The past decade has seen a remarkable expansion in the treatment options for multiple sclerosis (MS). Glatiramer acetate and the beta interferons have become the “gold standards” for treatment of relapsing-remitting MS (RRMS), while the immunosuppressant mitoxantrone is approved for the treatment of worsening RRMS, secondary-progressive MS (SPMS), and progressive-relapsing MS (PRMS). Researchers continue to build upon this foundation of agents and explore new avenues for MS treatment, including a glatiramer acetate/beta interferon combination, the immunosuppressive drug methotrexate, and the new experimental agent fampridine.

Because glatiramer acetate and the beta interferons appear to work through different mechanisms of action, some researchers have hypothesized that combining these agents will allow for a more effective attack on the pathologic processes of MS. However, a new study by Charlotte Ytterberg, Karolinska Institutet, Stockholm, Sweden, and colleagues^† comparing this combination therapy with monotherapy of either glatiramer acetate or intramuscular (IM) interferon found no additional benefit for the combination.

The study was a subgroup analysis of a 2-year, prospective, observational study of 219 MS patients who had received monotherapy with either glatiramer acetate or 1 of the 3 interferon therapies. In the subgroup analysis, 62 monotherapy patients continued on monotherapy for 24 months, while 20 IM interferon patients added glatiramer acetate to their treatment regimens, and 1 glatiramer acetate patient added IM interferon for a period of 16 to 24 months. No statistically significant difference was seen for the primary outcome measure, change in MS Functional Composite (MSFC) scores. However, the investigators also noted that glatiramer acetate and IM interferon produced no adverse interactions. They conclude that these results indicate the need for a phase III study of combination therapy.

Another distinct pathway for attacking MS is represented by the experimental drug fampridine, which is a selective blocker of voltage-dependent neuronal potassium channels that affect conduction in demyelinated axons, according to Andrew Goodman, University of Rochester Medical Center, Rochester, New York, and colleagues.^† Previous studies have shown that it can restore action potential conduction in damaged, partially myelinated nerve fibers and may also directly enhance synaptic transmission.

To assess whether these properties translate into clinical benefit, Dr. Goodman and colleagues randomized 206 patients to receive placebo or 10, 15, or 20 mg of a sustained-release formulation of fampridine twice daily. This study included a 2-week placebo run-in, 2 weeks of dose escalation, 12 weeks of stable treatment phase, 1 week of down-titration, and a 2-week follow up. A subset of patients in each fampridine treatment group (35% for 10 mg, 36% for 15 mg, 39% for 20 mg) consistently improved walking speed while on drug vs placebo (9%), as measured by the Timed 25-Foot Walk section of MSFC, that was maintained over the full course of treatment. These results, as well as positive findings for other scores, such as the Subject Global Impression test, support the continued investigation of fampridine for improvement of ambulatory function in MS patients.

Although RRMS responds well to currently approved therapies, SPMS and primary-progressive MS remain treatment challenges. A proportion of SPMS patients respond poorly to FDA-approved disease-modifying agents, while PPMS patients do not respond at all, noted Saud Sadiq, Albert Einstein College of Medicine, New York, New York.^† A new study by Dr. Sadiq evaluated pulsed intrathecal methotrexate for this patient population.

In this open-label phase I safety and tolerability study, 91 patients with RRMS/SPMS and 35 patients with PPMS were treated with intrathecal injections of 12 mg of methotrexate every 2 months. This was an open-ended study, and patients could discontinue treatment at any time; the longest treatment period in the study was approximately 2 years. Although the study lacked a control group, methotrexate treatment appeared to stabilize disease progression (as measured by Expanded Disability Status Scale scores) in about 90% of both SPMS and PPMS patients. In addition, quality of life was found to improve in 63% of SPMS patients and 40% of PPMS patients. The drug was well tolerated and appeared to be safe, without significant adverse effects. According to Dr. Sadiq and colleagues, these data suggest that methotrexate may be an important and safe option for patients with severe MS who are unresponsive to currently approved drugs.

^*Presented at EFNS, Athens, Greece, September 17–20, 2005.
^†Presented at ANA, San Diego, California, September 25–28, 2005.