Amifampridine Fails to Beat Placebo in AChR-Positive MG

Key Takeaways

• Neither the 30-mg nor the 60-mg regimen was associated with a significant MGII improvement versus placebo.
• No statistically significant association was observed between pharmacokinetic parameters and MGII.
• Adverse events were more common with amifampridine, no serious adverse events were reported, and the authors concluded add-on therapy was not superior to pyridostigmine alone.

In the 20-patient randomized crossover IMPACT-MG trial, add-on amifampridine modified release did not show a significant MGII advantage over placebo in acetylcholine receptor antibody-positive myasthenia gravis on background pyridostigmine. Patients continued pyridostigmine during short, double-blind crossover treatment periods comparing active regimens with placebo. Adverse events were more common with active treatment, and the crossover results did not show a clear efficacy signal.

This randomized, double-blind, placebo-controlled crossover trial was conducted at Leiden University Medical Center, a tertiary myasthenia gravis center in the Netherlands, as part 2 of IMPACT-MG. Eligible patients had acetylcholine receptor antibody-positive myasthenia gravis with insufficient symptom control on pyridostigmine, had completed part 1 or failed the initial 2-day washout, and had MGII scores above 10. Participants were randomized 1:1:1 to 1 of 3 treatment sequences involving 30 mg amifampridine modified release, 60 mg amifampridine modified release, and placebo. Each treatment period lasted 5 days, followed by a 2-day washout, and MGII was the primary outcome.

For MGII, the estimated mean difference versus placebo was −1.0 with 30 mg (95% CI, −4.1 to 2.0; p=0.681) and −1.7 with 60 mg (95% CI, −4.7 to 1.4; p=0.379). Neither comparison reached statistical significance. No statistically significant association was observed between pharmacokinetic parameters and MGII.

Safety and tolerability were assessed throughout the crossover periods. Adverse events were reported in 12 of 20 patients receiving 30 mg, 15 of 20 receiving 60 mg, and 6 of 20 receiving placebo. No serious adverse events were reported during the crossover periods. Three patients discontinued amifampridine early because of adverse events. The most frequently reported events were paresthesia, fatigue, numbness, dizziness, and sleep disturbances.

The authors concluded that adding amifampridine to pyridostigmine was not superior to pyridostigmine alone and was associated with a higher incidence of adverse events.