Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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 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.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

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.

References

  1. Rowland, L.P. & Shneider, N.A. Amyotrophic lateral sclerosis. N. Engl. J. Med. 344, 1688–1700 (2001).

    CAS  Article  Google Scholar 

  2. Wijesekera, L.C. & Leigh, P.N. Amyotrophic lateral sclerosis. Orphanet J. Rare Dis. 4, 3 (2009).

    Article  Google Scholar 

  3. Vucic, S. & Kiernan, M.C. Pathophysiology of neurodegeneration in familial amyotrophic lateral sclerosis. Curr. Mol. Med. 9, 255–272 (2009).

    CAS  Article  Google Scholar 

  4. Hervias, I., Beal, M.F. & Manfredi, G. Mitochondrial dysfunction and amyotrophic lateral sclerosis. Muscle Nerve 33, 598–608 (2006).

    CAS  Article  Google Scholar 

  5. Manfredi, G. & Xu, Z. Mitochondrial dysfunction and its role in motor neuron degeneration in ALS. Mitochondrion 5, 77–87 (2005).

    CAS  Article  Google Scholar 

  6. Baron, M., Kudin, A.P. & Kunz, W.S. Mitochondrial dysfunction in neurodegenerative disorders. Biochem. Soc. Trans. 35, 1228–1231 (2007).

    CAS  Article  Google Scholar 

  7. Corti, S. et al. Amyotrophic lateral sclerosis linked to a novel SOD1 mutation with muscle mitochondrial dysfunction. J. Neurol. Sci. 276, 170–174 (2009).

    CAS  Article  Google Scholar 

  8. Kawamata, H. & Manfredi, G. Mitochondrial dysfunction and intracellular calcium dysregulation in ALS. Mech. Ageing Dev. 131, 517–526 (2010).

    CAS  Article  Google Scholar 

  9. Shi, P., Wei, Y., Zhang, J., Gal, J. & Zhu, H. Mitochondrial dysfunction is a converging point of multiple pathological pathways in amyotrophic lateral sclerosis. J. Alzheimers Dis. 20 (suppl. 2), S311–S324 (2010).

    Article  Google Scholar 

  10. Messori, A., Trippoli, S., Becagli, P. & Zaccara, G. Cost effectiveness of riluzole in amyotrophic lateral sclerosis. Italian Cooperative Group for the Study of Meta-Analysis and the Osservatorio SIFO sui Farmaci. Pharmacoeconomics 16, 153–163 (1999).

    CAS  Article  Google Scholar 

  11. Stewart, A. et al. The clinical effectiveness and cost-effectiveness of riluzole for motor neurone disease: a rapid and systematic review. Health Technol. Assess. 5, 1–97 (2001).

    CAS  Article  Google Scholar 

  12. Gribkoff, V.K. & Bozik, M.E. KNS-760704 [(6R)-4,5,6,7-tetrahydro-N6-propyl-2, 6-benzothiazole-diamine dihydrochloride monohydrate] for the treatment of amyotrophic lateral sclerosis. CNS Neurosci. Ther. 14, 215–226 (2008).

    CAS  Article  Google Scholar 

  13. Wang, H. et al. R+ pramipexole as a mitochondrially focused neuroprotectant: initial early phase studies in ALS. Amyotroph. Lateral Scler. 9, 50–58 (2008).

    Article  Google Scholar 

  14. Bozik, M.E., Mather, J.M., Kramer, W.H., Gribkoff, V.K. & Ingersoll, E.W. Safety, tolerability and pharmacokinetics of KNS-760704 (dexpramipexole) in healthy adult subjects. J. Clin. Pharmacol. 51, 1177–1185 (2010).

    Article  Google Scholar 

  15. Cudkowicz, M.E. et al. Toward more efficient clinical trials for amyotrophic lateral sclerosis. Amyotroph. Lateral Scler. 11, 259–265 (2010).

    CAS  Article  Google Scholar 

  16. Cheung, Y.K., Gordon, P.H. & Levin, B. Selecting promising ALS therapies in clinical trials. Neurology 67, 1748–1751 (2006).

    CAS  Article  Google Scholar 

  17. Groeneveld, G.J., Graf, M., van, d.T.I., van den Berg, L.H. & Ludolph, A.C. Alternative trial design in amyotrophic lateral sclerosis saves time and patients. Amyotroph. Lateral Scler. 8, 266–269 (2007).

    Article  Google Scholar 

  18. Gordon, P.H. et al. Outcome measures for early phase clinical trials. Amyotroph. Lateral Scler. 8, 270–273 (2007).

    Article  Google Scholar 

  19. Schoenfeld, D.A. & Cudkowicz, M. Design of phase II ALS clinical trials. Amyotroph. Lateral Scler. 9, 16–23 (2008).

    CAS  Article  Google Scholar 

  20. Shefner, J.M. Designing clinical trials in amyotrophic lateral sclerosis. Phys. Med. Rehabil. Clin. N. Am. 19, 495–508 (2008).

