EClinicalMedicine (Mar 2024)
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 programResearch in context
- Maximilian Wiesenfarth,
- Johannes Dorst,
- David Brenner,
- Zeynep Elmas,
- Özlem Parlak,
- Zeljko Uzelac,
- Katharina Kandler,
- Kristina Mayer,
- Ulrike Weiland,
- Christine Herrmann,
- Joachim Schuster,
- Axel Freischmidt,
- Kathrin Müller,
- Reiner Siebert,
- Franziska Bachhuber,
- Tatiana Simak,
- Kornelia Günther,
- Elke Fröhlich,
- Antje Knehr,
- Martin Regensburger,
- Alexander German,
- Susanne Petri,
- Julian Grosskreutz,
- Thomas Klopstock,
- Peter Reilich,
- Florian Schöberl,
- Tim Hagenacker,
- Ute Weyen,
- René Günther,
- Maximilian Vidovic,
- Martin Jentsch,
- Thomas Haarmeier,
- Patrick Weydt,
- Ivan Valkadinov,
- Jasper Hesebeck-Brinckmann,
- Julian Conrad,
- Jochen Hans Weishaupt,
- Peggy Schumann,
- Peter Körtvélyessy,
- Thomas Meyer,
- Wolfgang Philipp Ruf,
- Simon Witzel,
- Makbule Senel,
- Hayrettin Tumani,
- Albert Christian Ludolph
Affiliations
- Maximilian Wiesenfarth
- Department of Neurology, Ulm University, 89081, Ulm, Germany
- Johannes Dorst
- Department of Neurology, Ulm University, 89081, Ulm, Germany; German Centre for Neurodegenerative Diseases (DZNE) Site Ulm, 89081, Ulm, Germany
- David Brenner
- Department of Neurology, Ulm University, 89081, Ulm, Germany
- Zeynep Elmas
- Department of Neurology, Ulm University, 89081, Ulm, Germany
- Özlem Parlak
- Department of Neurology, Ulm University, 89081, Ulm, Germany
- Zeljko Uzelac
- Department of Neurology, Ulm University, 89081, Ulm, Germany
- Katharina Kandler
- Department of Neurology, Ulm University, 89081, Ulm, Germany
- Kristina Mayer
- Department of Neurology, Ulm University, 89081, Ulm, Germany
- Ulrike Weiland
- Department of Neurology, Ulm University, 89081, Ulm, Germany
- Christine Herrmann
- Department of Neurology, Ulm University, 89081, Ulm, Germany
- Joachim Schuster
- Department of Neurology, Ulm University, 89081, Ulm, Germany; German Centre for Neurodegenerative Diseases (DZNE) Site Ulm, 89081, Ulm, Germany
- Axel Freischmidt
- Department of Neurology, Ulm University, 89081, Ulm, Germany
- Kathrin Müller
- Department of Neurology, Ulm University, 89081, Ulm, Germany; Institute of Human Genetics, Ulm University and Ulm University Medical Center, 89081, Ulm, Germany
- Reiner Siebert
- Institute of Human Genetics, Ulm University and Ulm University Medical Center, 89081, Ulm, Germany
- Franziska Bachhuber
- Department of Neurology, Ulm University, 89081, Ulm, Germany
- Tatiana Simak
- Department of Neurology, Ulm University, 89081, Ulm, Germany
- Kornelia Günther
- Department of Neurology, Ulm University, 89081, Ulm, Germany
- Elke Fröhlich
- Department of Neurology, Ulm University, 89081, Ulm, Germany
- Antje Knehr
- Department of Neurology, Ulm University, 89081, Ulm, Germany
- Martin Regensburger
- Department of Molecular Neurology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054, Erlangen, Germany; Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, 91054, Erlangen, Germany
- Alexander German
- Department of Molecular Neurology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054, Erlangen, Germany
- Susanne Petri
- Department of Neurology, Hannover Medical School, 30625, Hannover, Germany
- Julian Grosskreutz
- Precision Neurology of Neuromuscular and Motoneuron Diseases, University of Lübeck, 23538, Lübeck, Germany
- Thomas Klopstock
