain barrier. Unlike an antibody carrier, where each carrier-drug formulation would require separate approval by the Food & Drug Administration, such a permeability enhancer likely could be approved for a variety of uses if it proves to be safe and effective in humans. Wall says Alkermes hopes to begin human trials of the compound later this year. Rudy Baum
Crompton & Knowles retains large dye role In 1976, 21 companies produced dyes in the U.S. Now, that number has shrunk to 10. About 40% of U.S. dye capacity has been shut down and some of the largest U.S. chemical companies have exited the dye business. One of the survivors is the venerable Crompton & Knowles. Despite this attrition, Crompton & Knowles not only has survived, it has flourished. Indeed, it may have flourished because of the attrition, not in spite of it, says David S. Alcorn, president of the company's dyes and chemicals division. "It's easier to compete against nine other companies than it is against 20 others," he quips. But there are other reasons for Crompton & Knowles' success in the dye business. First, the company has received some fortuitous help from trends in dyes and intermediates tariffs. Duties on imported dyes have come down, but they have remained high enough to give domestic producers such as Crompton & Knowles some degree of protection from imports. Meanwhile, tariffs on dye intermediates also have dropped, enabling the firm to save money on intermediates imports.
Crompton & Knowles'Alcorn (right) discusses dye problems with Russell Steiner, vice president, R&D March 19, 1990 C&EN
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