Amifampridine safety and efficacy in spinal muscular atrophy ambulatory patients: a randomized, placebo-controlled, crossover phase 2 trial.

Autor: Bonanno S; Neuroimmunology and Neuromuscular Disease Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Via Celoria 11, 20133, Milan, Italy., Giossi R; Neuroimmunology and Neuromuscular Disease Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Via Celoria 11, 20133, Milan, Italy.; Department of Oncology and Onco-Hematology, Postgraduate School of Clinical Pharmacology and Toxicology, University of Milan, Milan, Italy., Zanin R; Developmental Neurology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy., Porcelli V; Department of Clinical Research and Innovation, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy., Iannacone C; SPARC Consulting, Milan, Italy., Baranello G; Developmental Neurology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.; Developmental Neuroscience Research and Teaching Department, Faculty of Population Health Sciences, Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health, London, UK.; NIHR Great Ormond Street Hospital Biomedical Research Centre, Great Ormond Street Hospital NHS Foundation Trust, London, UK., Ingenito G; Catalyst Pharmaceuticals, Inc., Coral Gables, USA., Iyadurai S; Catalyst Pharmaceuticals, Inc., Coral Gables, USA.; Johns Hopkins All Children's Hospital, St Petersburg, FL, 33701, USA., Stevic Z; Faculty of Medicine, Neurology Clinic, University Clinical Center of Serbia, University of Belgrade, Dr Subotica 6, 11000, Belgrade, Serbia., Peric S; Faculty of Medicine, Neurology Clinic, University Clinical Center of Serbia, University of Belgrade, Dr Subotica 6, 11000, Belgrade, Serbia., Maggi L; Neuroimmunology and Neuromuscular Disease Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Via Celoria 11, 20133, Milan, Italy. lorenzo.maggi@istituto-besta.it.
Jazyk: angličtina
Zdroj: Journal of neurology [J Neurol] 2022 Nov; Vol. 269 (11), pp. 5858-5867. Date of Electronic Publication: 2022 Jun 28.
DOI: 10.1007/s00415-022-11231-7
Abstrakt: Background: Spinal muscular atrophy (SMA) is an autosomal recessive disease where a deficient amount of SMN protein leads to progressive lower motor neuron degeneration. SMN-enhancing therapies are now available. Yet, fatigue and signs of impaired neuromuscular junction (NMJ) transmission could contribute to SMA phenotype. Amifampridine prolongs presynaptic NMJ terminal depolarization, enhancing neuromuscular transmission.
Methods: SMA-001 was a phase 2, 1:1 randomized, double-blind, placebo-controlled crossover study. Ambulatory (walking unaided at least 30 m) SMA Type 3 patients, untreated with SMN-enhancing medications, entered a run-in phase where amifampridine was titrated up to an optimized stable dose. Patients achieving at least three points improvement in Hammersmith Functional Motor Score Expanded (HFMSE) were randomized to amifampridine or placebo, alternatively, in the 28-day double-blind crossover phase. Safety was evaluated by adverse events (AE) collection. Primary efficacy measure was the HFMSE change from randomization. Secondary outcomes included timed tests and quality of life assessment. Descriptive analyses and a mixed effects linear model were used for statistics.
Results: From 14 January 2019, 13 patients, mean age 34.5 years (range 18-53), with 5/13 (38.5%) females, were included. No serious AE were reported. Transient paresthesia (33.3%) was the only amifampridine-related AE. Six patients for each treatment sequence were randomized. Amifampridine treatment led to a statistically significant improvement in HFMSE (mean difference 0.792; 95% CI from 0.22 to 1.37; p = 0.0083), compared to placebo, but not in secondary outcomes.
Discussion: SMA-001 study provided Class II evidence that amifampridine was safe and effective in treating ambulatory SMA type 3 patients.
Clinical Trial Registration: NCT03781479; EUDRACT 2017-004,600-22.
(© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)
Databáze: MEDLINE
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