Neurofilament light‐chain response during therapy with antisense oligonucleotide tofersen in SOD1‐related ALS: Treatment experience in clinical practice

• Published in: Muscle & nerve Vol. 67; no. 6; pp. 515 - 521
• Main Authors: Meyer, Thomas, Schumann, Peggy, Weydt, Patrick, Petri, Susanne, Koc, Yasemin, Spittel, Susanne, Bernsen, Sarah, Günther, René, Weishaupt, Jochen H., Dreger, Marie, Kolzarek, Felix, Kettemann, Dagmar, Norden, Jenny, Boentert, Matthias, Vidovic, Maximilian, Meisel, Christian, Münch, Christoph, Maier, André, Körtvélyessy, Péter
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.06.2023; Wiley Subscription Services, Inc
• Subjects: Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - drug therapy; Amyotrophic Lateral Sclerosis - genetics; Antisense oligonucleotides; Antisense therapy; Biomarkers; Cerebrospinal fluid; Genetics; Health services; Humans; Intermediate Filaments; Mutation; neurofilament light chain; Neurofilament Proteins; Oligonucleotides, Antisense - therapeutic use; Patients; Serum; Superoxide dismutase; Superoxide Dismutase-1 - genetics; tofersen; amyotrophic lateral sclerosis; neurofilament light chain; tofersen
• DOI: 10.1002/mus.27818
• ISSN: 0148-639X

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 III study (VALOR) and subsequently introduced in an expanded access program. In this study we assess 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) were investigated using the ALS Functional Rating Scale Revised (ALSFRS‐R) and ALS progression rate (ALS‐PR), defined by monthly decline of ALSFRS‐R. Results Three of the 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 (range 5 to 8) months. In all patients, NfL decreased (mean CSF‐NfL: −66%, range −52% to −86%; mean sNfL: −62%, range −36% to −84%). sNfL after 5 months of tofersen treatment was significantly reduced compared with the nearest pretreatment measurement (P = .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 after 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 supports the notion of tofersen having disease‐modifying activity.