Neurofilament light chain response during therapy with antisense oligonucleotide Tofersen in SOD1-related ALS - treatment experience in clinical practice.

INTRODUCTION/AIMS: In amyotrophic lateral sclerosis (ALS) caused by superoxide dismutase 1 (SOD1) gene mutations (SOD1-ALS), the antisense oligonucleotide tofersen had been investigated in a phase 3 study (VALOR) and subsequently introduced in an expanded access program. This study assesses neurofilament light chain (NfL) before and during tofersen treatment.

METHODS: In six SOD1-ALS patients treated with tofersen at three specialized ALS centers in Germany, NfL in cerebrospinal fluid (CSF-NfL) and/or serum (sNfL), the ALS Functional Rating Scale-Revised (ALSFRS-R), and ALS progression rate (ALS-PR), defined by monthly decline of ALSFRS-R, were investigated.

RESULTS: Three of six SOD1-ALS patients reported a negative family history. Three patients harbored a homozygous c.272A>C, p.(Asp91Ala) mutation. These and two other patients showed slower progressing ALS (defined by ALS-PR <0.9) whereas one patient demonstrated rapidly progressing ALS (ALS-PR=2.66). Mean treatment duration was 6.5 months (range 5-8). In all patients, NfL decreased (mean CSF-NfL -66%, range -52 to -86%, mean sNfL -62%, range -36 to -84%). sNfL at 5 months of tofersen was significantly reduced compared to the measurement closest before treatment (p=0.017). ALS-PR decreased in two patients whereas no changes in ALSFRS-R were observed in four participants who had very low ALS-PR or ALSFRS-R values before treatment.

DISCUSSION: In this case series, the significant NfL decline following tofersen treatment confirmed its value as response biomarker in an expanded clinical spectrum of SOD1-ALS. Given the previously reported strong correlation between sNfL and ALS progression, the NfL treatment response contributes to the notion of disease-modifying activity of tofersen. This article is protected by copyright. All rights reserved.