WASHINGTON - FDA drug reviewers Friday questioned whether there was sufficient evidence that a clinically meaningful effect has been established for Actelion Pharmaceuticals Ltd.'s Zavesca (miglustat) as a treatment for Niemann-Pick Type C disease, a rare, fatal autosomal-recessive disorder.
The Allschwil, Switzerland-based biotech's single randomized, controlled study missed its primary endpoint, but regulators said Actelion had provided an extensive battery of assessments of other endpoints and data from an extension and retrospective studies.
There currently are no treatments for NP-C, a neurological disease, which causes dysphagia, dysarthria, dystonia, seizures, abnormal saccadic eye movements and cognitive and psychiatric abnormalities. Patients with the disease progress to dementia and ultimately premature death.
Zavesca was first approved in 2003 to treat mild to moderate type 1 Gaucher disease for patients in which enzyme replacement therapy is not a therapeutic option.
The drug, a competitive inhibitor of the enzyme glucosylceramide synthase, has gained approval in Europe for the treatment of progressive neurological manifestations of NP-C in adult and pediatric patients and has been granted orphan drug designation in the U.S.
The primary defect in patients with NP-C, a lysosomal storage disorder, is severely impaired intracellular lipid transport and is caused by mutations in the NPC1 or NPC2 genes, with no primary defect in catabolic enzymes.
Zavesca has been shown to reduce glycosphingolipid accumulation and cellular pathology in the brain.
Nonetheless, clinical studies of the drug, either in type 1 Gaucher's or NP-C, have been small, with very few patients worldwide receiving the drug so far, drug reviewers noted in briefing documents posted Friday on the FDA's website.
"It is difficult to assess if patients' adverse events are related to their underlying condition or the drug," they said.
The FDA reviewers noted that there was no statistically significant difference in the change from baseline in horizontal saccadic eye movement in patients taking Zavesca vs. those on placebo.
Actelion used HSEM-alpha as the primary endpoint because the failure of saccadic initiation is often an early sign of NP-C and saccadic eye movement failure is associated with visual, learning and social handicap. But FDA officials noted that no information was presented to support the claims of saccadic eye movement failure being associated with those or other handicaps.
The safety review included data from nine Zavesca trials conducted in patients affected by five different lysosomal storage diseases: Gaucher disease types 1 and 3, NP-C, GM2 gangliosidosis and Fabry disease. During those studies, a total of 206 patients, including 40 NP-C patients, were exposed to Zavesca. The FDA noted that NP-C is the first indication for which Actelion is proposing to add pediatric patients to the approved population. However, they said, "weight loss is of particular concern in the pediatric population due to the risk of growth retardation."
The FDA Tuesday will ask its Endocrinologic and Metabolic Drugs Advisory Committee whether the endpoints in Actelion's randomized clinical trial were clinically meaningful, and if clinical data included in the Zavesca application for NP-C provided substantial evidence of efficacy.
The FDA specifically wants its outside experts to advise the agency on which clinical data - the studies and endpoints - provided substantial evidence, if any. Regulators also want the committee to evaluate the safety of Zavesca at the proposed dose in the NP-C patient population and whether that dose had been assessed adequately.