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. 2024 Jul 25;4(1):150.
doi: 10.1038/s43856-024-00573-0.

Tofersen decreases neurofilament levels supporting the pathogenesis of the SOD1 p.D91A variant in amyotrophic lateral sclerosis patients

Jochen H Weishaupt #  1 , Péter Körtvélyessy #  2   3 , Peggy Schumann  4 , Ivan Valkadinov  5 , Ute Weyen  6 , Jasper Hesebeck-Brinckmann  5 , Kanchi Weishaupt  5 , Matthias Endres  2 , Peter M Andersen  7 , Martin Regensburger  8   9 , Marie Dreger  2 , Jan C Koch  10 , Julian Conrad  5 , Thomas Meyer  11   12
Affiliations

Tofersen decreases neurofilament levels supporting the pathogenesis of the SOD1 p.D91A variant in amyotrophic lateral sclerosis patients

Jochen H Weishaupt et al. Commun Med (Lond). .

Abstract

Background: Since the antisense oligonucleotide tofersen has recently become available for the treatment of amyotrophic lateral sclerosis (ALS) caused by mutations in SOD1, determining the causality of the over 230 SOD1 variants has become even more important. The most common SOD1 variant worldwide is p.D91A (c.272A > C), whose causality for ALS is contested when in a heterozygous state. The reason is the high allele frequency of SOD1D91A in Europe, exceeding 1% in Finno-Scandinavia.

Methods: We present the clinical disease course and serum neurofilament light chain (NfL) results of treating 11 patients either homo- or heterozygous for the SOD1D91A allele for up to 16 months with tofersen.

Results: Tofersen decreases serum neurofilament levels (sNFL), which are associated with the ALS progression rate, in the 6 ALS patients homozygous for SOD1D91A. We observe significantly lower sNfL levels in the 5 patients heterozygous for SOD1D91A. The results indicate that both mono- and bi-allelic SOD1D91A are causally relevant targets, with a possibly reduced effect size of SOD1D91Ahet.

Conclusions: The finding is relevant for decision making regarding tofersen treatment, patient counseling and inclusion of SOD1D91A patients in drug trials. As far as we are aware, the approach is conceptually new since it provides evidence for the causality of an ALS variant based on a biomarker response to gene-specific treatment.

Plain language summary

Amyotrophic lateral sclerosis (ALS) is a disease that can be inherited which affects nerve cells in the brain and spinal cord. Changes within a gene called SOD1 that result in a mutation named p.D91A can lead to the development of ALS. People have two copies of the SOD1 gene. It has been unclear whether the presence of only one copy of p.D91A can cause ALS. We treated ALS patients with the p.D91A variant of SOD1 with a drug called tofersen. We found that a marker of disease progression was reduced in patients with one or two copies of the p.D91A mutation. This suggests that the presence of just one p.D91A variant of SOD1 contributes to disease development. This information could be used to improve treatment decisions for people with ALS.

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Conflict of interest statement

The authors declare the following competing interests: T.M. is on the advisory board of Biogen and has received consulting fees from Biogen. P.K. received consulting fees from Biogen. S.P. has participated on advisory boards of Biogen and has received consulting fees from Biogen. T.M. and C.M. are founders and shareholders of the Ambulanzpartner Soziotechnologie APST GmbH, which makes the internet platform Ambulanzpartner and the mobile application ALS-App. APST received a research grant from Biogen. P.M.A. has served on paid advisory boards for Biogen, Roche, Arrowhead, Avrion, Regeneron, uniQure, Voyager and Orphazyme A/S; he has been clinical trial site investigator for AB Science, AL-S Pharma and Lilly, Amylyx, Alexion Pharmaceuticals, Biogen Idec, IBT-Med, IONIS Pharmaceuticals, Orion Pharma, PTH Pharmaceuticals and Sanofi. He is external advisor to the European Medicine Agency. All other authors declare no competing interest.

Figures

Fig. 1
Fig. 1. Serum NfL course in tofersen-treated SOD1D91A mutant patients.
a Serum neurofilament light chain (sNfL) levels during treatment with tofersen. For better comparability, values were normalized to the timepoint directly before the start of treatment. Values from patients with heterozygous mutations are depicted with a dashed orange line, homozygous patients are depicted in blue. b Mean sNfL values ± S.D. of patients shown in b). Values were normalized to the timepoint directly before the start of treatment. Asterisk indicates significant reduction when compared to start of treatment in patients with a homozygous mutation (repeated measures ANOVA*: p < 0.05; orange asterisk (top row of asterisks): refers to heterozygous patients; black asterisks (bottom row of asterisks): homozygous patients; the exact p values can be found in Supplementary Data 1). Two NfL measurements have been missed for a heterozygous and homozygous patient at months 5 and 7, respectively. After the sixth injection the number of heterozygous patients was too low for a group-based analysis. The statistics are based on absolute values not normalized to treatment start.
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