526
Views
0
CrossRef citations to date
0
Altmetric
Review

Emerging clinical investigational drugs for the treatment of amyotrophic lateral sclerosis

ORCID Icon & ORCID Icon
Pages 141-160 | Received 25 Nov 2022, Accepted 06 Feb 2023, Published online: 16 Feb 2023

References

  • van Es MA, Hardiman O, Chio A, et al. Amyotrophic lateral sclerosis. Lancet. 2017;390(10107):2084–2098.
  • Al-Chalabi A, Hardiman O. The epidemiology of ALS: a conspiracy of genes, environment and time. Nat Rev Neurol. 2013;9(11):617–628.
  • Ingre C, Roos PM, Piehl F, et al. Risk factors for amyotrophic lateral sclerosis. Clin Epidemiol. 2015;7:181–193.
  • Oskarsson B, Gendron TF, Staff NP. Amyotrophic lateral sclerosis: an update for 2018. Mayo Clin Proc. 2018;93(11):1617–1628.
  • Renton AE, Chio A, Traynor BJ. State of play in amyotrophic lateral sclerosis genetics. Nat Neurosci. 2014;17(1):17–23.
  • Mejzini R, Flynn LL, Pitout IL, et al. ALS genetics, mechanisms, and therapeutics: where are we now? Front Neurosci. 2019;13:1310.
  • Rothstein JD. Edaravone: a new drug approved for ALS. Cell. 2017;171(4):725.
  • Miller RG, Mitchell JD, Moore DH. Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Cochrane Database Syst Rev. 2012;2012(3):CD001447.
  • Dharmadasa T, Kiernan MC. Riluzole, disease stage and survival in ALS. Lancet Neurol. 2018;17(5):385–386.
  • Jami MS, Salehi-Najafabadi Z, Ahmadinejad F, et al. Edaravone leads to proteome changes indicative of neuronal cell protection in response to oxidative stress. Neurochem Int. 2015;90:134–141.
  • Shimizu H, Nishimura Y, Shiide Y, et al. Bioequivalence study of oral suspension and intravenous formulation of edaravone in healthy adult subjects. Clin Pharmacol Drug Dev. 2021;10(10):1188–1197.
  • Petrov D, Mansfield C, Moussy A, et al. ALS clinical trials review: 20 years of failure. are we any closer to registering a new treatment? Front Aging Neurosci. 2017;9:68.
  • Bahrami F, Pourgholami MH, Mekkawy AH, et al. Monepantel induces autophagy in human ovarian cancer cells through disruption of the mTOR/p70S6K signalling pathway. Am J Cancer Res. 2014;4(5):558–571.
  • Querfurth H, Lee HK. Mammalian/mechanistic target of rapamycin (mTOR) complexes in neurodegeneration. Mol Neurodegener. 2021;16(1):44.
  • Benavides-Serrato A, Saunders JT, Holmes B, et al. Repurposing potential of riluzole as an ITAF inhibitor in mTOR therapy resistant glioblastoma. Int J Mol Sci. 2020;21(1):344.
  • Li J, Kim SG, Blenis J. Rapamycin: one drug, many effects. Cell Metab. 2014;19(3):373–379.
  • Bos PH, Lowry ER, Costa J, et al. Development of MAP4 kinase inhibitors as motor neuron-protecting agents. Cell Chem Biol. 2019;26(12):1703–1715 e37.
  • Smith HL, Mallucci GR. The unfolded protein response: mechanisms and therapy of neurodegeneration. Brain. 2016;139(Pt 8):2113–2121.
  • Wong YL, LeBon L, Basso AM, et al. eIF2B activator prevents neurological defects caused by a chronic integrated stress response. Elife. 2019;8:e42940.
  • GlobeNewswire [Internet]. California (South San Francisco): denali Therapeutics; [cited 2022 Sept 30]. Available from: https://www.globenewswire.com/news-release/2021/09/09/2294411/0/en/Denali-Therapeutics-Announces-Initiation-of-Phase-1b-Study-of-EIF2B-Activator-DNL343-in-ALS.html
  • Wen J, Li S, Zheng C, et al. Tetramethylpyrazine nitrone improves motor dysfunction and pathological manifestations by activating the PGC-1alpha/Nrf2/HO-1 pathway in ALS mice. Neuropharmacology. 2021;182:108380.