- Department of Neurology with Friedrich-Baur-Institute, LMU University Hospital, LMU Munich, 80336, München, Germany; German Centre for Neurodegenerative Diseases (DZNE) Site Munich, 81377, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), 81377, Munich, Germany
- Peter Reilich
- Department of Neurology with Friedrich-Baur-Institute, LMU University Hospital, LMU Munich, 80336, München, Germany
- Florian Schöberl
- Department of Neurology with Friedrich-Baur-Institute, LMU University Hospital, LMU Munich, 80336, München, Germany
- Tim Hagenacker
- Department of Neurology and Center for Translational Neuro and Behavioral Sciences (C-TNBS), University Hospital Essen, 45127, Essen, Germany
- Ute Weyen
- Department of Neurology, Ruhr-University Bochum, BG-Kliniken Bergmannsheil, 44789, Bochum, Germany
- René Günther
- Department of Neurology, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307, Dresden, Germany; German Center for Neurodegenerative Diseases (DZNE) Site Dresden, 01307, Dresden, Germany
- Maximilian Vidovic
- Department of Neurology, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307, Dresden, Germany
- Martin Jentsch
- Department of Neurology, Helios Klinikum Krefeld, 47805, Krefeld, Germany
- Thomas Haarmeier
- Department of Neurology, Helios Klinikum Krefeld, 47805, Krefeld, Germany
- Patrick Weydt
- Department for Neurodegenerative Disorders and Gerontopsychiatry, Bonn University, 53127, Bonn, Germany; German Centre for Neurodegenerative Diseases (DZNE) Site Bonn, 53127, Bonn, Germany
- Ivan Valkadinov
- Division for Neurodegenerative Diseases, Neurology Department, Mannheim Center for Translational Medicine, University Medicine Mannheim, Heidelberg University, 68167, Mannheim, Germany
- Jasper Hesebeck-Brinckmann
- Division for Neurodegenerative Diseases, Neurology Department, Mannheim Center for Translational Medicine, University Medicine Mannheim, Heidelberg University, 68167, Mannheim, Germany
- Julian Conrad
- Division for Neurodegenerative Diseases, Neurology Department, Mannheim Center for Translational Medicine, University Medicine Mannheim, Heidelberg University, 68167, Mannheim, Germany
- Jochen Hans Weishaupt
- Division for Neurodegenerative Diseases, Neurology Department, Mannheim Center for Translational Medicine, University Medicine Mannheim, Heidelberg University, 68167, Mannheim, Germany
- Peggy Schumann
- Ambulanzpartner Soziotechnologie GmbH, 13353, Berlin, Germany
- Peter Körtvélyessy
- 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; German Centre for Neurodegenerative Diseases (DZNE) Site Magdeburg, 39120, Magdeburg, Germany
- Thomas Meyer
- 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
- Wolfgang Philipp Ruf
- Department of Neurology, Ulm University, 89081, Ulm, Germany
- Simon Witzel
- Department of Neurology, Ulm University, 89081, Ulm, Germany
- Makbule Senel
- Department of Neurology, Ulm University, 89081, Ulm, Germany
- Hayrettin Tumani
- Department of Neurology, Ulm University, 89081, Ulm, Germany; German Centre for Neurodegenerative Diseases (DZNE) Site Ulm, 89081, Ulm, Germany
- Albert Christian Ludolph
- Department of Neurology, Ulm University, 89081, Ulm, Germany; German Centre for Neurodegenerative Diseases (DZNE) Site Ulm, 89081, Ulm, Germany; Corresponding author. Department of Neurology, Ulm University, Oberer Eselsberg 45, 89081, Ulm, Germany.
- Journal volume & issue
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Vol. 69
p. 102495
Abstract
Summary: 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.
