Biomarin Pharmaceuticals, Novato, Calif., recently announced the approval of Neglazyme (galsulfase), the first specific therapy approved for the treatment of mucopolysaccharidosis VI (MPS VI). The drug was granted orphan drug status in the US, conferring seven years of market exclusivity. There are several types of MPS disorders and the company was the first maker of a drug for MPS I called Aldurazyme (laronidase), which was approved in 2003.
“The strategy of the company has been to focus on diseases with high unmet medical need and, in particular, we have been working on genetic products where big pharma is not really focused and for which there is really clear biology on what would constitute a good drug,” says Emil Kakkis, MD, PhD, SVP. "We did that with Aldurazyme, which was approved in six years, for MPS I and we have done it again with Neglazyme for MPS VI."
MPS VI is a relatively rare and life-threatening disease that affects children and young adults, with 1,000 individuals in the developed world estimated to have the disease. The disease is caused by a deficiency of the enzyme N-acetylgalactosamine 4-sulfatase. This enzyme deficiency leads to the accumulation of certain complex carbohydrates, glycosaminoglycans (GAGs), in the lysosomes, causing progressive cellular, tissue, and organ system dysfunction.
MPS I is an inherited, often life-threatening lysosomal disorder caused by a deficiency of the lysosomal enzyme, alpha-L-iduronidase. Kakkis was instrumental in the development of Aldurazyme. Then at Harbor University of California, Los Angeles, Medical Center, he was the study's principal investigator, working with Elizabeth Neufeld, PhD, professor and chair of the biological chemistry department. Neufeld and Kakkis discovered how to produce a recombinant form of alpha-L-iduronidase that was later evaluated in the clinic.
Ever since, their approach for developing new drugs, says Kakkis, is working closely with academia, researchers, and physicians with compelling ideas. "There are a lot of strategies for developing a pipeline, but having good relationships with academics being apprised of the latest research is really the best way to find products that can potentially be developed." Neglazyme for MPS VI was based on the basic research of John Hopwood, PhD, professor and head of the Lysosomal Diseases Research Unit, Women's and Children's Hospital, North Adelaide, Australia, who had worked on the cat model of MPS VI.
“It's because of the animal genetic models that we knew this drug was highly likely to work and that the kind of doses that we would need were reasonable and approachable,” says Kakkis. MPS VI cats are a breed of cats that have the same genetic defect of the missing enzyme that humans have.Hopwood spent several years doing enzyme replacement work in the cat model. "He showed that by giving intravenous infusions of this enzyme, it then would get into the tissue and treat the disease," says Kakkis.
Clinical trials have demonstrated that Naglazyme provides clinically important benefits for MPS VI patients, specifically, improved endurance such as walking and stair-climbing capacity. Naglazyme reduced the excess GAGs that are excreted in the urine of patients with MPS VI, an indication of enzymatic bioactivity.
Biomarin also has a drug candidate in Phase 3 clinical trial, called Phenoptin (sapropterin hydrochloride), for phenylketonuria (PKU), an inherited metabolic disease caused by a deficiency of the enzyme phenylalanine hydroxylase (PAH). Insufficient quantities or reduced activity of PAH results in elevated levels of phenylalanine (Phe) in the blood, which can result in serious neurological damage. Sapropterin hydrochloride, the active ingredient in Phenoptin, is a synthetic form of 6R-BH4, an essential enzyme cofactor that works in conjunction with PAH to metabolize Phe. Results of the ongoing trial are expected later this year.By Elizabeth Tolchin