ClinicSpeak: fampridine trial results

Does fampridine, a chemical that drives axonal conduction, speed up progressive MS? #ClinicSpeak #MSResearch #MSBlog

"The fampridine/dalfampridine extension study below has mixed messages. The good news is that responders still respond; if you are a responder and come off the drug you will still respond when you go back onto the drug; there were no new safety signals seen with fampridine. The bad news is that MSers still progress. The million, or 100 million, dollar question is does fampridine/dalfampridine increase the rate of disease progression?"

"Fampridine is the name for slow-release 4-aminopyridine. We think fampridine works by lowering the requirements for axons (the electrical cables of nerves) to conduct an electrical impulse. Fampridine blocks a specific group of proteins on their surface called voltage-gated potassium channels. This makes it more likely for an electrical impulse or action potential to be transmitted across a demyelinated segment of an axon. Although this will improve motor function, i.e. walking speed, the effect on sensory and other pathways may make some symptoms worse, for example exacerbation of pain and increase in the frequency and severity of MS-related positive symptoms (pins & needles, muscle spasms) and it can trigger seizures." 

"Aminopyridines will almost certainly increase the energy requirements of damaged, vulnerable, demyelinated axons as they will require more energy for repolarization the process by which they get ready to transmit another electrical signal. There is now good evidence that increasing the energy requirements of axons may result in further axonal injury and loss. Essentially this is the theory underlying the use of sodium channel blockers, such as phenytoin and oxcarbazepine, as neuroprotective compounds in MS. By reducing transmission you reduce the energy requirements and hence protect vulnerable axons. We have shown neuroprotective effects of sodium channel blockers in our animal model many times. For these reasons I am wary about the long-term use of Fampridine in MS-related motor fatigue. I am worried that Fampridine may speed up the rate of disability progression. I stand to be proved incorrect on this; the only way to find out is by doing clinical trials and following up patients with progressive MS on these medications for long periods of time using standardised methods." 

"Several years ago we proposed two studies to Biogen-Idec, who market the drug in Europe, to look into whether or not Fampridine increases the rate of MS progression; again our suggestions fell on deaf ears. The first study we proposed was to use Fampridine in our animal model; as the tablet can't work we proposed administering 4-aminopyridine using small pumps. The pumps would release low levels of the drug slowly. The idea was to compare 4-aminopyridine to placebo and to a sodium channel blocker. Why to a sodium channel blocker? At the time Biogen-Idec though that contrary to our hypothesis fampridine may be neuroprotective. The second study was to use spinal fluid neurofilament levels to test this hypothesis. If fampridine exacerbated, or sped-up, progressive disease it would increase spinal fluid neurofilament levels, compared to placebo, in MSers going onto the drug. Neurofilaments are the structural, or scaffolding, proteins of nerves and axons and are released when nerves are damaged. Levels of neurofilament in the spinal fluid are proportional to the amount of nerve damage and predict a poor outcome. May be we will be proved wrong and these studies will show that Fampridine is safe and does not speed up disease progression. But until we do these studies we simply won't know what Fampridine does to the rate of MS disease progression."

"The following are Hugh Bostock’s videos, from Queen Square, on conduction in a normal nerve and a demyelinated nerve. These illustrate how slow and difficult it is to transmit an electrical impulse down a demyelinated nerve. When you watch the videos please try and imagine how much more effort/energy is required for conduction in demyelinated axons; aminopyridines are the chemical whip that keeps these axons firing."

Normal conduction

Conduction in a chronically demyelinated axon

"The following are two MSers who are clearly responders to Fampridine; despite these dramatic results we are not allowed to offer fampridine under the NHS. MSers wanting a trial of Fampridine have to pay for it themselves via a private prescription."

"Interestingly, fampridine may not work in the way we think it does. We don't think levels of the drug are high enough in the brain to block enough potassium channels to affect the so called resting membrane potential of nerves. If this is the case we need to go back to the drawing board to find out how it works. We think we may have an answer to this." 

Epub: Goodman et al. Long-term safety and efficacy of dalfampridine for walking impairment in patients with multiple sclerosis: Results of open-label extensions of two Phase 3 clinical trials. Mult Scler. 2015 Jan 12.

BACKGROUND: In Phase 3 double-blind trials (MS-F203 and MS-F204), dalfampridine extended release tablets 10 mg twice daily (dalfampridine-ER; prolonged-release fampridine in Europe; fampridine modified or sustained release elsewhere) improved walking speed relative to placebo in patients with multiple sclerosis (MS).

OBJECTIVES: Evaluation of long-term safety and efficacy of dalfampridine-ER in open-label extensions (MS-F203EXT, MS-F204EXT).

METHODS: MSers received dalfampridine-ER 10 mg twice daily; and had Timed 25-Foot Walk (T25FW) assessments at 2, 14 and 26 weeks, and then every 6 months. Subjects were categorized as dalfampridine-ER responders or non-responders, based on their treatment response in the double-blind parent trials that assessed T25FW.

RESULTS: We had 269 MSers enter MS-F203EXT and 154 MSers complete it; for a maximum exposure of 5 years. We had 214 MSers enter MS-F204EXT and 146 complete it; for a maximum exposure of 3.3 years. No new safety signals emerged and dalfampridine-ER tolerability was consistent with the double-blind phase. Improvements in walking speed were lost after dalfampridine-ER was discontinued in the parent trial, but returned by the 2-week assessment after re-initiation of the drug. Throughout the extensions, mean improvement in walking speed declined, but remained improved, among the double-blind responders as compared with non-responders.

CONCLUSIONS: The dalfamipridine-ER safety profile was consistent with the parent trials. Although walking speed decreased over time, dalfampridine-ER responders continued to show improved walking speed, which was sustained compared with non-responders.

CoI: multiple

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