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

Maximilian Wiesenfarth¹, Johannes Dorst^{1

2}, David Brenner¹, Zeynep Elmas¹, Özlem Parlak¹, Zeljko Uzelac¹, Katharina Kandler¹, Kristina Mayer¹, Ulrike Weiland¹, Christine Herrmann¹, Joachim Schuster^{1

2}, Axel Freischmidt¹, Kathrin Müller^{1

3}, Reiner Siebert³, Franziska Bachhuber¹, Tatiana Simak¹, Kornelia Günther¹, Elke Fröhlich¹, Antje Knehr¹, Martin Regensburger^{4

5}, Alexander German⁴, Susanne Petri⁶, Julian Grosskreutz⁷, Thomas Klopstock^{8

9

10}, Peter Reilich⁸, Florian Schöberl⁸, Tim Hagenacker¹¹, Ute Weyen¹², René Günther^{13

14}, Maximilian Vidovic¹³, Martin Jentsch¹⁵, Thomas Haarmeier¹⁵, Patrick Weydt^{16

17}, Ivan Valkadinov¹⁸, Jasper Hesebeck-Brinckmann¹⁸, Julian Conrad¹⁸, Jochen Hans Weishaupt¹⁸, Peggy Schumann¹⁹, Peter Körtvélyessy^{20

21}, Thomas Meyer²⁰, Wolfgang Philipp Ruf¹, Simon Witzel¹, Makbule Senel¹, Hayrettin Tumani^{1

2}, Albert Christian Ludolph^{1

2}

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
PMCID: PMC10878861
DOI: 10.1016/j.eclinm.2024.102495

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

Maximilian Wiesenfarth et al. EClinicalMedicine. 2024.

. 2024 Feb 15:69:102495.

doi: 10.1016/j.eclinm.2024.102495. eCollection 2024 Mar.

Authors

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
PMCID: PMC10878861
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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Conflict of interest statement

MW reports no competing interests. JD reports speaker honoraria from Biogen Inc. ZE, ÖP, KK, KM, UWei, CH, JS, KM, RS, FB, TS, KG, EF, AK, TK, PR, UWey, MV, MJ, THaa, IV, JH, JC, JHW, PS, PK, WPR and SW report no competing interests. DB reports stocks from Ionis Pharmaceuticals (100 stocks). ZU reports financial support from Biogen, Roche and Novartis for SMArtCARE data collection (site Ulm). He received grants, consulting fees for advisory boards, lectures, presentations, manuscript writing, educational events, and support for travel expenses from Biogen. He received payment for expert testimony (Case report, no guideline development) from Thieme and Biogen. AF reports grants or contracts from DFG (German Research Foundation, Project funding not related to this manuscript). MR received lecture honoraria from Zambon. AG reports grants from German Society of Cryobanks (GDK e.V.). SP reports grants or contracts from the German Israeli Foundation, the German Neuromuscular Society, and the Neurodegenerative Research Inc. SP reports consulting fees from Amylyx, Biogen, ITF Pharma, Roche, Zambon and Ferrer, and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Amylyx, Biogen, ITF Pharma, Roche, and Zambon. SP received support for travel and/or attend meetings from Amylyx, Zambon, and PTC Therapeutics. JG reports a startup grant from the University foundation of the University of Lübeck. He received consultation fees from Amylyx, Clene Nanomedicine for consultancy on drug development in ALS and payment for expert testimony on EU and national level from Amylyx. JG participated on Data Safety Monitoring Boards or Advisory Boards for UCB, ITF Pharma, and Ferrer. FS reports participation on Advisory Boards for Amylyx, Alnylam, and Alexion. THag reports grants and honoraria from Biogen, Roche, Novartis (all for SMA-Research), Sanofi Genzyme (Neuromuscular Diseases Research), and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Alexion, Argenx (both for Myasthenia gravis), Biogen, Novartis, Sanofi Genzyme, Roche (SMA) and Amylyx (ALS). THag participated on Data Safety Monitoring Boards or Advisory Boards for Biogen, Novartis, Roche (all for SMA), Alexion, Argenx, UCB (all for Myasthenia gravis), Amylyx (for ALS), Sanofi Genzyme (for LOPD). RG reports honoraria for lectures from Biogen, Roche, and Zambon. He participated on Advisory Boards for Biogen, Roche, Zambon, and ITF Pharma. RG reports research support from Biogen and Zambon. PW served on Advisory Boards for Zambon, and ITF Pharma. PK reports consulting fees from Biogen. TM is on the Advisory Board of Biogen and received consulting fees from Biogen. MS reports consulting fees from Alexion, Bayer, Biogen, Bristol-Myers-Squibb/Celgene, Merck, Horizon, Roche, and Sanofi Genzyme. MS reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Alexion, Horizon, Roche, and Sanofi Genzyme and support for attending meetings and/or travel from Alexion, Celgene, Horizon, Roche, and Sanofi Genzyme. MS participated on Data Safety Monitoring Board or Advisory Board for Alexion, Bayer, Biogen, Bristol-Myers-Squibb, Merck, Horizon, Roche, and Sanofi Genzyme. HT reports grants or contracts from Sanofi Genzyme, German Multiple Sclerosis Society (DMSG), AMSEL Ursula-Späth-Stiftung, Bayern-DMSG, Deutsche MS-Stiftung, Ministry of Science, Research and Arts of the State Baden-Württemberg (MWK-BW), Chemische Fabrik Karl Bucher. HT received consulting fees from Merck, Novartis, Roche and received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Alexion, Bayer, Biogen, Celgene, GSK, Janssen, Merck, Novartis, Roche, Sanofi Genzyme, Siemens, TEVA, Viatris. HT reports support for attending meetings and/or travel from Janssen, Merck, Novartis, Roche, Sanofi Genzyme. He reports leadership or fiduciary role in DGLN, DMSG and AMSEL. ACL is a member of Advisory Boards of Roche Pharma AG, Biogen, Alector and Amylyx. He received compensation for talks from Biologix, the German Society of Neurology, Biogen, Springer Medicine, Amylyx and the company Streamed Up! GmbH. He is involved in trials which are sponsored by Amylyx, Ferrer International, Novartis Research and Development, Mitsubishi Tanabe, Apellis Pharmaceuticals, Alexion, Orion Pharma, the European Union, BMBF, Biogen and Orphazyme, Ionis Pharmaceuticals, QurAlis and Alector.

