Dalfampridine: Review on its recent development for symptomatic improvement in patients with multiple sclerosis

1 Introduction

Dalfampridine was approved by United State Food and Drug Administration (FDA) on January 22, 2010 and it is launched by Acorda therapeutics under the trade name AMPYRA which is used to improve walking in people suffering from multiple sclerosis (MS). The FDA granted dalfampridine orphan drug status, providing them 7 years of market exclusivity for the drug (Confavreux et al., 2000). The drug, a potassium channel blocker, was shown in clinical trials to improve walking speeds vs placebo and it acts by enhancing conduction in damaged nerves. Trouble with walking is one of the most debilitating problems of MS patients. The drug was previously known as fampridine sustained release with the proposed brand name Ampyra, but is now called dalfampridine (Rudick et al., 2010). Multiple sclerosis is a chronic disease that attacks the immune system and results in the degradation of nervous system functioning. MS is a disorder of the body's immune system that affects the central nervous system (CNS). Normally, nerve fibers carry electrical impulses through the spinal cord, providing communication between the brain, arms and legs. In people with MS, the fatty sheath that surrounds and insulates the nerve fibers called myelin deteriorates, causing nerve impulses to be slowed or stopped (Compston and Coles, 2008; Rosati, 2001). So, the person suffering from multiple sclerosis may experience periods of muscle weakness, loss of vision, loss of coordination, paralysis, spasticity, physical fatigue and decreased ability to think or remember. So, continuing in the advancement of clinical research and expansion of therapeutic options for people with MS, including treatments for the most debilitating symptoms and challenges associated with this disease, is critical to helping people with MS (Clanet, 2008; Compston and Coles, 2002; Ascherio and Munger, 2007; Lublin and Reingold, 1996). Fampridine has been used clinically in Lambert–Eaton myasthenic syndrome and multiple sclerosis. It acts by blocking potassium channels, prolonging action potentials and thereby increasing neurotransmitter release at the neuromuscular junction. The drug has been shown to reverse tetrodotoxin toxicity in animal experiments (Weinshenker, 1994; Pittock and Rodriguez, 2008). Fampridine has been shown to improve visual function and relieve fatigue in patients with multiple sclerosis (Judge and Bever, 2006). 4-AP is most effective in patients with the chronic progressive form of MS, in patients who are temperature sensitive, and in patients who have been suffering from MS for longer than 3 years. These periods of illness may become exacerbations and go into remissions. Fampridine-SR is an experimental drug that has been reported to possibly improve muscle strength and walking ability for some people with MS (Wolswijk and Balesar, 2003). 4-Aminopyridine has a restricted use as an extremely effective bird poison sold under the brand name Avitrol, and may be dangerous to mammals and other animals. The most common target birds are pigeons, house sparrows, and starlings, if dosages are exceeded, compound forms of the active agent of sustained-release fampridine have been used in clinical practice for many years and are shown to improve walking ability in patients with multiple sclerosis. Clinical trials have now been completed that demonstrate effectiveness of the drug with statistical significance and a clinically meaningful end point. Approval of dalfampridine will enable patients to obtain a consistent exact dosage in a guaranteed time-released formula, and avoid the risk of getting an uncertain preparation from a compounding pharmacy with possible adverse effects (Vandiemen et al., 1993).

2 Chemistry

4-Aminopyridine (dalfampridine) is an organic compound with the chemical formula H₂NC₅H₄N. It is prepared by the decarbonylation of pyridine-4-carboxamide using sodium hypochlorite via Hoffman rearrangement. The pyridine carboxamide is generated from the corresponding nitrile, which in turn is obtained from the ammoxidation of 4-methylpyridine. The molecule is one of the three isomeric amines of pyridine. It is used primarily as a research tool, in characterizing subtypes of potassium channel, and has also been used to manage some of the symptoms of multiple sclerosis. The largest scale industrial application of 4-aminopyridine acts as a precursor to the drug pinacidil, which affects potassium ion channels. In the laboratory, 4-AP is a useful pharmacological tool in studying various potassium conductances in physiology and biophysics. It is a relatively selective blocker of members of Kv1 (family of voltage-activated K+ channels.). At concentration of 1 mM it selectively and reversibly inhibits shaker channels without significant effect on other sodium, calcium, and potassium conductances (Korenke et al., 2008).

