Ruzurgi (amifampridine, also called 3,4-diaminopyridine or 3,4-DAP) developed by Jacobus Pharmaceuticals is the first treatment approved by the U.S. Food and Drug Administration (FDA) to treat patients with Lambert-Eaton myasthenic syndrome, ages 6 to 16.
What is LEMS?
LEMS is a rare autoimmune disease in which the immune system generates autoantibodies against a protein called voltage-gated calcium channel (VGCC) in the nerve cell endings.
Normally, when the brain sends a nerve signal to muscles, the signal is sent as a depolarization of the nerve cells: ions flood in and out of the nerve cell, changing the ratio of charged particles in the cell, and thus, its electrical charge.
When this depolarization reaches the neuromuscular junction or the point where the nerve cell and muscles meet, this electrical signal is converted into a chemical signal; when the charge reaches the VGCC, the channel opens, allowing calcium to enter the nerve cell and cause the release of acetylcholine (a neurotransmitter or cell signaling molecule) into the neuromuscular junction.
Acetylcholine binds to its receptors on the other side of the junction, initiating a cascade of events that makes the muscles move. After the nerve signal has been sent, voltage-gated potassium channels on the nerve cell open and “reset” the nerve, which closes the VGCC, stopping the flow of calcium into the nerve cell and preparing it for the next signal from the brain.
In LEMS, nerve cells have many fewer VGCC molecules as a result of the attack by the immune system, meaning that little acetylcholine is released in response to nerve signals. Without sufficient stimulation from the nerve cells, muscles weaken over time.
How does Ruzurgi work?
Ruzurgi contains a small molecule (amifampridine) that binds to the voltage-gated potassium channels. By blocking these channels, Ruzurgi prevents the nerve cell from resetting after a nerve signal has been sent, and gives the nerve cell more time for the small number of VGCCs that remain to stay open. Even with fewer channels, the increase in calcium transported can increase the amount of acetylcholine that’s released from the nerve cell endings, and thereby increase muscle strength.
Ruzurgi in clinical trials
The decision to approve Ruzurgi for children with LEMS was based on clinical data collected from adult patients, combined with simulations to find the best dose for children. The data were collected from a Phase 2 clinical trial (NCT01511978) called DAPPER. The trial included 32 adult LEMS patients who had been taking Ruzurgi for at least three months as part of an FDA-approved compassionate use program. Patients were randomly assigned to either continue treatment with Ruzurgi at a dose of 30 to 100 mg daily (divided into three doses) or to a placebo.
The results of the trial were evaluated using the triple timed-up-and-go (3TUG) test, which measures the time it takes a patient to rise from a chair, walk a short distance, and return to the chair three times without pause. The results showed that patients who remained on Ruzurgi were able to perform the tasks in less time than those who were taking the placebo.
Ruzurgi may cause serious side effects, including seizures and allergic reactions. The most common side effects are stomach pain, indigestion, dizziness, and nausea.
Last updated: Oct. 30, 2019
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