DOI QR코드

DOI QR Code

Update of Therapeutic Clinical Trials for Amyotrophic Lateral Sclerosis

근위축측삭경화증에 대한 치료약물 임상시험 현황

  • Kim, Nam-Hee (Department of Neurology, Dongguk University Ilsan Hospital) ;
  • Lee, Min Oh (Department of Neurology, Dongguk University Ilsan Hospital)
  • 김남희 (동국대학교 일산병원 신경과) ;
  • 이민오 (동국대학교 일산병원 신경과)
  • Received : 2014.12.12
  • Accepted : 2015.05.29
  • Published : 2015.06.30

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that is characterized by progressive death of motor neurons in the cortex, brainstem, and spinal cord. Until now, many treatment strategies have been tested in ALS, but so far only Riluzole has shown efficacy of slightly slowing disease progression. The pathophysiological mechanisms underlying ALS are multifactorial, with a complex interaction between genetic factors and molecular pathways. Other motor neuron disease such as spinal muscular atrophy (SMA) and spinobulbar muscular atrophy (SBMA) are also progressive neurodegenerative disease with loss of motor neuron as ALS. This common thread of motor neuron loss has provided a target for the development of therapies for these motor neuron diseases. A better understanding of these pathogenic mechanisms and the potential pathological relationship between the various cellular processes have suggested novel therapeutic approaches, including stem cell and genetics-based strategies, providing hope for feasible treatment of ALS.

