Nat Med：新药或可治疗肌萎缩性脊髓侧索硬化症

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

Merit Cudkowicz, Michael E Bozik, Evan W Ingersoll, Robert Miller, Hiroshi Mitsumoto, Jeremy Shefner, Dan H Moore, David Schoenfeld, James L Mather, Donald Archibald, Mary Sullivan, Craig Amburgey, Juliet Moritz & Valentin K Gribkoff

Amyotrophic lateral sclerosis (ALS) is characterized by upper and lower motor neuron dysfunction and loss, rapidly progressive muscle weakness, wasting and death1, 2, 3. Many factors, including mitochondrial dysfunction, may contribute to ALS pathogenesis4, 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 ALS10, 11. We tested the putative mitochondrial modulator dexpramipexole (KNS-760704; (6R)-4,5,6,7-tetrahydro-N6-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.