Dalfampridine is a lipid-soluble small molecule that more readily crosses the blood-rain barrier and, therefore, its effects on the central nervous system (CNS) have been the subject of greater focus. The initial Phase 2 study determined the safety of escalating doses of dalfampridine in subjects with multiple sclerosis (MS), to explore a number of outcome measures, and examine dose related efficacy. A battery of assessments was performed weekly, including the MS Functional Composite (MSFC), fatigue questionnaires, lower extremity manual muscle testing, and spasticity assessment using the Ashworth scale. The results supported the idea that quantitative functional outcome measures (such as walking speed derived from timed gait and lower extremity muscle testing) were sufficiently sensitive to demonstrate efficacy. Based on evaluation, the US food and drug administration (FDA) approved the extended release (ER) formulation of dalfampridine (daily oral dose of 10 mg BID) for use in MS to improve walking.

The atypical characteristics of primary progressive multiple sclerosis (PPMS) have presented problems in the recruitment to and design of therapeutic trials. The problem areas in the implementation of therapeutic trials are: diagnostic criteria, sample size calculations, and choice of outcome measures. Although there is no definitively proven disease-modifying treatment available for PPMS, several randomized controlled trials have now been specifically designed for this group. The clinical trials in PPMS are based on glatiramer acetate and rituximab. The planned clinical trials in PPMS are based on fingolimod (FTY720) and cladribine. The smaller trials in PPMS are based on Interferon beta-1a, Interferon beta-1b, mitoxantrone and riluzole. A retrospective open-label study of intravenous cyclophosphamide and methylprednisolone in progressive MS included 128 patients with PPMS. PPMS may be the ideal model to investigate disease progression and neuronal protection, and is becoming an important focus for treatment trials in these areas.