Miglustat for Patients with Niemann-Pick Disease Type C

PICHON RIVIERE, A.; AUGUSTOVSKI, F.; GARCIA MARTI, S.; ALCARAZ, A.; GLUJOVSKY, D.; LOPEZ, A.; REY-ARES, L.; BARDACH, A.; CIAPPONI, A; URTASUN, M; SOTO, N

Documento de Evaluación de Tecnologías Sanitarias

IECS

Año: 2013 p. 1 - 30

1668-2793

Niemann-Pick disease Type C (NPC) is a lipid storage recessive autosomal disorder. It presents organ enlargement, progressive neurologic impairment and premature death. Its incidence is estimated in 1:120,000 live births. Mutations in the NPC1 gene (95% of the cases) and NPC2 gene (4% of the cases) result in impairment of lipids storage as glucosilceramide in different tissues and in the brain, leading to neurologic impairment. Typical neurological manifestations include: Abnormal saccadic eye movement, ataxia, dystonia, epilepsy, dysmetry, dysphagia and dysarthria. Diagnosis is based on clinical manifestations, laboratory and genetic testing. Current treatment alternatives are palliative, addressed to improving symptoms and patients? quality of life. At present, miglustat, is the only treatment approved for NPC in children and adults.TechnologyMiglustat acts by inhibiting the enzyme known as gucosilceramide synthase, responsible for the first step in the synthesis of most glucosphingolipids preventing storage of lipids such as glucosilceramide in the brain. It is orally administered in 200 mg tablets, three times a day.PurposeTo assess the available evidence on the efficacy, safety and coverage related aspects regarding the use of miglustat in patients with Niemann-Pick disease Type C.MethodsA bibliographic search was carried out on the main databases: DARE, NHS EED, on Internet general search engines, in health technology evaluation agencies and health sponsors. Priority was given to the inclusion of systematic reviews; controlled, randomized clinical trials (RCT); health technology assessments and economic evaluations; clinical practice guidelines and coverage policies of other health systems.ResultsOne randomized study followed by two open-label extension studies, one systematic review (SR), two clinical practice guidelines (CPG), three health technology assessments (HTA) and one coverage policy (CP) were found.In 2007, a randomized study on 29 patients over 12 years old with NPC was published. The patients were randomized to miglustat (n=20) vs. Standard treatment (n=9) for 12 months and 12 patients under 12 years old were added as control cohort where all the children received treatment. After 12 months, the group of patients treated with miglustat vs. those who did not receive any treatment improved in the speed of saccadic movements (p=0.028) and in the swallowing ability (p=0.044), and tended to improve gait (p=0.052).These two groups had a 24-month open-label extension phase where disease stabilization was reported.One SR published in 2012, assessed dysphagia as a mortality risk factor in patients with NPC under treatment with miglustat, considering a strong association of this problem with aspiration pneumonia and mortality. Eighty-two patients with NPC were included. The incidence of dysphagia was 55%. Overall, the patients were followed up for 12 to 48 months and 79 to 93 % of them showed stabilization or improved their swallowing function.Two CPG, based on an international consensus of experts, support the use of miglustat in NPC patients diagnosed with neurological impairment.Of the HTAs consulted, only the Catalan HTA issued an opinion after the publication of the already mentioned clinical trial, recommending its use in these patients.The two CPs, one from France and the other form the Ontario Canadian agency, support its use in patients with NPC confirmed by genetic testing and with neurologic manifestations.The FDA and EMA consider it an orphan drug for the treatment of NPC patients. The ANMAT also approves its use.ConclusionsThere is evidence of moderate methodological quality based on a randomized study, one systematic review and case series with few patients showing that miglustat stabilizes or discretely improves neurological progression measured as speed of saccadic movements and swallowing in NPC patients with neurologic manifestations. This was observed both in children and in children above 12 years old. Given the chronic and progressive neurodegenerative nature of the disease and its low frequency, it is difficult to find evidence of high quality or with important targets. In this type of diseases, stabilization or a decrease in disease progression are likely to be the expected objectives for the long-term specific treatment of the disease.