Qalsody (tofersen) / Biogen, Ionis - LARVOL DELTA

Long-Term Tofersen in SOD1 Amyotrophic Lateral Sclerosis. (PubMed, JAMA Neurol) - P3 | "Final data from VALOR and the OLE demonstrated the benefit of tofersen in SOD1-ALS and provide clear rationale for its use in this population. ClinicalTrials.gov Identifier: VALOR NCT02623699; OLE NCT03070119."

Clinical • Journal • Amyotrophic Lateral Sclerosis • CNS Disorders • SOD1

Gene-targeted versus broad-spectrum therapies in ALS: comparative lessons and strategic outlook. (PubMed, J Genet Genomics) - "While gene therapies like tofersen demonstrate clear molecular target engagement, their translation to robust clinical benefit remains a challenge...The future of ALS therapeutics therefore depends on a strategic pivot toward personalized medicine. This requires prospectively stratifying patients, developing rational combination therapies, and intervening earlier in the disease course, ultimately treating ALS as a syndrome of distinct molecular diseases rather than a single entity."

Journal • Amyotrophic Lateral Sclerosis • CNS Disorders • Gene Therapies • Rare Diseases • Respiratory Diseases

Introduction to the Supplement. (PubMed, Muscle Nerve) - "Three active pharmaceutical agents are currently approved by the United States Food and Drug Administration (FDA) for ALS: riluzole, edaravone (including intravenous [IV] and oral suspension formulations), and tofersen. Study MCI186-19 (Study 19) was a pivotal, phase 3 randomized controlled trial that demonstrated a significant reduction in physical functional decline vs. placebo in Japanese patients with ALS and contributed to FDA approval of IV edaravone in 2017...Topics include safety in clinical practice, generalizability of efficacy, clinical treatment outcomes, and health economics and outcomes research studies. Together, these findings aim to inform clinicians, researchers, and stakeholders regarding the evolving evidence base for edaravone in the management of ALS."

Journal • Amyotrophic Lateral Sclerosis • CNS Disorders

Tofersen: A Novel Option for the Treatment of Amyotrophic Lateral Sclerosis. (PubMed, Ann Pharmacother) - "Tofersen provides a promising targeted treatment option for pathogenic SOD1 ALS. Ongoing studies will clarify its long-term clinical impact."

Journal • Review • Amyotrophic Lateral Sclerosis • CNS Disorders • NEFL • Plasma NfL • SOD1

Addendum to the 2023 clinical practice guidelines for amyotrophic lateral sclerosis in Japan: approval and integration of novel disease-modifying therapies. (PubMed, Rinsho Shinkeigaku) - "Following the development of the 2023 guidelines, three additional medications-oral edaravone, high-dose intramuscular mecobalamin, and tofersen-have been introduced...The objectives of this addendum are twofold: to present these advances and recommendations in English to foster international collaboration, and to inform the global ALS community about the latest therapeutic strategies in Japan. In addition, ongoing efforts to harmonize clinical evaluation standards and promote international clinical trials are highlighted, with the goal of improving patient outcomes and advancing ALS research worldwide."

Clinical guideline • Journal • Amyotrophic Lateral Sclerosis • CNS Disorders

A Study to Learn More About the Long-Term Safety of Tofersen (Qalsody) in Chinese Participants With SOD-1 Amyotrophic Lateral Sclerosis (ALS) (clinicaltrials.gov) - P4 | N=12 | Recruiting | Sponsor: Biogen | Not yet recruiting ➔ Recruiting

Enrollment open • Amyotrophic Lateral Sclerosis • CNS Disorders

Pharmacotherapy of neuromuscular diseases : what's new in 2025 (PubMed, Rev Med Suisse) - "Two new drugs have recently become available for treating neuromuscular diseases: omaveloxolone and tofersen. Tofersen is an antisense oligonucleotide that induces posttranscriptional silencing of the SOD1 (superoxide dismutase 1) gene, which is involved in familial forms of amyotrophic lateral sclerosis. Although its efficacy has so far only been indirectly demonstrated through its ability to reduce serum neurofilament levels, it is available on a compassionate use basis in Switzerland."