    Article  Google Scholar 

  21. Bedlack, R.S., Pastula, D.M., Welsh, E., Pulley, D. & Cudkowicz, M.E. Scrutinizing enrollment in ALS clinical trials: room for improvement? Amyotroph. Lateral Scler. 9, 257–265 (2008).

    Article  Google Scholar 

  22. Laird, N.M. & Ware, J.H. Random-effects models for longitudinal data. Biometrics 38, 963–974 (1982).

    CAS  Article  Google Scholar 

  23. Aggarwal, S.P. et al. Safety and efficacy of lithium in combination with riluzole for treatment of amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 9, 481–488 (2010).

    CAS  Article  Google Scholar 

  24. Castrillo-Viguera, C., Grasso, D.L., Simpson, E., Shefner, J. & Cudkowicz, M.E. Clinical significance in the change of decline in ALSFRS-R. Amyotroph. Lateral Scler. 11, 178–180 (2010).

    Article  Google Scholar 

  25. Cedarbaum, J.M. et al. The ALSFRS-R: a revised ALS functional rating scale that incorporates assessments of respiratory function. BDNF ALS Study Group (phase III). J. Neurol. Sci. 169, 13–21 (1999).

    CAS  Article  Google Scholar 

  26. Miller, R. et al. Phase II/III randomized trial of TCH346 in patients with ALS. Neurology 69, 776–784 (2007).

    CAS  Article  Google Scholar 

  27. Gordon, P.H. & Cheung, Y.K. Progression rate of ALSFRS-R at time of diagnosis predicts survival time in ALS. Neurology 67, 1314–1315 (2006).

    Article  Google Scholar 

  28. Kollewe, K. et al. ALSFRS-R score and its ratio: a useful predictor for ALS-progression. J. Neurol. Sci. 275, 69–73 (2008).

    Article  Google Scholar 

  29. Liu, X.X., Fan, D.S., Zhang, J., Zhang, S. & Zheng, J.Y. Zhonghua Yi Xue Za Zhi [Revised amyotrophic lateral sclerosis functional rating scale at time of diagnosis predicts survival time in amyotrophic lateral sclerosis] 89, 2472–2475 (2009).

  30. Kaufmann, P. et al. The ALSFRSr predicts survival time in an ALS clinic population. Neurology 64, 38–43 (2005).

    CAS  Article  Google Scholar 

  31. Gordon, P.H., Miller, R.G. & Moore, D.H. ALSFRS-R. Amyotroph. Lateral Scler. Other Motor Neuron Disord. 5 (suppl. 1), 90–93 (2004).

    Google Scholar 

  32. Kaufmann, P. et al. Excellent inter-rater, intra-rater and telephone-administered reliability of the ALSFRS-R in a multicenter clinical trial. Amyotroph. Lateral Scler. 8, 42–46 (2007).

    Article  Google Scholar 

  33. Aggarwal, S.P. et al. Safety and efficacy of lithium in combination with riluzole for treatment of amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 9, 481–488 (2010).

    CAS  Article  Google Scholar 

  34. Cohen, S.R. et al. Validity of the McGill Quality of Life Questionnaire in the palliative care setting: a multi-centre Canadian study demonstrating the importance of the existential domain. Palliat. Med. 11, 3–20 (1997).

    Article  Google Scholar 

  35. Simmons, Z., Bremer, B.A., Robbins, R.A., Walsh, S.M. & Fischer, S. Quality of life in ALS depends on factors other than strength and physical function. Neurology 55, 388–392 (2000).

    CAS  Article  Google Scholar 

  36. Gordon, P.H. et al. Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomised trial. Lancet Neurol. 6, 1045–1053 (2007).

    CAS  Article  Google Scholar 

  37. Miller, R. et al. Phase II/III randomized trial of TCH346 in patients with ALS. Neurology 69, 776–784 (2007).

    CAS  Article  Google Scholar 

  38. Cudkowicz, M.E. et al. Trial of celecoxib in amyotrophic lateral sclerosis. Ann. Neurol. 60, 22–31 (2006).

    CAS  Article  Google Scholar 

  39. Finkelstein, D.M. & Schoenfeld, D.A. Combining mortality and longitudinal measures in clinical trials. Stat. Med. 18, 1341–1354 (1999).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

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).

Author information

Authors and Affiliations

Authors

Contributions

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.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

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

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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). https://doi.org/10.1038/nm.2579

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.2579

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing