Firdapse (amifampridine) is being developed by Catalyst Pharmaceuticals, along with BioMarin Pharmaceuticals. to treat a rare type of myasthenia gravis (MG) called MuSK-MG. People with MuSK-MG have antibodies in their blood against an enzyme called muscle-specific kinase (MuSK).
Although not yet been approved to treat MG, it has been sold in Europe since December 2009 as a therapy for Lambert-Eaton myasthenic syndrome (LEMS). The U.S. Food and Drug Administration granted orphan drug designation to Firdapse to treat MuSK-MG in September 2016.
How Firdapse works
To control muscle movement, the brain sends the muscles signals via nerve cells. At the neuromuscular junction between nerve and muscle cells, acetylcholine is released from nerve endings and binds to receptors on muscle cells. Acetylcholine is a type of neurotransmitter used to pass the signal. When enough acetylcholine interacts with receptors on muscle cells, a reaction is triggered in the muscle, causing it to contract.
In MuSK-MG, mistaken activation of the immune system against MuSK — which is essential for acetylcholine receptor clustering at the neuromuscular junction — can impair the muscle’s ability to pick up acetylcholine. This results in a loss of muscle control as well as weakness.
Acetylcholine is released from nerve cells during depolarization, when the electrical charge inside nerve cells rises in relation to outside the cells. One factor causing depolarization to end is positively charged potassium ions leaving the cell. By blocking potassium channels on the nerve cells, Firdapse prolongs depolarization and increases the duration of acetylcholine release. This results in more acetylcholine being present at the neuromuscular junction for a longe time, increasing the chance that a muscle contraction will be correctly stimulated.
Firdapse in clinical trials
It has been and is still being investigated in multiple clinical trials for several conditions including LEMS and congenital myasthenic syndrome. For example, a completed Phase 3 trial (NCT02970162) demonstrated that Firdapse significantly improved the symptoms of muscle weakness in LEMS patients.
In March 2017, Catalyst announced results of a proof-of-concept trial investigating Firdapse to treat MuSK-MG . The trial, registered with the EU Clinical Trials Register (2015-003127-62) was a randomized, double-blind, placebo-controlled study in Italy. Changes in Quantitative Myasthenia Gravis (QMG) and Myasthenia Gravis Activities of Daily Living (MG-ADL) scores were used as primary endpoints. Results suggested that Firdapse could benefit patients, who showed a statistically and clinically significant improvement in their scores after treatment with Firdapse compared to placebo.
This year, Catalyst will recruit 60 participants for a Phase 3 study (NCT03304054) at multiple U.S. sites to assess the safety and efficacy of Firdapse in MuSK-MG. Patients will receive either Firdapse or placebo three times a day, for 10 days. The main aim will be to determine whether Firdapse significantly improves the daily lives of patients, measured through the change in MG-ADL scale after 10 days. It will also assess the effect of Firdapse in a small sample of patients with a more common form of MG called AChR-MG, in which the body produces antibodies directly against the acetylcholine receptors.
The most common side effects linked to Firdapse are the sensation of pins and needles, as well as gastrointestinal problems such as stomach pain, diarrhea and nausea.
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