BRAIN and NERVE－神経研究の進歩76巻11号

2024年11月発行

特集 ALS 2024

ALS治療薬開発の現状

著者： 井口洋平¹ 勝野雅央²

所属機関： ¹名古屋大学医学部附属病院脳神経内科 ²名古屋大学大学院医学系研究科神経内科学

ページ範囲：P.1241 - P.1249

文献概要

筋萎縮性側索硬化症（amyotrophic lateral sclerosis：ALS）は進行性，難治性の運動ニューロン疾患である。ALSの治療薬としてはリルゾールとエダラボンが承認されているが，ALSは依然として急速に運動障害を引き起こす致死性の疾患であり，より効果的な治療法の開発が急務である。ALSの病態メカニズムの解明，効率的な臨床試験デザイン，研究支援プログラムの進歩などにより，多くのALSに対する臨床試験が国内外で進行中である。

参考文献

1）Nakamura R, Sone J, Atsuta N, Tohnai G, Watanabe H, et al: Next-generation sequencing of 28 ALS-related genes in a Japanese ALS cohort. Neurobiol Aging 39: 219.e1-219.e2198, 2016［doi: 10.1016/j.neurobiolaging.2015.11.030］

2）Shimizu H, Nishimura Y, Shiide Y, Yoshida K, Hirai M, et al: Bioequivalence study of oral suspension and intravenous formulation of edaravone in healthy adult subjects. Clin Pharmacol Drug Dev 10: 1188-1197, 2021

3）Genge A, Pattee GL, Sobue G, Aoki M, Yoshino H, et al: Oral edaravone demonstrated a favorable safety profile in patients with amyotrophic lateral sclerosis after 48 weeks of treatment. Muscle Nerve 67: 124-129, 2023

4）田辺三菱製薬株式会社: ALSを対象としたMT-1186（エダラボン経口懸濁剤）のグローバル第3b相臨床試験について. 2023　https://www.mt-pharma.co.jp/news/2023/MTPC230801.html（2024年7月27日閲覧）

5）Kaji R, Imai T, Iwasaki Y, Okamoto K, Nakagawa M, et al: Ultra-high-dose methylcobalamin in amyotrophic lateral sclerosis: a long-term phase II/III randomised controlled study. J Neurol Neurosurg Psychiatry 90: 451-457, 2019

6）Oki R, Izumi Y, Fujita K, Miyamoto R, Nodera H, et al: Efficacy and safety of ultrahigh-dose methylcobalamin in early-stage amyotrophic lateral sclerosis: a randomized clinical trial. JAMA Neurol 79: 575-583, 2022

7）Aizawa H, Kato H, Oba K, Kawahara T, Okubo Y, et al: Randomized phase 2 study of perampanel for sporadic amyotrophic lateral sclerosis. J Neurol 269: 885-896, 2022

8）MND-SMART: Breaking News: An update on Memantine, Trazodone and Placebo arms. 2023　https://mnd-smart.org/news/breaking-news-update-memantine-trazodone-and-placebo-arms（2024年7月27日閲覧）

9）Bhai S, Bowser R, Moser S, Taylor D, Heim A, et al: A 40-week phase 2B randomized, multicenter, double-blind, placebo-controlled study evaluating the safety and efficacy of memantine in amyotrophic lateral sclerosis (P8-8.011). Neurology 25; 100(17_supplement_2): 4795, 2023

10）Morimoto S, Takahashi S, Ito D, Daté Y, Okada K, et al: Phase 1/2a clinical trial in ALS with ropinirole, a drug candidate identified by iPSC drug discovery. Cell Stem Cell 30: 766-780.e9, 2023［doi: 10.1016/j.stem.2023.04.017］

11）Imamura K, Izumi Y, Nagai M, Nishiyama K, Watanabe Y, 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 53: 101707, 2022［doi: 10.1016/j.eclinm.2022.101707］

12）京都大学iPS細胞研究所CiRA（サイラ）.　http://www.cira.kyoto-u.ac.jp（2024年7月27日閲覧）

13）PhD MF. UCB stops zilucoplan arm in HEALEY trial for ALS stopped early for lack of benefit. 2022　https://alsnewstoday.com/news/ucb-stops-zilucoplan-arm-early-healey-trial-als-lack-of-efficacy/（2024年7月27日閲覧）

14）Genge A, van den Berg LH, Frick G, Han S, Abikoff C, et al: Efficacy and safety of ravulizumab, a complement C5 inhibitor, in adults with amyotrophic lateral sclerosis: a randomized clinical trial. JAMA Neurol 80: 1089-1097, 2023

