This review summarizes current evidence on the efficacy and safety of tofersen (Qalsody) in treating amyotrophic lateral sclerosis (ALS).
Data Sources:
PubMed, MEDLINE, Google Scholar, and ClinicalTrials.gov were searched using the keywords: Qalsody, BIIB067, antisense oligonucleotides, SOD1, and amyotrophic lateral sclerosis. Articles published from inception to November 2025 were included.
Study Selection and Data Extraction:
English-language studies assessing the pharmacokinetics, pharmacology, efficacy, and safety of tofersen were included. Prescribing information and real-world evidence were also reviewed.
Data Synthesis:
Tofersen is an intrathecally administered antisense oligonucleotide targeting superoxide dismutase 1 (SOD1) mRNA. Early trials demonstrate dose-dependent reductions in cerebrospinal fluid (CSF) SOD1 protein levels of −33% and slower ALS Functional Rating Scale (ALSFRS-R) decline compared to placebo (−1.19 vs −5.63 points). In Phase 3 trials, tofersen reduced CSF SOD1 by 29% and plasma neurofilament light chain (NfL) by 60%, while biomarkers increased in the placebo group. There was no significant difference in ALSFRS-R decline between tofersen and placebo (−6.98 vs −8.14; P = 0.97). Real-world data show favorable patient-related outcomes and improvement in ALSFRS-R. Adverse effects are primarily lumbar puncture related with serious neurologic events documented in 7% of tofersen recipients.
Relevance to Patient Care and Clinical Practice in Comparison to Existing Drugs:
As the first Food and Drug Administration (FDA)-approved gene-directed therapy for SOD1 ALS, tofersen directly targets the underlying genetic cause. Barriers include the need for genetic confirmation and intrathecal administration.
Conclusion:
Tofersen provides a promising targeted treatment option for pathogenic SOD1 ALS. Ongoing studies will clarify its long-term clinical impact.
van den BosMAJGeevasingaNHigashiharaMMenonPVucicS.Pathophysiology and diagnosis of ALS: insights from advances in neurophysiological techniques. Int J Mol Sci. 2019;20(11):2818. doi:10.3390/ijms20112818
2.
LonginettiEFangF.Epidemiology of amyotrophic lateral sclerosis: an update of recent literature. Curr Opin Neurol. 2019;32(5):771-776. doi:10.1097/WCO.0000000000000730
3.
GrieveSMMenonPKorgaonkarMS, et al. Potential structural and functional biomarkers of upper motor neuron dysfunction in ALS. Amyotroph Lateral Scler Frontotemporal Degener. 2015;17(1-2):85-92. doi:10.3109/21678421.2015.1074707
4.
CrockfordCNewtonJLonerganK, et al. ALS-specific cognitive and behavior changes associated with advancing disease stage in ALS. Neurology. 2018;91(15):e1370-e1380. doi:10.1212/WNL.0000000000006317
5.
MoriyamaHYokotaT.Recent progress of antisense oligonucleotide therapy for superoxide-dismutase-1-mutated amyotrophic lateral sclerosis: focus on tofersen. Genes. 2024;15(10):1342. doi:10.3390/genes15101342
6.
RentonAEChiòATraynorBJ.State of play in amyotrophic lateral sclerosis genetics. Nat Neurosci. 2014;17(1):17-23. doi:10.1038/nn.3584
7.
SmithSEMcCoy-GrossKMalcolmA, et al. Tofersen treatment leads to sustained stabilization of disease in SOD1 ALS in a “real-world” setting. Ann Clin Transl Neurol. 2025;12(2):311-319. doi:10.1002/acn3.52264
8.
MillerTMCudkowiczMEGengeA, et al. Trial of antisense oligonucleotide tofersen for SOD1 ALS. N Engl J Med. 2022;387(12):1099-1110. doi:10.1056/NEJMoa2204705
9.
Van DammePAl-ChalabiAAndersenPM, et al. European academy of neurology (EAN) guideline on the management of amyotrophic lateral sclerosis in collaboration with European reference network for neuromuscular diseases (ERN EURO-NMD). Eur J Neurol. 2024;31(6):e16264. doi:10.1111/ene.16264
10.
JohnsonSAFangTDe MarchiF, et al. Pharmacotherapy for amyotrophic lateral sclerosis: a review of approved and upcoming agents. Drugs. 2022;82(13):1367-1388. doi:10.1007/s40265-022-01769-1
11.
BensimonGLacomblezLMeiningerV.A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole study group. N Engl J Med. 1994;330(9):585-591. doi:10.1056/NEJM199403033300901
CantaraSSimoncelliGRicciC.Antisense oligonucleotides (ASOs) in motor neuron diseases: a road to cure in light and shade. Int J Mol Sci. 2024;25(9):4809. doi:10.3390/ijms25094809
14.
SainiAChawlaPA.Breaking barriers with tofersen: enhancing therapeutic opportunities in amyotrophic lateral sclerosis. Eur J Neurol. 2024;31(2):e16140. doi:10.1111/ene.16140
MillerTCudkowiczMShawPJ, et al. Phase 1–2 trial of antisense oligonucleotide tofersen for SOD1 ALS. N Engl J Med. 2020;383(2):109-119. doi:10.1056/NEJMoa2003715
17.
