2. Academic Validation
  3. Effects of tofersen treatment in patients with SOD1-ALS in a "real-world" setting - a 12-month multicenter cohort study from the German early access program

Effects of tofersen treatment in patients with SOD1-ALS in a "real-world" setting - a 12-month multicenter cohort study from the German early access program

  • EClinicalMedicine. 2024 Feb 15:69:102495. doi: 10.1016/j.eclinm.2024.102495.
Maximilian Wiesenfarth 1,  Johannes Dorst 1 2,  David Brenner 1,  Zeynep Elmas 1,  Özlem Parlak 1,  Zeljko Uzelac 1,  Katharina Kandler 1,  Kristina Mayer 1,  Ulrike Weiland 1,  Christine Herrmann 1,  Joachim Schuster 1 2,  Axel Freischmidt 1,  Kathrin Müller 1 3,  Reiner Siebert 3,  Franziska Bachhuber 1,  Tatiana Simak 1,  Kornelia Günther 1,  Elke Fröhlich 1,  Antje Knehr 1,  Martin Regensburger 4 5,  Alexander German 4,  Susanne Petri 6,  Julian Grosskreutz 7,  Thomas Klopstock 8 9 10,  Peter Reilich 8,  Florian Schöberl 8,  Tim Hagenacker 11,  Ute Weyen 12,  René Günther 13 14,  Maximilian Vidovic 13,  Martin Jentsch 15,  Thomas Haarmeier 15,  Patrick Weydt 16 17,  Ivan Valkadinov 18,  Jasper Hesebeck-Brinckmann 18,  Julian Conrad 18,  Jochen Hans Weishaupt 18,  Peggy Schumann 19,  Peter Körtvélyessy 20 21,  Thomas Meyer 20,  Wolfgang Philipp Ruf 1,  Simon Witzel 1,  Makbule Senel 1,  Hayrettin Tumani 1 2,  Albert Christian Ludolph 1 2
Affiliations

Affiliations

  • 1 Department of Neurology, Ulm University, 89081, Ulm, Germany.
  • 2 German Centre for Neurodegenerative Diseases (DZNE) Site Ulm, 89081, Ulm, Germany.
  • 3 Institute of Human Genetics, Ulm University and Ulm University Medical Center, 89081, Ulm, Germany.
  • 4 Department of Molecular Neurology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054, Erlangen, Germany.
  • 5 Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, 91054, Erlangen, Germany.
  • 6 Department of Neurology, Hannover Medical School, 30625, Hannover, Germany.
  • 7 Precision Neurology of Neuromuscular and Motoneuron Diseases, University of Lübeck, 23538, Lübeck, Germany.
  • 8 Department of Neurology with Friedrich-Baur-Institute, LMU University Hospital, LMU Munich, 80336, München, Germany.
  • 9 German Centre for Neurodegenerative Diseases (DZNE) Site Munich, 81377, Munich, Germany.
  • 10 Munich Cluster for Systems Neurology (SyNergy), 81377, Munich, Germany.
  • 11 Department of Neurology and Center for Translational Neuro and Behavioral Sciences (C-TNBS), University Hospital Essen, 45127, Essen, Germany.
  • 12 Department of Neurology, Ruhr-University Bochum, BG-Kliniken Bergmannsheil, 44789, Bochum, Germany.
  • 13 Department of Neurology, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307, Dresden, Germany.
  • 14 German Center for Neurodegenerative Diseases (DZNE) Site Dresden, 01307, Dresden, Germany.
  • 15 Department of Neurology, Helios Klinikum Krefeld, 47805, Krefeld, Germany.
  • 16 Department for Neurodegenerative Disorders and Gerontopsychiatry, Bonn University, 53127, Bonn, Germany.
  • 17 German Centre for Neurodegenerative Diseases (DZNE) Site Bonn, 53127, Bonn, Germany.
  • 18 Division for Neurodegenerative Diseases, Neurology Department, Mannheim Center for Translational Medicine, University Medicine Mannheim, Heidelberg University, 68167, Mannheim, Germany.
  • 19 Ambulanzpartner Soziotechnologie GmbH, 13353, Berlin, Germany.
  • 20 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, 13353, Berlin, Germany.
  • 21 German Centre for Neurodegenerative Diseases (DZNE) Site Magdeburg, 39120, Magdeburg, Germany.
PMID: 38384337 DOI: 10.1016/j.eclinm.2024.102495
Abstract

Background: In April 2023, the antisense oligonucleotide tofersen was approved by the U.S. Food and Drug Administration (FDA) for treatment of SOD1-amyotrophic lateral sclerosis (ALS), after a decrease of neurofilament light chain (NfL) levels had been demonstrated.

Methods: Between 03/2022 and 04/2023, 24 patients with SOD1-ALS from ten German ALS reference centers were followed-up until the cut-off date for ALS functional rating scale revised (ALSFRS-R), progression rate (loss of ALSFRS-R/month), NfL, phosphorylated neurofilament heavy chain (pNfH) in cerebrospinal fluid (CSF), and adverse events.

Findings: During the observation period, median ALSFRS-R decreased from 38.0 (IQR 32.0-42.0) to 35.0 (IQR 29.0-42.0), corresponding to a median progression rate of 0.11 (IQR -0.09 to 0.32) points of ALSFRS-R lost per month. Median serum NfL declined from 78.0 pg/ml (IQR 37.0-147.0 pg/ml; n = 23) to 36.0 pg/ml (IQR 22.0-65.0 pg/ml; n = 23; p = 0.02), median pNfH in CSF from 2226 pg/ml (IQR 1061-6138 pg/ml; n = 18) to 1151 pg/ml (IQR 521-2360 pg/ml; n = 18; p = 0.02). In the CSF, we detected a pleocytosis in 73% of patients (11 of 15) and an intrathecal immunoglobulin synthesis (IgG, IgM, or IgA) in 9 out of 10 patients. Two drug-related serious adverse events were reported.

Interpretation: Consistent with the VALOR study and its Open Label Extension (OLE), our results confirm a reduction of NfL serum levels, and moreover show a reduction of pNfH in CSF. The therapy was safe, as no persistent symptoms were observed. Pleocytosis and Ig synthesis in CSF with clinical symptoms related to myeloradiculitis in two patients, indicate the potential of an autoimmune reaction.

Funding: No funding was received towards this study.

Keywords

Amyotrophic lateral sclerosis; Antisense oligonucleotide; Early access program; SOD1; Tofersen.

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