4-Aminopyridine is an experimental drug that may reduce symptoms in some people with MS, particularly those who are more sensitive to heat. 4-AP blocks potassium channels on the surface of nerve fibers and may improve conduction of electrical impulses through nerves whose protective myelin sheath has been damaged or destroyed by MS.
Studies Show Drug Helps Some People
Early clinical trials of 4-AP, given either intravenously or orally, showed that the drug provided temporary improvement in symptoms such as weakness, imbalance, and decreased vision in small numbers of MS patients.
In a somewhat larger study, involving 68 MS patients over a three-month period, 27% reported improvement in symptoms while they were taking 4-AP, compared to only 2% (1 patient) who reported improvement while taking a placebo, an inactive substance used as a control in testing new drugs. In addition, 10 patients on 4-AP significantly improved their rating on a neurologic function scale called the Expanded Disability Status Scale, or EDSS, while none of the patients taking a placebo improved their EDSS rating.
Patients with more neurologic impairment and those more sensitive to heat were more likely to be helped by 4-AP. Although this was a controlled, double-blind study—neither the patients nor the investigators knew who was taking 4-AP or who was taking the placebo¾41 patients correctly guessed that they had received 4-AP rather than the placebo.
Side Effects Can Be Troublesome
Side effects in this trial included dizziness, numbness and tingling, and instability while walking. Less common side effects included nausea, vomiting, and abdominal pain. Some of these side effects, however, also occurred among patients taking the placebo.
Serious side effects of 4-AP treatment included generalized convulsions, confusion, and one case of liver inflammation (chemical hepatitis).
Timed-Release Formula—Fampridine-SR
A small-scale (36 subjects), controlled trial using a timed-release formulation of 4-AP (Fampridine-SR, developed by Acorda Therapeutics), was recently completed in which subjects were given gradually higher doses. Although the higher doses were not well-tolerated, even with the timed-release formula, people on lower doses showed some improvement in walking speed and leg strength. No benefit was found for fatigue. Side effects included dizziness, insomnia, numbness and tingling; at the higher doses, two subjects had seizures.
In a double-blind, placebo-controlled dosing study, 206 people with MS were randomized to receive either Fampridine (10 mg, 15 mg, or 20 mg) or an inactive placebo for 12 weeks. The results indicated a trend (an effect that does not quite reach statistical significance) toward improved walking speed in the groups receiving Fampridine, as well as a significant increase in leg strength. Side effects included dizziness, insomnia, and nausea, with two people in the 20-mg group having seizures (one related to an accidental overdose).
To look further at the safety of Fampridine and its capacity to improve walking ability, investigators at 33 centers in the United States and Canada conducted a 14-week, randomized, placebo-controlled trial involving 301 subjects. This phase III study included people with all types of MS, including all relapsing forms of MS and primary progressive MS. Study participants were able to continue taking their disease-modifying medications.
Results showed that compared to people taking an inactive placebo, people taking Fampridine had an average increase in walking speed of 25%. Other positive outcomes during the 14 weeks of therapy included increased leg strength in those on active treatment, even in some individuals whose walking speed did not improve. Patients that responded to the drug also reported feeling less disabled in daily activities requiring mobility. Common side effects experienced more often by those on active treatment included falls, back pain, dizziness, insomnia, fatigue, nausea and balance disorder. Serious adverse events that led to discontinuation of the drug included one case of anxiety and one seizure in a person who developed sepsis from a urinary tract infection.
Acorda is working with the FDA to determine next steps for bringing this symptomatic therapy to the market.
Related Compound Not as Effective
A related compound, 3, 4-diaminopyridine, has been reported to provide similar improvements in symptoms, but 3, 4-DAP is less able to get into the brain than 4-AP. One clinical trial showed that 3, 4-DAP was less effective than 4-AP and produced more side effects, such as nausea and abdominal pain.