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| August 4, 2006
BH4—ASAP! BY CAROL INKELLIS What if a whole range of cardiovascular-related health problems could be treated by a tiny molecule, one that the human body manufactures? And what if this molecule lowered blood pressure even in patients whose hypertension hasn’t responded to conventional medication? It would be an amazing breakthrough. But is it possible? That’s precisely what a group in Novato is bent on discovering.
According to Susan Ferris and Joshua Grass of BioMarin, the promising drug Phenoptin (using the same enzyme cofactor being tested on hypertension) is currently on the fast-track toward approval. It treats phenylketonuria (PKU), a rare genetic disorder affecting approximately 50,000 people worldwide. At this point, PKU can be managed, but there is no treatment or cure for it. Two drugs for another group of uncommon conditions, MPS disorders (mucopolysaccharidoses, in which the deficiency of certain lysosomal enzymes results in an inability to metabolize complex carbohydrates—causing a number of symptoms and abnormalities), are already on the market. Tetrahydrobiopterin, or 6R-BH4, the molecule being tested by BioMarin to treat high blood pressure, is an essential enzyme cofactor (an organic, nonprotein component of an enzyme) in the human body. It is a crucial component in the synthesis of nitric oxide, a key player throughout the cardiovascular system (among others). Many of us are familiar with nitric oxide as an “ingredient” of acid rain or smog, but not in our own bodies, where it produces such protective and positive effects as regulating vascular tone, relaxing smooth muscle, controlling inflammation and reducing platelet aggregation. Medical studies indicate that in some disease conditions 6R-BH4 becomes deficient, affecting nitric oxide production. Ferris and Grass say that in the testing so far, administering the coenzyme improves endothelial function, dilating arterial walls and allowing blood flow to improve. While it’s true that a whole host of medications currently exists to treat high blood pressure (and other ancillary cardiovascular-related disorders), many patients do not respond well—either their blood pressure is not controlled, or they experience side effects that keep them from continuing the medication. 6R-BH4 is being tested specifically in patients who have tried other drugs that have not worked. Under the direction of chief medical officer Emil D. Kakkis, BioMarin has designed a Phase II clinical trial to test BH4 (as it is affectionately known). Clinical trials are carried out in stages: Phase I, which had a positive outcome, allows an experimental drug to be tested on a small group of 20-80 people to evaluate its safety, determine a safe range of dosage and discover any side effects. Once this phase is successfully completed, the drug moves into Phase II. At this point, the study drug is given to a larger group—100 to 300 people—to study its effectiveness and further evaluate its safety. Clinical trials are tightly controlled and rigorously monitored. After the data is in—BioMarin anticipates that will be early in 2007—and the results are positive, BH4 must still go through Phase III and IV trials to further assess effectiveness as well as potential risks. The safety of BH4 may be in question, but there’s no doubt that hypertension is a major health problem. An estimated 65 million people (some sources say one in three) in the U.S. have blood pressure above 140/90. And, as anyone who keeps up with health findings knows, untreated hypertension can lead to a laundry list of disabling or fatal conditions—including atherosclerosis, heart attack, stroke and renal failure. It is expected that if BH4 does successfully control hypertension, it will also be useful in an array of cardiovascular-related problems, including diabetes. That a naturally occurring substance may have the potential to treat so many vascular-related afflictions is a remarkable development. Both Ferris and Grass express their excitement over the possibilities. If all goes well, BH4 could receive FDA approval by 2010 or 2011. By no means is the BioMarin team resting on its laurels. The researchers continue to comb the literature looking for more uses for the little coenzyme that could. PHOTO BY ROBERT VENTE: BioMarin researchers are hoping tetrahydrobiopterin spells stress relief. |
THE CUTTING EDGE Rising Suns 2006 Straus Family Creamery Jim McCullough and Onadime Brad Silen and PlanetQuest Nicholas and Michael Broffman Gareth Loy Christi Graham and Veronica Galvin and the Buck Institute’s Alzheimer’s research |
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BioMarin, founded in 1997, develops innovative therapies for serious diseases and medical conditions using enzyme technology. The company is primarily known for its research into and development of so-called “orphan drugs,” a class of medications that treat diseases afflicting a very small percentage of the population. |
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