WeishauptJHKörtvélyessyPSchumannP, et al. Tofersen decreases neurofilament levels supporting the pathogenesis of the SOD1 p.D91A variant in amyotrophic lateral sclerosis patients. Commun Med. 2024;4:150. doi:10.1038/s43856-024-00573-0
18.
MeyerTSchumannPGrehlT, et al. SOD1 gene screening in ALS—frequency of mutations, patients’ attitudes to genetic information and transition to tofersen treatment in a multi-center program. Amyotroph Lateral Scler Frontotemporal Degener. 2025;26(1-2):162-171. doi:10.1080/21678421.2024.2401131
19.
DuanCKangMPanX, et al. Intrathecal administration of a novel siRNA modality extends survival and improves motor function in the SOD1G93A ALS mouse model. Mol Ther Nucleic Acids. 2024;35(1):102147. doi:10.1016/j.omtn.2024.102147
20.
McCampbellAColeTWegenerAJ, et al. Antisense oligonucleotides extend survival and reverse decrement in muscle response in ALS models. J Clin Invest. 2018;128(8):3558-3567. doi:10.1172/JCI99081
MaierABoentertMReilichP, et al. ALSFRS-R-SE: an adapted, annotated, and self-explanatory version of the revised amyotrophic lateral sclerosis functional rating scale. Neurol Res Pract. 2022;4:60. doi:10.1186/s42466-022-00224-6
23.
BenatarMWuuJAndersenPM, et al. Design of a randomized, placebo-controlled, phase 3 trial of tofersen initiated in clinically presymptomatic SOD1 variant carriers: the ATLAS study. Neurotherapeutics. 2022;19(4):1248-1258. doi:10.1007/s13311-022-01237-4
24.
Neurofilament light chain response during therapy with antisense oligonucleotide tofersen in SOD1 related ALS: treatment experience in clinical practice—Meyer—2023—muscle & nerve—Wiley online library. Accessed November 14, 2025. https://onlinelibrary-wiley-com-443.web.bisu.edu.cn/doi/10.1002/mus.27818
25.
WiesenfarthMDorstJBrennerD, et al. 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. EClinicalMedicine. 2024;69:102495. doi:10.1016/j.eclinm.2024.102495
26.
MeyerTSchumannPWeydtP, et al. Clinical and patient-reported outcomes and neurofilament response during tofersen treatment in SOD1-related ALS—a multicenter observational study over 18 months. Muscle Nerve. 2024;70(3):333-345. doi:10.1002/mus.28182
27.
BernsenSFabianRKocY, et al. Serum cardiac troponin T levels as a therapy response marker in tofersen-treated ALS. Muscle Nerve. 2025;72(3):509-514. doi:10.1002/mus.28453
28.
SteffkeCBaskarKBachhuberF, et al. Targeted proteomics upon treatment with Tofersen identifies novel response markers for superoxide dismutase 1-linked amyotrophic lateral sclerosis. Ann Neurol. 2025;98(6):1318-1334. doi:10.1002/ana.70025
29.
LovettACharySBabuS, et al. Serious neurologic adverse events in tofersen clinical trials for amyotrophic lateral sclerosis. Muscle Nerve. 2025;71(6):1006-1015. doi:10.1002/mus.28372
30.
Biogen. An extension study to assess the long-term safety, tolerability, pharmacokinetics, and effect on disease progression of BIIB067 administered to previously treated adults with amyotrophic lateral sclerosis caused by superoxide dismutase 1 mutation.2024. Accessed March 20, 2025. https://clinicaltrials.gov/study/NCT03070119
HamadAAAlkhawaldehIMNashwanAJMeshrefMImamY.Tofersen for SOD1 amyotrophic lateral sclerosis: a systematic review and meta-analysis. Neurol Sci. 2025;46(5):1977-1985. doi:10.1007/s10072-025-07994-2
33.
RoggenbuckJEubankBHFWrightJHarmsMBKolbSJ; ALS Genetic Testing and Counseling Guidelines Expert Panel. Evidence-based consensus guidelines for ALS genetic testing and counseling. Ann Clin Transl Neurol. 2023;10(11):2074-2091. doi:10.1002/acn3.51895
NeupanePThadaPKSinghP, et al. Investigating edaravone use for management of amyotrophic lateral sclerosis (ALS): a narrative review. Cureus. 2023;15(1):e33746. doi:10.7759/cureus.33746
39.
JiangJWangYDengM.New developments and opportunities in drugs being trialed for amyotrophic lateral sclerosis from 2020 to 2022. Front Pharmacol. 2022;13:1054006. doi:10.3389/fphar.2022.1054006
40.
WitzelSMaierASteinbachR, et al. Safety and effectiveness of long-term intravenous administration of edaravone for treatment of patients with amyotrophic lateral sclerosis. JAMA Neurol. 2022;79(2):121-130. doi:10.1001/jamaneurol.2021.4893
