Tolerability and Efficacy of L-Serine in Patients With Amyotrophic Lateral Sclerosis (ALS)

Summary

The purpose of this study is to determine the tolerability of L-Serine oral doses for ALS patients and assess preliminary indications of efficacy

Timeline

Start

2018-10-24

Primary completion

2022-08-03

Completion

2022-12-20

Publications

• Background Abe K, Itoyama Y, Sobue G, Tsuji S, Aoki M, Doyu M, Hamada C, Kondo K, Yoneoka T, Akimoto M, Yoshino H; Edaravone ALS Study Group. 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 Dec;15(7-8):610-7. doi: 10.3109/21678421.2014.959024. Epub 2014 Oct 6.
• Background Andrew AS, Caller TA, Tandan R, Duell EJ, Henegan PL, Field NC, Bradley WG, Stommel EW. Environmental and Occupational Exposures and Amyotrophic Lateral Sclerosis in New England. Neurodegener Dis. 2017;17(2-3):110-116. doi: 10.1159/000453359. Epub 2017 Jan 26.
• Background Brannath W, Burger HU, Glimm E, Stallard N, Vandemeulebroecke M, Wassmer G. Comments on the draft guidance on "adaptive design clinical trials for drugs and biologics" of the U.S. Food and Drug Administration. J Biopharm Stat. 2010 Nov;20(6):1125-31. doi: 10.1080/10543406.2010.514453.
• Background Banack SA, Murch SJ, Cox PA. Neurotoxic flying foxes as dietary items for the Chamorro people, Marianas Islands. J Ethnopharmacol. 2006 Jun 15;106(1):97-104. doi: 10.1016/j.jep.2005.12.032. Epub 2006 Feb 7.
• Background Braak H, Braak E. Staging of Alzheimer's disease-related neurofibrillary changes. Neurobiol Aging. 1995 May-Jun;16(3):271-8; discussion 278-84. doi: 10.1016/0197-4580(95)00021-6.
• Background Caller TA, Andrews A, Field NC, Henegan PL, Stommel EW. The Epidemiology of Amyotrophic Lateral Sclerosis in New Hampshire, USA, 2004-2007. Neurodegener Dis. 2015;15(4):202-6. doi: 10.1159/000374117. Epub 2015 Apr 16.
• Background Canu N, Ciotti MT, Pollegioni L. Serine racemase: a key player in apoptosis and necrosis. Front Synaptic Neurosci. 2014 Apr 21;6:9. doi: 10.3389/fnsyn.2014.00009. eCollection 2014.
• Background Cox PA, Banack SA, Murch SJ. Biomagnification of cyanobacterial neurotoxins and neurodegenerative disease among the Chamorro people of Guam. Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13380-3. doi: 10.1073/pnas.2235808100.
• Background Cox PA, Davis DA, Mash DC, Metcalf JS, Banack SA. Dietary exposure to an environmental toxin triggers neurofibrillary tangles and amyloid deposits in the brain. Proc Biol Sci. 2016 Jan 27;283(1823):20152397. doi: 10.1098/rspb.2015.2397.
• Background de Koning TJ. Treatment with amino acids in serine deficiency disorders. J Inherit Metab Dis. 2006 Apr-Jun;29(2-3):347-51. doi: 10.1007/s10545-006-0269-0.
• Background Desai JR, Bowen EA, Danielson MM, Allam RR, Cantor MN. Creation and implementation of a historical controls database from randomized clinical trials. J Am Med Inform Assoc. 2013 Jun;20(e1):e162-8. doi: 10.1136/amiajnl-2012-001257. Epub 2013 Feb 28.
• Background 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 Sep 25;8(9):e75376. doi: 10.1371/journal.pone.0075376. eCollection 2013.
• Background Dunlop RA, Powell J, Guillemin GJ, Cox PA. Mechanisms of L-Serine Neuroprotection in vitro Include ER Proteostasis Regulation. Neurotox Res. 2018 Jan;33(1):123-132. doi: 10.1007/s12640-017-9829-3. Epub 2017 Nov 2.
