Firdapse Oral Therapy Expected to Become LEMS’ Treatment of Choice, Review Says

Catarina Silva, MSc avatar

by Catarina Silva, MSc |

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Scientists believe Firdapse (amifampridine phosphate) will soon become first-line management therapy for Lambert-Eaton myasthenic syndrome (LEMS), due to its stability, low-dose variability, good tolerability, and effectiveness, a review says.

The study, “Amifampridine for the Management of Lambert-Eaton Myasthenic Syndrome: A New Take on an Old Drug,” was published in Annals of Pharmacotherapy.

The mainstay for symptomatic treatment of LEMS is 3,4-diaminopyridine (3,4-DAP). However, despite its long history as a LEMS first-line treatment, the therapy was never formally approved by the U.S. Food and Drug Administration (FDA). That was due to issues with variability, and reliability of the product between batches. Because of this, 3,4-DAP was modified into a salt formulation called amifampridine phosphate.

Firdapse, developed by Catalyst Pharmaceuticals, is an oral prescription therapy for patients age 17 and older for the symptomatic treatment of LEMS. It was cleared by the FDA less than a year ago, in November 2018. The treatment restores the communication between muscle cells, thus improving patients’ muscle function.

To learn more, researchers at the OhioHealth Riverside Methodist Hospital reviewed all available literature on both 3,4-DAP and amifampridine phosphate for the treatment of LEMS. They used three biomedical databases, and searched the literature for the following terms: “amifampridine,” “3,4-diaminopyridine,” and “Lambert-Eaton myasthenic syndrome.” Studies included in the review had to feature human subjects aged 18 or older, and be Phase 2 or 3 clinical trials.

Six clinical trials, including a total 105 participants, were used to evaluate the impact of varying doses of 3,4-DAP in LEMS.

In general, the therapy was seen to improve muscle function, as well as muscular strength, and reduce patients’ disability and disease severity. In some of the studies, 3,4-DAP was associated with adverse effects like lightheadedness and heavy headedness, epigastric discomfort (meaning “in the upper abdomen, below the ribcage but above the intestines”), seizures, and digital and perioral numbness or tingling sensation (paresthesia).

On the other hand, two placebo-controlled Phase 3 studies (NCT02970162 and NCT01377922) have confirmed amifampridine phosphate is well-tolerated and effective in managing disease symptoms. “No reported adverse effect in either trial was considered to be serious or attributed to treatment,” the researchers said.

Nonetheless, the treatment has been associated with a dose-dependent increased risk of seizures. As such, the therapy is contraindicated in people with a history of seizure activity.

Compared with 3,4-DAP, amifampridine phosphate has an improved stability profile and decreased dose variability, making it more attractive both for medication prescribers and LEMS patients. In pharmacology, stability refers to the extent to which a given medicine retains — within specified limits and throughout its period of storage and use — the same properties and characteristics that it possessed at the time of its manufacture.

“[A]mifampridine will likely assume the role of first-line management of LEMS,” the investigators said.

The recommended initial dose of amifampridine phosphate is 15 to 30 mg once a day, taken in three to four divided doses without regard to meals. Each single dose should not exceed 20 mg, and the maximum total daily dosage should be below 80 mg. That is due to therapy-related risk of seizures.

“Prior to the approval of Firdapse, 3,4-DAP was provided to patients at no cost by Jacobus Pharmaceuticals under a compassionate use program. Firdapse is now the only available formulation of 3,4-DAP and is estimated to cost more than $300000 annually,” the researchers said. ” With the approval of Firdapse, cost may be of concern because patients were previously receiving 3,4-DAP free of charge,” they added.

Nonetheless, “Practitioners should familiarize themselves with Firdapse because this agent is now the only available formulation of 3,4-DAP for adults,” the study concluded.