On occasion, these problems can be life threatening when the weakness involves respiratory muscles. Around 50% of those with LEMS have an underlying malignancy, most commonly small cell lung cancer. LEMS is therefore regarded as a paraneoplastic syndrome (a condition that arises as a result of cancer elsewhere in the body).
CORAL GABLES, Fla., July 22, 2015 (GLOBE NEWSWIRE) — Catalyst Pharmaceuticals, Inc. (Nasdaq:CPRX), a biopharmaceutical company focused on developing and commercializing innovative therapies for people with rare debilitating diseases, today announced the initiation of a rolling submission of a New Drug Application (NDA) to the United States (U.S.) Food and Drug Administration (FDA) for Firdapse® […]
|AHFS/Drugs.com||UK Drug Information|
|Metabolism||Acetylation to 3-N-acetylamifampridine|
2.5 hrs (amifampridine)|
4 hrs (3-N-acetylamifampridine)
|Excretion||Renal (19% unmetabolized, 74–81% 3-N-acetylamifampridine|
|Chemical and physical data|
|Molar mass||109.13 g·mol−1|
|3D model (JSmol)|
|Melting point||218 to 220 °C (424 to 428 °F) decomposes|
|Solubility in water||24 mg/mL (20 °C)|
|Y (what is this?)|
Amifampridine (pyridine-3,4-diamine, 3,4-diaminopyridine, 3,4-DAP) is used as a drug, predominantly in the treatment of a number of rare muscle diseases. The free base form of the drug has been used to treat congenital myasthenic syndromes and Lambert–Eaton myasthenic syndrome (LEMS) through compassionate use programs since the 1990s and was recommended as a first line treatment for LEMS in 2006, using ad hoc forms of the drug, since there was no marketed form.
Around 2000 doctors at Assistance Publique – Hôpitaux de Paris created a phosphate salt form, which was developed through a series of companies ending with BioMarin Pharmaceutical which obtained European approval in 2009 under the trade name Firdapse, and which licensed the US rights to Catalyst Pharmaceuticals in 2012. As of January 2017, Catalyst and another US company, Jacobus Pharmaceuticals, which had been manufacturing the free base form and giving it away for free since the 1990s, were racing to obtain FDA approval for their versions first; the company that obtained the approval would have seven years of marketing exclusivity.
Amifampridine is 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. It is also used to treat psoriasis. It is also used to treat symptoms of Lambert–Eaton myasthenic syndrome.
Because it affects voltage-gated ion channels, it is contraindicated in people with long QT syndrome and in people taking a drug that might prolong QT like sultopride, disopyramide, cisapride, domperidone, rifampicin or ketoconazol. It is also contraindicated in people with epilepsy or badly controlled asthma.
Mechanism of action
In Lambert–Eaton myasthenic syndrome, acetylcholine release is inhibited as antibodies involved in the host response against certain cancers cross-react with Ca2+ channels on the prejunctional membrane. 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.
Amifampridine is quickly and almost completely (93–100%) absorbed from the gut. In a study with 91 healthy subjects, maximum amifampridine concentrations in blood plasma were reached after 0.6 (±0.25) hours when taken without food, or after 1.3 (±0.9) hours after a fatty meal, meaning that the speed of absorption varies widely. Biological half-life (2.5±0.7 hrs) and the area under the curve (AUC = 117±77 ng∙h/ml) also vary widely between subjects, but are nearly independent of food intake.
The substance is deactivated by acetylation via N-acetyltransferases to the single metabolite 3-N-acetylamifampridine. Activity of these enzymes (primarily N-acetyltransferase 2) in different individuals seems to be primarily responsible for the mentioned differences in half-life and AUC: the latter is increased up to 9-fold in slow metabolizers as compared to fast metabolizers.
Amifampridine is eliminated via the kidneys and urine to 74–81% as N-acetylamifampridine and to 19% in unchanged form.
3,4-Diaminopyridine is a pale yellow to pale brown crystalline powder that melts at about 218–220 °C (424–428 °F) under decomposition. It is readily soluble in methanol, ethanol and hot water, but only slightly in diethyl ether. Solubility in water at 20 °C (68 °F) is 25 g/L.
The drug formulation amifampridine phosphate contains the phosphate salt, more specifically 4-aminopyridine-3-ylammonium dihydrogen phosphate. This salt forms prismatic, monoclinic crystals (space group C2/c) and is readily soluble in water. The phosphate salt is stable, and does not require refrigeration.
The development of amifampridine and its phosphate has brought attention to orphan drug policies that grant market exclusivity as an incentive for companies to develop therapies for conditions that affect small numbers of people.