Keywords

References

  1. Morren JA, Galvez-Jimenez N. Current and prospective diseasemodifying therapies for amyotrophic lateral sclerosis. Expert Opin Investig Drugs 2012;21:297-320. https://doi.org/10.1517/13543784.2012.657303
  2. Bensimon G, Lacomblez L, Meininger V. A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole Study Group. N Engl J Med 1994;330:585-591. https://doi.org/10.1056/NEJM199403033300901
  3. Miller RG, Mitchell JD, Moore DH. Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Cochrane Database Syst Rev 2012;3:CD001447.
  4. Miller RG, Moore DH, 2nd, Gelinas DF, Dronsky V, Mendoza M, Barohn RJ, et al. Phase III randomized trial of gabapentin in patients with amyotrophic lateral sclerosis. Neurology 2001;56:843-848.
  5. Cudkowicz ME, Shefner JM, Schoenfeld DA, Brown RH, Jr., Johnson H, Qureshi M, et al. A randomized, placebo-controlled trial of topiramate in amyotrophic lateral sclerosis. Neurology 2003;61:456-464. https://doi.org/10.1212/WNL.61.4.456
  6. Ryberg H, Askmark H, Persson LI. A double-blind randomized clinical trial in amyotrophic lateral sclerosis using lamotrigine: effects on CSF glutamate, aspartate, branched-chain amino acid levels and clinical parameters. Acta Neurol Scand 2003;108:1-8.
  7. Piepers S, Veldink JH, de Jong SW, van der Tweel I, van der Pol WL, Uijtendaal EV, et al. Randomized sequential trial of valproic acid in amyotrophic lateral sclerosis. Ann Neurol 2009;66:227-234. https://doi.org/10.1002/ana.21620
  8. ClinicalTrials.gov. Amyotrophic lateral sclerosis [Internet]. Bethesda (MD, US): U.S. National Institutes of Health; c2015 [cited 2015 Feb 9]. Available from: https://clinicaltrials.gov/ct2/results?term=ALS+AND+Amyotrophic+Lateral+Sclerosis+%28ALS%29.
  9. Tateishi N, Mori T, Kagamiishi Y, Satoh S, Katsube N, Morikawa E, et al. Astrocytic activation and delayed infarct expansion after permanent focal ischemia in rats. Part II: suppression of astrocytic activation by a novel agent (R)-(-)-2-propyloctanoic acid (ONO-2506) leads to mitigation of delayed infarct expansion and early improvement of neurologic deficits. J Cereb Blood Flow Metab 2002;22:723-734. https://doi.org/10.1097/00004647-200206000-00011
  10. de Carvalho M, Pinto S, Costa J, Evangelista T, Ohana B, Pinto A. A randomized, placebo-controlled trial of memantine for functional disability in amyotrophic lateral sclerosis. Amyotroph Lateral Scler 2010;11:456-460. https://doi.org/10.3109/17482968.2010.498521
  11. Goyal NA, Mozaffar T. Experimental trials in amyotrophic lateral sclerosis: a review of recently completed, ongoing and planned trials using existing and novel drugs. Expert Opin Investig Drugs 2014;23:1541-1551. https://doi.org/10.1517/13543784.2014.933807
  12. Pascuzzi RM, Shefner J, Chappell AS, Bjerke JS, Tamura R, Chaudhry V, et al. A phase II trial of talampanel in subjects with amyotrophic lateral sclerosis. Amyotroph Lateral Scler 2010;11:266-271. https://doi.org/10.3109/17482960903307805
  13. Berry JD, Shefner JM, Conwit R, Schoenfeld D, Keroack M, Felsenstein D, et al. Design and initial results of a multi-phase randomized trial of ceftriaxone in amyotrophic lateral sclerosis. PLoS One 2013;8:e61177. https://doi.org/10.1371/journal.pone.0061177
  14. Kong Q, Chang LC, Takahashi K, Liu Q, Schulte DA, Lai L, et al. Small-molecule activator of glutamate transporter EAAT2 translation provides neuroprotection. J Clin Invest 2014;124:1255-1267. https://doi.org/10.1172/JCI66163
  15. Izumi Y, Kaji R. [Clinical trials of ultra-high-dose methylcobalamin in ALS]. Brain Nerve 2007;59:1141-1147.
  16. Desnuelle C, Dib M, Garrel C, Favier A. A double-blind, placebo- controlled randomized clinical trial of alpha-tocopherol (vitamin E) in the treatment of amyotrophic lateral sclerosis. ALS riluzole-tocopherol Study Group. Amyotroph Lateral Scler Other Motor Neuron Disord 2001;2:9-18. https://doi.org/10.1080/146608201300079364
  17. Orrell RW. AEOL-10150 (Aeolus). Curr Opin Investig Drugs 2006;7:70-80.