  • Huang C, Li J, Zhang G, et al. TBN improves motor function and prolongs survival in a TDP-43M337V mouse model of ALS. Hum Mol Genet. 2021;30(16):1484–1496.
  • Liu C, Arnold R, Henriques G, et al. Inhibition of JAK-STAT signaling with baricitinib reduces inflammation and improves cellular homeostasis in progeria cells. Cells. 2019;8(10):1276.
  • Shan G, Li Y, Zhang J, et al. A small molecule enhances RNA interference and promotes microRNA processing. Nat Biotechnol. 2008;26(8):933–940.
  • Emde A, Eitan C, Liou LL, et al. Dysregulated miRNA biogenesis downstream of cellular stress and ALS-causing mutations: a new mechanism for ALS. EMBO J. 2015;34(21):2633–2651.
  • Felicetti T, Cecchetti V, Manfroni G. Modulating microRNA processing: enoxacin, the progenitor of a new class of drugs. J Med Chem. 2020;63(21):12275–12289.
  • ema.europa.eu [Internet]. Amsterdam: European Medicines Agency; [cited 2022 Oct 31]. Available from: https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu3151459
  • Wright CJ, McCormack PL. Trametinib: first global approval. Drugs. 2013;73(11):1245–1254.
  • Palomo V, Nozal V, Rojas-Prats E, et al. Protein kinase inhibitors for amyotrophic lateral sclerosis therapy. Br J Pharmacol. 2021;178(6):1316–1335.
  • Sahana TG. Mitogen-Activated Protein ZK, Kinase pathway in amyotrophic lateral sclerosis. Biomedicines. 2021;9(8):696.
  • Shi Y, Lin S, Staats KA, et al. Haploinsufficiency leads to neurodegeneration in C9ORF72 ALS/FTD human induced motor neurons. Nat Med. 2018;24(3):313–325.
  • Imamura K, Izumi Y, Watanabe A, et al. The Src/c-Abl pathway is a potential therapeutic target in amyotrophic lateral sclerosis. Sci Transl Med. 2017;9(391):eaaf3962.
  • Imamura K, Izumi Y, Nagai M, et al. Safety and tolerability of bosutinib in patients with amyotrophic lateral sclerosis (iDReAM study): a multicentre, open-label, dose-escalation phase 1 trial. eClinicalMedicine. 2022;53:101707. cited 2022 Nov 5.
  • Han J, Chitu V, Stanley ER. Inhibition of colony stimulating factor-1 receptor (CSF-1R) as a potential therapeutic strategy for neurodegenerative diseases: opportunities and challenges. Cell Mol Life Sci. 2022;79(4):219.
  • Zhao J, Zhou D, Guo J, et al. Effect of fasudil hydrochloride, a protein kinase inhibitor, on cerebral vasospasm and delayed cerebral ischemic symptoms after aneurysmal subarachnoid hemorrhage. Neurol Med Chir (Tokyo). 2006;46(9):421–428.
  • Takata M, Tanaka H, Kimura M, et al. Fasudil, a rho kinase inhibitor, limits motor neuron loss in experimental models of amyotrophic lateral sclerosis. Br J Pharmacol. 2013;170(2):341–351.
  • Lingor P, Weber M, Camu W, et al. ROCK-ALS: protocol for a randomized, placebo-controlled, double-blind phase iia trial of safety, tolerability and efficacy of the Rho Kinase (ROCK) inhibitor fasudil in amyotrophic lateral sclerosis. Front Neurol. 2019;10:293.
  • Mifflin L, Hu Z, Dufort C, et al. A RIPK1-regulated inflammatory microglial state in amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A. 2021;118(13):e2025102118.
  • ALS NewsToday [Internet]. Florida: bioNews, Inc.; [cited 2022 Oct 30]. Available from: https://alsnewstoday.com/news/patient-dosing-starts-phase-2-trial-oral-sar443820-als/
  • NeuroSence [Internet]. Cambridge: neuroSence Therapeutics; [cited 2022 Jun 28]. Available from: https://www.neurosense-tx.com/primec/
  • Salomon-Zimri S, Pushett A, Russek-Blum N, et al. Combination of ciprofloxacin/celecoxib as a novel therapeutic strategy for ALS. Amyotroph Lateral Scler Frontotemporal Degener. 2022;1–9. DOI:10.1080/21678421.2022.2119868
  • De Nicola AF, Meyer M, Guennoun R, et al. Insights into the therapeutic potential of glucocorticoid receptor modulators for neurodegenerative diseases. Int J Mol Sci. 2020;21(6):2137.
