Fampridine-SR – Treatment for Multiple Sclerosis

Developed by Acorda Therapeutics, fampridine-SR is a selective neuronal potassium (K+) channel blocker under investigation for the treatment of multiple sclerosis (MS) and spinal cord injury (SCI).

Fampridine-SR, a slow-release formulation of 4-aminopyridine, has a longer half-life and lower peak serum levels than immediate release formulations. It has been developed to increase duration of therapeutic effect and reduce dosing burden, as well as to reduce the incidence and severity of drug-related adverse events.

Phase III clinical trials are ongoing in both MS and SCI patients.

DEMYELINATING DISEASES

MS is an inflammatory autoimmune-mediated disease of the nervous system characterised by recurrent relapses followed by periods of remission. After trauma, it is the second most common neurological disability to affect young and middle-aged adults. It affects twice as many women as men, with the relapsing forms of MS the most common.

Patients with MS display a range of symptoms that arise from demyelination (loss of myelin sheath) in the central nervous system (CNS), which includes the brain, spinal cord and optic nerves.

While symptoms vary between patients, they commonly include blurred vision, slurred speech, numbness or tingling in the limbs and problems with balance and coordination, due to the loss of control over vital functions such as seeing, walking and talking.

Prominent inflammatory and autoimmune responses are also evident in patients with traumatic and compressive SCI, in whom there may also be demyelination.

Demyelination alters the structural and functional relationships of voltage-gated ion channels along the axonal membrane of the nerve cell. Exposed channels cause potassium ions to leak, so causing the axon to 'short circuit'. By closing exposed potassium channels in these damaged nerve fibres, fampridine-SR enables the axon to transmit nerve impulses again.

CLINICAL TRIALS POINT TO EFFICACY IN MS AND SCI

Fampridine-SR has advanced to phase III development in MS, following encouraging results from earlier phase II trials. Data from these trials showed that in comparison with placebo, treatment with fampridine-SR led to an improvement in walking speed and a significant improvement in leg muscle strength. Impaired walking and muscle weakness are two of the most common and devastating aspects of MS.

The phase III programme now underway includes the MS-F204 trial, in which fampridine-SR will be administered to about 200 MS patients. In this trial the safety of fampridine-SR will be evaluated together with its effectiveness in improving walking ability. A consistent improvement in walking speed as measured by the timed 25-foot walk will be the primary outcome measure, with the lower extremity manual muscle test a secondary endpoint.

Improvements over placebo were also observed in the two trials in which fampridine-SR was administered to SCI patients, although the results failed to reach statistical significance for the two primary endpoints: reduction of spasticity as measured by the Ashworth score and improvement of patients' Subject Global Impression (SGI) rating. Despite these results, Acorda Therapeutics remains committed to the continued development of fampridine-SR for SCI.

EXPANDING TREATMENT OPTIONS FOR MS

The advent of the first generation of disease-modifying drugs, which include interferon beta-1a and 1b as well as glatiramer acetate, represented an important advance in the treatment of MS when introduced into clinical practice. Approved for the treatment of relapsing forms of MS, they reduce the frequency and severity of exacerbations as well as the number of lesions seen on magnetic resonance imaging (MRI).

However, while these agents have an immunomodulatory effect that alters the course of the disease, they do not reverse the neurological damage that occurs in MS. Currently, no marketed treatments for MS can produce remyelination and so treatment aims to:

• Reduce the rate of relapse
• Prevent fixed disability directly associated to relapse
• Provide symptomatic management of fixed neurological deficits
• Prevent disability arising from disease progression

Results from trials on fampridine-SR suggest that it may have a beneficial effect on walking and muscle weakness, symptoms of the disease that are not well met by available therapies.

MARKETING COMMENTARY

MS is a chronic and disabling disease, with healthcare costs disproportionate to the numbers affected. In the US alone, costs are estimated to exceed $10bn a year. Walking impairment is a pervasive and seriously debilitating effect of MS. Treatments that have potential to address muscle weakness and improve walking ability could make a significant contribution to improved quality of life in MS and other demyelinating diseases.

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