Efficacy and safety of arimoclomol in Niemann-Pick disease type C: Results from a double-blind, randomised, placebo-controlled, multinational phase 2/3 trial of a novel treatment.

Niemann-Pick disease type C (NPC) is a rare, genetic, progressive neurodegenerative disorder with high unmet medical need. We investigated the safety and efficacy of arimoclomol, which amplifies the heat shock response to target NPC protein misfolding and improve lysosomal function, in patients with NPC. In a 12-month, prospective, randomised, double-blind, placebo-controlled, phase 2/3 trial (ClinicalTrials.gov identifier: NCT02612129), patients (2-18 years) were randomised 2:1 to arimoclomol:placebo, stratified by miglustat use. Routine clinical care was maintained. Arimoclomol was administered orally three times daily. The primary endpoint was change in 5-domain NPC Clinical Severity Scale (NPCCSS) score from baseline to 12 months. Fifty patients enrolled; 42 completed. At month 12, the mean progression from baseline in the 5-domain NPCCSS was 0.76 with arimoclomol vs 2.15 with placebo. A statistically significant treatment difference in favour of arimoclomol of -1.40 (95% confidence interval: -2.76, -0.03; P = .046) was observed, corresponding to a 65% reduction in annual disease progression. In the prespecified subgroup of patients receiving miglustat as routine care, arimoclomol resulted in stabilisation of disease severity over 12 months with a treatment difference of -2.06 in favour of arimoclomol (P = .006). Adverse events occurred in 30/34 patients (88.2%) receiving arimoclomol and 12/16 (75.0%) receiving placebo. Fewer patients had serious adverse events with arimoclomol (5/34, 14.7%) vs placebo (5/16, 31.3%). Treatment-related serious adverse events (n = 2) included urticaria and angioedema. Arimoclomol provided a significant and clinically meaningful treatment effect in NPC and was well tolerated.

Structural and cognitive correlates of fatigue in progressive multiple sclerosis.

BACKGROUND: Fatigue in multiple sclerosis (MS) is a debilitating symptom and experienced by most patients. In recent studies investigating this phenomenon, the majority of patients had a relapsing-remitting disease course. METHODS: Patients with progressive MS participating in one of three treatment trials during a period from 2010 to 2014 were included. Fatigue was assessed with the Fatigue Scale for Motor and Cognitive Functions (FSMC) and patients were further examined with a cognitive test battery, including Symbol Digit Modalities Test (SDMT), and 3 T MRI with subsequent quantitative analyses of 13 cortical regions of interest, deep grey matter and lesion volume. RESULTS: Twenty-two patients were enrolled. The thickness of the pre-central gyrus correlated significantly with motor fatigue. We found only a non-significant trend towards a correlation between cognitive fatigue and the thickness of the pre-central gyrus, the parietal inferior supra-marginal gyrus and the opercular part of the inferior frontal gyrus. 36% of participants had impaired processing speed and 9% had normal function on all tests. The scores on the FSMC-cognitive scale were related to performance on SDMT. CONCLUSION: In this exploratory study of patients with progressive MS, fatigue was related to processing speed. Motor fatigue was also related to the cortical thickness of the primary motor cortex and there was a trend towards a relationship between cognitive fatigue and the thickness of cortical areas involved in attentional processes. Additional studies are needed to further elucidate the relationship between regional cortical atrophy, cognitive functioning and the perception of fatigue. ABBREVIATIONS: FSMC: Motor and Cognitive Functions; MS: Multiple Sclerosis; SDMT: Symbol Digit Modalities Test; MRI: Magnetic Resonance Imaging; RRMS: Relapsing-Remitting Disease Course; EDSS: Kurtzke Expanded Disability Status Scale; FLAIR: Fluid Attenuated Inversion Recovery; NAWM: Normal-Appearing White Matter; CGM: Cortical Grey Matter; CTh: Cortical Thickness; ROIs: Regions of Interest; Raven: Raven Progressive Matrices; TM A: Trail Making A; TM B: Trail Making B; Rey: Rey Complex Figure; Similarities: WAIS III Similarities; Stroop: Stroop Colour Naming Test; BDI: Becks Depression Inventory II.