15）Apellis Pharmaceuticals, Inc.: Apellis reports top-line results from phase 2 MERIDIAN study in ALS. 2023　https://investors.apellis.com/news-releases/news-release-details/apellis-reports-top-line-results-phase-2-meridian-study-als（2024年7月27日閲覧）

16）Biohaven Pharmaceutical Holding Company Ltd: Biohaven provides update from pivotal phase 2/3 trial with verdiperstat in amyotrophic lateral sclerosis (Healy ALS Platform Trial).　https://www.prnewswire.com/news-releases/biohaven-provides-update-from-pivotal-phase-23-trial-with-verdiperstat-in-amyotrophic-lateral-sclerosis-healy-als-platform-trial-301636535.html（2024年7月27日閲覧）

17）Clene Inc.: Clene presents extended survival data through 3.5 years and new NfL responder results with CNM-Au8®30 mg treatment from the HEALEY ALS platform trial open label extension at the 2024 ENCALS Meeting.　https://invest.clene.com/news-releases/news-release-details/clene-presents-extended-survival-data-through-35-years-and-new/（2024年7月27日閲覧）

18）Shefner J, Oskarsson B, Cohen Y, Chen K, Leitner M, et al: Pridopidine for the treatment of ALS: results from the Phase 2 Healey ALS platform trial (S5.003). Neurology 102(17_supplement_1): 6524, 2024

19）Inc ST: Seelos Therapeutics provides update on top-line results from its amyotrophic lateral sclerosis (ALS) study with SLS-005 (IV Trehalose)　https://www.prnewswire.com/news-releases/seelos-therapeutics-provides-update-on-top-line-results-from-its-amyotrophic-lateral-sclerosis-als-study-with-sls-005-iv-trehalose-302092918.html（2024年7月27日閲覧）

20）Baradaran-Heravi Y, Van Broeckhoven C, van der Zee J: Stress granule mediated protein aggregation and underlying gene defects in the FTD-ALS spectrum. Neurobiol Dis 134: 104639, 2020［doi: 10.1016/j.nbd.2019.104639］

21）Oskarsson B, Maragakis N, Bedlack RS, Goyal N, Meyer JA, et al: MN-166 (ibudilast) in amyotrophic lateral sclerosis in a Phase IIb/III study: COMBAT-ALS study design. Neurodegener Dis Manag 11: 431-443, 2021

22）NeuroSense: NeuroSense's PARADIGM ALS clinical trial demonstrates up to 73% improved complication-free survival following statistically significant slowing of disease progression.　https://www.prnewswire.com/news-releases/neurosenses-paradigm-als-clinical-trial-demonstrates-up-to-73-improved-complication-free-survival-following-statistically-significant-slowing-of-disease-progression-302191862.html（2024年7月27日閲覧）

23）Beers DR, Zhao W, Wang J, Zhang X, Wen S, et al: ALS patients' regulatory T lymphocytes are dysfunctional, and correlate with disease progression rate and severity. JCI Insight 2: e89530, 2017［doi: 10.1172/jci.insight.89530］

24）Camu W, Mickunas M, Veyrune JL, Payan C, Garlanda C, et al: Repeated 5-day cycles of low dose aldesleukin in amyotrophic lateral sclerosis (IMODALS): A phase 2a randomised, double-blind, placebo-controlled trial. EBioMedicine 59: 102844, 2020［doi: 10.1016/j.ebiom.2020.102844］

25）Thonhoff JR, Beers DR, Zhao W, Faridar A, Thome A, et al: A phase 1 proof-of-concept study evaluating safety, tolerability, and biological marker responses with combination therapy of CTLA4-Ig and interleukin-2 in amyotrophic lateral sclerosis. Front Neurol 15: 1415106, 2024［doi: 10.3389/fneur.2024.1415106］

26）Cudkowicz ME, Lindborg SR, Goyal NA, Miller RG, Burford MJ, et al: A randomized placebo-controlled phase 3 study of mesenchymal stem cells induced to secrete high levels of neurotrophic factors in amyotrophic lateral sclerosis. Muscle Nerve 65: 291-302, 2022

27）Becker LA, Huang B, Bieri G, Ma R, Knowles DA, et al: Therapeutic reduction of ataxin-2 extends lifespan and reduces pathology in TDP-43 mice. Nature 544: 367-371, 2017

28）Inc IP: Ionis and Biogen announce topline phase 1/2 study results of investigational drug in amyotrophic lateral sclerosis.　https://www.prnewswire.com/news-releases/ionis-and-biogen-announce-topline-phase-12-study-results-of-investigational-drug-in-amyotrophic-lateral-sclerosis-302147377.html（2024年7月27日閲覧）

