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

Abstract

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.

Keywords: 3,4-diaminopyridine; Amifampridine; Fatigue; Hammersmith functional motor score expanded; Randomized controlled trial; Spinal muscular atrophy.

Conflict of interest statement

S. Bonanno received honoraria for advisory board activities and compensation for travel and congress participation from Sanofi Genzyme, Biogen and Roche; R. Giossi received support for congress participation from Mylan; R. Zanin received funds for travel and congress participation from Biogen; V. Porcelli has nothing to disclose; C. Iannacone has received honoraria for statistical consultancy from Roche, Bayer-Schering, ReiThera, Abiogen, and MolMed; G. Baranello received speaker and consulting fees from Biogen, Novartis Gene Therapies, Inc. (AveXis), and Roche and has worked as principal investigator of SMA studies sponsored by Novartis Gene Therapies, Inc., and Roche; G. Ingenito has corporate appointment with Catalyst Pharmaceuticals; S. Iyadurai has corporate appointment with Catalyst Pharmaceuticals; Z. Stevic reports following conflicts of interest, all outside this work: receiving lecture honoraria from Pfizer and Roche; S. Peric reports following conflicts of interest, all outside this work: receiving lecture honoraria from Pfizer, Teva Actavis, Berlin Chemie Menarini, Mylan, Worwag, Adoc, and Salveo, research grants from Kedrion and Octapharma, consultant fees from argenx and Mylan, and travel grants from Octapharma, Kedrion, Teva Actavis, Sanofi Genzyme, Pfizer, Roche, Adoc, and Berlin Chemie Menarini, and reports no other conflicts of interest outside or related to this work; L. Maggi has received honoraria for speaking, advisory boards and compensation for congress participations from Sanofi Genzyme, Roche and Biogen, outside the submitted work.

© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.