Efficacy and Safety of Amifampridine in Myasthenia Gravis: A Randomized, Double-Blind, Placebo-Controlled Crossover Trial

Clinical Snapshot

Key Findings

• P Value: 30mg: p=0.681; 60mg: p=0.379

• Effect Size: 30mg: -1.0 points; 60mg: -1.7 points (both non-significant)

• Primary Outcome: MGII score difference between amifampridine and placebo

• Nnt Or Sensitivity: Not applicable - no significant benefit demonstrated

• Confidence Interval: 30mg: -4.1 to 2.0; 60mg: -4.7 to 1.4

Clinical Application

Limited by high adverse event rate (60-75%) and lack of efficacy benefit Results applicable to Australian MG patients; amifampridine available through Special Access Scheme but this study suggests limited benefit as add-on therapy in MG AChR-positive myasthenia gravis patients with inadequate response to pyridostigmine monotherapy

Abstract

BACKGROUND AND OBJECTIVES: Amifampridine, a short-acting potassium-channel blocker, is the first-line treatment for Lambert-Eaton myasthenic syndrome. Its benefit as add-on to pyridostigmine in acetylcholine receptor (AChR)-positive myasthenia gravis (MG) has been proposed, but no randomized controlled trials have been conducted. We aimed to evaluate the efficacy and safety of amifampridine in AChR-MG with insufficient symptom control on pyridostigmine. METHODS: A randomized, double-blind, placebo-controlled crossover trial was conducted at Leiden University Medical Center, a tertiary center for the treatment of MG in the Netherlands, as part 2 of the IMPACT-MG trial. Eligible patients had either completed part 1 (pyridostigmine vs placebo) or failed the initial 2-day pyridostigmine washout, and had an Myasthenia Gravis Impairment Index (MGII) score >10. Participants were randomized (1:1:1) to 1 of 3 treatment sequences. Each treatment period lasted 5 days, with a 2-day washout between treatments, during which participants received either 30 mg or 60 mg of amifampridine modified release, or placebo. The primary outcome was the difference in MGII score between the 2 amifampridine dosages and placebo. Pharmacokinetics, safety, and tolerability were assessed throughout the trial. RESULTS: Between March 2023 and April 2024, 20 patients were enrolled (median age 60 years, 55% female). For the MGII score, the estimated mean differences were -1.0 (95% CI -4.1 to 2.0, p = 0.681) for amifampridine 30 mg vs placebo and -1.7 (95% CI -4.7 to 1.4, p = 0.379) for amifampridine 60 mg vs placebo. No statistically significant association was observed between pharmacokinetic parameters and the MGII. No serious adverse events were reported. Adverse events were more common with amifampridine 30 mg (12 patients [60%]) and 60 mg (15 patients [75%]), compared with placebo (6 patients [30%]), with paresthesia, fatigue, numbness, dizziness, and sleep disturbances most frequently reported. Three patients discontinued amifampridine early due to adverse events. DISCUSSION: The addition of amifampridine to pyridostigmine was not superior to treatment with pyridostigmine alone and was associated with a higher incidence of adverse events. TRIAL REGISTRATION INFORMATION: The trial was registered at EudraCT (2021-004110-20, registration date: July 12, 2022) and ClinicalTrials.gov (NCT05919407, registration date: June 16, 2023). First patient enrolled: March 23, 2023. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that in patients with AChRAb+ MG, the addition of amifampridine to pyridostigmine was not superior to treatment with pyridostigmine alone and was associated with a higher incidence of adverse events.

References

1. 1.Remijn-Nelissen, L., Bakker, W. R., van Gelder, T., Moes, D. J. A. R., Ruiter, A. M., Campman, Y. J. M., Badrising, U. A., Straathof, C. S. M., Verschuuren, J. J. G. M., & Tannemaat, M. R. (2026). Efficacy and Safety of Amifampridine in Myasthenia Gravis: A Randomized, Double-Blind, Placebo-Controlled Crossover Trial. Neurology. https://doi.org/10.1212/WNL.0000000000214715