VP.54 Amifampridine safety and efficacy in spinal muscular atrophy ambulatory patients: a randomized placebo-controlled, crossover, phase 2 trial

Abstract

Spinal muscular atrophy (SMA) is an autosomal recessive disease where a deficient amount of SMN protein leads to progressive degeneration of bulbar and spinal motor neurons. Therapies for the restoration of SMN production are now available. Yet, fatigue and signs of impaired neuromuscular junction (NMJ) transmission have been documented as possible contributors to SMA phenotype. Amifampridine (3,4-diaminopyridine), a voltage-dependent K+ channel blocker, prolongs depolarization of the presynaptic NMJ terminal, enhancing neuromuscular transmission. Here, we evaluated the safety and efficacy of amifampridine in ambulatory patients with SMA Type 3. SMA-001 was a phase 2, 1:1 randomized, double-blind, placebo-controlled, 2-period, 2-treatment, crossover study. Genetically confirmed SMA Type 3, able to walk unaided for 30 m, not treated with nusinersen in the previous 6 months, entered the run-in phase for at least 21 days during which amifampridine was titrated up to 80 mg/day to reach an optimized stable dose. Then, patients with at least 3-points improvement in Hammersmith Functional Motor Score Extended (HFMSE) were randomized to receive either amifampridine or placebo for 2 weeks, alternatively, for a total of 28 days of double-blind treatment. Safety was evaluated from the first day of Run-In to the end of the study (primary safety outcome). Efficacy was evaluated by changes from randomization of HFMSE (primary efficacy outcome), quality of life, 6-minute walk test, and timed test (secondary outcomes). Descriptive analyses and a mixed effects linear model were used for statistic. Thirteen adult patients were included in the study, no serious adverse events (SAEs) attributed to Amifampridine were reported. Transient paresthesias (33,3%) were the only amifampridine-related AEs reported. Six patients for each sequence of treatment were randomized. Amifampridine treatment led to a statistically significant improvement in HFMSE (LS Mean Difference 0.792; 95% CI from 0.22 to 1.37; p=0.0083), compared to placebo, but not in the secondary endpoints. SMA-001 study provided Class I evidence that AP was safe and effective in treating ambulatory patients affected by SMA type 3.