Firdapse and Ruzurgi are Safe and Effective Options to Treat LEMS, Review Finds

Firdapse and Ruzurgi are Safe and Effective Options to Treat LEMS, Review Finds

Treatment with Firdapse (Amifampridine phosphate) or Ruzurgi (3,4‐diaminopyridine, or 3,4‐DAP) is effective and well-tolerated among people with Lambert-Eaton myasthenic syndrome (LEMS), even in the presence of immunosuppressants or other medications that alter the responsiveness of the immune system, a review has found.

The review study, “Amifampridine tablets for the treatment of Lambert-Eaton myasthenic syndrome,” was published in Expert Review of Clinical Pharmacology.

LEMS is an autoimmune disease that affects the neuromuscular junction — the region where motor neurons and muscle fibers communicate — leading to muscle weakness, reduced reflexes, and high fatigability.

Treatment with 3,4‐DAP has become standard for LEMS in the E.U. and the U.S. since the 1980s, helping to restore communication between muscle cells in patients. It’s marketed under the brand name Ruzurgi, developed by Jacobus Pharmaceutical.

A more stable salt formulation of 3,4‐DAP called amifampridine phosphate — sold under the brand name Firdapse by Catalyst Pharmaceuticals — has been named an orphan drug for the treatment of LEMS. It was approved first by the European Medicines Agency in 2010, and then by the U.S. Food and Drug Administration in 2018.

The review study focused on summarizing the main findings of published studies that investigated the safety and effectiveness of amifampridine phosphate or 3,4‐DAP for the treatment of people with LEMS.

After performing a thorough literature search in the Medline database looking for studies published between 1990 and 2019, researcher Renato Mantegazza, from the Fondazione IRCCS Istituto Neurologico “Carlo Besta” in Italy, described the main findings of four Phase 2 and three Phase 3 clinical trials testing the effects of amifampridine phosphate or 3,4‐DAP in patients with LEMS.

Between 1989 and 2009, four randomized Phase 2 trials were performed to assess the effects of 3,4‐DAP in people with LEMS. In all cases, the medication led to significant improvements in muscle function when administered at an average dose of 40 mg, subdivided into three to four daily administrations.

One of the studies also reported significant improvements in the quantitative myasthenia gravis score, a test that measures the degree of muscle weakness; and three studies found improvements on the compound muscle action potential, a test that measures muscle conduction.

Subsequent Phase 3 trials (NCT01377922; NCT01511978; NCT02970162) confirmed the effectiveness of amifampridine phosphate and 3,4‐DAP in ameliorating muscle function in people with LEMS.

One of the Phase 3 studies called DAPPER (NCT01511978) also reported that patients who gradually discontinued treatment with 3,4‐DAP — after taking the medication for at least three months — experienced a significant degradation of muscle function (defined as having a decline higher than 30% in the triple timed up-and-go test since their last examination).

Treatment side effects were negligible, and no serious adverse events were reported in any of the trials analyzed. Moreover, findings indicated that the effectiveness of both amifampridine phosphate and the base formulation of 3,4‐DAP were similar, provided that 3,4‐DAP was properly prepared before being administered to patients.

“Both the phosphate and the base formulations have provided class I evidence of efficacy on the basis of clinical trials, but direct comparison has not been performed, (…) hence no possibility exists to claim any difference between them,” Mantegazza said.

“The possibility of using amifampridine in disease of the NMJ [neuromuscular junction] different from LEMS, such as (…) MG [myasthenia gravis], open a therapeutic window for these diseases that either have no specific drug or are insufficiently treated with the conventional therapies of MG,” he added.

Joana holds a BSc in Biology and a MSc in Evolutionary and Developmental Biology from Universidade de Lisboa. She is currently finishing her PhD in Biomedicine and Clinical Research at Universidade de Lisboa. Her work has been focused on the impact of non-canonical Wnt signaling in the collective behavior of endothelial cells — cells that made up the lining of blood vessels — found in the umbilical cord of newborns.
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Margarida graduated with a BS in Health Sciences from the University of Lisbon and a MSc in Biotechnology from Instituto Superior Técnico (IST-UL). She worked as a molecular biologist research associate at a Cambridge UK-based biotech company that discovers and develops therapeutic, fully human monoclonal antibodies.
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Joana holds a BSc in Biology and a MSc in Evolutionary and Developmental Biology from Universidade de Lisboa. She is currently finishing her PhD in Biomedicine and Clinical Research at Universidade de Lisboa. Her work has been focused on the impact of non-canonical Wnt signaling in the collective behavior of endothelial cells — cells that made up the lining of blood vessels — found in the umbilical cord of newborns.
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