Disease modifying treatment of amyotrophic lateral sclerosis
- Rabia B Choudry, MD
Rabia B Choudry, MD
- Attending Neurologist
- Albert Einstein Medical Center
- Nestor Galvez-Jimenez, MD, MSc, MHSA, FACP
Nestor Galvez-Jimenez, MD, MSc, MHSA, FACP
- The Pauline M. Braathen Endowed Chair
- Chairman, Department of Neurology
- Cleveland Clinic Florida
- Clinical Professor of Neurology
- Herbert Wertheim College of Medicine
- Merit E Cudkowicz, MD, MSc
Merit E Cudkowicz, MD, MSc
- Professor of Neurology
- Harvard Medical School
- Section Editors
- Jeremy M Shefner, MD, PhD
Jeremy M Shefner, MD, PhD
- Section Editor — Neuromuscular Disease
- Professor and Chair of Neurology, Barrow Neurological Institute
- Professor of Neurology, University of Arizona, Phoenix
- Clinical Professor of Neurology, Creighton University
- Ira N Targoff, MD
Ira N Targoff, MD
- Section Editor — Muscle Disease
- Professor of Medicine, Section of Rheumatology
- University of Oklahoma Health Sciences Center
Amyotrophic lateral sclerosis (ALS), first described by Charcot in the nineteenth century , is a progressive neurodegenerative disorder that causes muscle weakness, disability, and eventually death, with a median survival of three to five years.
The hallmark of ALS is the combination of upper motor neuron (UMN) and lower motor neuron (LMN) involvement. The LMN findings of weakness, atrophy, and fasciculations are a direct consequence of muscle denervation. The UMN findings of hyperreflexia and spasticity result from degeneration of the lateral corticospinal tracts in the spinal cord .
The existing and experimental disease modifying pharmacologic treatment of ALS will be reviewed here. The symptomatic management and the clinical features and diagnosis of ALS are discussed separately. (See "Symptom-based management of amyotrophic lateral sclerosis" and "Clinical features of amyotrophic lateral sclerosis and other forms of motor neuron disease" and "Diagnosis of amyotrophic lateral sclerosis and other forms of motor neuron disease".)
●In a prospective, double-blind, placebo-controlled trial in 155 outpatients with ALS, survival at 12 months was significantly higher for patients receiving riluzole (100 mg/day) compared with controls (74 versus 58 percent) . For the subset of patients with bulbar-onset ALS, an even greater advantage for survival at 12 months emerged for the riluzole group (73 versus 35 percent).
- Rowland LP. How amyotrophic lateral sclerosis got its name: the clinical-pathologic genius of Jean-Martin Charcot. Arch Neurol 2001; 58:512.
- Miller RG, Mitchell JD, Moore DH. Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Cochrane Database Syst Rev 2012; :CD001447.
- 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.
- Lacomblez L, Bensimon G, Leigh PN, et al. Dose-ranging study of riluzole in amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis/Riluzole Study Group II. Lancet 1996; 347:1425.
- Riviere M, Meininger V, Zeisser P, Munsat T. An analysis of extended survival in patients with amyotrophic lateral sclerosis treated with riluzole. Arch Neurol 1998; 55:526.
- Kennel P, Revah F, Bohme GA, et al. Riluzole prolongs survival and delays muscle strength deterioration in mice with progressive motor neuronopathy (pmn). J Neurol Sci 2000; 180:55.
- Miller RG, Jackson CE, Kasarskis EJ, et al. Practice parameter update: the care of the patient with amyotrophic lateral sclerosis: drug, nutritional, and respiratory therapies (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2009; 73:1218.
- Practice advisory on the treatment of amyotrophic lateral sclerosis with riluzole: report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 1997; 49:657.
- Brooks BR. El Escorial World Federation of Neurology criteria for the diagnosis of amyotrophic lateral sclerosis. Subcommittee on Motor Neuron Diseases/Amyotrophic Lateral Sclerosis of the World Federation of Neurology Research Group on Neuromuscular Diseases and the El Escorial "Clinical limits of amyotrophic lateral sclerosis" workshop contributors. J Neurol Sci 1994; 124 Suppl:96.
- Weber G, Bitterman H. Riluzole-induced neutropenia. Neurology 2004; 62:1648.
- Bensimon G, Lacomblez L, Delumeau JC, et al. A study of riluzole in the treatment of advanced stage or elderly patients with amyotrophic lateral sclerosis. J Neurol 2002; 249:609.
- Rilutek® (riluzole) Tablets. Prescribing information. http://products.sanofi.us/rilutek/rilutek.pdf (Accessed on May 15, 2017).
- Abe K, Itoyama Y, Sobue G, 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.
