Amifampridine is used as a drug, predominantly in the treatment of a number of rare muscle diseases. The
free base
Free base (freebase, free-base) is the conjugate base (deprotonated) form of an amine, as opposed to its conjugate acid (protonated) form. The amine is often an alkaloid, such as nicotine, cocaine, morphine, and ephedrine, or derivatives thereo ...
form of the drug has been used to treat
congenital myasthenic syndrome
Congenital myasthenic syndrome (CMS) is an inherited neuromuscular disorder caused by defects of several types at the neuromuscular junction. The effects of the disease are similar to Lambert-Eaton Syndrome and myasthenia gravis, the difference ...
s and
Lambert–Eaton myasthenic syndrome
Lambert–Eaton myasthenic syndrome (LEMS) is a rare autoimmune disorder characterized by muscle weakness of the limbs.
Around 60% of those with LEMS have an underlying malignancy, most commonly small-cell lung cancer; it is therefore regarded ...
(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
Assistance is an act of helping behavior.
Assistance may also refer to:
Types of help
* Aid, in international relations, a voluntary transfer of resources from one country to another
* Assistance dog, a dog trained to aid or assist a person ...
created a phosphate
salt
Salt is a mineral composed primarily of sodium chloride (NaCl), a chemical compound belonging to the larger class of salts; salt in the form of a natural crystalline mineral is known as rock salt or halite. Salt is present in vast quantitie ...
form, which was developed through a series of companies ending with
BioMarin Pharmaceutical
BioMarin Pharmaceutical Inc. is an American biotechnology company headquartered in San Rafael, California. It has offices and facilities in the United States, South America, Asia, and Europe. BioMarin's core business and research is in enzyme re ...
which obtained European approval in 2009 under the trade name Firdapse, and which licensed the US rights to
Catalyst Pharmaceuticals
Catalyst Pharmaceuticals Inc. is a biopharmaceutical company based in Coral Gables, Florida. The company is developing medicines for rare diseases, including the phosphate salt of amifampridine for the treatment of Lambert–Eaton myasthenic synd ...
in 2012. As of January 2017, Catalyst and another US company,
Jacobus Pharmaceutical
A Jacobus is an English gold coin of the reign of James I, worth 25 shillings. The name of the coin comes from the Latin inscription surrounding the King's head on the obverse of the coin, IACOBUS D G MAG BRIT FRA ET HI REX ("James, by the grace o ...
, which had been manufacturing and giving it away for free since the 1990s, were both seeking FDA approval for their iterations and marketing rights.
Amifampridine phosphate has
orphan drug
An orphan drug is a pharmaceutical agent developed to treat medical conditions which, because they are so rare, would not be profitable to produce without government assistance. The conditions are referred to as orphan diseases.
The assignment of ...
status in the EU for Lambert–Eaton myasthenic syndrome and Catalyst holds both an orphan designation and a
breakthrough therapy
Breakthrough therapy is a United States Food and Drug Administration designation that expedites drug development that was created by Congress under Section 902 of the 9 July 2012 Food and Drug Administration Safety and Innovation Act. The FDA's "br ...
designation in the US. In May 2019 the U.S.
Food and Drug Administration (FDA) approved amifampridine tablets under the trade name Ruzurgi for the treatment of Lambert-Eaton myasthenic syndrome (LEMS) in patients 6 to less than 17 years of age. This is the first FDA approval of a treatment specifically for pediatric patients with LEMS. The FDA granted the approval of Ruzurgi to Jacobus Pharmaceutical. The only other treatment approved for LEMS (Firdapse) is only approved for use in adults.
Medical uses
Amifampridine is used to treat many of the
congenital myasthenic syndrome
Congenital myasthenic syndrome (CMS) is an inherited neuromuscular disorder caused by defects of several types at the neuromuscular junction. The effects of the disease are similar to Lambert-Eaton Syndrome and myasthenia gravis, the difference ...
s, particularly those with defects in
choline acetyltransferase
Choline acetyltransferase (commonly abbreviated as ChAT, but sometimes CAT) is a transferase enzyme responsible for the synthesis of the neurotransmitter acetylcholine. ChAT catalyzes the transfer of an acetyl group from the coenzyme acetyl-Co ...
,
downstream kinase 7, and those where any kind of defect causes "fast channel" behaviour of the
acetylcholine receptor
An acetylcholine receptor (abbreviated AChR) is an integral membrane protein that responds to the binding of acetylcholine, a neurotransmitter.