  • Moser JM, Bigini P, Schmitt-John T. The wobbler mouse, an ALS animal model. Mol Genet Genomics. 2013;288(5–6):207–229.
  • Meyer M, Kruse MS, Garay L, et al. Long-term effects of the glucocorticoid receptor modulator CORT113176 in murine motoneuron degeneration. Brain Res. 2020;1727:146551.
  • Kallstig E, McCabe BD, Schneider BL. The Links between ALS and NF-kappaB. Int J Mol Sci. 2021;22(8):3875.
  • Dutta K, Patel P, Julien JP. Protective effects of Withania somnifera extract in SOD1(G93A) mouse model of amyotrophic lateral sclerosis. Exp Neurol. 2018;309:193–204.
  • Dutta K, Patel P, Rahimian R, et al. Withania somnifera Reverses Transactive Response DNA Binding Protein 43 Proteinopathy in a Mouse Model of Amyotrophic Lateral Sclerosis/Frontotemporal Lobar Degeneration. Neurotherapeutics. 2017;14(2):447–462.
  • Kumar S, Phaneuf D, Julien JP. Withaferin-A treatment alleviates TAR DNA-binding protein-43 pathology and improves cognitive function in a mouse model of FTLD. Neurotherapeutics. 2021;18(1):286–296.
  • Ovadia E, inventor; Immunity Pharma Ltd, assignee. Compositions and methods of using same for treating amyotrophic lateral sclerosis (ALS). United States patent US 2021/0100869 A1. 2020 Nov 6.
  • ALS NewsToday [Internet]. Florida: bioNews, Inc.; [cited 2022 Oct 31]. Available from: https://alsnewstoday.com/news/investigational-treatment-ipl344-safely-slows-als-progression-in-small-phase-1-2a-trial/
  • Chen Y, Podojil JR, Kunjamma RB, et al. Sephin1, which prolongs the integrated stress response, is a promising therapeutic for multiple sclerosis. Brain. 2019;142(2):344–361.
  • Das I, Krzyzosiak A, Schneider K, et al. Preventing proteostasis diseases by selective inhibition of a phosphatase regulatory subunit. Science. 2015;348(6231):239–242.
  • Carrara M, Sigurdardottir A, Bertolotti A. Decoding the selectivity of eIF2alpha holophosphatases and PPP1R15A inhibitors. Nat Struct Mol Biol. 2017;24(9):708–716.
  • ALS NewsToday [Internet]. Florida: bioNews, Inc.; [cited 2022 Oct 29]. Available from: https://alsnewstoday.com/news/inflectis-okd-to-start-phase-2-trial-of-ifb-088-for-bulbar-onset-als/
  • Crippa V, D’Agostino VG, Cristofani R, et al. Transcriptional induction of the heat shock protein B8 mediates the clearance of misfolded proteins responsible for motor neuron diseases. Sci Rep. 2016;6(1):22827.
  • Mandrioli J, Crippa V, Cereda C, et al. Proteostasis and ALS: protocol for a phase II, randomised, double-blind, placebo-controlled, multicentre clinical trial for colchicine in ALS (Co-ALS). BMJ Open. 2019;9(5):e028486.
  • Dunlop RA, Carney JM. Mechanisms of L-Serine-Mediated Neuroprotection Include Selective Activation of Lysosomal Cathepsins B and L. Neurotox Res. 2021;39(1):17–26.
  • Davis DA, Cox PA, Banack SA, et al. l-Serine Reduces Spinal Cord Pathology in a Vervet Model of Preclinical ALS/MND. J Neuropathol Exp Neurol. 2020;79(4):393–406.
  • Levine TD, Miller RG, Bradley WG, et al. Phase I clinical trial of safety of L-serine for ALS patients. Amyotroph Lateral Scler Frontotemporal Degener. 2017;18(1–2):107–111.
  • Posa D, Martinez-Gonzalez L, Bartolome F, et al. Recapitulation of Pathological TDP-43 Features in Immortalized Lymphocytes from Sporadic ALS Patients. Mol Neurobiol. 2019;56(4):2424–2432.
  • Martinez-Gonzalez L, Gonzalo-Consuegra C, Gomez-Almeria M, et al. Tideglusib, a Non-ATP Competitive Inhibitor of GSK-3beta as a Drug Candidate for the Treatment of Amyotrophic Lateral Sclerosis. Int J Mol Sci. 2021;22(16):8975.