29）Baughn MW, Melamed Z, López-Erauskin J, Beccari MS, Ling K, et al: Mechanism of STMN2 cryptic splice-polyadenylation and its correction for TDP-43 proteinopathies. Science 379: 1140-1149, 2023

30）Shi Y, Lin S, Staats KA, Li Y, Chang WH, et al: Haploinsufficiency leads to neurodegeneration in C9ORF72 ALS/FTD human induced motor neurons. Nat Med 24: 313-325, 2018

31）Hung ST, Linares GR, Chang WH, Eoh Y, Krishnan G, et al: PIKFYVE inhibition mitigates disease in models of diverse forms of ALS. Cell 186: 786-802.e28, 2023［doi: 10.1016/j.cell.2023.01.005］

32）Babu S, Nicholson KA, Rothstein JD, Swenson A, Sampognaro PJ, et al: Apilimod dimesylate in C9orf72 amyotrophic lateral sclerosis: a randomized phase 2a clinical trial. Brain: awae109, 2024［doi: 10.1093/brain/awae109］

33）Steiner JP, Bachani M, Malik N, DeMarino C, Li W, et al: Human endogenous retrovirus K envelope in spinal fluid of amyotrophic lateral sclerosis is toxic. Ann Neurol 92: 545-561, 2022

34）Garcia-Montojo M, Simula ER, Fathi S, McMahan C, Ghosal A, et al: Antibody response to HML-2 may be protective in amyotrophic lateral sclerosis. Ann Neurol 92: 782-792, 2022

35）Tam OH, Rozhkov NV, Shaw R, Kim D, Hubbard I, et al: Postmortem cortex samples identify distinct molecular subtypes of ALS: retrotransposon activation, oxidative stress, and activated glia. Cell Rep 29: 1164-1177.e5, 2019［doi: 10.1016/j.celrep.2019.09.066］

36）Gold J, Rowe DB, Kiernan MC, Vucic S, Mathers S, et al: Safety and tolerability of triumeq in amyotrophic lateral sclerosis: the Lighthouse trial. Amyotroph Lateral Scler Frontotemporal Degener 20: 595-604, 2019

37）Ishihara T, Koyama A, Hatano Y, Takeuchi R, Koike Y, et al: Endogenous human retrovirus-K is not increased in the affected tissues of Japanese ALS patients. Neurosci Res 178: 78-82, 2022

38）Shefner JM, Andrews JA, Genge A, Jackson C, Lechtzin N, et al: A phase 2, double-blind, randomized, dose-ranging trial of reldesemtiv in patients with ALS. Amyotroph Lateral Scler Frontotemporal Degener 22: 287-299, 2021

39）Cytokinetics: Cytokinetics announces COURAGE-ALS Met criteria for futility at second interim analysis.　https://ir.cytokinetics.com/news-releases/news-release-details/cytokinetics-announces-courage-als-met-criteria-futility-second（2024年7月27日閲覧）

40）Ito Y, Ofengeim D, Najafov A, Das S, Saberi S, et al: RIPK1 mediates axonal degeneration by promoting inflammation and necroptosis in ALS. Science 353: 603-608, 2016

41）Clinical Trials Arena: Sanofi and Denali's ALS therapy misses primary endpoint in phase II. 2024　https://www.clinicaltrialsarena.com/news/sanofi-and-denalis-als-therapy-misses-primary-endpoint-in-phase-ii/（2024年7月27日閲覧）

42）Al-Chalabi A, Shaw P, Leigh PN, van den Berg L, Hardiman O, et al: Oral levosimendan in amyotrophic lateral sclerosis: a phase II multicentre, randomised, double-blind, placebo-controlled trial. J Neurol Neurosurg Psychiatry 90: 1165-1170, 2019

43）Cudkowicz M, Genge A, Maragakis N, Petri S, van den Berg L, et al: Safety and efficacy of oral levosimendan in people with amyotrophic lateral sclerosis (the REFALS study): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Neurol 20: 821-831, 2021

44）Paganoni S, Macklin EA, Hendrix S, Berry JD, Elliott MA, et al: Trial of sodium phenylbutyrate-taurursodiol for amyotrophic lateral sclerosis. N Engl J Med 383: 919-930, 2020

45）Amylyx: Amylyx Pharmaceuticals announces topline results from global phase 3 PHOENIX trial of AMX0035 in ALS. 2024　https://www.amylyx.com/news/amylyx-pharmaceuticals-announces-topline-results-from-global-phase-3-phoenix-trial-of-amx0035-in-als（2024年7月27日閲覧）

46）TUDCA ALS: Announcement of top-line results. 2024　https://www.tudca.eu/top-line-results-announcement/（2024年7月27日閲覧）