Classification
Like other transmembrane receptors, acetylcholine receptors are classified according ...
.
It is also used to treat symptoms of
Lambert–Eaton myasthenic syndrome
Lambert–Eaton myasthenic syndrome (LEMS) is a rare autoimmune disorder characterized by muscle weakness of the limbs.
Around 60% of those with LEMS have an underlying malignancy, most commonly small-cell lung cancer; it is therefore regarded ...
.
[ Se]
EMA Index page, product tab
/ref>
Contraindications
Because it affects voltage-gated ion channels in the heart, it is contraindicated in people with long QT syndrome
Long QT syndrome (LQTS) is a condition affecting repolarization (relaxing) of the heart after a heartbeat, giving rise to an abnormally lengthy QT interval. It results in an increased risk of an irregular heartbeat which can result in fainting, d ...
and in people taking a drug that might prolong QT time like sultopride
Sultopride (trade names Barnetil, Barnotil, Topral) is an atypical antipsychotic of the benzamide chemical class used in Europe, Japan, and Hong Kong for the treatment of schizophrenia. It was launched by Sanofi-Aventis in 1976. Sultopride acts a ...
, disopyramide
Disopyramide (INN, trade names Norpace and Rythmodan) is an antiarrhythmic medication used in the treatment of ventricular tachycardia. It is a sodium channel blocker and therefore classified as a Class 1a anti-arrhythmic agent. Disopyramide has ...
, cisapride
Cisapride is a gastroprokinetic agent, a drug that increases motility in the upper gastrointestinal tract. It acts directly as a serotonin 5-HT4 receptor agonist and indirectly as a parasympathomimetic. Stimulation of the serotonin receptors incr ...
, domperidone
Domperidone, sold under the brand name Motilium among others, is a dopamine antagonist medication which is used to treat nausea and vomiting and certain gastrointestinal problems like gastroparesis (delayed gastric emptying). It raises the le ...
, rifampicin
Rifampicin, also known as rifampin, is an ansamycin antibiotic used to treat several types of bacterial infections, including tuberculosis (TB), mycobacterium avium complex, ''Mycobacterium avium'' complex, leprosy, and Legionnaires’ disease. ...
or ketoconazol
Ketoconazole, sold under the brand name Nizoral among others, is an antiandrogen and antifungal medication used to treat a number of fungal infections. Applied to the skin it is used for fungal skin infections such as tinea, cutaneous candidia ...
. It is also contraindicated in people with epilepsy
Epilepsy is a group of non-communicable neurological disorders characterized by recurrent epileptic seizures. Epileptic seizures can vary from brief and nearly undetectable periods to long periods of vigorous shaking due to abnormal electrical ...
or badly controlled asthma
Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, cou ...
.
Adverse effects
The dose-limiting side effects include tingling or numbness, difficulty sleeping, fatigue, and loss of muscle strength.
Amifampridine can cause seizures, especially but not exclusively when given at high doses and/or in particularly vulnerable individuals who have a history of seizures.
Interactions
The combination of amifampridine with pharmaceuticals that prolong QT time increases the risk of ventricular tachycardia
Ventricular tachycardia (V-tach or VT) is a fast heart rate arising from the lower chambers of the heart. Although a few seconds of VT may not result in permanent problems, longer periods are dangerous; and multiple episodes over a short period ...
, especially torsade de pointes
''Torsades de pointes, torsade de pointes'' or ''torsades des pointes'' (TdP) (, , translated as "twisting of peaks") is a specific type of abnormal heart rhythm that can lead to sudden cardiac death. It is a polymorphic ventricular tachycardia t ...
; and combination with drugs that lower the seizure threshold increases the risk of seizures. Interactions via the liver's cytochrome P450
Cytochromes P450 (CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are ...
enzyme system are considered unlikely.
Pharmacology
Mechanism of action
In Lambert–Eaton myasthenic syndrome, acetylcholine
Acetylcholine (ACh) is an organic chemical that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Part ...
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
Potassium channels are the most widely distributed type of ion channel found in virtually all organisms. They form potassium-selective pores that span cell membranes. Potassium channels are found in most cell types and control a wide variety of cel ...
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.
Pharmacokinetics
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
Blood plasma is a light amber-colored liquid component of blood in which blood cells are absent, but contains proteins and other constituents of whole blood in suspension. It makes up about 55% of the body's total blood volume. It is the intra ...