• Background Dunlop RA, Powell JT, Metcalf JS, Guillemin GJ, Cox PA. L-Serine-Mediated Neuroprotection Includes the Upregulation of the ER Stress Chaperone Protein Disulfide Isomerase (PDI). Neurotox Res. 2018 Jan;33(1):113-122. doi: 10.1007/s12640-017-9817-7. Epub 2017 Oct 3.
• Background Fiandaca MS, Kapogiannis D, Mapstone M, Boxer A, Eitan E, Schwartz JB, Abner EL, Petersen RC, Federoff HJ, Miller BL, Goetzl EJ. Identification of preclinical Alzheimer's disease by a profile of pathogenic proteins in neurally derived blood exosomes: A case-control study. Alzheimers Dement. 2015 Jun;11(6):600-7.e1. doi: 10.1016/j.jalz.2014.06.008. Epub 2014 Aug 15.
• Background Garofalo K, Penno A, Schmidt BP, Lee HJ, Frosch MP, von Eckardstein A, Brown RH, Hornemann T, Eichler FS. Oral L-serine supplementation reduces production of neurotoxic deoxysphingolipids in mice and humans with hereditary sensory autonomic neuropathy type 1. J Clin Invest. 2011 Dec;121(12):4735-45. doi: 10.1172/JCI57549.
• Background Goetzl EJ, Boxer A, Schwartz JB, Abner EL, Petersen RC, Miller BL, Kapogiannis D. Altered lysosomal proteins in neural-derived plasma exosomes in preclinical Alzheimer disease. Neurology. 2015 Jul 7;85(1):40-7. doi: 10.1212/WNL.0000000000001702. Epub 2015 Jun 10.
• Background Hirtz D, Thurman DJ, Gwinn-Hardy K, Mohamed M, Chaudhuri AR, Zalutsky R. How common are the "common" neurologic disorders? Neurology. 2007 Jan 30;68(5):326-37. doi: 10.1212/01.wnl.0000252807.38124.a3.
• Background Kabashi E, Valdmanis PN, Dion P, Spiegelman D, McConkey BJ, Vande Velde C, Bouchard JP, Lacomblez L, Pochigaeva K, Salachas F, Pradat PF, Camu W, Meininger V, Dupre N, Rouleau GA. TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat Genet. 2008 May;40(5):572-4. doi: 10.1038/ng.132. Epub 2008 Mar 30.
• Background Kaufmann P, Levy G, Thompson JL, Delbene ML, Battista V, Gordon PH, Rowland LP, Levin B, Mitsumoto H. The ALSFRSr predicts survival time in an ALS clinic population. Neurology. 2005 Jan 11;64(1):38-43. doi: 10.1212/01.WNL.0000148648.38313.64.
• Background Logroscino G, Traynor BJ, Hardiman O, Chio A, Mitchell D, Swingler RJ, Millul A, Benn E, Beghi E; EURALS. Incidence of amyotrophic lateral sclerosis in Europe. J Neurol Neurosurg Psychiatry. 2010 Apr;81(4):385-90. doi: 10.1136/jnnp.2009.183525. Epub 2009 Aug 25.
• Background Mehta P, Kaye W, Bryan L, Larson T, Copeland T, Wu J, Muravov O, Horton K. Prevalence of Amyotrophic Lateral Sclerosis - United States, 2012-2013. MMWR Surveill Summ. 2016 Aug 5;65(8):1-12. doi: 10.15585/mmwr.ss6508a1.
• Background Metcalf JS, Dunlop RA, Powell JT, Banack SA, Cox PA. L-Serine: a Naturally-Occurring Amino Acid with Therapeutic Potential. Neurotox Res. 2018 Jan;33(1):213-221. doi: 10.1007/s12640-017-9814-x. Epub 2017 Sep 19.
• Background Metcalf JS, Lobner D, Banack SA, Cox GA, Nunn PB, Wyatt PB, Cox PA. Analysis of BMAA enantiomers in cycads, cyanobacteria, and mammals: in vivo formation and toxicity of D-BMAA. Amino Acids. 2017 Aug;49(8):1427-1439. doi: 10.1007/s00726-017-2445-y. Epub 2017 Jun 15.
• Background Murch SJ, Cox PA, Banack SA. A mechanism for slow release of biomagnified cyanobacterial neurotoxins and neurodegenerative disease in Guam. Proc Natl Acad Sci U S A. 2004 Aug 17;101(33):12228-31. doi: 10.1073/pnas.0404926101. Epub 2004 Aug 4.