  • Martinez NW, Gomez FE, Matus S. The Potential Role of Protein Kinase R as a Regulator of Age-Related Neurodegeneration. Front Aging Neurosci. 2021;13:638208.
  • Zu T, Guo S, Bardhi O, et al. Metformin inhibits RAN translation through PKR pathway and mitigates disease in C9orf72 ALS/FTD mice. Proc Natl Acad Sci U S A. 2020;117(31):18591–18599.
  • Kaneb HM, Sharp PS, Rahmani-Kondori N, et al. Metformin treatment has no beneficial effect in a dose-response survival study in the SOD1(G93A) mouse model of ALS and is harmful in female mice. PLoS One. 2011;6(9):e24189.
  • Tsang CK, Qi H, Liu LF, et al. Targeting mammalian target of rapamycin (mTOR) for health and diseases. Drug Discov Today. 2007;12(3–4):112–124.
  • Zhang X, Li L, Chen S, et al. Rapamycin treatment augments motor neuron degeneration in SOD1(G93A) mouse model of amyotrophic lateral sclerosis. Autophagy. 2011;7(4):412–425.
  • Caccamo A, Majumder S, Deng JJ, et al. Rapamycin rescues TDP-43 mislocalization and the associated low molecular mass neurofilament instability. J Biol Chem. 2009;284(40):27416–27424.
  • Cheng CW, Lin MJ, Shen CK. Rapamycin alleviates pathogenesis of a new Drosophila model of ALS-TDP. J Neurogenet. 2015;29(2–3):59–68.
  • Chennampally P, Sayed-Zahid A, Soundararajan P, et al. A microfluidic approach to rescue ALS motor neuron degeneration using rapamycin. Sci Rep. 2021;11(1):18168.
  • Mandrioli J, D’Amico R, Zucchi E, et al. Rapamycin treatment for amyotrophic lateral sclerosis: protocol for a phase II randomized, double-blind, placebo-controlled, multicenter, clinical trial (RAP-ALS trial). Medicine (Baltimore). 2018;97(24):e11119.
  • Cunha-Oliveira T, Montezinho L, Mendes C, et al. Oxidative Stress in Amyotrophic Lateral Sclerosis: pathophysiology and Opportunities for Pharmacological Intervention. Oxid Med Cell Longev. 2020;2020:5021694.
  • Shichiri M. The role of lipid peroxidation in neurological disorders. J Clin Biochem Nutr. 2014;54(3):151–160.
  • Zesiewicz T, Heerinckx F, De Jager R, et al. Randomized, clinical trial of RT001: early signals of efficacy in Friedreich’s ataxia. Mov Disord. 2018;33(6):1000–1005.
  • Adams D, Midei M, Dastgir J, et al. Treatment of infantile neuroaxonal dystrophy with RT001: a di-deuterated ethyl ester of linoleic acid: report of two cases. JIMD Rep. 2020;54(1):54–60.
  • Yerton M, Winter A, Kostov A, et al. An expanded access protocol of RT001 in amyotrophic lateral sclerosis-Initial experience with a lipid peroxidation inhibitor. Muscle Nerve. 2022;66(4):421–425.
  • Kantor PF, Lucien A, Kozak R, et al. The antianginal drug trimetazidine shifts cardiac energy metabolism from fatty acid oxidation to glucose oxidation by inhibiting mitochondrial long-chain 3-ketoacyl coenzyme A thiolase. Circ Res. 2000;86(5):580–588.
  • Scaricamazza S, Salvatori I, Amadio S, et al. Repurposing of Trimetazidine for amyotrophic lateral sclerosis: a study in SOD1(G93A) mice. Br J Pharmacol. 2022;179(8):1732–1752.
  • de la Rubia JE, Drehmer E, Platero JL, et al. Efficacy and tolerability of EH301 for amyotrophic lateral sclerosis: a randomized, double-blind, placebo-controlled human pilot study. Amyotroph Lateral Scler Frontotemporal Degener. 2019;20(1–2):115–122.
  • Bedlack R, Group AL. ALSUntangled 44: curcumin. Amyotroph Lateral Scler Frontotemporal Degener. 2018;19(7–8):623–629.