Journal • Amyotrophic Lateral Sclerosis • Ataxia • CNS Disorders • Friedreich ataxia • Movement Disorders • SOD1

Facial-onset SOD1 amyotrophic lateral sclerosis: A case report and systematic review. (PubMed, J Clin Neurosci) - "Facial-onset SOD1 ALS defines a distinctive phenotype characterised by LMN-predominant facial palsy in early phases, near-neighbour spread, and an aggressive course exceeding genotype-based expectations. Prompt recognition and genetic testing in progressive facial palsy unresponsive to immunotherapy are essential to ensure access to gene-targeted treatments."

IO biomarker • Journal • Review • Amyotrophic Lateral Sclerosis • CNS Disorders

PRECLINICAL BLOOD-BRAIN BARRIER DELIVERY PLATFORM BASED ON LOW-INTENSITY PULSED ULTRASOUND (LIPU) SONOCLOUD (ADPD 2026) - "The current LIPU+MB protocol improved the BBB crossing of Tofersen, suggesting that SonoCloud® is a promising platform to improve brain uptake of oligonucleotides and potentially other therapeutic modalities. This platform, combined with behavioral, electrophysiological, and translational biomarker readouts, can be used to generate comprehensive preclinical efficacy and safety data."

Preclinical • CNS Disorders • Plasma NfL • SOD1

New Drug Therapies Against Targeting Neurodegenerative Diseases: A Comprehensive Review. (PubMed, Cent Nerv Syst Agents Med Chem) - "In Alzheimer's disease, specific antibodies targeting the β-amyloid protein (aducanumab, lecanemab, and others) are gaining special interest due to the approval of the first particular drugs against this disease...In amyotrophic lateral sclerosis, the appearance of newly approved drugs such as tofersen and edaravone, and some others in clinical Phase II (bosutinib), opens a new era in the understanding and treatment of this condition...In vascular dementia, numerous in vivo trials with molecules of different natures (flavonoids and lactones) have yielded positive results, delaying the progression of the disease. This review examines recent reports on molecules evaluated in vivo and in vitro models of the primary neurodegenerative diseases."

Journal • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Cognitive Disorders • Dementia • Frontotemporal Lobar Degeneration • Lewy Body Disease • Movement Disorders • Parkinson's Disease • Psychiatry • Schizophrenia

Tofersen, SOD1, and the Treatability of Amyotrophic Lateral Sclerosis. (PubMed, JAMA Neurol) - No abstract available

Journal • Amyotrophic Lateral Sclerosis • CNS Disorders

The Journal of the American Medical Association (JAMA) Neurology Publishes Long Term Results from the QALSODY Phase 3 VALOR Study and its Open-Label Extension in SOD1-ALS (Biogen Press Release) - "These results show that early initiation of QALSODY was associated with numerically slower decline in measures of clinical function, breathing and strength, as well as reduction in the risk of death or permanent ventilation. Sustained reductions in neurofilament, a marker of neurodegeneration, further validate the clinical results and demonstrate QALSODY’s impact on the underlying biology of SOD1-ALS."

P3 data • Amyotrophic Lateral Sclerosis

Tofersen in Non-SOD1 ALS (clinicaltrials.gov) - P2 | N=30 | Recruiting | Sponsor: Washington University School of Medicine

New P2 trial • Amyotrophic Lateral Sclerosis • CNS Disorders • CSF NfL • Plasma NfL