Figures

**Fig. 1**
**ALSFRS-R total scores and progression rates.** Boxplots show median (IQR; minimum–maximum) of ALSFRS-R total scores and progression rates (ALSFRS-R points lost/month) prior to and during therapy with tofersen. **(A)** ALSFRS-R at first administration (blue), last administration (red), and after six months of therapy (grey) **(B)** progression rates pre-baseline (blue) compared to the entire treatment period (between first and last administration (red)) and during the first six months of therapy (grey) (first administration until six months of therapy). Experimental units n = number, n = 23 comparisons first administration to last administration and pre-baseline to period between first and last administration, n = 12 comparisons to ALSFRS-R at six months of therapy and progression rate between first administration and six months of therapy. Median time from first to last ALSFRS-R 6.0 months (IQR 2.8–10.5 months). Changes over time were analyzed by Wilcoxon matched-pairs signed rank test. A p-value of ≤ 0.05 was regarded as statistically significant. ALSFRS-R: Amyotrophic lateral sclerosis functional rating scale revised. ns: not significant.

**Fig. 2**
**ALSFRS-R on individual level.** Graphs show changes in ALSFRS-R on individual level prior to first administration of tofersen, after three and six months of therapy, and at the time of the last tofersen administration. Experimental units n = number first and last administration n = 23, three months n = 18, six months n = 12. Time from first to last assessment of ALSFRS-R median 6.0 months (IQR 2.8–10.5 months). ALSFRS-R: Amyotrophic lateral sclerosis functional rating scale revised.

**Fig. 3**
**Neurofilaments.** Graphs show mean (SEM) of NfL levels (pg/ml) in serum and p-NfH levels (pg/ml) in CSF prior to first administration of tofersen, after three, six, nine, twelve months of therapy and at the time of last the last tofersen administration. **(A)** NfL in serum (pg/ml) **(B)** p-NfH in CSF (pg/ml). Experimental units n = number (A) first and last administration n = 23, three months n = 18, six months n = 11, nine months n = 8 and twelve months n = 4 (B) first and last administration n = 18, three months n = 15, six months n = 9, nine months n = 7 and twelve months n = 4. Time from first to last measurement of NfL in serum median 5.1 months (IQR 2.8–10.3 months) and of pNfH in CSF median 5.5 months (IQR 2.8–11.5 months). Changes over time were analyzed by one-way ANOVA-analysis and adjusting for multiple comparisons was performed by Holm-Šídák's test. A p-value of ≤ 0.05 was regarded as statistically significant. CSF: cerebrospinal fluid. NfL: neurofilament light chain. pNfH: phosphorylated neurofilament heavy chain.

**Fig. 4**
**Neurofilaments on individual level.** Graphs show changes in NfL levels (pg/ml) in serum and pNfH levels (pg/ml) in CSF on subject level prior to first administration of tofersen, after three, six, nine, twelve months of therapy and at the time of the last tofersen administration. **(A)** NfL in serum (pg/ml) **(B)** pNfH in CSF (pg/ml). Experimental units n = number (A) first and last administration n = 23, three months n = 18, six months n = 11, nine months n = 8 and twelve months n = 4 (B) first and last administration n = 18, three months n = 15, six months n = 9, nine months n = 7 and twelve months n = 4. Time from first to last measurement of NfL in serum median 5.1 months (IQR 2.8–10.3 months) and of pNfH in CSF median 5.5 months (IQR 2.8–11.5 months). In p.Asp91Ala (c.272A > C), the dashed line indicates a heterozygous allele genotype. CSF: cerebrospinal fluid. NfL: neurofilament light chain. pNfH: phosphorylated neurofilament heavy chain.

**Fig. 5**
**CSF and serum findings per visit. (A)** mean (SEM) leukocyte counts in CSF **(B)** mean (SEM) protein levels in CSF **(C)** CSF and serum findings over time, graphs show proportion and time of first occurrence of pleocytosis ≥5 leukocytes/μl in CSF (blue), elevated protein levels >500 mg/l in CSF (violet), intrathecal immunoglobulin synthesis (black) and oligoclonal bands (green). Experimental units n = number (A) n = 18 (B) n = 19 (C) (blue) n = 15 (violet) n = 17 (black) n = 10 (green) n = 10. First occurrence of pleocytosis median 3.7 weeks (IQR 1.9–14.2 weeks, n = 9; additionally pre-existing n = 2), first occurrence of elevated protein levels median 20.4 weeks (IQR 5.5–44.7 weeks, n = 8; additionally pre-existing n = 5), first occurrence of intrathecal immunoglobulin synthesis median 3.9 weeks (IQR 2.9–14.5 weeks, n = 9), first occurrence of oligoclonal bands (OCBs) in one patient after 7.6 weeks (additionally pre-existing n = 6). CSF: cerebrospinal fluid. Ig: immunoglobulin. OCB: oligoclonal bands.

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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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

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