Amifampridine Phosphate

An Important Milestone

Amifampridine phosphate has been granted “orphan drug designation” by the FDA for the treatment of patients with Lambert-Eaton myasthenic syndrome (LEMS), congenital myasthenic syndromes (CMS), and MuSK-positive myasthenia gravis (MuSK-MG). The FDA has also designated amifampridine phosphate as a Breakthrough Therapy in the treatment of LEMS. Also, there is an ongoing investigational program for amifampridine phosphate in the treatment of patients with spinal muscular atrophy (SMA).

The European Medicines Agency (EMA) has approved amifampridine phosphate in the treatment of LEMS, and the European Federation of Neurological Societies recommends amifampridine phosphate as a first-line treatment for patients with LEMS. In the United States, amifampridine phosphate has undergone a rigorous clinical development program and has demonstrated safety and efficacy in 2, randomized, double-blind, placebo-controlled phase 3 trials.

Catalyst has undertaken the clinical development of amifampridine phosphate, a stable salt form of the amifampridine base compound, in order to provide patients access to a well-studied and consistent product. This novel formulation allows for storage and transportation at room temperature and will be produced using Good Manufacturing Practices (GMP).

Mechanism of Action

Amifampridine phosphate is a nonspecific, voltage-dependent, potassium (K+) channel blocker that causes depolarization of the presynaptic membrane and slows or inhibits repolarization. This action results in the opening of slow voltage-dependent calcium (Ca2+) channels, allowing for a subsequent influx of Ca2+. In turn, it induces the exocytosis of synaptic vesicles containing ACh to release more ACh into the synaptic cleft, enhancing neuromuscular transmission, and providing for improved muscle function.

History

In October 2012, Catalyst announced a strategic collaboration with BioMarin Pharmaceuticals, Inc., which included the in-licensing of the North American rights to amifampridine phosphate and responsibility for its clinical development program. Amifampridine phosphate had previously received orphan medicinal product designation by the European Union (EU) and has been marketed in the European Commission (EC) for the treatment of LEMS since 2010.

Amifampridine phosphate is an investigational product and is NOT currently available commercially in the United States.

To date, support for the clinical efficacy of amifampridine phosphate for treatment of patients with LEMS has been documented in several published randomized, double-blind, placebo-controlled studies and one double-blind study with an active comparator in patients with LEMS. Data from the randomized controlled studies demonstrate statistically significant improvements across a number of independent measures of neurological function, including Quantitative Myasthenia Gravis (QMG) score and compound muscle action potential (CMAP), which have been demonstrated to be clinically relevant in patients with LEMS.

In 2018, Catalyst will file a new drug application (NDA) with the FDA for amifampridine phosphate, seeking approval for its use in LEMS and CMS.

Publications

For more information about amifampridine phosphate, please choose from the list of clinical publications and reviews below.

Oh SJ and Sieb JP. Update on Amifampridine as a Drug of Choice in Lambert-Eaton Myasthenic Syndrome. US Neurology. 2014; 10(2): i-vii Go to publication

Oh SJ, Shcherbakova N, Kostera-Pruszczyk A, et al. Amifampridine phosphate (Firdapse®) is effective and safe in a phase 3 clinical trial in LEMS. Muscle Nerve. 2016;53(5):717-725. Go to publication

Lindquist S, Stangel M. 3,4-Diaminopyridine (amifampridine) for the treatment of Lambert–Eaton myasthenic syndrome. Expert Opin Orph Drugs. 2014; 2(3):293-300. Go to publication

Sedehizadeh S, Keogh M, Maddison P. The use of aminopyridines in neurological disorders. Clin Neuropharmacol. 2012; 35(4):191-200. Go to publication

Harms L, Sieb JP, Williams AE, et al. Long-term disease history, clinical symptoms, health status, and healthcare utilization in patients suffering from Lambert Eaton myasthenic syndrome: Results of a patient interview survey in Germany. J Med Econ. 2012; 15(3):1-10. Go to publication

Green DM, Jones AC, Brain KR. Content variability of active drug substance in compounded oral 3,4-diaminopyridine products. J Clin Pharm Ther. 2012; 37:53–7. Go to publication

Lindquist S and Stangel M. Update on treatment options for Lambert–Eaton myasthenic syndrome: focus on use of amifampridine  Neuropsychiatr Dis Treat. 2011;7(1):341–349. Go to publication

Quartel A, Turbeville S, Lounsbury D. Current therapy for Lambert-Eaton myasthenic syndrome: development of 3,4-diaminopyridine phosphate salt as first-line symptomatic treatment. Curr Med Res Opin. 2010; 26(6):1363-75. Go to publication

Raust JA, Goulay-Dufaÿ S, Le Hoang MD, et al. Stability studies of ionised and non-ionised 3,4-diaminopyridine: hypothesis of degradation pathways and chemical structure of degradation products. J Pharm Biomed Anal. 2007; 43(1):83-8. Go to publication