Small RNA or oligonucleotide drugs and challenges in evaluating drug-drug interactions. (PubMed, Front Pharmacol) - "Widespread adoption of these strategies has further enabled the application of oligonucleotides as viable drugs and expanded the class of RNA therapeutics, with thirteen antisense oligonucleotides (ASOs) (fomiversen, mipomersen, nusinersen, inotersen, eteplirsen, golodirsen, casimersen, viltolarsen, tofersen, eplontersen, olezarsen, and donidalorsen), seven small interfering RNAs (siRNAs) (patisiran, givosiran, lumasiran, inclisiran, vutrisiran, nedosiran, and fitusiran), and two aptamers (pegaptanib and avacincaptad pegol) that have been approved by the United States Food and Drug Administration (FDA). This article provides an overview of FDA-approved oligonucleotide therapies, emphasizing chemical modifications, molecular targets for mechanistic actions, and available ADME and PK/PD properties, followed by the discussion of critical needs for risk assessment strategies suited for this unique modality that focuses on possible DDIs with concomitant drugs. The latter may..."

Journal • Review

Anti-PF4 antibodies are a potential mediator of antisense oligonucleotide (ASO)-induced thrombocytopenia. (ASH 2025) - "Twelve ASOs, Inotersen, Eplontersen,Olezarsen, Fomivirsen, Mipomersen, Tofersen, Nusinersen, Eteplirsen, Golodirsen, Viltolarsen,Casimersen (all FDA approved) and Volanesorsen (EMA approved) were evaluated in this study. With two ASOs, Fomivirsen and Eteplirsen, direct activation of platelets was noted. Studieswith additional ASOs revealed a novel immune mechanism involving ASO-PF4 complex formation andanti-PF4 antibody recognition that can plausibly mediate ASO-induced thrombocytopenia. These findingshighlight the key role PS linkages may play in ASO immunogenicity and provide a mechanistic frameworkfor risk mitigation in ASO drug design, supporting the safer development and broader application of ASOtherapeutics."

Hematological Disorders • Thrombocytopenia

Canadian HTA Assessments Recognize Therapeutic Value of QALSODY (tofersen injection) and its Potential to Modify Disease Progression in Individuals Living with SOD1-ALS (Canada Newswire) - "CDA issues positive reimbursement recommendation for QALSODY; INESSS recognizes QALSODY's promising clinical value and highlights path toward reimbursement."

Reimbursement • Amyotrophic Lateral Sclerosis

Real-world evidence supporting orphan drugs approvals for rare neuromuscular disorders in the European Union and the United States: Review of public assessment reports (2015-2025). (PubMed, Curr Opin Pharmacol) - "Only tofersen incorporated all COA types. The use of RWE for the evaluation of ODs is increasing for both the FDA and the EMA, more so for the former than for the latter. Harmonized methodological standards and transparent reporting frameworks are urgently needed to generate quality evidence that benefits stakeholders."

HEOR • Journal • Real-world evidence • Review • Amyotrophic Lateral Sclerosis • Ataxia • CNS Disorders • Duchenne Muscular Dystrophy • Friedreich ataxia • Genetic Disorders • Movement Disorders • Muscular Dystrophy • Myasthenia Gravis • Rare Diseases

A Study to Learn More About the Long-Term Safety of Tofersen (Qalsody) in Participants With Superoxide Dismutase 1 (SOD-1) Amyotrophic Lateral Sclerosis (ALS) (clinicaltrials.gov) - P=N/A | N=69 | Not yet recruiting | Sponsor: Biogen

New trial • Amyotrophic Lateral Sclerosis • CNS Disorders

Comparative safety analysis of Riluzole, Edaravone and Tofersen in ALS management: insights from FAERS database. (PubMed, Front Pharmacol) - "This comprehensive evaluation underscores the importance of understanding the distinct AE profiles of Riluzole, Edaravone, and Tofersen in clinical practice, providing valuable insights for personalized ALS management. Future research with rigorous prospective designs is recommended to validate these findings and explore the mechanisms underlying the reported adverse events."

Journal • Amyotrophic Lateral Sclerosis • Cardiovascular • CNS Disorders • Hematological Disorders • Pain • Thrombosis • MMP9

Amyotrophic lateral sclerosis in Saudi Arabia: a multicenter descriptive study. (PubMed, Amyotroph Lateral Scler Frontotemporal Degener) - "Prespecified variables included demographics, family history, initial phenotype, MRI/EMG, genetics, treatments (riluzole, edaravone, SPT, tofersen for SOD1), times to noninvasive ventilation (NIV), gastrostomy and invasive ventilation. The younger age of onset and the high familial prevalence are notable findings that warrant further investigation. Future studies focusing on genetic and environmental influences in Saudi Arabia may help improve diagnosis and therapeutic approaches."

