Regulatory Decision Summary for Firdapse

Lambert-Eaton Myasthenic Syndrome (LEMS) is a rare autoimmune disease affecting the neuromuscular junction and characterized by proximal weakness and autonomic dysfunction. There is currently no approved treatment for LEMS.

The mechanism by which amifampridine exerts its therapeutic effect in LEMS patients has not been fully elucidated. In vitro, amifampridine at high concentrations is a voltage-gated potassium (K+) channel blocker.

The sponsor submitted two randomized, double-blind, withdrawal studies to support the safety and efficacy of Firdapse for the symptomatic treatment of LEMS in adults. The double-blind periods for these studies were 14 and 4 days, respectively. Study 1 was followed by a 2-year open-label safety study. The two co-primary endpoints in both pivotal studies were the change from baseline to the end of the discontinuation period in the Quantitative Myasthenia Gravis (QMG) and in the Subject Global Impression (SGI) scores. The QMG is a 13-item physician-rated categorical scale assessing muscle weakness. The SGI is a 7-point scale on which patients rate their global impression of the effects of the study treatment on their physical well-being.

In study 1, patients were individually dosed to efficacy and tolerability during an initial open-label run-in phase. Then, patients (n = 38) were randomized to either continue treatment with Firdapse (n = 16) or to a downward titration to placebo (n = 22) over 7 days. Efficacy was assessed at day 14 of the double-blind discontinuation period. There was statistically significant greater worsening in the QMG and SGI scores in the placebo group compared to the Firdapse group, between baseline and day 14.

In study 2, patients were enrolled from an open-label expanded access program on stable treatment with Firdapse, randomized 1:1 in a double-blind fashion to either continue treatment with Firdapse (n = 13) or change to placebo (n = 13) for 4 days. Efficacy was assessed at the end of the 4-day double-blind discontinuation period. From baseline to day 4, there was statistically significantly greater worsening in the QMG and SGI scores in the placebo group compared to the Firdapse group.

The overall results of the randomized withdrawal studies were positive: the patients randomized to placebo had a statistically significant greater worsening of muscle weakness and of global impression of the effects of the study treatment on their physical well-being, compared to patients who continued on Firdapse.

The most commonly reported (>10%) adverse reactions for both healthy individuals and LEMS patients receiving Firdapse in clinical studies included peripheral and perioral paresthesia, dizziness, headache, and oral hypoesthesia. Serious adverse events associated with Firdapse include the occurrence of seizures and QT-prolongation. Significant safety uncertainties with Firdapse include risk of schwannomas detected in rat carcinogenicity studies, the potential risk for respiratory adverse events such as worsening of asthma symptoms and the lack of data in patients with any degree of hepatic impairment. Adverse events are more frequent and serious in N-acetyltransferase 2 (NAT2) slow acetylators. The adverse events associated with Firdapse have been labelled in the Product Monograph (PM).

Considering the supporting data, the serious and orphan nature of LEMS, and limited treatment options, the benefit-harm-uncertainty profile of Firdapse is considered positive.

For more information on Health Canadas decision, please view the Summary Basis of Decision.