3 Mechanism of action

Dalfampridine blocks tiny pores, or potassium channels, on the surface of nerve fibers, which may improve the conduction of nerve signals along nerve fibers whose insulating myelin coating has been damaged by MS, available in 10 mg tablet strength. It is a broad-spectrum potassium channel blocker that does not have a clinically important effect on duration of the QRS interval and it does not prolong the QTc interval, according to the FDA-approved for Ampyra. In animal studies, dalfampridine-mediated inhibition of potassium channels increased the conductivity of demyelinated nerve fibers. Electrophysiologic studies of demyelinated axons show that augmented potassium currents increase extracellular potassium ion concentration which decreases action potential duration and amplitude which may cause conduction failure. Potassium channel blockade reverses this effect. However, a recent study has shown that 4-AP is a potent calcium channel activator and can improve synaptic and neuromuscular function by directly acting on the calcium channel beta subunit (β₁). MS patients treated with 4-AP exhibited a response rate of 29.5% to 80%. A long-term study (32 months) indicated that 80–90% of patients who initially responded to 4-AP exhibited long-term benefits. Although improving symptoms, 4-AP does not inhibit the progression of MS. Spinal cord injury patients have also seen improvement with 4-AP therapy. These improvements include sensory, motor and pulmonary function, with a decrease in spasticity and pain (Zi-Zhen et al., 2009; Shrager, 1989; Chiu and Ritchie, 1980).

4 Pharmacodynamics

In Idiopathic unknown Pharmacodynamics, dalfampridine is a broad-spectrum voltage-gated potassium channel blocker, can increase action potential duration and amplitude, leading to improved demyelinated nerve fibers (loss of the myelin sheath insulating the nerves, and is the hallmark of some neurodegenerative autoimmune diseases, including multiple sclerosis, acute disseminated encephalomyelitis, transverse myelitis, chronic inflammatory demyelinating polyneuropathy, Guillain–Barré syndrome, central pontine myelinosis, inherited demyelinating diseases such as Leukodystrophy, and Charcot Marie Tooth) conduction and increase of neurotransmitter release at the synaptic ending. The metabolites have been shown to have no pharmacologic activity on potassium channels. Blocking voltage-gated potassium channels facilitates direct blocking of the synaptic and neuromuscular transmits ions conventionally and it was also suggested that fampridine can directly target presynaptic high voltage-activated calcium channels to potentiate neurotransmitter release independent of potassium channels. AMPYRA does not prolong the QTc interval and does not have a clinically important effect on QRS duration (Robert and Jeffrey, 2011; Peter et al., 2011).

5 Pharmacokinetics

Dalfampridine, a sustained-release oral preparation of fampridine, is rapidly absorbed, but relative bioavailability is 96% when compared to an aqueous oral solution. It gives a slower rise to a lower peak concentration C_max (term used in pharmacokinetics refers to the maximum concentration that a drug achieves in the tested area after the drug has been administrated and prior to the administration of a second dose) i.e. 3–4 h post administration, with no effect on the extent of absorption AUC (area under curve). When dalfampridine is taken with food, there is a slight increase in C_max (12–17%) and a slight decrease in AUC (4–7%). Dalfampridine was nearly completely (95.5%) and rapidly eliminated within 24 h as unchanged drug via urinary excretion and 0.5% recovered in feces suggesting that it is unlikely to undergo substantial metabolic transformation with mean terminal disk position, half-life is 6.4 h and plasma half life of about 7.6 h in healthy individuals. Dalfampridine is largely unbound to plasma proteins (97–99%). The apparent volume of distribution is 2.6 L/kg. Two metabolites were identified: 3-Hydroxy-4-aminopyridine (4.3%) and 3-hydroxy-4-aminopyridine sulfate (2.6%). In vitro studies with human liver microsomes indicate that CYP2E1 was the major enzyme responsible for the 3-hydroxylation of dalfampridine. The identity of the CYP enzymes suspected of playing a minor role in the 3-hydroxylation of dalfampridine could not be established unequivocally (Vollmert and Henney, 2009; Judge et al., 2006; Bever and Judge, 2009; Oh et al., 2009; Chang et al., 1997; Uges et al., 1982).