  • Chico L, Ienco EC, Bisordi C, et al. Amyotrophic Lateral Sclerosis and Oxidative Stress: a Double-Blind Therapeutic Trial After Curcumin Supplementation. CNS Neurol Disord Drug Targets. 2018;17(10):767–779.
  • Dost FS, Kaya D, Ontan MS, et al. Theracurmin Supplementation May be a Therapeutic Option for Older Patients with Alzheimer’s Disease: a 6-Month Retrospective Follow-Up Study. Curr Alzheimer Res. 2021;18(14):1087–1092.
  • Meira Martins LA, Vieira MQ, Ilha M, et al. The interplay between apoptosis, mitophagy and mitochondrial biogenesis induced by resveratrol can determine activated hepatic stellate cells death or survival. Cell Biochem Biophys. 2015;71(2):657–672.
  • Madruga E, Maestro I, Mitophagy Modulation MA. a New Player in the Race against ALS. Int J Mol Sci. 2021;22(2):740.
  • Albani D, Polito L, Signorini A, et al. Neuroprotective properties of resveratrol in different neurodegenerative disorders. Biofactors. 2010;36(5):370–376.
  • Mancuso R, Del Valle J, Modol L, et al. Resveratrol improves motoneuron function and extends survival in SOD1(G93A) ALS mice. Neurotherapeutics. 2014;11(2):419–432.
  • Proano B, Casani-Cubel J, Benlloch M, et al. Is dutasteride a therapeutic alternative for amyotrophic lateral sclerosis? Biomedicines. 2022;10(9):2084.
  • Mori A, Cross B, Uchida S, et al. How are Adenosine and Adenosine A2A receptors involved in the pathophysiology of amyotrophic lateral sclerosis? Biomedicines. 2021;9(8):1027.
  • Sebastiao AM, Rei N, Ribeiro JA. Amyotrophic Lateral Sclerosis (ALS) and Adenosine Receptors. Front Pharmacol. 2018;9:267.
  • Ng SK, Higashimori H, Tolman M, et al. Suppression of adenosine 2a receptor (A2aR)-mediated adenosine signaling improves disease phenotypes in a mouse model of amyotrophic lateral sclerosis. Exp Neurol. 2015;267:115–122.
  • Gibson LC, Hastings SF, McPhee I, et al. The inhibitory profile of Ibudilast against the human phosphodiesterase enzyme family. Eur J Pharmacol. 2006;538(1–3):39–42.
  • Schwenkgrub J, Zaremba M, Mirowska-Guzel D, et al. Ibudilast: a nonselective phosphodiesterase inhibitor in brain disorders. Postepy Hig Med Dosw Online. 2017;71137–148.
  • Babu S, Hightower BG, Chan J, et al. Ibudilast (MN-166) in amyotrophic lateral sclerosis- an open label, safety and pharmacodynamic trial. Neuroimage Clin. 2021;30:102672.
  • Matsuda K, Iwaki Y, Makhay M, et al. Interaction (nonuniformity) of ALS progression and the efficacy of MN-166 (ibudilast). Amyotroph Lateral Scler Frontotemporal Degener. 2019;20(1):262–288.
  • Oskarsson B, Maragakis N, Bedlack RS, et al. MN-166 (ibudilast) in amyotrophic lateral sclerosis in a Phase IIb/III study: COMBAT-ALS study design. Neurodegener Dis Manag. 2021;11(6):431–443.
  • Huang X, El-Sayed IH, Yi X, et al. Gold nanoparticles: catalyst for the oxidation of NADH to NAD(+). J Photochem Photobiol B. 2005;81(2):76–83.
  • Vucic S, Kiernan MC, Menon P, et al. Study protocol of RESCUE-ALS: a Phase 2, randomised, double-blind, placebo-controlled study in early symptomatic amyotrophic lateral sclerosis patients to assess bioenergetic catalysis with CNM-Au8 as a mechanism to slow disease progression. BMJ Open. 2021;11(1):e041479.
  • ALS NewsToday [Internet]. Florida: bioNews, Inc.; [cited 2022 Nov 3]. Available from: https://alsnewstoday.com/news/early-cnm-au8-treatment-als-continues-show-survival-benefits/
  • Joo IS, Hwang DH, Seok JI, et al. Oral administration of memantine prolongs survival in a transgenic mouse model of amyotrophic lateral sclerosis. J Clin Neurol. 2007;3(4):181–186.
