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大学・研究所にある論文を検索できる 「Safety and tolerability of bosutinib in patients with amyotrophic lateral sclerosis (iDReAM study): A multicentre, open-label, dose-escalation phase 1 trial」の論文概要。リケラボ論文検索は、全国の大学リポジトリにある学位論文・教授論文を一括検索できる論文検索サービスです。
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Safety and tolerability of bosutinib in patients with amyotrophic lateral sclerosis (iDReAM study): A multicentre, open-label, dose-escalation phase 1 trial

Imamura, Keiko Izumi, Yuishin Nagai, Makiko Nishiyama, Kazutoshi Watanabe, Yasuhiro Hanajima, Ritsuko Egawa, Naohiro Ayaki, Takashi Oki, Ryosuke Fujita, Koji Uozumi, Ryuji Morinaga, Akiko Hirohashi, Tomoko Fujii, Yosuke Yamamoto, Takuya Tatebe, Harutsugu Tokuda, Takahiko Takahashi, Naoto Morita, Satoshi Takahashi, Ryosuke Inoue, Haruhisa 京都大学 DOI:10.1016/j.eclinm.2022.101707

2022.11

概要

[Background] Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease caused by the loss of motor neurons, and development of effective medicines is urgently required. Induced pluripotent stem cell (iPSC)-based drug repurposing identified the Src/c-Abl inhibitor bosutinib, which is approved for the treatment of chronic myelogenous leukemia (CML), as a candidate for the molecular targeted therapy of ALS. [Methods] An open-label, multicentre, dose-escalation phase 1 study using a 3 + 3 design was conducted in 4 hospitals in Japan to evaluate the safety and tolerability of bosutinib in patients with ALS. Furthermore, the exploratory efficacy was evaluated using Revised ALS Functional Rating Scale (ALSFRS-R), predictive biomarkers including plasma neurofilament light chain (NFL) were explored, and single-cell RNA sequencing of iPSC-derived motor neurons was conducted. Patients, whose total ALSFRS-R scores decreased by 1–3 points during the 12-week, received escalating doses starting from 100 mg quaque die (QD) up to 400 mg QD based on dose-limiting toxicity (DLT) occurrence, and all participants who received one dose of the study drug were included in the primary analysis. This trial is registered with ClinicalTrials.gov, NCT04744532, as Induced pluripotent stem cell-based Drug Repurposing for Amyotrophic Lateral Sclerosis Medicine (iDReAM) study. [Findings] Between March 29, 2019 and May 7, 2021, 20 patients were enrolled, 13 of whom received bosutinib treatment and 12 were included in the safety and efficacy analyses. No DLTs were observed up to 300 mg QD, but DLTs were observed in 3/3 patients of the 400 mg QD cohort. In all patients receiving 100 mg–400 mg, the prevalent adverse events (AEs) were gastrointestinal AEs in 12 patients (92.3%), liver function related AEs in 7 patients (53.8%), and rash in 3 patients (23.1%). The safety profile was consistent with that known for CML treatment, and ALS-specific AEs were not observed. A subset of patients (5/9 patients) was found to respond well to bosutinib treatment over the 12-week treatment period. It was found that the treatment-responsive patients could be distinguished by their lower levels of plasma NFL. Furthermore, single-cell RNA sequencing of iPSC-derived motor neurons revealed the pathogenesis related molecular signature in patients with ALS showing responsiveness to bosutinib. [Interpretation] This is the first trial of a Src/c-Abl inhibitor, bosutinib, for patients with ALS. The safety and tolerability of bosutinib up to 300 mg, not 400 mg, in ALS were described, and responsiveness of patients on motor function was observed. Since this was an open-label trial within a short period with a limited number of patients, further clinical trials will be required.

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参考文献

1 Maurel C, Dangoumau A, Marouillat S, et al. Causative genes in amyotrophic lateral sclerosis and protein degradation pathways: a link to neurodegeneration. Mol Neurobiol. 2018;55(8):6480–6499.