  18. Abe K, Itoyama Y, Sobue G, Tsuji S, Aoki M, Doyu M, et al. Confirmatory double-blind, parallel-group, placebo-controlled study of efficacy and safety of edaravone (MCI-186) in amyotrophic lateral sclerosis patients. Amyotroph Lateral Scler Frontotemporal Degener 2014;15:610-617. https://doi.org/10.3109/21678421.2014.959024
  19. Yoshino H, Kimura A. Investigation of the therapeutic effects of edaravone, a free radical scavenger, on amyotrophic lateral sclerosis (Phase II study). Amyotroph Lateral Scler 2006;7:241-245. https://doi.org/10.1080/17482960600664870
  20. ALSTDI homepage. Research center: Clinical Trials [Internet]. Cambridge, (MA, USA): ALS Therapy Development Institute; c2015 [cited 2015 Feb 9]. Available from: http://www.als.net/ALS-Research/ALS-Clinical-Trials/.
  21. Louwerse ES, Weverling GJ, Bossuyt PM, Meyjes FE, de Jong JM. Randomized, double-blind, controlled trial of acetylcysteine in amyotrophic lateral sclerosis. Arch Neurol 1995;52:559-564. https://doi.org/10.1001/archneur.1995.00540300031009
  22. Paganoni S, Zhang M, Quiroz Zarate A, Jaffa M, Yu H, Cudkowicz ME, et al. Uric acid levels predict survival in men with amyotrophic lateral sclerosis. J Neurol 2012;259:1923-1928. https://doi.org/10.1007/s00415-012-6440-7
  23. Zinman L, Cudkowicz M. Emerging targets and treatments in amyotrophic lateral sclerosis. Lancet Neurol 2011;10:481-490. https://doi.org/10.1016/S1474-4422(11)70024-2
  24. Gordon PH, Moore DH, Miller RG, Florence JM, Verheijde JL, Doorish C, et al. Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomised trial. Lancet Neurol 2007;6:1045-1053. https://doi.org/10.1016/S1474-4422(07)70270-3
  25. Shefner JM, Cudkowicz ME, Schoenfeld D, Conrad T, Taft J, Chilton M, et al. A clinical trial of creatine in ALS. Neurology 2004;63:1656-1661. https://doi.org/10.1212/01.WNL.0000142992.81995.F0
  26. Kaufmann P, Thompson JL, Levy G, Buchsbaum R, Shefner J, Krivickas LS, et al. Phase II trial of CoQ10 for ALS finds insufficient evidence to justify phase III. Ann Neurol 2009;66:235-244. https://doi.org/10.1002/ana.21743
  27. Cudkowicz M, Bozik ME, Ingersoll EW, Miller R, Mitsumoto H, Shefner J, et al. The effects of dexpramipexole (KNS-760704) in individuals with amyotrophic lateral sclerosis. Nat Med 2011;17:1652-1656. https://doi.org/10.1038/nm.2579
  28. Cudkowicz ME, van den Berg LH, Shefner JM, Mitsumoto H, Mora JS, Ludolph A, et al. Dexpramipexole versus placebo for patients with amyotrophic lateral sclerosis (EMPOWER): a randomised, double-blind, phase 3 trial. Lancet Neurol 2013;12:1059-1067. https://doi.org/10.1016/S1474-4422(13)70221-7
  29. Lenglet T, Lacomblez L, Abitbol JL, Ludolph A, Mora JS, Robberecht W, et al. A phase II-III trial of olesoxime in subjects with amyotrophic lateral sclerosis. Eur J Neurol 2014;21:529-536. https://doi.org/10.1111/ene.12344
  30. Min JH, Hong YH, Sung JJ, Kim SM, Lee JB, Lee KW. Oral solubilized ursodeoxycholic acid therapy in amyotrophic lateral sclerosis: a randomized cross-over trial. J Korean Med Sci 2012;27:200-206. https://doi.org/10.3346/jkms.2012.27.2.200
  31. Weishaupt JH, Bartels C, Polking E, Dietrich J, Rohde G, Poeggeler B, et al. Reduced oxidative damage in ALS by highdose enteral melatonin treatment. J Pineal Res 2006;41:313-323. https://doi.org/10.1111/j.1600-079X.2006.00377.x
  32. Keep M, Elmer E, Fong KS, Csiszar K. Intrathecal cyclosporin prolongs survival of late-stage ALS mice. Brain Res 2001;894:327-331. https://doi.org/10.1016/S0006-8993(01)02012-1
  33. Cudkowicz ME, Shefner JM, Schoenfeld DA, Zhang H, Andreasson KI, Rothstein JD, et al. Trial of celecoxib in amyotrophic lateral sclerosis. Ann Neurol 2006;60:22-31. https://doi.org/10.1002/ana.20903
  34. Stommel EW, Cohen JA, Fadul CE, Cogbill CH, Graber DJ, Kingman L, et al. Efficacy of thalidomide for the treatment of amyotrophic lateral sclerosis: a phase II open label clinical trial. Amyotroph Lateral Scler 2009;10:393-404. https://doi.org/10.3109/17482960802709416
  35. Meininger V, Drory VE, Leigh PN, Ludolph A, Robberecht W, Silani V. Glatiramer acetate has no impact on disease progression in ALS at 40 mg/day: a double-blind, randomized, multicentre, placebo-controlled trial. Amyotroph Lateral Scler 2009;10:378-383. https://doi.org/10.3109/17482960902803432