  • de Carvalho M, Pinto S, Costa J, et al. A randomized, placebo-controlled trial of memantine for functional disability in amyotrophic lateral sclerosis. Amyotroph Lateral Scler. 2010;11(5):456–460.
  • Westergard T, McAvoy K, Russell K, et al. Repeat-associated non-AUG translation in C9orf72-ALS/FTD is driven by neuronal excitation and stress. EMBO Mol Med. 2019;11(2):e9423.
  • Wong C, Dakin RS, Williamson J, et al. Motor neuron disease systematic multi-arm adaptive randomised trial (MND-SMART): a multi-arm, multi-stage, adaptive, platform, phase III randomised, double-blind, placebo-controlled trial of repurposed drugs in motor neuron disease. BMJ Open. 2022;12(7):e064173.
  • Wang L, Li C, Chen X, et al. Abnormal serum iron-status indicator changes in Amyotrophic Lateral Sclerosis (ALS) patients: a meta-analysis. Front Neurol. 2020;11:380.
  • Moreau C, Danel V, Devedjian JC, et al. Could conservative iron chelation lead to neuroprotection in amyotrophic lateral sclerosis? Antioxid Redox Signal. 2018;29(8):742–748.
  • Hider RC, Hoffbrand AV, Longo DL. The role of deferiprone in iron chelation. N Engl J Med. 2018;379(22):2140–2150.
  • Soon CPW, Donnelly PS, Turner BJ, et al. Diacetylbis(N(4)-methylthiosemicarbazonato) copper(II) (CuII(atsm)) protects against peroxynitrite-induced nitrosative damage and prolongs survival in amyotrophic lateral sclerosis mouse model. J Biol Chem. 2011;286(51):44035–44044.
  • Kuo MTH, Beckman JS, Shaw CA. Neuroprotective effect of CuATSM on neurotoxin-induced motor neuron loss in an ALS mouse model. Neurobiol Dis. 2019;130:104495.
  • als-mnd.org [Internet]. Glasgow: international Alliance of ALS/MND Associations; [cited 2022 Nov 5]. Available from: https://www.als-mnd.org/support-for-pals-cals/drugs-in-development/cmd-cuatsm/
  • Couly S, Khalil B, Viguier V, et al. Sigma-1 receptor is a key genetic modulator in amyotrophic lateral sclerosis. Hum Mol Genet. 2020;29(4):529–540.
  • Estevez-Silva HM, Mediavilla T, Giacobbo BL, et al. Pridopidine modifies disease phenotype in a SOD1 mouse model of amyotrophic lateral sclerosis. Eur J Neurosci. 2022;55(5):1356–1372.
  • Ionescu A, Gradus T, Altman T, et al. Targeting the sigma-1 receptor via pridopidine ameliorates central features of ALS pathology in a SOD1(G93A) model. Cell Death Dis. 2019;10(3):210.
  • ALS NewsToday [Internet]. Florida: bioNews, Inc.; [cited 2022 Nov 4]. Available from: https://alsnewstoday.com/news/pridopidine-fda-orphan-drug-designation-als-treatment/
  • Asla MM, Nawar AA, Abdelsalam A, et al. The efficacy and safety of pridopidine on treatment of patients with huntington’s disease: a systematic review and meta-analysis. Mov Disord Clin Pract. 2022;9(1):20–30.
  • ALS NewsToday [Internet]. Florida: bioNews, Inc.; [cited 2022 Oct 28]. Available from: https://alsnewstoday.com/news/als-therapy-verdiperstat-fails-healey-trial-efficacy-goals/
  • Castillo K, Nassif M, Valenzuela V, et al. Trehalose delays the progression of amyotrophic lateral sclerosis by enhancing autophagy in motoneurons. Autophagy. 2013;9(9):1308–1320.
  • Collibee SE, Bergnes G, Chuang C, et al. Discovery of reldesemtiv, a fast skeletal muscle troponin activator for the treatment of impaired muscle function. J Med Chem. 2021;64(20):14930–14941.
  • Shefner JM, Andrews JA, Genge A, et al. A phase 2, double-blind, randomized, dose-ranging trial of reldesemtiv in patients with ALS. Amyotroph Lateral Scler Frontotemporal Degener. 2021;22(3–4):287–299.
  • Fels JA, Dash J, Leslie K, et al. Effects of PB-TURSO on the transcriptional and metabolic landscape of sporadic ALS fibroblasts. Ann Clin Transl Neurol. 2022;9(10):1551–1564.
