Serious Neurologic Adverse Events in Tofersen Clinical Trials for Amyotrophic Lateral Sclerosis

Document Type

Article

Abstract

INTRODUCTION/AIMS: Tofersen is approved for the treatment of amyotrophic lateral sclerosis (ALS) due to superoxide dismutase 1 mutations (SOD1-ALS). Here we report serious neurologic adverse events (AEs) that occurred in the tofersen clinical trials in people with SOD1-ALS. METHODS: Serious neurologic AEs of myelitis, radiculitis, aseptic meningitis, and papilledema reported in the tofersen clinical trials are described. Serious AEs were defined according to International Conference for Harmonization guidelines, and neurologic AEs in clinical trials were diagnosed by investigators based on symptoms, clinical examination findings, and diagnostic workup. RESULTS: Ten participants (approximately 7% of tofersen 100-mg-treated trial participants) experienced a total of 12 serious neurologic AEs-4 of myelitis, 2 of radiculitis, 2 of aseptic meningitis, and 4 of intracranial hypertension (ICH) and/or papilledema. All events but one resolved either spontaneously, with dosing interruption/modification, or with concomitant therapies. One event was ongoing but improved as of December 2022. While 3 events led to tofersen treatment discontinuation, all other participants were able to remain on treatment. No event was life-threatening or fatal. DISCUSSION: Some antisense oligonucleotides (ASOs) have been described as having pro-inflammatory properties. Aseptic meningitis has been reported with nusinersen; however, myelitis, radiculitis, increased intracranial pressure, and papilledema have not been reported with ASO treatment. These neurologic AEs should be considered when assessing the overall benefit/risk of tofersen treatment for SOD1-ALS. Safety data from the open-label extension and expanded access program will continue to characterize these events and further inform the safety profile of tofersen in SOD1-ALS.

Medical Subject Headings

Humans; Amyotrophic Lateral Sclerosis (drug therapy, genetics); Middle Aged; Male; Female; Oligonucleotides (adverse effects, therapeutic use); Adult; Aged; Superoxide Dismutase-1 (genetics); Myelitis (chemically induced); Papilledema (chemically induced)

Publication Date

6-1-2025

Publication Title

Muscle & nerve

E-ISSN

1097-4598

Volume

71

Issue

6

First Page

1006

Last Page

1015

PubMed ID

40017137

Digital Object Identifier (DOI)

10.1002/mus.28372

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