Firdapse (amifampridine) is the first and only oral therapy available for the symptomatic treatment of patients age 17 and older with Lambert-Eaton myasthenic syndrome (LEMS), a rare autoimmune disease.

How Firdapse works

LEMS develops because the body makes autoantibodies against a protein called voltage-gated calcium channels (VGCC) found at the ends of nerve cells. This prevents the nerve cells from taking up calcium, which is required for releasing vesicles containing a neurotransmitter or cell-signaling molecule called acetylcholine into the neuromuscular junction, the point where nerve and muscle cells meet. It is through acetylcholine that nerve cells communicate with muscle cells and control their movement.

Firdapse is a small molecule drug that non-specifically blocks another protein channel found on nerve cells called voltage-dependent potassium channels. This causes the opening of any remaining healthy VGCC, allowing the influx of calcium ions into the nerve cells. The calcium ions bind to the synaptic vesicles that contain acetylcholine and induce their release into the neuromuscular junction. This potentially restores the acetylcholine that is required for the transmission of nervous signals to the muscles and improves muscle function in LEMS patients.

Firdapse in clinical trials

In a study published in the journal Muscle & Nerve, LEMS patients were treated for seven to 91 days with Firdapse followed by randomization for 14 days into Firdapse or placebo. Patients were analyzed for changes in quantitative myasthenia gravis (QMG) and subject global impression (SGI) scores from baseline. QMG is a 13-item grading scale where a physician grades the patient for parameters related to eye, brain, respiratory, and limb functions. SGI score represents a seven-point scale where the patient rates the global impression of the effects of the study treatment. The results showed that Firdapse was well-tolerated by LEMS patients and there were significant improvements in both QMG and SGI scores on day 14 compared to baseline.

A study published in Clinical Pharmacology and Therapeutics reported the results of a randomized, placebo-controlled, double-dummy, crossover study in nine patients with LEMS. The study compared the efficacy of Firdapse and pyridostigmine, either alone or in combination, and in comparison with a placebo. The effects of the treatments on muscle strength were measured by determining the isometric strength of the hip flexion muscle. Their effects on nerve stimulation were determined using the compound muscle action potential (CMAP) amplitudes of the hand muscles. These parameters were measured every 20 minutes for up to 170 minutes after administration of the treatments. Muscle strength and CMAP amplitude increased significantly with Firdapse alone and the combined treatment compared with the placebo, but not with pyridostigmine alone. No significant benefits were obtained in the combination treatment compared with Firdapse alone. These results further demonstrated the effectiveness of Firdapse in the treatment of LEMS.

A Phase 2, multi-center, randomized, double-blind, placebo-controlled study (NCT01511978) called DAPPER was performed in 32 participants to further assess the safety and efficacy of Firdapse. The participants had to be on a stable regimen of LEMS-related treatments, including Firdapse, for at least three months prior to the study. They were randomized in a 1:1 ratio either to continue treatment or to receive placebo for four days. They were then assessed using the triple timed up-and-go (3TUG) walking test. The 3TUG walking test is a simple, non-invasive test of functional mobility where the patient is asked to stand up from a straight-backed armchair, walk three meters, turn around, walk back, and sit down in the chair. This is repeated three times. The patient’s 3TUG time is an average of the three lap times. The results of this trial were published in the journal Muscle & Nerve and showed that while none of the 14 participants who received continuous Firdapse treatment showed significant deterioration in the 3TUG test, 72 percent of the 18 participants who received placebo did. This study provided evidence that Firdapse is effective in maintaining muscle strength in LEMS patients.

Another Phase 3 randomized, double-blind, placebo-controlled trial (NCT02970162) was conducted in 26 adults with LEMS to analyze the efficacy of Firdapse over a four-day period. The participants were on an optimal dose of Firdapse for at least one week before the study. After baseline measurements on day 0, the patients were randomly assigned to either continue on Firdapse or receive placebo from day 1 to day 3. They were then assessed after taking their medication on day 4. The results of the study, published in the Journal of Clinical Neuromuscular Disease, showed significant benefits of Firdapse treatment over placebo in all parameters analyzed. These included primary outcome measures such as QMG and SGI scores, and secondary measures such as the 3TUG test and clinical global impression-improvement (CGI-I) score, where a physician grades changes in symptoms, behavior, and functional abilities on a seven-point scale. Mild adverse events such as back pain, pain in the arms and legs, or headaches were noted in those being treated with Firdapse, whereas those on placebo reported some fatigue and muscle weakness, which was expected because of withdrawal from Firdapse for four days.  This study provided further evidence that Firdapse is effective in the symptomatic treatment of LEMS.

Another Phase 3 multi-center, double-blind, placebo-controlled, randomized study (NCT01377922) was conducted in 38 participants. Changes from baseline were analyzed at day 14 for both the Firdapse treatment and placebo groups. The primary outcome measures were QMG and SGI scores; the secondary outcome measures included the timed 25-foot walking test (T25FW) and CGI-I scores. The T25FW test is a quantitative mobility and leg function test where a patient is directed to walk a marked 25-foot course as quickly as possible, then walk back. The average time for the two 25-foot walks is calculated before and after treatments. The Firdapse treatment group demonstrated statistically significant changes in all the measures analyzed compared with the placebo group.

An expanded access open protocol (NCT02189720) is available for LEMS patients, age 2 and older, to receive Firdapse until the treatment is commercially available, and to study the long-term effects of the treatment. This study is intended to establish the safety and efficacy of Firdapse in children, which has not yet been confirmed.

Other information

Firdapse was originally developed by BioMarin Pharmaceuticals and approved by the European Commission (EC) in 2009 for commercial use in Europe. Its licensing rights for drug development and commercialization in North America have belonged to Catalyst Pharmaceuticals since October 2012. Catalyst Pharma amended its license agreement for Firdapse to expand its commercial territory to Japan in May 2019.

The U.S. Food and Drug Administration (FDA) approved the treatment for use in adult patients in November 2018.

 

Last updated: July 22, 2019

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