Tofersen 100mg/15ml solution for injection vials

OBJECTIVE: Tofersen, an antisense oligonucleotide, has recently received FDA and EMA approval for treating amyotrophic lateral sclerosis (ALS) in adults with SOD1 gene mutations. This systematic review and meta-analysis synthesized evidence on tofersen's safety and efficacy in patients with SOD1-related ALS. METHODS: A comprehensive search of three databases was conducted from inception through October 2024. Eligible studies included clinical trials, observational studies, and case studies. Meta-analyses were conducted using a random-effects model in RevMan. RESULTS: Twelve studies involving 195 patients treated with tofersen met the inclusion criteria, comprising two randomized controlled trials (RCTs), five cohort studies, one case series, and four case reports. Tofersen demonstrated promising effects, notably reducing SOD1 levels in cerebrospinal fluid and neurofilament light chain (NfL) in plasma, a biomarker strongly correlated with ALS progression and survival. Meta-analysis of RCTs showed a significantly lower rate of decline in ALS Functional Rating Scale-Revised (ALSFRS-R) scores from baseline in the tofersen group compared to placebo (SMD = 0.44, 95% CI [0.05 to 0.83], P = 0.03) and a significant reduction in the decline of predicted Slow Vital Capacity (P = 0.005). In a pre-post meta-analysis of five studies, a significant decrease in ALS progression rate (ALSFRS-R decline rate) was observed (MD = -0.28, 95% CI [-0.40 to -0.15], P < 0.0001). Reported adverse events were consistent with ALS progression or procedural effects. CONCLUSION: Current evidence suggests that tofersen effectively reduces SOD1 and NfL levels and slow disease progression in SOD1 ALS, showing promise as a targeted therapeutic option.

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BackgroundIn April 2023, the antisense oligonucleotide tofersen was approved by the U.S. Food and Drug Administration (FDA) for treatment of SOD1-amyotrophic lateral sclerosis (ALS), after a decrease of neurofilament light chain (NfL) levels had been demonstrated.MethodsBetween 03/2022 and 04/2023, 24 patients with SOD1-ALS from ten German ALS reference centers were followed-up until the cut-off date for ALS functional rating scale revised (ALSFRS-R), progression rate (loss of ALSFRS-R/month), NfL, phosphorylated neurofilament heavy chain (pNfH) in cerebrospinal fluid (CSF), and adverse events.FindingsDuring the observation period, median ALSFRS-R decreased from 38.0 (IQR 32.0–42.0) to 35.0 (IQR 29.0–42.0), corresponding to a median progression rate of 0.11 (IQR −0.09 to 0.32) points of ALSFRS-R lost per month. Median serum NfL declined from 78.0 pg/ml (IQR 37.0–147.0 pg/ml; n = 23) to 36.0 pg/ml (IQR 22.0–65.0 pg/ml; n = 23; p = 0.02), median pNfH in CSF from 2226 pg/ml (IQR 1061–6138 pg/ml; n = 18) to 1151 pg/ml (IQR 521–2360 pg/ml; n = 18; p = 0.02). In the CSF, we detected a pleocytosis in 73% of patients (11 of 15) and an intrathecal immunoglobulin synthesis (IgG, IgM, or IgA) in 9 out of 10 patients. Two drug-related serious adverse events were reported.InterpretationConsistent with the VALOR study and its Open Label Extension (OLE), our results confirm a reduction of NfL serum levels, and moreover show a reduction of pNfH in CSF. The therapy was safe, as no persistent symptoms were observed. Pleocytosis and Ig synthesis in CSF with clinical symptoms related to myeloradiculitis in two patients, indicate the potential of an autoimmune reaction.FundingNo funding was received towards this study.

Abstract licence: CC BY

Amyotrophic lateral sclerosis (ALS) is a refractory neurodegenerative disease characterized by the degeneration and loss of motor neurons, typically resulting in death within five years of onset. There have been few effective treatments, making the development of robust therapies an urgent challenge. Genetic mutations have been identified as contributors to ALS, with mutations in superoxide dismutase 1 (SOD1), which neutralizes the harmful reactive oxygen species superoxide, accounting for approximately 2% of all ALS cases. To counteract the toxic gain of function caused by SOD1 mutations, therapeutic strategies aimed at suppressing SOD1 gene expression have shown promise. Antisense oligonucleotide (ASO) is an artificially synthesized, short, single-stranded DNA/RNA molecule that binds to target RNA to alter gene expression, representing a next-generation therapeutic approach. In 2023, tofersen became the first ASO drug approved by the FDA for ALS. Administered intrathecally, tofersen specifically binds to SOD1 mRNA, inhibiting the production of toxic SOD1 protein, thereby improving biomarkers of ALS. The long-term efficacy and safety of tofersen require further validation, and the development of more optimized treatment protocols is essential. A series of studies and therapeutic developments related to SOD1 mutations have advanced the understanding of ALS pathophysiology and significantly contributed to treatment strategies for central nervous system disorders. This review focuses on an overview of SOD1 mutations and the development process of tofersen, aiming to deepen the understanding of advancements in ALS research and discuss future challenges and directions for ASO therapy.

Abstract licence: CC BY

Despite thorough investigation, amyotrophic lateral sclerosis (ALS) continues to be adegenerative neurological condition that is inevitably fatal and progresses over time. The limitedunderstanding of the fundamental causes of ALS has posed challenges in addressing the initialbiological processes of the disease, resulting in therapeutic interventions typically being appliedat later stages of the illness.The existence of genetic variants in ALS presents a distinctive chance for advancing therapeuticapproaches, as studying genetic associations could unveil valuable information about the causesof the disease. In the case of genetic ALS, there is a possibility to explore early intervention byidentifying individuals who are at risk and have not yet shown symptoms but possess specificgenetic variations that contribute to the condition. Tofersen, an oligonucleotide, has beenspecifically created to diminish the production of superoxide dismutase 1 (SOD1) protein bybreaking down SOD1 mRNA.

Abstract licence: CC BY-NC-ND

BACKGROUND AND PURPOSE: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that primarily affects adults, characterized by muscle weakness resulting from the specific death of motor neurons in the spinal cord and brain. The pathogenesis of ALS is associated with the accumulation of mutant superoxide dismutase 1 (SOD1) proteins and neurofilaments in motor neurons, highlighting the critical need for disease-modifying treatments. Current therapies, such as riluzole and edaravone, provide only symptomatic relief. Recently, tofersen gained approval from the US FDA under the brand name Qalsody as the first and only gene therapy for ALS, addressing a significant pathological aspect of the disease. METHODS: We carried out a literature survey using PubMed, Scopus, National Institutes of Health, and Biogen for articles published in the English language concerned with "amyotrophic lateral sclerosis", pathophysiology, current treatment, treatment under clinical trial, and the newly approved drug "tofersen" and its detailed summary. RESULTS: A comprehensive review of the literature on the pathophysiology, available treatment, and newly approved drug for this condition revealed convincing evidence that we are now able to better monitor and treat ALS. CONCLUSIONS: Although treatment of ALS is difficult, the newly approved drug tofersen has emerged as a potential therapy to slow down the progression of ALS by targeting SOD1 mRNA, representing a significant advancement in the treatment of ALS.

Abstract licence: CC BY