  36. Miller RG, Zhang R, Block G, Katz J, Barohn R, Kasarskis E, et al. NP001 regulation of macrophage activation markers in ALS: A phase I clinical and biomarker study. Amyotroph Lateral Scler Frontotemporal Degener 2014;15:601-609. https://doi.org/10.3109/21678421.2014.951940
  37. Dupuis L, Dengler R, Heneka MT, Meyer T, Zierz S, Kassubek J, et al. A randomized, double blind, placebo-controlled trial of pioglitazone in combination with riluzole in amyotrophic lateral sclerosis. PLoS One 2012;7:e37885. https://doi.org/10.1371/journal.pone.0037885
  38. Sorenson EJ, Windbank AJ, Mandrekar JN, Bamlet WR, Appel SH, Armon C, et al. Subcutaneous IGF-1 is not beneficial in 2-year ALS trial. Neurology 2008;71:1770-1775. https://doi.org/10.1212/01.wnl.0000335970.78664.36
  39. Hansen R, Saikali KG, Chou W, Russell AJ, Chen MM, Vijayakumar V, et al. Tirasemtiv amplifies skeletal muscle response to nerve activation in humans. Muscle Nerve 2014;50:925-931. https://doi.org/10.1002/mus.24239
  40. Meininger V, Bensimon G, Bradley WR, Brooks B, Douillet P, Eisen AA, et al. Efficacy and safety of xaliproden in amyotrophic lateral sclerosis: results of two phase III trials. Amyotroph Lateral Scler Other Motor Neuron Disord 2004;5:107-117. https://doi.org/10.1080/14660820410019602
  41. Scelsa SN, MacGowan DJ, Mitsumoto H, Imperato T, LeValley AJ, Liu MH, et al. A pilot, double-blind, placebo-controlled trial of indinavir in patients with ALS. Neurology 2005;64:1298-1300. https://doi.org/10.1212/01.WNL.0000156913.24701.72
  42. Miller R, Bradley W, Cudkowicz M, Hubble J, Meininger V, Mitsumoto H, et al. Phase II/III randomized trial of TCH346 in patients with ALS. Neurology 2007;69:776-784. https://doi.org/10.1212/01.wnl.0000269676.07319.09
  43. Meininger V, Asselain B, Guillet P, Leigh PN, Ludolph A, Lacomblez L, et al. Pentoxifylline in ALS: a double-blind, randomized, multicenter, placebo-controlled trial. Neurology 2006;66:88-92. https://doi.org/10.1212/01.wnl.0000191326.40772.62
  44. Cross AH, Naismith RT. Established and novel disease-modifying treatments in multiple sclerosis. J Intern Med 2014;275:350-363. https://doi.org/10.1111/joim.12203
  45. Cudkowicz ME, Andres PL, Macdonald SA, Bedlack RS, Choudry R, Brown RH Jr., et al. Phase 2 study of sodium phenylbutyrate in ALS. Amyotroph Lateral Scler 2009;10:99-106. https://doi.org/10.1080/17482960802320487
  46. Kalmar B, Lu CH, Greensmith L. The role of heat shock proteins in Amyotrophic Lateral Sclerosis: The therapeutic potential of Arimoclomol. Pharmacol Ther 2014;141:40-54. https://doi.org/10.1016/j.pharmthera.2013.08.003
  47. Cudkowicz ME, Shefner JM, Simpson E, Grasso D, Yu H, Zhang H, et al. Arimoclomol at dosages up to 300 mg/day is well tolerated and safe in amyotrophic lateral sclerosis. Muscle Nerve 2008;38:837-844. https://doi.org/10.1002/mus.21059
  48. Aggarwal SP, Zinman L, Simpson E, McKinley J, Jackson KE, Pinto H, 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 2010;9:481-488. https://doi.org/10.1016/S1474-4422(10)70068-5
  49. Dunlop RA, Cox PA, Banack SA, Rodgers KJ. The non-protein amino acid BMAA is misincorporated into human proteins in place of L-serine causing protein misfolding and aggregation. PLoS One 2013;8:e75376. https://doi.org/10.1371/journal.pone.0075376
  50. Miller TM, Pestronk A, David W, Rothstein J, Simpson E, Appel SH, et al. An antisense oligonucleotide against SOD1 delivered intrathecally for patients with SOD1 familial amyotrophic lateral sclerosis: a phase 1, randomised, first-in-man study. Lancet Neurol 2013;12:435-442. https://doi.org/10.1016/S1474-4422(13)70061-9
  51. Shefner J, Cedarbaum JM, Cudkowicz ME, Maragakis N, Lee J, Jones D, et al. Safety, tolerability and pharmacodynamics of a skeletal muscle activator in amyotrophic lateral sclerosis. Amyotroph Lateral Scler 2012;13:430-438. https://doi.org/10.3109/17482968.2012.684214
  52. Thomsen GM, Gowing G, Svendsen S, Svendsen CN. The past, present, and future of stem cell clinical trials for ALS. Exp Neurol 2014;262:127-137. https://doi.org/10.1016/j.expneurol.2014.02.021