  • Paganoni S, Macklin EA, Hendrix S, et al. Trial of sodium phenylbutyrate-taurursodiol for amyotrophic lateral sclerosis. N Engl J Med. 2020;383(10):919–930.
  • Amylyx’s MA. ALS therapy secures FDA approval, as regulatory flexibility trumps underwhelming data. Nat Rev Drug Discov. 2022;21(11):786.
  • Zou S, Cannabinoid KU. Receptors and the endocannabinoid system: signaling and function in the central nervous system. Int J Mol Sci. 2018;19(3):833.
  • Raman C, McAllister SD, Rizvi G, et al. Amyotrophic lateral sclerosis: delayed disease progression in mice by treatment with a cannabinoid. Amyotroph Lateral Scler Other Motor Neuron Disord. 2004;5(1):33–39.
  • Moreno-Martet M, Espejo-Porras F, Fernandez-Ruiz J, et al. Changes in endocannabinoid receptors and enzymes in the spinal cord of SOD1(G93A) transgenic mice and evaluation of a Sativex((R)) -like combination of phytocannabinoids: interest for future therapies in amyotrophic lateral sclerosis. CNS Neurosci Ther. 2014;20(9):809–815.
  • Urbi B, Broadley S, Bedlack R, et al. Study protocol for a randomised, double-blind, placebo-controlled study evaluating the Efficacy of cannabis-based Medicine Extract in slowing the disease pRogression of Amyotrophic Lateral sclerosis or motor neurone Disease: the EMERALD trial. BMJ Open. 2019;9(11):e029449.
  • Lapchak PA. A critical assessment of edaravone acute ischemic stroke efficacy trials: is edaravone an effective neuroprotective therapy? Expert Opin Pharmacother. 2010;11(10):1753–1763.
  • Shimizu H, Nishimura Y, Shiide Y, et al. Evaluation of pharmacokinetics, safety, and drug-drug interactions of an oral suspension of edaravone in healthy adults. Clin Pharmacol Drug Dev. 2021;10(10):1174–1187.
  • Mora JS, Bradley WG, Chaverri D, et al. Long-term survival analysis of masitinib in amyotrophic lateral sclerosis. Ther Adv Neurol Disord. 2021;14:17562864211030365.
  • ALS NewsToday [Internet]. BioNews, Inc.; [cited 2022 Nov 20]. Available from: https://alsnewstoday.com/masitinib/
  • Khalaf K, Tornese P, Cocco A, et al. Tauroursodeoxycholic acid: a potential therapeutic tool in neurodegenerative diseases. Transl Neurodegener. 2022;11(1):33.
  • Rodrigues CM, Sola S, Sharpe JC, et al. Tauroursodeoxycholic acid prevents Bax-induced membrane perturbation and cytochrome C release in isolated mitochondria. Biochemistry. 2003;42(10):3070–3080.
  • Elia AE, Lalli S, Monsurro MR, et al. Tauroursodeoxycholic acid in the treatment of patients with amyotrophic lateral sclerosis. Eur J Neurol. 2016;23(1):45–52.
  • Albanese A, Ludolph AC, McDermott CJ, et al. Tauroursodeoxycholic acid in patients with amyotrophic lateral sclerosis: the TUDCA-ALS trial protocol. Front Neurol. 2022;13:1009113.
  • Miller TM, Cudkowicz ME, Genge A, et al. Trial of antisense oligonucleotide tofersen for SOD1 ALS. N Engl J Med. 2022;387(12):1099–1110.
  • Martinez A, Palomo Ruiz MD, Perez DI, et al. Drugs in clinical development for the treatment of amyotrophic lateral sclerosis. Expert Opin Investig Drugs. 2017;26(4):403–414.
  • Kiernan MC, Vucic S, Talbot K, et al. Improving clinical trial outcomes in amyotrophic lateral sclerosis. Nat Rev Neurol. 2021;17(2):104–118.
  • Mead RJ, Shan N, Reiser HJ, et al. Amyotrophic lateral sclerosis: a neurodegenerative disorder poised for successful therapeutic translation. Nat Rev Drug Discov. 2022;1–28. DOI:10.1038/s41573-022-00612-2
  • Paganoni S, Berry JD, Quintana M, et al. Adaptive platform trials to transform amyotrophic lateral sclerosis therapy development. Ann Neurol. 2022;91(2):165–175.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.