A small, orally administered molecule designed to increase production of the muscle protein utrophin, is being tested in healthy volunteers, according to its developer, BioMarin Pharmaceutical of Novato, Calif.
Increasing utrophin production is among the many strategies being pursued to treat Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD), both of which are caused by lack of the muscle protein dystrophin.Without dystrophin, muscle fibers are abnormally fragile. Experiments in mice have suggested that utrophin, a muscle protein that's very similar to dystrophin, is capable of at least partially compensating for dystrophin’s absence.
About BMN195 development
BioMarin announced Jan. 11, 2010, that the first subject in the BMN195 safety trial, a healthy volunteer who does not have DMD or BMD, has begun treatment with this experimental compound. This phase 1 trial will assess BMN195's safety, tolerability and pharmacokinetics (the body's handling of the drug) in people without any disease.
BioMarin says it plans to conduct a single-dose and then a multiple-dose study of BMN195 in healthy volunteers, and that those studies will allow subsequent studies in people with DMD. The company expects its first results from the healthy volunteer studies in the third quarter of 2010.
About DMD and BMD molecular mechanisms
DMD is a disease in which any of a number of mutations in the gene for the muscle protein dystrophin leads to an absence of this protein at the muscle-fiber membrane, resulting in overly fragile membranes and progressive weakness of skeletal, cardiac and respiratory muscles.
The related disease BMD results from mutations in the dystrophin gene that reduce, but do not completely eliminate, dystrophin protein in the membrane. This disease is generally less severe than DMD, although cardiac complications can be life-threatening.
Clusters of proteins are embedded around the periphery of each muscle fiber and help keep the fiber intact during muscle contractions. A lack of the protein dystrophin leads to DMD or BMD, while loss of any of the four sarcoglycan proteins leads to limb-girdle muscular dystrophy (LGMD). These protein clusters are mainly linked to the inside of the muscle fiber by dystrophin, although utrophin performs this function on some parts of the fiber border.
Among the many avenues being pursued in DMD and BMD research is raising levels of utrophin, which is normally present in muscle fibers during fetal development and which remains in the mature fibers at the places where nerve and muscle fibers meet.
DMD and BMD patients have normal utrophin genes and produce plenty of utrophin protein, but utrophin protein from these genes isn't sufficient to compensate fully for the missing dystrophin.
Raising utrophin to sufficient levels by injecting utrophin genes or protein, or by increasing utrophin production from existing genes, has been a goal of ongoing laboratory investigations for more than a decade. (See Utrophin Strategies Excite Duchenne Researchers, Utrophin Gene Therapy Benefits DMD Mice, Utrophin Gets In and Obesity Drug Increases Utrophin.) MDA has supported these strategies since the 1990s and continues to support them.
Meaning for people with DMD and BMD
If the studies of BMN195 in healthy volunteers show the drug is safe and well tolerated and that other criteria for its further development are met, the company may take the drug into clinical trials for people with DMD or BMD.
MDA will follow these developments on its Web site and in its print magazine, Quest.
Editor's note 8/3/10: On Aug. 2, 2010, BioMarin announced it would not pursue development of BMN195 for Duchenne muscular dystrophy, after the molecule failed to achieve adequate concentrations in the bloodstream of healthy volunteers. See BioMarin Announces Results for Phase 1 Clinical Study of BMN 195 for Duchenne Muscular Dystrophy.