The effects of dexpramipexole (KNS-760704) in individuals with amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that primarily affects motor neurons. Now, Valentin Gribkoff and his colleagues show some preliminary evidence that the drug dexpramipexole may have clinical activity in a small placebo-controlled trial in patients with ALS. Amyotrophic lateral sclerosis (ALS) is characterized by upper and lower motor neuron dysfunction and loss, rapidly progressive muscle weakness, wasting and death 1 , 2 , 3 . Many factors, including mitochondrial dysfunction, may contribute to ALS pathogenesis 4 , 5 , 6 , 7 , 8 , 9 . Riluzole, which has shown only modest benefits in a measure of survival time without demonstrated effects on muscle strength or function, is the only approved treatment for ALS 10 , 11 . We tested the putative mitochondrial modulator dexpramipexole (KNS-760704; (6 R )-4,5,6,7-tetrahydro- N 6-propyl-2,6-benzothiazole-diamine) 12 , 13 , 14 in subjects with ALS in a two-part, double-blind safety and tolerability study, with a preliminary assessment of its effects on functional decline and mortality. In part 1, the effects of dexpramipexole (50, 150 or 300 mg d −1 ) versus placebo were assessed over 12 weeks. In part 2, after a 4-week, single-blind placebo washout, continuing subjects were re-randomized to dexpramipexole at 50 mg d −1 or 300 mg d −1 as double-blind active treatment for 24 weeks. Dexpramipexole was safe and well tolerated. Trends showing a dose-dependent attenuation of the slope of decline of the ALS Functional Rating Scale-Revised (ALSFRS-R) in part 1 and a statistically significant ( P = 0.046) difference between groups in a joint rank test of change from baseline in ALSFRS-R and mortality in part 2 strongly support further testing of dexpramipexole in ALS.