In-depth analysis of data from the RAS-ALS study reveals new insights in rasagiline treatment for amyotrophic lateral sclerosis.
amyotrophic lateral sclerosis
randomized controlled trial
rasagiline
subgroup analysis
Journal
European journal of neurology
ISSN: 1468-1331
Titre abrégé: Eur J Neurol
Pays: England
ID NLM: 9506311
Informations de publication
Date de publication:
19 Jan 2024
19 Jan 2024
Historique:
revised:
26
10
2023
received:
30
06
2023
accepted:
22
12
2023
medline:
19
1
2024
pubmed:
19
1
2024
entrez:
19
1
2024
Statut:
aheadofprint
Résumé
In 2016, we concluded a randomized controlled trial testing 1 mg rasagiline per day add-on to standard therapy in 252 amyotrophic lateral sclerosis (ALS) patients. This article aims at better characterizing ALS patients who could possibly benefit from rasagiline by reporting new subgroup analysis and genetic data. We performed further exploratory in-depth analyses of the study population and investigated the relevance of single nucleotide polymorphisms (SNPs) related to the dopaminergic system. Placebo-treated patients with very slow disease progression (loss of Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised [ALSFRS-R] per month before randomization of ≤0.328 points) showed a per se survival probability after 24 months of 0.85 (95% confidence interval = 0.65-0.94). The large group of intermediate to fast progressing ALS patients showed a prolonged survival in the rasagiline group compared to placebo after 6 and 12 months (p = 0.02, p = 0.04), and a reduced decline of ALSFRS-R after 18 months (p = 0.049). SNP genotypes in the MAOB gene and DRD2 gene did not show clear associations with rasagiline treatment effects. These results underline the need to consider individual disease progression at baseline in future ALS studies. Very slow disease progressors compromise the statistical power of studies with treatment durations of 12-18 months using clinical endpoints. Analysis of MAOB and DRD2 SNPs revealed no clear relationship to any outcome parameter. More insights are expected from future studies elucidating whether patients with DRD2
Sections du résumé
BACKGROUND AND PURPOSE
OBJECTIVE
In 2016, we concluded a randomized controlled trial testing 1 mg rasagiline per day add-on to standard therapy in 252 amyotrophic lateral sclerosis (ALS) patients. This article aims at better characterizing ALS patients who could possibly benefit from rasagiline by reporting new subgroup analysis and genetic data.
METHODS
METHODS
We performed further exploratory in-depth analyses of the study population and investigated the relevance of single nucleotide polymorphisms (SNPs) related to the dopaminergic system.
RESULTS
RESULTS
Placebo-treated patients with very slow disease progression (loss of Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised [ALSFRS-R] per month before randomization of ≤0.328 points) showed a per se survival probability after 24 months of 0.85 (95% confidence interval = 0.65-0.94). The large group of intermediate to fast progressing ALS patients showed a prolonged survival in the rasagiline group compared to placebo after 6 and 12 months (p = 0.02, p = 0.04), and a reduced decline of ALSFRS-R after 18 months (p = 0.049). SNP genotypes in the MAOB gene and DRD2 gene did not show clear associations with rasagiline treatment effects.
CONCLUSIONS
CONCLUSIONS
These results underline the need to consider individual disease progression at baseline in future ALS studies. Very slow disease progressors compromise the statistical power of studies with treatment durations of 12-18 months using clinical endpoints. Analysis of MAOB and DRD2 SNPs revealed no clear relationship to any outcome parameter. More insights are expected from future studies elucidating whether patients with DRD2
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e16204Subventions
Organisme : Teva Pharmaceutical Industries
Informations de copyright
© 2024 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.
Références
Benjaminsen E, Alstadhaug KB, Gulsvik M, Baloch FK, Odeh F. Amyotrophic lateral sclerosis in Nordland county, Norway, 2000-2015: prevalence, incidence, and clinical features. Amyotroph Lateral Scler Frontotemporal Degener. 2018;19(7-8):522-527.
Braak H, Brettschneider J, Ludolph AC, Lee VM, Trojanowski JQ, Del Tredici K. Amyotrophic lateral sclerosis-a model of corticofugal axonal spread. Nat Rev Neurol. 2013;9(12):708-714.
Neumann M, Sampathu DM, Kwong LK, et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science. 2006;314(5796):130-133.
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.
Rascol O, Fitzer-Attas CJ, Hauser R, et al. A double-blind, delayed-start trial of rasagiline in Parkinson's disease (the ADAGIO study): prespecified and post-hoc analyses of the need for additional therapies, changes in UPDRS scores, and non-motor outcomes. Lancet Neurol. 2011;10(5):415-423.
Kostic V, Gurney ME, Deng HX, Siddique T, Epstein CJ, Przedborski S. Midbrain dopaminergic neuronal degeneration in a transgenic mouse model of familial amyotrophic lateral sclerosis. Ann Neurol. 1997;41(4):497-504.
Borasio GD, Linke R, Schwarz J, et al. Dopaminergic deficit in amyotrophic lateral sclerosis assessed with [I-123] IPT single photon emission computed tomography. J Neurol Neurosurg Psychiatry. 1998;65(2):263-265.