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
Biological half-life (also known as elimination half-life, pharmacologic half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the bl ...
(2.5±0.7 hrs) and the area under the curve
In mathematics, an integral assigns numbers to functions in a way that describes displacement, area, volume, and other concepts that arise by combining infinitesimal data. The process of finding integrals is called integration. Along with ...
(AUC = 117±77 ng∙h/ml) also vary widely between subjects, but are nearly independent of food intake.
The substance is deactivated by acetylation
:
In organic chemistry, acetylation is an organic esterification reaction with acetic acid. It introduces an acetyl group into a chemical compound. Such compounds are termed ''acetate esters'' or simply '' acetates''. Deacetylation is the oppo ...
via N-acetyltransferase N-acetyltransferase (NAT) is an enzyme that catalyzes the transfer of acetyl groups from acetyl-CoA to arylamines, arylhydroxylamines and arylhydrazines. They have wide specificity for aromatic amines, particularly serotonin, and can also catal ...
s to the single metabolite
In biochemistry, a metabolite is an intermediate or end product of metabolism.
The term is usually used for small molecules. Metabolites have various functions, including fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, c ...
3-''N''-acetylamifampridine. Activity of these enzymes (primarily N-acetyltransferase 2
N-acetyltransferase 2 (arylamine N-acetyltransferase), also known as NAT2, is an enzyme which in humans is encoded by the ''NAT2'' gene.
Function
This gene encodes a type of N-acetyltransferase. The NAT2 isozyme functions to both activate and ...
) 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.
Chemistry
3,4-Diaminopyridine is a pale yellow to pale brown crystalline powder that melts at about under decomposition. It is readily soluble in methanol
Methanol (also called methyl alcohol and wood spirit, amongst other names) is an organic chemical and the simplest aliphatic alcohol, with the formula C H3 O H (a methyl group linked to a hydroxyl group, often abbreviated as MeOH). It is a ...
, ethanol
Ethanol (abbr. EtOH; also called ethyl alcohol, grain alcohol, drinking alcohol, or simply alcohol) is an organic compound. It is an Alcohol (chemistry), alcohol with the chemical formula . Its formula can be also written as or (an ethyl ...
and hot water, but only slightly in diethyl ether
Diethyl ether, or simply ether, is an organic compound in the ether class with the formula , sometimes abbreviated as (see Pseudoelement symbols). It is a colourless, highly volatile, sweet-smelling ("ethereal odour"), extremely flammable liq ...
. Solubility in water at 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
In crystallography, the monoclinic crystal system is one of the seven crystal systems. A crystal system is described by three vectors. In the monoclinic system, the crystal is described by vectors of unequal lengths, as in the orthorhombic s ...
crystals (space group
In mathematics, physics and chemistry, a space group is the symmetry group of an object in space, usually in three dimensions. The elements of a space group (its symmetry operations) are the rigid transformations of an object that leave it unchan ...
C2/c) and is readily soluble in water. The phosphate salt is stable, and does not require refrigeration.
History
The development of amifampridine and its phosphate has brought attention to orphan drug
An orphan drug is a pharmaceutical agent developed to treat medical conditions which, because they are so rare, would not be profitable to produce without government assistance. The conditions are referred to as orphan diseases.
The assignment of ...
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
The Muscular Dystrophy Association (MDA) is an American 501(c)(3) umbrella organization that works to support people with neuromuscular diseases. Founded in 1950 by Paul Cohen, who lived with muscular dystrophy, it works to combat neuromuscular di ...
, approached a small family-owned manufacturer of active pharmaceutical ingredients
An active ingredient is any ingredient that provides biologically active or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the structure or any function of the body of humans or animals. Th ...
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 to about 200 patients out of the estimated 1500-3000 LEMS patients in the U.S.. Jacobus elected to give the drug away to this subset of LEMS patients, and did so for about twenty years.
Doctors at the Assistance Publique – Hôpitaux de Paris
Assistance is an act of helping behavior.
Assistance may also refer to:
Types of help
* Aid, in international relations, a voluntary transfer of resources from one country to another
* Assistance dog, a dog trained to aid or assist a person ...
had created a phosphate salt
Salt is a mineral composed primarily of sodium chloride (NaCl), a chemical compound belonging to the larger class of salts; salt in the form of a natural crystalline mineral is known as rock salt or halite. Salt is present in vast quantitie ...
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
The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of medicinal products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products or Euro ...
