Amifampridine for myasthenia gravis

Last updated Oct. 22, 2024, by Joana Carvalho, PhD
Fact-checked by Inês Martins, PhD

What is amifampridine for myasthenia gravis?

Amifampridine is an oral therapy that was being explored by Catalyst Pharmaceuticals as a symptomatic treatment for certain myasthenia gravis (MG) patients. Its development for MG was halted after a Phase 3 clinical trial failed to meet its goals.

The company was specifically developing amifampridine for patients who carried antibodies against the muscle-specific kinase (MuSK) protein, the second most common type of MG-causing antibody. Catalyst concluded that an approval of amifampridine as a first-line treatment for MuSK-MG was unlikely based on data from the Phase 3 trial and input from regulatory authorities and advisors, leading the company to decide not to continue to pursue this indication.

Amifampridine is approved under the brand name Firdapse for treating Lambert-Eaton myasthenic syndrome (LEMS), a rare autoimmune condition marked by impairments in nerve-muscle communication.

Therapy snapshot

How does amifampridine work in myasthenia gravis?

MG is a rare neuromuscular disease in which a person’s immune system produces self-reactive antibodies that mistakenly attack proteins involved in nerve-muscle communication. In most cases, these autoantibodies target acetylcholine receptors (AChRs) found on the surface of muscle cells. Less commonly, patients have antibodies that target another protein called MuSK, which plays a key role in clustering and anchoring AChRs to the neuromuscular junction, the region where nerve cells and muscles communicate to coordinate voluntary movements.

AChRs normally respond to a cell signaling molecule called acetylcholine, which is sent from nerve cells to muscle cells to instruct them to contract. Both anti-MuSK and anti-AChR antibodies can alter, block, or destroy the activity of those receptors, disrupting the communication between nerves and muscles, and leading to the typical MG symptoms of muscle weakness and fatigue.

Amifampridine is a small molecule that nonspecifically blocks certain potassium channels on nerve cells, which helps keep nerve cells “switched on” for an extended period of time after sending a signal. This extra time allows cells to release more acetylcholine into the neuromuscular junction, which was expected to help increase muscle strength.

How was amifampridine administered in myasthenia gravis?

In clinical trials involving MG patients, amifampridine was given in the form of oral tablets. Total daily dosages ranged from 30-100 mg and were divided into doses taken three to four times per day.

Amifampridine in myasthenia gravis clinical trials

Amifampridine has been tested in a couple of clinical trials involving people with MuSK-MG. Its clinical development for this indication was stopped after a Phase 3 clinical trial failed to demonstrate the therapy’s ability to provide clear clinical benefits over a placebo, however.

MuSK-001 trial

A proof-of-concept Phase 2b clinical trial called MuSK-001 (EudraCT 2015-003127-62) assessed the safety, tolerability, and potential efficacy of amifampridine as a symptomatic treatment for patients with MuSK-MG.

The trial enrolled seven adult patients. After a run-in period in which amifampridine’s effective dose was determined for each patient (total daily dosages ranging from 30-100 mg), all the participants were randomly assigned to receive amifampridine or a placebo in divided doses taken three to four times a day for one week. Then, for another week, the patients originally assigned to amifampridine switched to placebo and vice versa. In a final treatment period, patients switched treatments again to their originally assigned group for another week. After completing all three treatment periods, patients stopped taking amifampridine or the placebo and were followed for another week.

The study’s main goals were to assess safety, as well as changes in MG Activities of Daily Living (MG-ADL), a patient-reported measure of MG severity, and Quantitative MG (QMG), a clinician-reported measure of disease severity. Secondary measures such as fatigue, quality of life, and other measures of disease severity were also assessed.

Across all treatment periods, MG-ADL and QMG scores were significantly higher, meaning worse, when patients were receiving a placebo than when they were being treated with amifampridine. Similar observations were made for other measures of MG severity. Fatigue and quality of life worsened while patients were on a placebo, but amifampridine significantly improved these measures.

Amifampridine was generally safe and well tolerated. The only side effects associated with its use were mild temporary paresthesias (numbness, tingling, or burning sensations) in the limbs and around the mouth.

MSK-002 trial

Promising findings from the proof-of-concept Phase 2b study prompted the launch of a Phase 3 clinical trial called MSK-002 (NCT03304054), which focused on evaluating amifampridine in a larger group of about 93 MuSK-MG patients.

The participants were randomly assigned to receive 10 mg tablets of amifampridine, upped to an effective and tolerable dose, or a matching placebo, three to four times daily for 10 days. Changes in MG-ADL and QMG scores were assessed as the study’s primary and secondary goals, respectively.

Top-line data announced in August 2020 showed the trial failed to meet both goals, with no statistically significant differences in MG-ADL or QMG scores seen between the two treatment groups. These negative results ultimately led Catalyst to stop the development of amifampridine for MuSK-MG.

Amifampridine was also deemed safe and well tolerated in MSK-002, with the therapy’s safety profile in MG patients being similar to that in LEMS patients.

Common side effects of amifampridine

The most common side effects associated with the use of amifampridine by MG patients were paresthesias. The therapy’s specific safety profile in this patient population was never fully disclosed, however.

In people with LEMS, an indication for which amifampridine is approved, common side effects include paresthesia, upper respiratory tract infection, abdominal pain, nausea, diarrhea, headache, high levels of liver enzymes, back pain, high blood pressure, and muscle spasms.

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