Advances in Disease-Modifying Therapeutics for Chronic Neuromuscular Disorders

Abstract

Neuromuscular disorders can cause respiratory impairment by affecting the muscle fibers, neuromuscular junction, or innervation of respiratory muscles, leading to significant morbidity and mortality. Over the past few years, new disease-modifying therapies have been developed and made available for treating different neuromuscular disorders. Some of these therapies have remarkable effectiveness, resulting in the prevention and reduction of respiratory complications. For myasthenia gravis (MG), efgartigimod, ravulizumab, rozanolixizumab, and zilucoplan have been Food and Drug Administration (FDA)-approved for the treatment of acetylcholine receptor (AChR) antibody-positive generalized MG in the past 2 years. Rozanolixiumab is also approved for treating MG caused by muscle-specific tyrosine kinase (MuSK) antibodies. The new MG therapeutics target the complement system or block the neonatal fragment crystallizable (Fc) receptors (FcRn), leading to significant clinical improvement. For spinal muscular atrophy (SMA), nusinersen (intrathecal route) and risdiplam (oral route) modify the splicing of the SMN2 gene, increasing the production of normal survival motor neuron (SMN) protein. Onasemnogene abeparvovec is a gene replacement therapy that encodes a functional SMN protein. All SMA medications, particularly onasemnogene abeparvovec, have led to clinically meaningful improvement. For late-onset Pompe disease (LOPD), avalglucosidase alfa has shown a greater improvement in respiratory function, ambulation, and functional outcomes in comparison to alglucosidase alfa, and cipaglucosidase alfa combined with miglustat has shown improvement in respiratory and motor function in a cohort of enzyme replacement therapy-experienced LOPD patients. Amyotrophic lateral sclerosis (ALS) remains a challenge. The two most recent FDA-approved medications, namely sodium phenylbutyrate and tofersen, may slow down the disease by a few months in a selected population but do not stop the progression of the disease.

Keywords

amyotrophic lateral sclerosis - myasthenia gravis - spinal muscular atrophy - late-onset Pompe disease - neuromuscular disorders - therapy

