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

Abstract

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.

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

“… 21 The cohort contains data of three patients, which have been published previously by Meyer and colleagues. 22 …”

Superoxide dismutase nanozymes: current status and future perspectives on brain disease treatment and diagnosis

“…A shared critical route should be the focus of any therapy strategy because of this complicated pathophysiology. 29…”

Big versus small: The impact of aggregate size in disease

“…Antisense oligonucleotide therapy uses short strands of modified nucleotides to target RNA and reduce the protein expression (Kuijper et al, 2021). This therapy is currently being tested to reduce SOD1 (Meyer et al, 2023; Miller et al, 2022), tau (Mummery et al, 2021), huntingtin (Smith & Tabrizi, 2020), amylin (Novials et al, 1998), α‐synuclein (Alarcón‐Arís et al, 2018), FUS (Korobeynikov et al, 2022), and TTR (Teresa Coelho et al, 2013) with various degrees of success in clinical trials. To reduce the amount of Aβ, strategies focus on decreasing the activity of β and γ‐secratases (A. K. Ghosh & Osswald, 2014).…”