In-depth analysis of data from the RAS-ALS study reveals new insights in rasagiline treatment for amyotrophic lateral sclerosis.

Jochen H Weishaupt, Bettina Göricke, Siw Johannesen, Berthold Schrank, Stéphane Dieterlé, Karla Mönkemöller, Albert C Ludolph, Thomas Meyer, Michael T Heneka, Jan Kassubek, Luc Dupuis, Andreas Hermann, Daniel Zeller, Jens Dreyhaupt, Julian Grosskreutz, Torsten Grehl, Susanne Petri, Johannes Dorst, Andrea S Winkler, Joachim Schuster, Simon Witzel, Johannes Prudlo, Matthias Boentert, Alexander Emmer

Journal: European journal of neurology 2024;31(4):e16204

PMID: 38240416

Free Full Text on PubMed Central View on PubMed

Abstract

BACKGROUND AND PURPOSE

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

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

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

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 genotype (Rs2283265) show a pronounced benefit from treatment with rasagiline, pointing to the opportunities precision medicine could open up for ALS patients in the future.

Address: Department of Neurology, University of Ulm, Ulm, Germany.; German Center for Neurodegenerative Diseases, Ulm, Germany.; Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm, Germany.; Department of Clinical and Health Psychology, Institute of Education and Psychology, University of Ulm, Ulm, Germany.; Université de Strasbourg, Inserm, UMR-S1118, Centre de Recherches en biomédecine de Strasbourg, Strasbourg, France.; Division of Neurodegeneration, Department of Neurology, Mannheim Center for Translational Neurosciences, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.; Department of Neurology, Hannover Medical School, Hannover, Germany.; Department of Neurology, Center for ALS and other Motor Neuron Disorders, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Berlin, Germany.; Department of Neurology, University Clinic Schleswig-Holstein, Campus Lübeck, Lübeck, Germany.; Department of Neurology, DKD HELIOS Klinik Wiesbaden, Wiesbaden, Germany.; Department of Neurology, University Hospital Münster, Münster, Germany.; Department of Neurology, University Hospital Halle, Halle, Germany.; Translational Neurodegeneration Section "Albrecht Kossel," Department of Neurology, University Medical Center Rostock, Rostock, Germany.; German Center for Neurodegenerative Diseases, Rostock/Greifswald, Rostock, Germany.; Department of Neurology, University of Würzburg, Würzburg, Germany.; German Center for Neurodegenerative Diseases, Rostock/Greifswald, Rostock, Germany.; Department of Neurology, Rostock University Medical Center, Rostock, Germany.; Department of Neurology, Technical University Munich, Munich, Germany.; Department of Neurology, Alfried Krupp Hospital, Essen, Germany.; Luxembourg Center for Systems Biomedicine, University of Luxembourg, Belval, Luxembourg.; Neurology, BG Hospital Murnau, Murnau, Germany.; Department of Neurology, University Hospital of Göttingen, Göttingen, Germany.; Department of Neurology, University of Ulm, Ulm, Germany.

DOI: 10.1111/ene.16204