Dentel C, Palamiuc L, Henriques A, et al. Degeneration of serotonergic neurons in amyotrophic lateral sclerosis: a link to spasticity. Brain. 2013;136(Pt 2):483-493.
Vermeiren Y, Janssens J, Van Dam D, De Deyn PP. Serotonergic dysfunction in amyotrophic lateral sclerosis and Parkinson's disease: similar mechanisms, dissimilar outcomes. Front Neurosci. 2018;12:185.
Abu-Raya S, Blaugrund E, Trembovler V, Shilderman-Bloch E, Shohami E, Lazarovici P. Rasagiline, a monoamine oxidase-B inhibitor, protects NGF-differentiated PC12 cells against oxygen-glucose deprivation. J Neurosci Res. 1999;58(3):456-463.
Chen JJ, Swope DM. Clinical pharmacology of rasagiline: a novel, second-generation propargylamine for the treatment of Parkinson disease. J Clin Pharmacol. 2005;45(8):878-894.
Finberg JP, Takeshima T, Johnston JM, Commissiong JW. Increased survival of dopaminergic neurons by rasagiline, a monoamine oxidase B inhibitor. Neuroreport. 1998;9(4):703-707.
Maruyama W, Akao Y, Youdim MB, Davis BA, Naoi M. Transfection-enforced Bcl-2 overexpression and an anti-Parkinson drug, rasagiline, prevent nuclear accumulation of glyceraldehyde-3-phosphate dehydrogenase induced by an endogenous dopaminergic neurotoxin, N-methyl(R)salsolinol. J Neurochem. 2001;78(4):727-735.
Riederer P, Lachenmayer L, Laux G. Clinical applications of MAO-inhibitors. Curr Med Chem. 2004;11(15):2033-2043.
Riederer P, Laux G. MAO-inhibitors in Parkinson's disease. Exp Neurobiol. 2011;20(1):1-17.
Naoi M, Maruyama W, Shamoto-Nagai M. Type A and B monoamine oxidases distinctly modulate signal transduction pathway and gene expression to regulate brain function and survival of neurons. J Neural Transm (Vienna). 2018;125(11):1635-1650.
Inaba-Hasegawa K, Shamoto-Nagai M, Maruyama W, Naoi M. Type B and A monoamine oxidase and their inhibitors regulate the gene expression of Bcl-2 and neurotrophic factors in human glioblastoma U118MG cells: different signal pathways for neuroprotection by selegiline and rasagiline. J. Neural Transm. (Vienna). 2017;124(9):1055-1066.
Weishaupt JH, Hyman T, Dikic I. Common molecular pathways in amyotrophic lateral sclerosis and frontotemporal dementia. Trends Mol Med. 2016;22(9):769-783.
Waibel S, Reuter A, Malessa S, Blaugrund E, Ludolph AC. Rasagiline alone and in combination with riluzole prolongs survival in an ALS mouse model. J Neurol. 2004;251(9):1080-1084.
Ludolph AC, Schuster J, Dorst J, et al. Safety and efficacy of rasagiline as an add-on therapy to riluzole in patients with amyotrophic lateral sclerosis: a randomised, double-blind, parallel-group, placebo-controlled, phase 2 trial. Lancet Neurol. 2018;17(8):681-688.
Orru S, Mascia V, Casula M, et al. Association of monoamine oxidase B alleles with age at onset in amyotrophic lateral sclerosis. Neuromuscul Disord. 1999;9(8):593-597.
Jakubauskiene E, Janaviciute V, Peciuliene I, Soderkvist P, Kanopka A. G/a polymorphism in intronic sequence affects the processing of MAO-B gene in patients with Parkinson disease. FEBS Lett. 2012;586(20):3698-3704.
Masellis M, Collinson S, Freeman N, et al. Dopamine D2 receptor gene variants and response to rasagiline in early Parkinson's disease: a pharmacogenetic study. Brain. 2016;139(Pt 7):2050-2062.
Brooks BR, Miller RG, Swash M, Munsat TL. El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord. 2000;1(5):293-299.
Wu RM, Cheng CW, Chen KH, et al. The COMT L allele modifies the association between MAOB polymorphism and PD in Taiwanese. Neurology. 2001;56(3):375-382.
Zhang Y, Bertolino A, Fazio L, et al. Polymorphisms in human dopamine D2 receptor gene affect gene expression, splicing, and neuronal activity during working memory. Proc. Natl. Acad. Sci. U. S. A. 2007;104(51):20552-20557.
Lohle M, Mangone G, Hermann W, et al. Functional MAOB gene intron 13 polymorphism predicts dyskinesia in Parkinson's disease. Parkinsons Dis. 2022;2022:5597503.
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.
Bardakjian T, Gonzalez-Alegre P. Towards precision medicine. Handb Clin Neurol. 2018;147:93-102.
Elemento O. The future of precision medicine: towards a more predictive personalized medicine. Emerg Top Life Sci. 2020;4(2):175-177.