- Writing Group, Edaravone (MCI-186) ALS 19 Study Group. Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet Neurol 2017; 16:505.
- Castrillo-Viguera C, Grasso DL, Simpson E, et al. Clinical significance in the change of decline in ALSFRS-R. Amyotroph Lateral Scler 2010; 11:178.
- FDA approves drug to treat ALS. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm557102.htm (Accessed on May 09, 2017).
- Hardiman O, van den Berg LH. Edaravone: a new treatment for ALS on the horizon? Lancet Neurol 2017; 16:490.
- Radicava prescibing information. https://www.radicava.com/assets/dist/pdfs/radicava-prescibing-information.pdf (Accessed on May 09, 2017).
- Statement on the clinical trial of ceftriaxone. ALS association. 2012; Aug 10. http://www.alsworldwide.org/ceftriaxone.html (Accessed on August 21, 2014).
- Cudkowicz ME, Shefner JM, Schoenfeld DA, et al. Trial of celecoxib in amyotrophic lateral sclerosis. Ann Neurol 2006; 60:22.
- Bongioanni P, Reali C, Sogos V. Ciliary neurotrophic factor (CNTF) for amyotrophic lateral sclerosis/motor neuron disease. Cochrane Database Syst Rev 2004; :CD004302.
- Kaufmann P, Thompson JL, Levy G, et al. Phase II trial of CoQ10 for ALS finds insufficient evidence to justify phase III. Ann Neurol 2009; 66:235.
- Groeneveld GJ, Veldink JH, van der Tweel I, et al. A randomized sequential trial of creatine in amyotrophic lateral sclerosis. Ann Neurol 2003; 53:437.
- Shefner JM, Cudkowicz ME, Schoenfeld D, et al. A clinical trial of creatine in ALS. Neurology 2004; 63:1656.
- Cudkowicz ME, van den Berg LH, Shefner JM, et al. Dexpramipexole versus placebo for patients with amyotrophic lateral sclerosis (EMPOWER): a randomised, double-blind, phase 3 trial. Lancet Neurol 2013; 12:1059.
- Miller RG, Moore DH 2nd, Gelinas DF, et al. Phase III randomized trial of gabapentin in patients with amyotrophic lateral sclerosis. Neurology 2001; 56:843.
- Diana A, Pillai R, Bongioanni P, et al. Gamma aminobutyric acid (GABA) modulators for amyotrophic lateral sclerosis/motor neuron disease. Cochrane Database Syst Rev 2017; 1:CD006049.
- 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.
- Aggarwal SP, Zinman L, Simpson E, 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.
- Chiò A, Borghero G, Calvo A, et al. Lithium carbonate in amyotrophic lateral sclerosis: lack of efficacy in a dose-finding trial. Neurology 2010; 75:619.
- Verstraete E, Veldink JH, Huisman MH, et al. Lithium lacks effect on survival in amyotrophic lateral sclerosis: a phase IIb randomised sequential trial. J Neurol Neurosurg Psychiatry 2012; 83:557.
- UKMND-LiCALS Study Group, Morrison KE, Dhariwal S, et al. Lithium in patients with amyotrophic lateral sclerosis (LiCALS): a phase 3 multicentre, randomised, double-blind, placebo-controlled trial. Lancet Neurol 2013; 12:339.
- Gordon PH, Moore DH, Miller RG, et al. Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomised trial. Lancet Neurol 2007; 6:1045.
- Meininger V, Genge A, van den Berg LH, et al. Safety and efficacy of ozanezumab in patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Neurol 2017; 16:208.
- Beauverd M, Mitchell JD, Wokke JH, Borasio GD. Recombinant human insulin-like growth factor I (rhIGF-I) for the treatment of amyotrophic lateral sclerosis/motor neuron disease. Cochrane Database Syst Rev 2012; 11:CD002064.
- Sorenson EJ, Windbank AJ, Mandrekar JN, et al. Subcutaneous IGF-1 is not beneficial in 2-year ALS trial. Neurology 2008; 71:1770.
- Press release. Teva provides update on talampanel for the treatment of amyotrophic lateral sclerosis (ALS). www.tevapharm.com/en-US/Media/News/Pages/2010/1555496.aspx (Accessed on December 21, 2011).
- Miller R, Bradley W, Cudkowicz M, et al. Phase II/III randomized trial of TCH346 in patients with ALS. Neurology 2007; 69:776.
- Cudkowicz ME, Shefner JM, Schoenfeld DA, et al. A randomized, placebo-controlled trial of topiramate in amyotrophic lateral sclerosis. Neurology 2003; 61:456.
- Piepers S, Veldink JH, de Jong SW, et al. Randomized sequential trial of valproic acid in amyotrophic lateral sclerosis. Ann Neurol 2009; 66:227.