Publication History

Article published online:
21 December 2024

• References

• 1 Masrori P, Van Damme P. Amyotrophic lateral sclerosis: a clinical review. Eur J Neurol 2020; 27 (10) 1918-1929
• 2 Chiò A, Logroscino G, Traynor BJ. et al. Global epidemiology of amyotrophic lateral sclerosis: a systematic review of the published literature. Neuroepidemiology 2013; 41 (02) 118-130
• 3 Chiò A, Logroscino G, Hardiman O. et al; Eurals Consortium. Prognostic factors in ALS: a critical review. Amyotroph Lateral Scler 2009; 10 (5–6): 310-323
• 4 Mejzini R, Flynn LL, Pitout IL, Fletcher S, Wilton SD, Akkari PA. ALS genetics, mechanisms, and therapeutics: where are we now?. Front Neurosci 2019; 13: 1310
• 5 Johnson SA, Fang T, De Marchi F. et al. Pharmacotherapy for amyotrophic lateral sclerosis: a review of approved and upcoming agents. Drugs 2022; 82 (13) 1367-1388
• 6 Shatunov A, Al-Chalabi A. The genetic architecture of ALS. Neurobiol Dis 2021; 147: 105156
• 7 Taylor JP, Brown Jr RH, Cleveland DW. Decoding ALS: from genes to mechanism. Nature 2016; 539 (7628): 197-206
• 8 Tzeplaeff L, Wilfling S, Requardt MV, Herdick M. Current state and future directions in the therapy of ALS. Cells 2023; 12 (11) 1523
• 9 Bensimon G, Lacomblez L, Meininger V. ALS/Riluzole Study Group. A controlled trial of riluzole in amyotrophic lateral sclerosis. N Engl J Med 1994; 330 (09) 585-591
• 10 Lacomblez L, Bensimon G, Leigh PN. et al; ALS/Riluzole Study Group-II. A confirmatory dose-ranging study of riluzole in ALS. Neurology 1996; 47 (6 Suppl 4): S242-S250
• 11 Andrews JA, Jackson CE, Heiman-Patterson TD, Bettica P, Brooks BR, Pioro EP. Real-world evidence of riluzole effectiveness in treating amyotrophic lateral sclerosis. Amyotroph Lateral Scler Frontotemporal Degener 2020; 21 (7-8): 509-518
• 12 Abe K, Itoyama Y, Sobue G. et al; 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; 15 (7-8): 610-617
• 13 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 (07) 505-512
• 14 Witzel S, Maier A, Steinbach R. et al; German Motor Neuron Disease Network (MND-NET). Safety and effectiveness of long-term intravenous administration of edaravone for treatment of patients with amyotrophic lateral sclerosis. JAMA Neurol 2022; 79 (02) 121-130
• 15 Lunetta C, Moglia C, Lizio A. et al; EDARAVALS Study Group. The Italian multicenter experience with edaravone in amyotrophic lateral sclerosis. J Neurol 2020; 267 (11) 3258-3267
• 16 Cudkowicz ME, Andres PL, Macdonald SA. et al; Northeast ALS and National VA ALS Research Consortiums. Phase 2 study of sodium phenylbutyrate in ALS. Amyotroph Lateral Scler 2009; 10 (02) 99-106
• 17 Elia AE, Lalli S, Monsurrò MR. et al. Tauroursodeoxycholic acid in the treatment of patients with amyotrophic lateral sclerosis. Eur J Neurol 2016; 23 (01) 45-52
• 18 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
• 19 Paganoni S, Hendrix S, Dickson SP. et al. Effect of sodium phenylbutyrate/taurursodiol on tracheostomy/ventilation-free survival and hospitalisation in amyotrophic lateral sclerosis: long-term results from the CENTAUR trial. J Neurol Neurosurg Psychiatry 2022; 93 (08) 871-875
• 20 Paganoni S, Hendrix S, Dickson SP. et al. Long-term survival of participants in the CENTAUR trial of sodium phenylbutyrate-taurursodiol in amyotrophic lateral sclerosis. Muscle Nerve 2021; 63 (01) 31-39
• 21 Del Signore SJ, Amante DJ, Kim J. et al. Combined riluzole and sodium phenylbutyrate therapy in transgenic amyotrophic lateral sclerosis mice. Amyotroph Lateral Scler 2009; 10 (02) 85-94
• 22 Ryu H, Smith K, Camelo SI. et al. Sodium phenylbutyrate prolongs survival and regulates expression of anti-apoptotic genes in transgenic amyotrophic lateral sclerosis mice. J Neurochem 2005; 93 (05) 1087-1098
• 23 Kusaczuk M. Tauroursodeoxycholate-bile acid with chaperoning activity: molecular and cellular effects and therapeutic perspectives. Cells 2019; 8 (12) 1471
• 24 Dionísio PA, Amaral JD, Ribeiro MF, Lo AC, D'Hooge R, Rodrigues CMP. Amyloid-β pathology is attenuated by tauroursodeoxycholic acid treatment in APP/PS1 mice after disease onset. Neurobiol Aging 2015; 36 (01) 228-240
• 25 Zou ZY, Zhou ZR, Che CH, Liu CY, He RL, Huang HP. Genetic epidemiology of amyotrophic lateral sclerosis: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry 2017; 88 (07) 540-549
• 26 Miller TM, Cudkowicz ME, Genge A. et al; VALOR and OLE Working Group. Trial of antisense oligonucleotide tofersen for SOD1 ALS. N Engl J Med 2022; 387 (12) 1099-1110s
• 27 Cartwright MS, Ward ZT, White EP, West TG. Intrathecal delivery of nusinersen in individuals with complicated spines. Muscle Nerve 2020; 62 (01) 114-118
• 28 Iannaccone ST, Paul D, Castro D, Weprin B, Swift D. Delivery of nusinersen through an ommaya reservoir in spinal muscular atrophy. J Clin Neuromuscul Dis 2021; 22 (03) 129-134
• 29 Finkel RS, Mercuri E, Darras BT. et al; ENDEAR Study Group. Nusinersen versus sham control in infantile-onset spinal muscular atrophy. N Engl J Med 2017; 377 (18) 1723-1732
• 30 Mercuri E, Darras BT, Chiriboga CA. et al; CHERISH Study Group. Nusinersen versus sham control in later-onset spinal muscular atrophy. N Engl J Med 2018; 378 (07) 625-635