2 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(9):585–591.

3 Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo- controlled trial. Lancet Neurol. 2017;16(7):505–512.

4 Witzel S, Maier A, Steinbach R, et al. Safety and effectiveness of long-term intravenous administration of edaravone for treatment of patients with amyotrophic lateral sclerosis. JAMA Neurol. 2022;79(2):121–130.

5 Miller T, Cudkowicz M, Shaw PJ, et al. Phase 1-2 trial of antisense oligonucleotide tofersen for SOD1 ALS. N Engl J Med. 2020;383(2):109–119.

6 Tran H, Moazami MP, Yang H, et al. Suppression of mutant C9orf72 expression by a potent mixed backbone antisense oligo- nucleotide. Nat Med. 2022;28(1):117–124.

7 Wainger BJ, Kiskinis E, Mellin C, et al. Intrinsic membrane hy- perexcitability of amyotrophic lateral sclerosis patient-derived mo- tor neurons. Cell Rep. 2014;7(1):1–11.

8 Korecka JA, Talbot S, Osborn TM, et al. Neurite collapse and altered ER Ca(2+) control in human Parkinson disease patient iPSC- derived neurons with LRRK2 G2019S mutation. Stem Cell Rep. 2019;12(1):29–41.

9 Vadodaria KC, Mendes APD, Mei A, et al. Altered neuronal support and inflammatory response in bipolar disorder patient-derived as- trocytes. Stem Cell Rep. 2021;16(4):825–835.

10 Okano H, Morimoto S. iPSC-based disease modeling and drug discovery in cardinal neurodegenerative disorders. Cell Stem Cell. 2022;29(2):189–208.

11 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.

12 Takahashi N, Cortes JE, Sakaida E, et al. Safety profile of bosutinib in Japanese versus non-Japanese patients with chronic myeloid leukemia: a pooled analysis. Int J Hematol. 2022;115(6):838–851.

13 Hino M, Matsumura I, Fujisawa S, et al. Phase 2 study of bosutinib in Japanese patients with newly diagnosed chronic phase chronic myeloid leukemia. Int J Hematol. 2020;112(1):24–32.

14 Toepfer M, Folwaczny C, Klauser A, Riepl RL, Müller-Felber W, Pongratz D. Gastrointestinal dysfunction in amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord. 1999;1(1):15–19.

15 Costa J, Swash M, de Carvalho M. Awaji criteria for the diagnosis of amyotrophic lateral sclerosis: a systematic review. Arch Neurol. 2012;69(11):1410–1416.

16 Imamura K, Izumi Y, Banno H, et al. Induced pluripotent stem cell-based drug repurposing for amyotrophic lateral sclerosis medicine (iDReAM) study: protocol for a phase I dose escalation study of bosutinib for amyotrophic lateral sclerosis patients. BMJ Open. 2019;9(12):e033131.

17 Sun Q, Zhao X, Li S, et al. CSF neurofilament light chain elevation predicts ALS severity and progression. Front Neurol. 2020;11:919.

18 Shepheard SR, Wuu J, Cardoso M, et al. Urinary p75(ECD): a prognostic, disease progression, and pharmacodynamic biomarker in ALS. Neurology. 2017;88(12):1137–1143.

19 Vu L, An J, Kovalik T, Gendron T, Petrucelli L, Bowser R. Cross- sectional and longitudinal measures of chitinase proteins in amyotrophic lateral sclerosis and expression of CHI3L1 in activated astrocytes. J Neurol Neurosurg Psychiatry. 2020;91(4): 350–358.

20 Chiò A, Calvo A, Bovio G, et al. Amyotrophic lateral sclerosis outcome measures and the role of albumin and creatinine: a population-based study. JAMA Neurol. 2014;71(9):1134–1142.

21 Lu CH, Macdonald-Wallis C, Gray E, et al. Neurofilament light chain: a prognostic biomarker in amyotrophic lateral sclerosis. Neurology. 2015;84(22):2247–2257.