- Miller RG, Smith SA, Murphy JR, et al. A clinical trial of verapamil in amyotrophic lateral sclerosis. Muscle Nerve 1996; 19:511.
- Rothstein JD, Kuncl RW. Neuroprotective strategies in a model of chronic glutamate-mediated motor neuron toxicity. J Neurochem 1995; 65:643.
- Pasinelli P, Borchelt DR, Houseweart MK, et al. Caspase-1 is activated in neural cells and tissue with amyotrophic lateral sclerosis-associated mutations in copper-zinc superoxide dismutase. Proc Natl Acad Sci U S A 1998; 95:15763.
- Pasinelli P, Houseweart MK, Brown RH Jr, Cleveland DW. Caspase-1 and -3 are sequentially activated in motor neuron death in Cu,Zn superoxide dismutase-mediated familial amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A 2000; 97:13901.
- Flanagan SW, Anderson RD, Ross MA, Oberley LW. Overexpression of manganese superoxide dismutase attenuates neuronal death in human cells expressing mutant (G37R) Cu/Zn-superoxide dismutase. J Neurochem 2002; 81:170.
- Wegorzewska I, Bell S, Cairns NJ, et al. TDP-43 mutant transgenic mice develop features of ALS and frontotemporal lobar degeneration. Proc Natl Acad Sci U S A 2009; 106:18809.
- Wils H, Kleinberger G, Janssens J, et al. TDP-43 transgenic mice develop spastic paralysis and neuronal inclusions characteristic of ALS and frontotemporal lobar degeneration. Proc Natl Acad Sci U S A 2010; 107:3858.
- Zhou H, Huang C, Chen H, et al. Transgenic rat model of neurodegeneration caused by mutation in the TDP gene. PLoS Genet 2010; 6:e1000887.
- Wong PC, Pardo CA, Borchelt DR, et al. An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria. Neuron 1995; 14:1105.
- Philips T, Rothstein JD. Rodent Models of Amyotrophic Lateral Sclerosis. Curr Protoc Pharmacol 2015; 69:5.67.1.
- Casci I, Pandey UB. A fruitful endeavor: modeling ALS in the fruit fly. Brain Res 2015; 1607:47.
- Therrien M, Parker JA. Worming forward: amyotrophic lateral sclerosis toxicity mechanisms and genetic interactions in Caenorhabditis elegans. Front Genet 2014; 5:85.
- Sances S, Bruijn LI, Chandran S, et al. Modeling ALS with motor neurons derived from human induced pluripotent stem cells. Nat Neurosci 2016; 19:542.
- Myszczynska M, Ferraiuolo L. New In Vitro Models to Study Amyotrophic Lateral Sclerosis. Brain Pathol 2016; 26:258.
- 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.
- Graf M, Ecker D, Horowski R, et al. High dose vitamin E therapy in amyotrophic lateral sclerosis as add-on therapy to riluzole: results of a placebo-controlled double-blind study. J Neural Transm (Vienna) 2005; 112:649.
- Louwerse ES, Weverling GJ, Bossuyt PM, et al. Randomized, double-blind, controlled trial of acetylcysteine in amyotrophic lateral sclerosis. Arch Neurol 1995; 52:559.
- Traub R, Mitsumoto H, Rowland LP. Research advances in amyotrophic lateral sclerosis, 2009 to 2010. Curr Neurol Neurosci Rep 2011; 11:67.
- Zinman L, Cudkowicz M. Emerging targets and treatments in amyotrophic lateral sclerosis. Lancet Neurol 2011; 10:481.
- Moujalled D, White AR. Advances in the Development of Disease-Modifying Treatments for Amyotrophic Lateral Sclerosis. CNS Drugs 2016; 30:227.
- Gilenya in amyotrophic lateral sclerosis (ALS). http://clinicaltrials.gov/show/NCT01786174 (Accessed on August 26, 2014).
- Levine TD, Bowser R, Hank N, Saperstein D. A pilot trial of memantine and riluzole in ALS: correlation to CSF biomarkers. Amyotroph Lateral Scler 2010; 11:514.
- Weiss MD, Macklin EA, Simmons Z, et al. A randomized trial of mexiletine in ALS: Safety and effects on muscle cramps and progression. Neurology 2016; 86:1474.
- A study of NP001 in subjects with amyotrophic lateral sclerosis (ALS). http://clinicaltrials.gov/show/NCT01281631 (Accessed on August 26, 2014).
- Wainger BJ, Kiskinis E, Mellin C, et al. Intrinsic membrane hyperexcitability of amyotrophic lateral sclerosis patient-derived motor neurons. Cell Rep 2014; 7:1.
