Clinicians who treat persons with Gaucher disease will soon be able to offer their patients the first oral treatment option for this condition to be approved in the U.S. The FDA recently approved miglustat (Zavesca, Actelion Pharmaceuticals) for the treatment of adult patients with mild to moderate type I Gaucher disease for whom enzyme replacement therapy is not a therapeutic option. Miglustat will be available to patients later this year.
Clinicians treating persons with Gaucher disease will soon be able to offer their patients the first oral treatment option for this condition approved in the United States. The Food & Drug Administration has cleared miglustat (Zavesca, Actelion Pharmaceuticals) for the treatment of adult patients with mild to moderate type 1 Gaucher disease for whom enzyme replacement therapy is not a therapeutic option. Miglustat will be available to patients later this year.
Type 1 Gaucher disease is caused by a functional deficiency of glucocerebrosidase, which mediates the degradation of the glycosphingolipid glucosylceramide, explained Gregory Pastores, M.D., assistant professor of neurology and pediatrics, New York University School of Medicine, New York City. The failure to degrade glucosylceramide results in the lysosomal storage of this material within tissue macrophages, leading to widespread pathology.
The goal of miglustat therapy is to reduce the rate of glycosphingolipid biosynthesis so that the amount of glycosphingolipid substrate is reduced to a level that allows the residual activity of the deficient glucocerebrosidase enzyme to be sufficient in preventing its buildup, effectively establishing glycosphingolipid metabolic balance, said Pastores, who is also codirector of the neurogenetics laboratory at New York University School of Medicine. This mechanism of action is called substrate reduction therapy, and miglustat is the first agent to treat Gaucher disease in this manner.
Miglustat is classified as Pregnancy Category X, so its use is contraindicated in pregnant or lactating women, said Pastores. Actelion recommends that men use reliable contraception while taking miglustat, because studies in rats have shown that miglustat adversely affects spermatogenesis and sperm parameters. The manufacturer also cautions that miglustat is contraindicated for use in persons known to be hypersensitive to the active ingredient or any of the excipients.
Adverse events associated with miglustat therapy in clinical trials included diarrhea and weight loss, which were reported by approximately 85% and up to 65% of patients, respectively, Pastores said. Diarrhea appeared to be the result of the disaccharidase inhibitory activity of miglustat, he explained. This problem is transient and responsive to dietary modification. Weight loss was most evident during the first 12 months of treatment.
Approximately 30% of patients who participated in the initial clinical trials reported tremor or exacerbation of existing tremor during treatment with miglustat, Pastores reported. However, the tremors were mild and did not interfere with the performance of normal daily activities, he said. Tremor usually began within the first month of treatment, and often resolved after one to three months of treatment. According to the manufacturer, dose reduction may ameliorate the tremor, but discontinuation of therapy may be required.
Peripheral neuropathy has been reported in persons treated with miglustat, Pastores continued. The manufacturer recommends that all patients receiving treatment with miglustat undergo baseline and repeat neurological evaluations at approximately six-month intervals.
The recommended dosage for the treatment of adults with type 1 Gaucher disease is one 100-mg capsule administered orally three times daily at regular intervals. In those who experience adverse effects, it may be necessary to reduce the dosage to one 100-mg capsule twice daily. Those with mild renal impairment, defined as creatinine clearance of 50-70 mL/min., should begin miglustat therapy at a dosage of one 100-mg capsule twice daily. Those with moderate renal impairment, or a creatinine clearance of 30-50 mL/min., should begin therapy at a dosage of one 100-mg capsule once daily. Miglustat is not recommended for use in those with a creatinine clearance of less than 30 mL/min.
Gaucher disease, which is inherited as an autosomal recessive disorder, occurs in approximately one in 20,000 persons among the general population, said John Barranger, M.D., Ph.D., professor of human genetics, University of Pittsburgh School of Public Health. He noted that it is the most common genetic disorder among the Eastern European Jewish population.
Charlotte LoBuono. New therapy for Gaucher disease is first of its kind.
Oct. 6, 2003;147:32.