22 Zhou YN, Chen YH, Dong SQ, et al. Role of blood neurofilaments in the prognosis of amyotrophic lateral sclerosis: a meta-analysis. Front Neurol. 2021;12:712245.

23 Imamura K, Yada Y, Izumi Y, et al. Prediction model of amyo- trophic lateral sclerosis by deep learning with patient induced pluripotent stem cells. Ann Neurol. 2021;89(6):1226–1233.

24 Guo W, Vandoorne T, Steyaert J, Staats KA, Van Den Bosch L. The multifaceted role of kinases in amyotrophic lateral sclerosis: ge- netic, pathological and therapeutic implications. Brain. 2020;143(6): 1651–1673.

25 Mora JS, Genge A, Chio A, et al. Masitinib as an add-on therapy to riluzole in patients with amyotrophic lateral sclerosis: a random- ized clinical trial. Amyotroph Lateral Scler Frontotemporal Degener. 2020;21(1-2):5–14.

26 Katsumata R, Ishigaki S, Katsuno M, et al. c-Abl inhibition delays motor neuron degeneration in the G93A mouse, an animal model of amyotrophic lateral sclerosis. PLoS One. 2012;7(9): e46185.

27 Wenqiang C, Lonskaya I, Hebron ML, et al. Parkin-mediated reduction of nuclear and soluble TDP-43 reverses behavioral decline in symptomatic mice. Hum Mol Genet. 2014;23(18): 4960–4969.

28 Fang F, Valdimarsdóttir U, Fürst CJ, et al. Suicide among patients with amyotrophic lateral sclerosis. Brain. 2008;131(Pt 10): 2729–2733.

29 Vu LT, Bowser R. Fluid-based biomarkers for amyotrophic lateral sclerosis. Neurotherapeutics. 2017;14(1):119–134.

30 Andrews JA, Bruijn LI, Shefner JM. ALS drug development guid- ances and trial guidelines: consensus and opportunities for align- ment. Neurology. 2019;93(2):66–71.

31 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.

32 Baxi EG, Thompson T, Li J, et al. Answer ALS, a large-scale resource for sporadic and familial ALS combining clinical and multi-omics data from induced pluripotent cell lines. Nat Neurosci. 2022;25(2):226–237.

33 Watanabe H, Atsuta N, Hirakawa A, et al. A rapid functional decline type of amyotrophic lateral sclerosis is linked to low expression of TTN. J Neurol Neurosurg Psychiatry. 2016;87(8):851–858.

34 Faghri F, Brunn F, Dadu A, et al. Identifying and predicting amyotrophic lateral sclerosis clinical subgroups: a population- based machine-learning study. Lancet Digit Health. 2022;4(5): e359–e369.

35 Petri S. Major research advances in amyotrophic lateral sclerosis in 2021. Lancet Neurol. 2022;21(1):14–15.

36 Thompson AG, Gray E, Verber N, et al. Multicentre appraisal of amyotrophic lateral sclerosis biofluid biomarkers shows primacy of blood neurofilament light chain. Brain Commun. 2022;4(1):fcac029.

37 Tollervey JR, Curk T, Rogelj B, et al. Characterizing the RNA targets and position-dependent splicing regulation by TDP-43. Nat Neu- rosci. 2011;14(4):452–458.

38 Chen KW, Chen JA. Functional roles of long non-coding RNAs in motor neuron development and disease. J Biomed Sci. 2020;27(1):38.

39 Yamamoto I, Azuma Y, Yamaguchi M. Cancer-related genes and ALS. Front Biosci (Landmark Ed). 2019;24:1241–1258.

40 Xie T, Deng L, Mei P, et al. Genome-wide association study combining pathway analysis for typical sporadic amyotrophic lateral sclerosis in Chinese Han populations. Neurobiol Aging. 2014;35(7):1778.e9–1778.e23.

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