title: The effects of dexpramipexole (KNS-760704) in individuals with amyotrophic lateral sclerosis.
abstract: Amyotrophic lateral sclerosis (ALS) is characterized by upper and lower motor neuron dysfunction and loss, rapidly progressive muscle weakness, wasting and death. Many factors, including mitochondrial dysfunction, may contribute to ALS pathogenesis. 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. We tested the putative mitochondrial modulator dexpramipexole (KNS-760704; (6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazole-diamine) 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.
authors.affiliation: Neurology Clinical Trial Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Merit
authors.initials: M
authors.lastname: Cudkowicz
authors.forename: Michael E
authors.initials: ME
authors.lastname: Bozik
authors.forename: Evan W
authors.initials: EW
authors.lastname: Ingersoll
authors.forename: Robert
authors.initials: R
authors.lastname: Miller
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mitsumoto
authors.forename: Jeremy
authors.initials: J
authors.lastname: Shefner
authors.forename: Dan H
authors.initials: DH
authors.lastname: Moore
authors.forename: David
authors.initials: D
authors.lastname: Schoenfeld
authors.forename: James L
authors.initials: JL
authors.lastname: Mather
authors.forename: Donald
authors.initials: D
authors.lastname: Archibald
authors.forename: Mary
authors.initials: M
authors.lastname: Sullivan
authors.forename: Craig
authors.initials: C
authors.lastname: Amburgey
authors.forename: Juliet
authors.initials: J
authors.lastname: Moritz
authors.forename: Valentin K
authors.initials: VK
authors.lastname: Gribkoff
mesh_terms: D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy*; D052160:Benzothiazoles / Q000009:adverse effects / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects; D053580:Muscle Strength / Q000187:drug effects; D009132:Muscles / Q000503:physiopathology*; D000077487:Pramipexole; D019782:Riluzole / Q000627:therapeutic use; D016037:Single-Blind Method
chemical_list: D052160:Benzothiazoles; D019782:Riluzole; D000077487:Pramipexole
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