Abstract
BackgroundNiemann-Pick disease type C (NP-C) is a rare neurovisceral disease characterised by progressive neurological degeneration, where the rate of neurological disease progression varies depending on age at neurological onset. We report longitudinal data on functional disease progression and safety observations in patients in the international NPC Registry who received continuous treatment with miglustat.MethodsThe NPC Registry is a prospective observational cohort of NP-C patients. Enrolled patients who received ≥1 year of continuous miglustat therapy (for ≥90 % of the observation period, with no single treatment interruption >28 days) were included in this analysis. Disability was measured using a scale rating the four domains, ambulation, manipulation, language and swallowing from 0 (normal) to 1 (worst). Neurological disease progression was analysed in all patients based on: 1) annual progression rates between enrolment and last follow up, and; 2) categorical analysis with patients categorised as ‘improved/stable’ if ≥3/4 domain scores were lower/unchanged, and as ‘progressed’ if <3 scores were lower/unchanged between enrolment and last follow-up visit.ResultsIn total, 283 patients were enrolled from 28 centers in 13 European countries, Canada and Australia between September 2009 and October 2013; 92 patients received continuous miglustat therapy. The mean (SD) miglustat exposure during the observation period (enrolment to last follow-up) was 2.0 (0.7) years. Among 84 evaluable patients, 9 (11 %) had early-infantile (<2 years), 27 (32 %) had late-infantile (2 to <6 years), 30 (36 %) had juvenile (6 to <15 years) and 18 (21 %) had adolescent/adult (≥15 years) onset of neurological manifestations. The mean (95%CI) composite disability score among all patients was 0.37 (0.32,0.42) at enrolment and 0.44 (0.38,0.50) at last follow-up visit, and the mean annual progression rate was 0.038 (0.018,0.059). Progression of composite disability scores appeared highest among patients with neurological onset during infancy or childhood and lowest in those with adolescent/adult-onset. Overall, 59/86 evaluable patients (69 %) were categorized as improved/stable and the proportion of improved/stable patients increased with age at neurological onset. Safety findings were consistent with previous data.ConclusionsDisability status was improved/stable in the majority of patients who received continuous miglustat therapy for an average period of 2 years.
Highlights
Niemann-Pick disease type C (NP-C) is a rare neurovisceral disease characterised by progressive neurological degeneration, where the rate of neurological disease progression varies depending on age at neurological onset
Based on data from a randomized controlled clinical trial [5], long-term extension studies [6, 7], and a retrospective observational cohort study [8], miglustat was approved for the treatment of progressive neurological manifestations in pediatric and adult patients with NP-C in the EU in 2009 [4], and has since been approved in a number of other countries
The international NPC Registry was initiated in May 2009 as a post-approval commitment to the European Medicines Agency (EMA) following approval of a new indication for miglustat for the treatment of progressive neurological deterioration in adults and children with NP-C [4]
Summary
The international NPC Registry was initiated in May 2009 as a post-approval commitment to the European Medicines Agency (EMA) following approval of a new indication for miglustat for the treatment of progressive neurological deterioration in adults and children with NP-C [4]. The 0–1 scoring system was chosen for use in the Registry [14] as this scale has been employed in key studies on the natural history of NP-C [8, 15], is listed among the useful assessment tools in the international recommendations for managing NP-C [2, 3], and has been employed in describing miglustat treatment outcome on NP-C disease progression in previous national cohorts [12]. Disease progression was assessed by two statistical methods: 1) annual progression rates were calculated as the change in composite disability score from enrolment to last follow-up visit divided by time in years from enrolment to last follow-up visit; 2) categorical analysis, where patients were categorized as ‘improved/stable’ when at least three out of four individual disability domain scores were decreased or unchanged between enrolment and last follow-up visit, and patients with fewer than three out of four domain scores decreased or unchanged were categorized as ‘progressing’ [8, 15]. The participation rate of miglustattreated patients in Europe was calculated as the number of miglustat-treated patients enrolled in the Registry divided by the estimated number of NP-C patients treated with miglustat in European countries
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