• Background Phukan J, Elamin M, Bede P, Jordan N, Gallagher L, Byrne S, Lynch C, Pender N, Hardiman O. The syndrome of cognitive impairment in amyotrophic lateral sclerosis: a population-based study. J Neurol Neurosurg Psychiatry. 2012 Jan;83(1):102-8. doi: 10.1136/jnnp-2011-300188. Epub 2011 Aug 11.
• Background Polman CH, Reingold SC, Barkhof F, Calabresi PA, Clanet M, Cohen JA, Cutter GR, Freedman MS, Kappos L, Lublin FD, McFarland HF, Metz LM, Miller AE, Montalban X, O'Connor PW, Panitch H, Richert JR, Petkau J, Schwid SR, Sormani MP, Thompson AJ, Weinshenker BG, Wolinsky JS. Ethics of placebo-controlled clinical trials in multiple sclerosis: a reassessment. Neurology. 2008 Mar 25;70(13 Pt 2):1134-40. doi: 10.1212/01.wnl.0000306410.84794.4d.
• Background Ringholz GM, Appel SH, Bradshaw M, Cooke NA, Mosnik DM, Schulz PE. Prevalence and patterns of cognitive impairment in sporadic ALS. Neurology. 2005 Aug 23;65(4):586-90. doi: 10.1212/01.wnl.0000172911.39167.b6.
• Background Splawinski J, Kuzniar J. Clinical trials: active control vs placebo--what is ethical? Sci Eng Ethics. 2004 Jan;10(1):73-9. doi: 10.1007/s11948-004-0065-x.
• Background Thall PF, Simon RM, Estey EH. Bayesian sequential monitoring designs for single-arm clinical trials with multiple outcomes. Stat Med. 1995 Feb 28;14(4):357-79. doi: 10.1002/sim.4780140404.
• Background Thompson AG, Gray E, Heman-Ackah SM, Mager I, Talbot K, Andaloussi SE, Wood MJ, Turner MR. Extracellular vesicles in neurodegenerative disease - pathogenesis to biomarkers. Nat Rev Neurol. 2016 Jun;12(6):346-57. doi: 10.1038/nrneurol.2016.68. Epub 2016 May 13.
• Background Viele K, Berry S, Neuenschwander B, Amzal B, Chen F, Enas N, Hobbs B, Ibrahim JG, Kinnersley N, Lindborg S, Micallef S, Roychoudhury S, Thompson L. Use of historical control data for assessing treatment effects in clinical trials. Pharm Stat. 2014 Jan-Feb;13(1):41-54. doi: 10.1002/pst.1589. Epub 2013 Aug 5.
• Background Wheaton MW, Salamone AR, Mosnik DM, McDonald RO, Appel SH, Schmolck HI, Ringholz GM, Schulz PE. Cognitive impairment in familial ALS. Neurology. 2007 Oct 2;69(14):1411-7. doi: 10.1212/01.wnl.0000277422.11236.2c.
• Background Winston CN, Goetzl EJ, Akers JC, Carter BS, Rockenstein EM, Galasko D, Masliah E, Rissman RA. Prediction of conversion from mild cognitive impairment to dementia with neuronally derived blood exosome protein profile. Alzheimers Dement (Amst). 2016 May 7;3:63-72. doi: 10.1016/j.dadm.2016.04.001. eCollection 2016.
• Background Brooks BR, Miller RG, Swash M, Munsat TL; World Federation of Neurology Research Group on Motor Neuron Diseases. El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord. 2000 Dec;1(5):293-9. doi: 10.1080/146608200300079536. No abstract available.
• Background Cedarbaum JM, Stambler N, Malta E, Fuller C, Hilt D, Thurmond B, Nakanishi A. The ALSFRS-R: a revised ALS functional rating scale that incorporates assessments of respiratory function. BDNF ALS Study Group (Phase III). J Neurol Sci. 1999 Oct 31;169(1-2):13-21. doi: 10.1016/s0022-510x(99)00210-5.
• Background Levine TD, Miller RG, Bradley WG, Moore DH, Saperstein DS, Flynn LE, Katz JS, Forshew DA, Metcalf JS, Banack SA, Cox PA. Phase I clinical trial of safety of L-serine for ALS patients. Amyotroph Lateral Scler Frontotemporal Degener. 2017 Feb;18(1-2):107-111. doi: 10.1080/21678421.2016.1221971. Epub 2016 Sep 2.

Drugs

Indications