Profiling tofersen as a treatment of superoxide dismutase 1 amyotrophic lateral sclerosis

ABSTRACT

Introduction

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive motor neuron disorder with a fatal outcome 3–5 years after disease onset due to respiratory complications. Superoxide dismutase 1 (SOD1) mutations are found in about 2% of all patients. Tofersen is a novel oligonucleotide antisense drug specifically developed to treat SOD1-ALS patients.

Areas covered

Our review covers and discusses tofersen pharmacological properties and its phase I/II and III clinical trials results. Other available drugs and their limitations are also addressed.

Expert opinion

VALOR study failed to meet the primary endpoint (change in the revised Amyotrophic Lateral Sclerosis Functional Rating Scale score from baseline to week 28, tofersen arm vs. placebo), but a significant reduction in plasma neurofilament light chain (NfL) levels was observed in tofersen arm (60% vs. 20%). PrefALS study has proposed plasma NfL has a potential biomarker for presymptomatic treatment, since it increases 6–12 months before phenoconversion. There is probably a delay between plasma NfL reduction and the clinical benefit. ATLAS study will allow more insights regarding tofersen clinical efficacy in disease progression rate, survival, and even disease onset delay in presymptomatic SOD1 carriers.

KEYWORDS:

• Amyotrophic lateral sclerosis
• antisense oligonucleotide
• genetics
• neurofilament light chain
• superoxide dismutase 1
• tofersen

Article highlights

• ALS is fast progressive neurodegenerative disease with no treatment able to halt disease progression.

• Superoxide dismutase 1 (SOD1) was the first ALS-related gene identified and is associated with 2% of the total ALS cases in the Western-population.

• Riluzole and tofersen are approved by U.S. FDA and EMA, but intravenous edaravone is only approved by U.S. FDA.

• Riluzole has a modest effect in increasing survival, but both phase III phenylbutyrate-taurursodiol and oral edaravone trials were negative.

• Tofersen is a novel antisense oligonucleotide (ASO) drug, specifically designed for SOD1-ALS patients’ treatment.

• The phase III trial (VALOR), evaluating the efficacy and safety of tofersen, showed a striking decrease in CSF SOD1 protein concentration and plasma NfL levels, in comparison to placebo over 28 weeks.

• Earlier initiation of tofersen leads to a notable deceleration in the decline of clinical and respiratory function.

• The ongoing ATLAS study is designed to evaluate the impact of initiating tofersen in SOD1 presymptomatic carriers, and further assessing the utility of employing serum NfL as a reliable disease-related biomarker.

• Tofersen is a precision treatment tool for ALS, targeting patients with SOD1 pathogenic mutations.

Declaration of interest

Both authors are investigators of the ADORE and Phoenix trials which investigated oral Edaravone and AMX-0035 respectively. Oral Edaravone and AMX-0035 are both therapeutic options for ALS. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.