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.
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
David William Donald Cameron (born 9 October 1966) is a British former politician who served as Prime Minister of the United Kingdom from 2010 to 2016 and Leader of the Conservative Party from 2005 to 2016. He previously served as Leader o ...
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''. In 2007 the drug's international nonproprietary name was published by the WHO.
In the face of the seven-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 Pharmaceuticals Inc. is a biopharmaceutical company based in Coral Gables, Florida. The company is developing medicines for rare diseases, including the phosphate salt of amifampridine for the treatment of Lambert–Eaton myasthenic synd ...
. Catalyst anticipated that it could earn $300 to $900 million per year in sales at peak 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
Breakthrough therapy is a United States Food and Drug Administration designation that expedites drug development that was created by Congress under Section 902 of the 9 July 2012 Food and Drug Administration Safety and Innovation Act. The FDA's "br ...
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
Myasthenia gravis (MG) is a long-term neuromuscular junction disease that leads to varying degrees of skeletal muscle weakness. The most commonly affected muscles are those of the eyes, face, and swallowing. It can result in double vision, dro ...
in 2016.
In August 2013, analysts anticipated that FDA approval would be granted to Catalyst in LEMS by 2015.
In October 2014, Catalyst began making available under an expanded access program
Expanded access or compassionate use is the use of an unapproved drug or medical device under special forms of investigational new drug, investigational new drug applications (IND) or Investigational device exemption, IDE application for devices, o ...
.
In March 2015, Catalyst obtained an orphan designation for the use of 3,4-DAPP to treat of congenital myasthenic syndrome. In April 2015, Jacobus presented clinical trial results with 3,4-DAP at a scientific meeting.
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. Catalyst responded to this editorial with a response in 2016 that explained that Catalyst was conducting a full range of clinical and non-clinical studies necessary to obtain approval in order to specifically address the unmet need among the estimated 1500-3000 LEMs patients since about 200 were receiving the product through compassionate use – and that this is exactly what the Orphan Drug Act was intended to do: deliver approved products to orphan drug populations so that all patients have full access.
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. In April 2016 the FDA told Catalyst it would have to gather further data. Catalyst cut 30% of its workforce, mainly from the commercial team it was building to support an approved product, to save money to conduct the trials. In March 2018 the company re-submitted its NDA. The FDA approved amifampridine for the treatment of adults with Lambert-Eaton myasthenic syndrome on November 29, 2018.
In February 2019, U.S. Senator Bernie Sanders
Bernard Sanders (born September8, 1941) is an American politician who has served as the junior United States senator from Vermont since 2007. He was the U.S. representative for the state's at-large congressional district from 1991 to 2007 ...
questioned the high price ($375,000) charged by Catalyst Pharmaceuticals for Firdapse.
In May 2019, the privately held US company Jacobus Pharmaceutical, Princeton
Princeton University is a private research university in Princeton, New Jersey. Founded in 1746 in Elizabeth as the College of New Jersey, Princeton is the fourth-oldest institution of higher education in the United States and one of the nine ...
, New Jersey
New Jersey is a state in the Mid-Atlantic and Northeastern regions of the United States. It is bordered on the north and east by the state of New York; on the east, southeast, and south by the Atlantic Ocean; on the west by the Delaware ...
gained approval by the FDA for amifampridine tablets (''Ruzurgi'') for the treatment of LEMS in patients 6 to less than 17 years of age. This is the first FDA approval of a treatment specifically for pediatric patients with LEMS. ''Firdapse'' is only approved for use in adults. Although ''Ruzurgi'' has been approved for pediatric patients, this approval makes it possible for adults with LEMS to get the drug off-label
Off-label use is the use of pharmaceutical drugs for an unapproved indication or in an unapproved age group, dosage, or route of administration. Both prescription drugs and over-the-counter drugs (OTCs) can be used in off-label ways, although m ...
. Jacobus Pharmaceutical had been manufacturing and giving it away for free since the 1990s. The FDA decision dropped the stock of Catalyst Pharmaceuticals. The company's stock price has dropped about 50%.
Research
Amifampridine has also been proposed for the treatment of multiple sclerosis
Multiple (cerebral) sclerosis (MS), also known as encephalomyelitis disseminata or disseminated sclerosis, is the most common demyelinating disease, in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This d ...
(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.
References
External links
*
*
{{Portal bar , Medicine
Orphan drugs
Potassium channel blockers
Aminopyridines