Recent Progress of Antisense Oligonucleotide Therapy for Superoxide-Dismutase-1-Mutated Amyotrophic Lateral Sclerosis: Focus on Tofersen
Abstract
:1. Introduction
2. Genetic Background of ALS
2.1. Overview
2.2. ALS with SOD1 Mutations
3. Treatment of ALS
4. ASO in CNS Disorders
4.1. ASO Overview
4.2. Challenges of ASO Therapy for CNS Disorders
5. ASO Therapy for SOD1 ALS
5.1. Background Leading to the Development of Tofersen
5.2. Preclinical Study of Tofersen
5.3. Clinical Study of Tofersen
5.3.1. Phase 1/2 VALOR
5.3.2. Phase 3 VALOR
5.3.3. Phase 3 Extension Study
5.4. Trends after Tofersen Approval
Phase 3 ATLAS
6. Future Directions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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---|---|---|---|---|
riluzole | 1995 | Oral | Glutamate antagonist | Thickened riluzole was approved in 2018. Oral film was approved in 2019. |
edaravone | 2017 | Intravenous, Oral | Free radical scavenger | Oral formation was approved in 2022. |
PB/TURSO | 2022 | Oral | Inhibition of motor neuron apoptosis | Voluntarily removed from the market in 2024 based on the results from the Phase 3 PHOENIX trial. |
tofersen | 2023 | Intrathecal | ASO (2′-MOE gapmer) | For ALS patients with SOD1 mutation. |
Drug | Phase Study Type Study Objective | Number of Patients Administration, Dose | Outcome |
---|---|---|---|
ASO333611 | Phase 1 (NCT01041222) Randomized, double-blind, placebo-controlled Safety and tolerability study of ASO333611 in SOD1 ALS | 33 patients 12 h intrathecal infusion of 0.15, 0.5, 1.5, and 3 mg | No drug-related safety issues. No reduction in SOD1 protein levels in CSF. |
BIIB067 tofersen | Phase 1/2 VALOR (NCT02623699) Randomized, double-blind, placebo-controlled Safety, tolerability and pharmacokinetics study of tofersen in SOD1 ALS | 50 patients Intrathecal injection of 20, 40, 60, and 100 mg | Tofersen was generally well-tolerated and safe. The highest concentration of tofersen decreased CSF SOD1 concentrations the most. |
BIIB067 tofersen | Phase 3 VALOR (NCT02623699) Randomized, double-blind, placebo-controlled Efficacy study of tofersen in SOD1 ALS | 108 patients Intrathecal injection of 100 mg | Tofersen did not improve the ALSFRS-R total score from baseline to week 28 in the faster-progression group. Tofersen resulted in a greater reduction in CSF SOD1 and pNFL concentrations. |
BIIB067 tofersen | Phase 3 (NCT03070119) Open-label extension Long-term evaluation of tofersen in SOD1 ALS | 138 patients Intrathecal injection of 100 mg | Ongoing |
BIIB067 tofersen | Phase 3 ATLAS (NCT04856982) Randomized, double-blind, placebo-controlled and subsequent open-label extension Long-term efficacy study of tofersen in presymptomatic carriers of SOD1 | 150 patients (estimated) Intrathecal injection of 100 mg | Ongoing |
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Moriyama, H.; Yokota, T. Recent Progress of Antisense Oligonucleotide Therapy for Superoxide-Dismutase-1-Mutated Amyotrophic Lateral Sclerosis: Focus on Tofersen. Genes 2024, 15, 1342. https://doi.org/10.3390/genes15101342
Moriyama H, Yokota T. Recent Progress of Antisense Oligonucleotide Therapy for Superoxide-Dismutase-1-Mutated Amyotrophic Lateral Sclerosis: Focus on Tofersen. Genes. 2024; 15(10):1342. https://doi.org/10.3390/genes15101342
Chicago/Turabian StyleMoriyama, Hidenori, and Toshifumi Yokota. 2024. "Recent Progress of Antisense Oligonucleotide Therapy for Superoxide-Dismutase-1-Mutated Amyotrophic Lateral Sclerosis: Focus on Tofersen" Genes 15, no. 10: 1342. https://doi.org/10.3390/genes15101342