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


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.

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Figure 1: Schematic of the design of parts 1 and 2 of the study.
Figure 2: The effects of dexpramipexole in parts 1 and 2 of the study.


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We wish to thank the members of the KNS-760704-CL201 study group and acknowledge their substantial contributions to the success of this project (see list of members in the Supplementary Acknowledgments).

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Authors and Affiliations



M.C., R.M., H.M., J.S., D.H.M. and D.S. served as expert clinical and statistical advisors to the sponsor, Knopp Biosciences, and collaborated with M.E.B., E.W.I., J.L.M., D.A., M.S., C.A., J.M. and V.K.G. with respect to the design of the study. E.W.I., J.L.M., C.A., and J.M. were principally responsible for the clinical operations and execution of the study. M.E.B. was principally responsible for medical monitoring and patient safety assessments for the study. D.A. was principally responsible for the statistical analysis of the study with input from D.H.M. and D.S. who served in an advisory capacity. M.S. and E.W.I. were principally responsible for ensuring regulatory compliance with US federal regulations governing sponsored clinical research for the duration of the study. V.K.G., E.W.I., M.E.B., D.A., J.L.M. and M.C. collaborated to write the manuscript.

Corresponding author

Correspondence to Valentin K Gribkoff.

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The authors declare no competing financial interests.

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Supplementary Figures 1 and 2, Supplementary Tables 1–9 and Supplementary Methods (PDF 493 kb)

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Cudkowicz, M., Bozik, M., Ingersoll, E. et al. The effects of dexpramipexole (KNS-760704) in individuals with amyotrophic lateral sclerosis. Nat Med 17, 1652–1656 (2011).

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