• 31 Baranello G, Darras BT, Day JW. et al; FIREFISH Working Group. Risdiplam in type 1 spinal muscular atrophy. N Engl J Med 2021; 384 (10) 915-923
• 32 Mercuri E, Deconinck N, Mazzone ES. et al; SUNFISH Study Group. Safety and efficacy of once-daily risdiplam in type 2 and non-ambulant type 3 spinal muscular atrophy (SUNFISH part 2): a phase 3, double-blind, randomised, placebo-controlled trial. Lancet Neurol 2022; 21 (01) 42-52
• 33 Day JW, Finkel RS, Chiriboga CA. et al. Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy in patients with two copies of SMN2 (STR1VE): an open-label, single-arm, multicentre, phase 3 trial. Lancet Neurol 2021; 20 (04) 284-293
• 34 Mercuri E, Muntoni F, Baranello G. et al; STR1VE-EU study group. Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy type 1 (STR1VE-EU): an open-label, single-arm, multicentre, phase 3 trial. Lancet Neurol 2021; 20 (10) 832-841
• 35 Strauss KA, Farrar MA, Muntoni F. et al. Onasemnogene abeparvovec for presymptomatic infants with two copies of SMN2 at risk for spinal muscular atrophy type 1: the Phase III SPR1NT trial. Nat Med 2022; 28 (07) 1381-1389
• 36 Gilhus NE. Myasthenia gravis. N Engl J Med 2016; 375 (26) 2570-2581
• 37 Neumann B, Angstwurm K, Mergenthaler P. et al; German Myasthenic Crisis Study Group. Myasthenic crisis demanding mechanical ventilation: a multicenter analysis of 250 cases. Neurology 2020; 94 (03) e299-e313
• 38 McConville J, Farrugia ME, Beeson D. et al. Detection and characterization of MuSK antibodies in seronegative myasthenia gravis. Ann Neurol 2004; 55 (04) 580-584
• 39 Chan KH, Lachance DH, Harper CM, Lennon VA. Frequency of seronegativity in adult-acquired generalized myasthenia gravis. Muscle Nerve 2007; 36 (05) 651-658
• 40 Cutter G, Xin H, Aban I. et al. Cross-sectional analysis of the Myasthenia Gravis Patient Registry: disability and treatment. Muscle Nerve 2019; 60 (06) 707-715
• 41 Howard Jr JF, Utsugisawa K, Benatar M. et al; REGAIN Study Group. Safety and efficacy of eculizumab in anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis (REGAIN): a phase 3, randomised, double-blind, placebo-controlled, multicentre study. Lancet Neurol 2017; 16 (12) 976-986
• 42 Hehir MK, Burns TM, Alpers J, Conaway MR, Sawa M, Sanders DB. Mycophenolate mofetil in AChR-antibody-positive myasthenia gravis: outcomes in 102 patients. Muscle Nerve 2010; 41 (05) 593-598
• 43 Howard Jr JF, Bril V, Vu T. et al; ADAPT Investigator Study Group. Safety, efficacy, and tolerability of efgartigimod in patients with generalised myasthenia gravis (ADAPT): a multicentre, randomised, placebo-controlled, phase 3 trial. Lancet Neurol 2021; 20 (07) 526-536
• 44 argenx. argenx Announces Positive Topline Phase 3 Data From ADAPT-SC Study Evaluating Subcutaneous Efgartigimod for Generalized Myasthenia Gravis. News release. March 22, 2022. Accessed October 29, 2023 at: https://www.us.argenx.com/news/argenx-announces-positive-topline-phase-3-data-adapt-sc-study-evaluating-subcutaneous
• 45 Vu T, Meisel A, Mantegazza R. et al. Terminal complement inhibitor ravulizumab in generalized myasthenia gravis. NEJM Evid 2022; 1 (05) a2100066
• 46 Bril V, Drużdż A, Grosskreutz J. et al; MG0003 study team. Safety and efficacy of rozanolixizumab in patients with generalised myasthenia gravis (MycarinG): a randomised, double-blind, placebo-controlled, adaptive phase 3 study. Lancet Neurol 2023; 22 (05) 383-394
• 47 Howard Jr JF, Bresch S, Genge A. et al; RAISE Study Team. Safety and efficacy of zilucoplan in patients with generalised myasthenia gravis (RAISE): a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Neurol 2023; 22 (05) 395-406
• 48 American Association of Neuromuscular & Electrodiagnostic Medicine. Diagnostic criteria for late-onset (childhood and adult) Pompe disease. Muscle Nerve 2009; 40 (01) 149-160
• 49 Kuperus E, Kruijshaar ME, Wens SCA. et al. Long-term benefit of enzyme replacement therapy in Pompe disease: a 5-year prospective study. Neurology 2017; 89 (23) 2365-2373
• 50 Zhou Q, Avila LZ, Konowicz PA. et al. Glycan structure determinants for cation-independent mannose 6-phosphate receptor binding and cellular uptake of a recombinant protein. Bioconjug Chem 2013; 24 (12) 2025-2035
• 51 Diaz-Manera J, Kishnani PS, Kushlaf H. et al; COMET Investigator Group. Safety and efficacy of avalglucosidase alfa versus alglucosidase alfa in patients with late-onset Pompe disease (COMET): a phase 3, randomised, multicentre trial. Lancet Neurol 2021; 20 (12) 1012-1026
• 52 Lachmann R, Schoser B. The clinical relevance of outcomes used in late-onset Pompe disease: can we do better?. Orphanet J Rare Dis 2013; 8: 160
• 53 Kishnani PS, Diaz-Manera J, Toscano A. et al; COMET Investigator Group. Efficacy and safety of avalglucosidase alfa in patients with late-onset Pompe disease after 97 weeks: a phase 3 randomized clinical trial. JAMA Neurol 2023; 80 (06) 558-567
• 54 Schoser B, Roberts M, Byrne BJ. et al; PROPEL Study Group. Safety and efficacy of cipaglucosidase alfa plus miglustat versus alglucosidase alfa plus placebo in late-onset Pompe disease (PROPEL): an international, randomised, double-blind, parallel-group, phase 3 trial. Lancet Neurol 2021; 20 (12) 1027-1037