- Feldman EL, Boulis NM, Hur J, et al. Intraspinal neural stem cell transplantation in amyotrophic lateral sclerosis: phase 1 trial outcomes. Ann Neurol 2014; 75:363.
- Chen KS, Sakowski SA, Feldman EL. Intraspinal stem cell transplantation for amyotrophic lateral sclerosis. Ann Neurol 2016; 79:342.
- Petrou P, Gothelf Y, Argov Z, et al. Safety and Clinical Effects of Mesenchymal Stem Cells Secreting Neurotrophic Factor Transplantation in Patients With Amyotrophic Lateral Sclerosis: Results of Phase 1/2 and 2a Clinical Trials. JAMA Neurol 2016; 73:337.
- Glass JD, Hertzberg VS, Boulis NM, et al. Transplantation of spinal cord-derived neural stem cells for ALS: Analysis of phase 1 and 2 trials. Neurology 2016; 87:392.
- Tamoxifen treatment in patients with motor neuron disease. http://clinicaltrials.gov/show/NCT02166944 (Accessed on August 26, 2014).
- Mizwicki MT, Fiala M, Magpantay L, et al. Tocilizumab attenuates inflammation in ALS patients through inhibition of IL6 receptor signaling. Am J Neurodegener Dis 2012; 1:305.
- Fiala M, Mizwicki MT, Weitzman R, et al. Tocilizumab infusion therapy normalizes inflammation in sporadic ALS patients. Am J Neurodegener Dis 2013; 2:129.
- Batulan Z, Shinder GA, Minotti S, et al. High threshold for induction of the stress response in motor neurons is associated with failure to activate HSF1. J Neurosci 2003; 23:5789.
- Kieran D, Kalmar B, Dick JR, et al. Treatment with arimoclomol, a coinducer of heat shock proteins, delays disease progression in ALS mice. Nat Med 2004; 10:402.
- Phase II/III randomized, placebo-controlled trial of arimoclomol in SOD1 positive familial amyotrophic lateral sclerosis. https://clinicaltrials.gov/ct2/show/NCT00706147 (Accessed on May 24, 2017).
- Kaspar BK, Lladó J, Sherkat N, et al. Retrograde viral delivery of IGF-1 prolongs survival in a mouse ALS model. Science 2003; 301:839.
- Abe K, Manabe Y, Murakami T. [Gene therapy and neurotrophic factor treatment for amyotrophic lateral sclerosis]. Rinsho Shinkeigaku 2001; 41:1160.
- Jin KL, Mao XO, Greenberg DA. Vascular endothelial growth factor: direct neuroprotective effect in in vitro ischemia. Proc Natl Acad Sci U S A 2000; 97:10242.
- Carmeliet P. Blood vessels and nerves: common signals, pathways and diseases. Nat Rev Genet 2003; 4:710.
- Storkebaum E, Lambrechts D, Dewerchin M, et al. Treatment of motoneuron degeneration by intracerebroventricular delivery of VEGF in a rat model of ALS. Nat Neurosci 2005; 8:85.
- Smith RA, Miller TM, Yamanaka K, et al. Antisense oligonucleotide therapy for neurodegenerative disease. J Clin Invest 2006; 116:2290.
- Miller TM, Pestronk A, David W, 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.
- Russell AJ, Hartman JJ, Hinken AC, et al. Activation of fast skeletal muscle troponin as a potential therapeutic approach for treating neuromuscular diseases. Nat Med 2012; 18:452.
- Gibson SB, Bromberg MB. Amyotrophic lateral sclerosis: drug therapy from the bench to the bedside. Semin Neurol 2012; 32:173.
- Hansen R, Saikali KG, Chou W, et al. Tirasemtiv amplifies skeletal muscle response to nerve activation in humans. Muscle Nerve 2014; 50:925.
- Hwee DT, Kennedy A, Ryans J, et al. Fast skeletal muscle troponin activator tirasemtiv increases muscle function and performance in the B6SJL-SOD1G93A ALS mouse model. PLoS One 2014; 9:e96921.
- Shefner J, Cedarbaum JM, Cudkowicz ME, et al. Safety, tolerability and pharmacodynamics of a skeletal muscle activator in amyotrophic lateral sclerosis. Amyotroph Lateral Scler 2012; 13:430.
- Shefner JM, Watson ML, Meng L, et al. A study to evaluate safety and tolerability of repeated doses of tirasemtiv in patients with amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener 2013; 14:574.
- Shefner JM, Wolff AA, Meng L. The relationship between tirasemtiv serum concentration and functional outcomes in patients with ALS. Amyotroph Lateral Scler Frontotemporal Degener 2013; 14:582.