In type 1 Gaucher disease
Zavesca® (miglustat) 100 mg is the only oral drug available for the treatment of type 1 Gaucher disease, and was approved on the basis of three international open-label clinical trials. The rationale for the use of miglustat in type 1 Gaucher disease is to help balance the overall level of glucosylceramide by reducing its production to a level compatible with breakdown by residual glucocerebrosidase activity, a unique mode of action known as "substrate reduction therapy". Results from a pooled analysis of the three open-label clinical trials have recently shown that miglustat monotherapy may reduce the incidence of bone crisis and improve bone mineral density in type 1 Gaucher disease patients, including those with a history of splenectomy and/or osteoporosis.
In Niemann-Pick type C disease
In order to gain approval for Zavesca® in Niemann-Pick type C disease (NP-C), a set of clinical data were obtained from one clinical trial OGT918-007 and two multicenter retrospective cohort studies in patients with NP-C.
The usual dose of Zavesca® in adult NP-C patients was 200 mg miglustat three times a day, and was adjusted according to body surface area in pediatric NP-C patients.
In the clinical trial OGT918-007, adult and juvenile patients with NP-C (n=29, age >=12 years) were randomized to either miglustat 200 mg t.i.d. (n=20) or standard of care (n=9) for 12 months. In addition, 12 children aged 4-12 years received miglustat at a dose adjusted for body surface area. All patients were then given miglustat for another 12 months. Horizontal saccadic eye movement (HSEM) velocity was the primary endpoint. Other endpoints included swallowing, ambulation, neurological examination, neuropsychological assessment, tremor and quality of life. At 12 months, HSEM velocity had improved in patients treated with miglustat versus those receiving standard care; results were significant when patients taking benzodiazepines were excluded (p=0.028). Children showed an improvement in HSEM velocity of similar size at 12 months. Improvement in swallowing capacity, stable auditory acuity, and a slower deterioration in ambulatory index were also seen in treated patients older than 12 years.
In an uncontrolled extension phase of the OGT918-007 trial, data indicated that treatment with miglustat can provide disease stabilization for important markers of neurological dysfunction in NP-C disease, both in the juvenile/adult and pediatric cohorts, further strengthening the interpretation of a treatment effect of miglustat observed at 12 months in the controlled phase of the trial.
The safety and tolerability of miglustat 200 mg three times a day in clinical trial participants was consistent with previous trials in type 1 Gaucher disease, where half this dose was used.
A first retrospective cohort study was performed in 25 centers in 12 countries to assess data on changes of neurological status and overall utility of treatment with miglustat in 66 NP-C patients receiving miglustat outside of the clinical trial OGT918-007 for a mean duration of 1.5 years. A disease-specific disability scale was used to evaluate the severity of dysphagia (swallowing), dystonia (manipulation), ataxia (ambulation) and dysarthria (language articulation) at diagnosis, treatment initiation and last visit. A majority of patients remained at least stable after treatment with regard to the four parameters, indicating that miglustat provides clinically relevant benefits on neurological disease progression in patients with NP-C.
A second retrospective cohort study was performed in 7 centers in 6 countries to assess data on changes in neurological status in 57 patients not treated with miglustat during the natural course of the disease for a mean duration of 5.5 years. The same disease-specific disability scale was used to evaluate the severity of dysphagia, dystonia, ataxia and dysarthria at the time of diagnosis until the last visit. The results will be presented in the first half of 2009.
The benefit of treatment with Zavesca® for neurological manifestations in patients with Niemann-Pick type C disease should be evaluated on a regular basis, e.g. every 6 months; continuation of therapy should be re-appraised after at least 1 year of treatment with Zavesca®.