Amifampridine, also called 3,4-DAP, was discovered in Scotland in the 1970s, and doctors in Sweden first showed its use in LEMS in the 1980s.
In the 1990s, doctors in the US, on behalf of Muscular Dystrophy Association, approached a small family-owned manufacturer of active pharmaceutical ingredients in New Jersey, Jacobus Pharmaceuticals, about manufacturing amifampridine so they could test it in clinical trials. Jacobus did so, and when the treatment turned out to be effective, Jacobus and the doctors were faced with a choice — invest in clinical trials to get FDA approval or give the drug away for free under a compassionate use program. Jacobus elected to give the drug away, and did so for about twenty years.
Doctors at the Assistance Publique – Hôpitaux de Paris had created a phosphate salt of 3,4-DAP (3,4-DAPP), and obtained an orphan designation for it in Europe in 2002. The hospital licensed the intellectual property on the phosphate form to the French biopharma company OPI, which was acquired by EUSA Pharma in 2007, and the orphan application was transferred to EUSA in 2008. In 2008 EUSA submitted an application for approval to market the phosphate form to the European Medicines Agency under the brand name, Zenas. EUSA, through a vehicle called Huxley Pharmaceuticals, sold the rights to 3,4-DAPP to Biomarin in 2009, the same year that 3,4-DAPP was approved in Europe under the new name Firdapse. BioMarin launched the drug in Europe in April 2010 and through the first nine months of 2012 year had sales of $10.8 million.
The licensing of Firdapse in 2010 in Europe 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 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. A 2011 Cochrane review compared the cost of the 3,4-DAP and 3,4-DAPP in the UK and found an average price for 3,4-DAP base of £1/tablet and an average price for 3,4-DAP phosphate of £20/tablet; and the authors estimated a yearly cost per person of £730 for the base versus £29,448 for the phosphate formulation.
Meanwhile, in Europe, a task force of neurologists had recommended 3,4-DAP as the firstline treatment for LEMS symptoms in 2006, even though there was no approved form for marketing; it was being supplied ad hoc.:5 In 2007 the drug's international nonproprietary name was published by the WHO.
In the face of the 7 year exclusivity that an orphan approval would give to Biomarin, and of the increase in price that would accompany it, Jacobus began racing to conduct formal clinical trials in order to get approval for the free base form before BioMarin; its first Phase II trial was opened in January 2012.
In October 2012, while BioMarin had a Phase III trial ongoing in the US, it licensed the US rights to 3,4-DAPP, including the orphan designation and the ongoing trial, to Catalyst Pharmaceuticals. Catalyst anticipated that it could earn $300 to $900 million per year in sales for treatment of people with LEMS and other indications, and analysts anticipated the drug would be priced at around. $100,000 in the US. Catalyst went on to obtain a breakthrough therapy designation for 3,4-DAPP in LEMS in 2013, an orphan designation for congenital myasthenic syndromes in 2015 and an orphan designation for myasthenia gravis in 2016.
In August 2013, analysts anticipated that FDA approval would be granted to Catalyst in LEMS by 2015.
In March 2015 Catalyst obtained an orphan designation for the use of 3,4-DAPP to treat of congenital myasthenic syndromes, causing its stock to rise a bit. In April 2015, Jacobus presented clinical trial results with 3,4-DAP at a scientific meeting, causing Catalyst shares to fall by 42%.
In December 2015 a group of 106 neuromuscular doctors who had worked with both Jacobus and BioMarin/Catalyst published an editorial in the journal, Muscle & Nerve, expressing concern about the potential for the price of the drug to be dramatically increased should Catalyst obtain FDA approval, and stating that 3,4-DAPP represented no real innovation and didn't deserve exclusivity under the Orphan Drug Act, which was meant to spur innovation to meet unmet needs. Other commentators noted, however, that Jacobus was not able to meet the needs of all people who could benefit from the drug via its free program, and that its manufacturing practices had quality control problems, with 483 FDA citations in 2011 and 2012. Similarly, at the urging of Assistance Publique-Hôpitaux de Paris, the French drug authority had reviewed the use of the free base in light of the manufactured phosphate form in 2006, and had urged doctors in France not to use the free base form due to quality issues.
In December 2015 Catalyst submitted its new drug application to the FDA, and in February 2016 the FDA refused to accept it, on the basis that it wasn't complete and in April 2016 the FDA told Catalyst it would have to gather further data. Catalyst cut 30% of its workforce to save money to conduct the trials. In March 2018 the company re-submitted its NDA.
Amifampridine has also been proposed for the treatment of multiple sclerosis (MS),. A 2002 Cochrane systematic review found that there was no unbiased data to support its use for treating MS. There was no change as of 2012.
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Other nervous system drugs (N07X)