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The compound 3,4-diaminopyridine has the International Nonproprietary Name amifampridine and is used as a drug, predominantly in the treatment of a number of rare muscle diseases. Firdapse, the phosphate salt of amifampridine, is marketed in the EU by BioMarin Pharmaceutical and designated as an orphan medicine in the EU. In the United States, Firdapse is under investigation for the treatment of Lambert-Eaton myasthenic syndrome by Catalyst Pharmaceuticals, and was granted a breakthrough therapy designation by the FDA in 2013. In a Phase 3 clinical trial, Firdapse demonstrated superiority over placebo in both co-primary endpoints. LEMS patients can receive Firdapse at no cost under an ongoing expanded access program. A clinical trial of the free-base form of amifampridine has also been completed, by Jacobus Pharmaceutical Co. This form of amifampridine remains available at no cost to patients with Lambert-Eaton myasthenic syndrome and congenital myasthenic syndromes under a long-standing compassionate use program, with FDA oversight, from Jacobus Pharmaceutical Co. (see also Uses and Cost, below.)
In Lambert-Eaton syndrome, acetylcholine release is inhibited as antibodies meant to target certain cancers target Ca2+ channels on the prejunctional membrane instead. Amifampridine works by blocking potassium channel efflux in nerve terminals so that action potential duration is increased. Ca2+ channels can then be open for a longer time and allow greater acetylcholine release to stimulate muscle at the end plate. A 2011 systematic review from the Cochrane Collaboration found data favoring its use in LEMS. Although not approved for pharmaceutical use in the United States, amifampridine is available under compassionate use regulations for the treatment of Lambert-Eaton myasthenic syndrome (LEMS).
Amifampridine is also used to treat many of the congenital myasthenic syndromes, particularly those with defects in choline acetyltransferase, downstream kinase 7, and those where any kind of defect causes "fast channel" behaviour of the acetylcholine receptor. In the US, Firdapse is under development as an orphan drug for congenital myasthenic syndrome  and 3,4-diaminopyridine is available at no cost for patients with congenital myasthenic syndromes under a long-standing compassionate use program from Jacobus Pharmaceutical Co.
The licensing of Firdapse in 2010 led to a sharp increase in price for the drug. In some cases, this has led to hospitals using an unlicensed form rather than the licensed agent, as the price difference proved prohibitive. BioMarin has been criticized for licensing the drug on the basis of previously conducted research, and yet charging exorbitantly for it. A group of UK neurologists and pediatricians have petitioned to prime minister David Cameron in an open letter to review the situation. The company responded that it submitted the licensing request at the suggestion of the French government, and points out that the increased cost of a licensed drug also means that it is monitored by regulatory authorities (e.g. for uncommon side-effects), a process that was previously not present in Europe. In 2010, Biomarin company scientists published evidence that amifampridine should be the first-line treatment for LEMS.
In the United States, 3,4-diaminopyridine phosphate (Firdapse), a more stable formulation of amifampridine that does not require refrigeration, and 3.4-diaminopyridine free base have completed clinical trials to treat the Lambert-Eaton myasthenic syndrome (LEMS). Both formulations are available to LEMS patients in the U.S.: the free base is available to patients with LEMS and congenital myasthenic syndromes under a compassionate distribution program by Jacobus Pharmaceutical Company, and the phosphate salt is available to LEMS patients under an expanded access program by Catalyst Pharmaceuticals. Patients must be diagnosed with Lambert-Eaton myasthenic syndrome or congenital myasthenic syndrome and meet appropriate inclusion criteria.
Compounding pharmacies may also be a source of amifampridine in the U.S. In Europe, 3,4-diaminopyridine phosphate is sold by BioMarin under the name Firdapse, and the free base is compounded, usually by hospital pharmacies.
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- ANA presentation
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