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

Wiesenfarth, Maximilian; Dorst, Johannes; Brenner, David; Elmas, Zeynep; Parlak, Oezlem; Uzelac, Zeljko; Kandler, Katharina; Mayer, Kristina; Weiland, Ulrike; Herrmann, Christine; Schuster, Joachim; Freischmidt, Axel; Mueller, Kathrin; Siebert, Reiner; Bachhuber, Franziska; Simak, Tatiana; Guenther, Kornelia; Froehlich, Elke; Knehr, Antje; Regensburger, Martin; German, Alexander; Petri, Susanne; Grosskreutz, Julian; Klopstock, Thomas; Reilich, Peter; Schoeberl, Florian; Hagenacker, Tim; Weyen, Ute; Guenther, Rene; Vidovic, Maximilian; Jentsch, Martin; Haarmeier, Thomas; Weydt, Patrick; Valkadinov, Ivan; Hesebeck-Brinckmann, Jasper; Conrad, Julian; Weishaupt, Jochen Hans; Schumann, Peggy; Koertvelyessy, Peter; Meyer, Thomas; Ruf, Wolfgang Philipp; Witzel, Simon; Senel, Makbule; Tumani, Hayrettin und Ludolph, Albert Christian (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 program. In: Eclinicalmedicine, Bd. 69, 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-relatedserious adverse events were reported. InterpretationConsistent with the VALOR study and its Open Label Extension (OLE), our results confirm a reductionof NfL serum levels, and moreover show a reduction of pNfH in CSF. The therapy was safe, as no persistentsymptoms were observed. Pleocytosis and Ig synthesis in CSF with clinical symptoms related to myeloradiculitis intwo patients, indicate the potential of an autoimmune reaction. FundingNo funding was received towards this study. Copyright (c) 2024 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license(http://creativecommons.org/licenses/by/4.0/)

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin > Munich Cluster for Systems Neurology (SyNergy)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198