Journal • Amyotrophic Lateral Sclerosis • CNS Disorders • Gene Therapies

Concurrent nanotherapeutics and regulatory updates for the management of amyotrophic lateral sclerosis: a focused review for orphan drug (Tofersen). (PubMed, Orphanet J Rare Dis) - "Integrating regulatory updates, clinical evidence, and innovative therapeutic strategies, the review uniquely contributes to the ALS literature by bridging current treatment realities with potential future therapies, aiming to inform researchers, clinicians, and policymakers on optimizing ALS management."

Journal • Orphan drug • Review • Amyotrophic Lateral Sclerosis • CNS Disorders • Gene Therapies • SOD1

Markers of presymptomatic amyotrophic lateral sclerosis: State of the art, practical implications and perspectives. (PubMed, Rev Neurol (Paris)) - "While riluzole remains the standard treatment, mutation-specific therapies such as tofersen, that was recently approved in SOD1-ALS, are emerging. These biomarkers may support early surveillance and intervention strategies. The present review provides an overview of current evidence on presymptomatic biomarkers in ALS mutation carriers and their potential role in genetic counseling, monitoring, and early therapeutic decisions."

Biomarker • Journal • Review • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Dementia • Frontotemporal Lobar Degeneration • NEFL • Plasma NfL • SOD1

Validation in Drosophila of the in silico predicted clomipramine as repurposable for SOD1-ALS. (PubMed, Neurotherapeutics) - "Current Food and Drug Administration-approved drugs -riluzole, edaravone, and tofersen - offer limited clinical benefit due to ALS multifactorial etiology and high heterogeneity...Leveraging the SAveRUNNER algorithm, we identified several potentially repurposable candidates, including clomipramine (Anafranil®), mianserin (Lantanon®/Tolvon®), and modafinil (Provigil®)...Our results demonstrate that clomipramine is the most promising candidate, ameliorating lifespan reduction, improving climbing abilities, and mitigating both genomic instability and inflammation, key pathological hallmarks of these SOD1-ALS models. Despite needing further validation in higher organisms, our Drosophila findings represent preliminary yet significant support for clomipramine's action as an add-on treatment for SOD1-ALS."

Journal • Amyotrophic Lateral Sclerosis • CNS Disorders • Inflammation • Respiratory Diseases

Central Nervous System Biodistribution and Pharmacokinetics of Radiolabeled Tofersen in Rodents, Nonhuman Primates, and Humans. (PubMed, J Nucl Med) - "Broad uptake of the ASO in the brain and spinal cord is consistent with the clinical effects of tofersen observed in individuals with the SOD1-ALS variation. In preclinical and human SPECT/CT studies, [99mTc]Tc-MAG3-tofersen mirrored unlabeled drug distribution, showing broad spinal cord and brain uptake, with some differences in kinetics among species."

Journal • PK/PD data • Preclinical • Amyotrophic Lateral Sclerosis • CNS Disorders • SOD1

Preliminary biodistribution of a phosphorodiamidate morpholino oligomer at high doses in the mouse central nervous system (ALS-MND 2025) - "There are currently 17 FDA-approved AO drugs that target a range of diseases through different mechanisms, including QALSODYVto treat SOD1-linked ALS...No significant changes in blood biochemistry or liver and kidney histopathology were detected. We show that high doses of a PMO in the CNS are safe and distributed to mouse CNS tissues and motor neurons, indicating that unconjugated PMOs at high doses may be an option for AO therapeutics to treat MND/ALS."

Preclinical • CNS Disorders • Developmental Disorders • Duchenne Muscular Dystrophy • Genetic Disorders • Muscular Dystrophy • Rare Diseases