6 Preclinical acute study

7 Clinical study

It was estimated that about 400,000 Americans were suffering from multiple sclerosis and 64–85% of patients will have difficulty in walking within 15 years of diagnosis. Dalfampridine is the first and only FDA-approved oral drug addressing walking impairment in patients with multiple sclerosis (Goodman et al., 2009; Johnson and Morgan, 2006).

8 Dosage and administration

The maximum recommended dose of AMPYRA is one 10 mg tablet twice daily, taken with or without food. Doses should be taken approximately 12 h apart. Patients should not taken double or extra doses if a dose is missed. No additional benefit was demonstrated at doses greater than 10 mg twice daily and adverse reactions and discontinuations were more frequent at higher doses. Tablets should only be taken whole; do not divide, crush, chew, or dissolved. AMPYRA is contraindicated in patients with moderate or severe renal impairment. The seizures in patients with mild renal impairment (CrCl 51–80 mL/min) is unknown, but AMPYRA is contraindicated in patients with moderate or severe renal impairment. The risk of seizures in patients with mild renal impairment (CrCl 51–80 mL/min) is unknown, but AMPYRA plasma exposure in these patients may approach that seen at a dose of 15 mg twice daily dose that may be associated with an increased risk of seizures; estimated CrCl should be known before initiating treatment with AMPYRA (Lawrence and Andrew, 2011).

9 Contraindication

Dalfampridine is contraindicated in patients with moderate to severe kidney disease because the blood levels with the drug approach those associated with the occurrence of seizures. Because of concern for this adverse event, dalfampridine is contraindicated in patients with a prior history of seizure and should be discontinued in patients in which seizure occurs. Dalfampridine should not be consumed by pregnant women, children less then 18 years of age and it should not be taken with other aminopyridine medications. Dalfampridine demonstrated efficacy in all four major types of MS, including relapsing-remitting, secondary progressive, progressive relapsing, and primary progressive, and can be used alone or in combination with immunomodulatory drugs (Smith et al., 2010; Peter et al., 2011).

10 FDA approval and market authorization

On January 30, 2009 Acorda Therapeutics, announced the submission of a new drug application to the U.S. (FDA) for Fampridine-SR. Fampridine-SR was accepted by the FDA on May 5, 2009. The FDA set a prescription drug user fee act (PDUFA) on October 22, 2009; the PDUFA date is the target date for the FDA to complete its review. On May 6, 2009 acorda therapeutics, announced that the U.S. (FDA) has accepted the Fampridine-SR New Drug Application (NDA) for filing, assigning priority review and on Aug 25, 2009 Acorda Therapeutics, announced that the U.S. (FDA) has confirmed that its Peripheral and Central Nervous System Drugs Advisory Committee will review the Company’s New Drug Application (NDA) for Fampridine-SR on October 14, 2009 and Acorda submitted additional information on its proposed Risk Evaluation and Mitigation Strategy (REMS) program. The Company also announced that it has received preliminary approval for the proposed trade name Amaya from the FDA. On 12 January 2010, Biogen Idec announced that the submission of a Marketing Authorization Application (MAA) to the European Medicines Agency for prolonged release fampridine tablets helpful in the walking ability of adult patients suffering from multiple sclerosis. The US FDA accepted this submission as a solicited major amendment to the Fampridine-SR NDA. FDA approved dalfampridine in patients with multiple sclerosis on January 22, 2010. Biogen Idec will commercialize fampridine as a prolonged release tablet in markets outside the U.S.

11 Conclusion

In the case of multiple sclerosis there is conduction abnormality, including conduction delay or block due to the loss of the oligodendrocyte myelin complex which in turn results in the reorganization of axolemmal ion channels. So, the agents which block potassium channels have been investigated in the context of clinical trials with positive impact on impulse conduction in experimentally-induced demyelination in MS patients. Dalfampridine is an extended release form of fampridine (4-aminopyridine), which has been recently been approved by the US FDA for symptomatic treatment of MS patients. While this new oral blocker of voltage-gated potassium channels does not have any impact on the underlying pathology of MS, it has been demonstrated to improve fatigue and walking ability in these patients.