The Food and Drug Administration's approval of a sustained-release formulation of the potassium channel blocker dalfampridine in January marked the first multiple sclerosis drug that has been specifically indicated for improving walking.
But only a minority of patients appears to respond to the drug, which was approved with a risk evaluation and mitigation strategy (REMS) that addresses the increased risk of seizures associated with higher than recommended doses of the drug.
The approval of dalfampridine extended-release tablets was based on studies that found patients treated with the drug had faster walking speeds than did those treated with placebo, according to an FDA statement.
At a meeting in October 2009, the majority of the FDA's Peripheral and Central Nervous System Drugs Advisory Committee panel voted that the manufacturer, Acorda Therapeutics Inc., had provided “substantial evidence” of effectiveness for this indication, although only one-third of the patients in the two pivotal trials were considered responders. Most of the panel also agreed that the drug could be considered safe for use in people with MS, but not in patients who have a history of seizures and those with severe renal insufficiency.
In an interview, Dr. Jonathan Carter, an MS specialist in the department of neurology at the Mayo Clinic, Scottsdale, Ariz., said that the approval is “encouraging because it offers a therapy to a large number of MS patients” with walking impairment who could potentially benefit from this treatment. “It will be a trial and error process in terms of whether a patient responds to the drug or not and whether they find it useful,” he added.
At the time of the advisory committee meeting, the drug was called fampridine, but was changed to dalfampridine. It will be marketed by Acorda under the trade name Ampyra.
The REMS program includes a medication guide that is provided with each filled prescription and a communication plan, which will educate patients about the risks, according to Acorda. The drug is expected to be available in March and will be distributed through a network of special pharmacies.
While the mechanism of dalfampridine has not been “fully eludicated,” it has been shown to increase conduction of action potentials in demyelinated axons through inhibition of potassium channels in animal studies, according to the drug's label.
Although it had never been approved in the United States, immediate-release versions of the drug have been compounded in pharmacies and used with the intent of improving walking in people with various neurologic conditions for years. However, its narrow therapeutic range makes plasma levels difficult to regulate with the immediate-release formulation, which has been associated with an increased risk of seizures and the sustained formulation was developed to overcome these limitations.
The recommended dose of dalfampridine is 10 mg twice a day. However, the drug should not be taken by patients with moderate to severe kidney disease, whose blood levels with dalfampridine approach the levels that have been associated with seizures, according to the agency.
In clinical trials, one patient on the drug had a seizure, compared with none on placebo. The most common adverse reactions in patients taking dalfampridine included urinary tract infections, insomnia, dizziness, headache, nausea, weakness, back pain, balance disorder, swelling in the nose or throat, constipation, diarrhea, indigestion, throat pain, and skin sensations including burning, tingling, and itching, according to the agency.
The low responder rate in clinical trials “tempers one's enthusiasm…and it also remains to be seen how clinically relevant that response is going to be in those who do respond,” Dr. Carter said.
An official for Acorda at the advisory committee meeting said that the high non-responder rate may have been the result of axonal destruction, which would make the drug ineffective because it relies on demyelinated axons as a “substrate.”
However, Dr. Carter views the approval as a positive development and plans to use the drug in his practice. The risk of seizures remains a concern and while the risk of seizures appears to be fairly low with the sustained formulation, it is not zero, said Dr. Carter, who did not prescribe the compounded version because of some reports of status epilepticus due to compounding mistakes.
He is particularly interested in seeing whether the drug will be effective in his heat-sensitive patients, whose symptoms get worse when they are hot—an issue in Arizona—and those whose symptoms get worse with exercise, “because presumably, that's an issue of conduction block as body temperature rises…and failure of transmission.”
The cost of the drug could be a major issue, affecting how widely the drug is used, Dr. Carter added. (At press time, the price of the drug was not available from Acorda.) Dr. Carter had no disclosures related to Acorda, or to Elan, the global manufacturer of dalfampridine.
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