Qalsody (tofersen) / Biogen, Ionis - LARVOL DELTA

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

Clinical development of LTX-002, an ASO for the treatment for ALS (ALS-MND 2025) - "Current therapies afford minimal benefits, with the exception of tofersen, an intrathecally-delivered antisense oligonucleotide (ASO) directed against SOD1. LTX-002 is an ASO targeting SPTLC1 being developed for the treatment of ALS. This study will provide safety and tolerability data for LTX-002, and will provide exploratory clinical and biomarker data for further development."

Clinical • Amyotrophic Lateral Sclerosis • CNS Disorders

Discovery of novel hyperphosphorylation sites in familial SOD1 ALS model correlating with the efficacy of novel borsantrazole, a novel edaravone analogue (ALS-MND 2025) - "Background: Since ALS was discovered in 1869, only two FDA-approved drugs, Edaravone (EDR) and Riluzole, have had clinically validated impacts on disease progression...Recently, the FDA granted accelerated approval to tofersen based on its ability to reduce neurofilament light chain (NfL), a pharmacodynamic response biomarker... A longitudinal early-phase study demonstrated the in vivo proof of concept for the efficacy of a new ALS therapeutic, BSZ. Biomarker analysis showed widespread changes in the neurofilament phosphoproteome of spinal cord samples from SOD1 ALS mice, correlating with the therapeutic effects of our novel and biofriendly BSZ drug candidate. These findings represent the discovery of a best-in-class, biofriendly EDR analogue with a naturally occurring boron micronutrient."

Clinical • CNS Disorders • NEFH • NEFL

Serum cardiac troponin T levels as a therapy response marker in tofersen treated ALS (ALS-MND 2025) - "cTnT levels increased in the control ALS-cohort over time (p < 0.0001) but not in the tofersen group (p = 0.36). Creatine kinase (CK), and CK-MB levels did not show significant changes over time. The median monthly increase of cTnT was 0.045 points (IQR 0.02–0.08) in the control ALS cohort and 0.01 points (IQR −0.01 to 0.03) in the tofersen group (p = 0.0013)."

Amyotrophic Lateral Sclerosis • CNS Disorders • NEFL • SOD1

Compassionate use of C9ORF72 targeted ASOs in ALS – experience from eight patients at three German centers (ALS-MND 2025) - P1, P1b/2a | "Disease modifying therapies are limited, but recently an ASO against another form of autosomal dominantly inherited ALS, tofersen (Qalsody) against SOD1, has demonstrated clinical and biomarker (neurofilament, NfL) efficacy...In contrast, two industry programs testing ASOs targeting C9ORF72, (BIIB078, Biogen/Ionis) and (WVE004, Wave), were discontinued after disappointing results of the corresponding phase 1/2 trials (NCT03626012 and NCT04931862)... Our C9ORF72 ASO (Afinersen), which targets both the sense and anti-sense strands of C9ORF72, is well tolerated and produces robust target engagement at (>70% polyGP lowering after six months of treatment) and has a favorable risk profile and long-term tolerability in patients with C9ORF72 familial ALS. Treatment associated clinical and biomarker effects were monitored and the primary results of these analyses and interpretation of our experience will be presented at the conference. In our view, these data..."

Clinical • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Dementia

Elucidating the pathological interplay between cytoskeletal alterations and mRNA metabolism in Profilin1-mutant human motor neurons (ALS-MND 2025) - "Considering the promising results recently obtained with Tofersen in SOD1-ALS patients, these observations qualify PFN1 as an interesting candidate for the development of gene-specific therapies ( 2 ).We took advantage of hiPSC-derived MN to elucidate the exact pathomechanisms linked to PFN1 mutations...All in all, we performed the first study in human PFN1-mutant motor neurons, which revealed, in line with its actin-binding function ( 4 ), cytoskeletal and axonal-synaptic alterations, as well as mitochonia dysfunction and impaired autophagic flux. Additionally, we found a novel relation between PFN1-mutation and compromised mRNA-metabolism, which could be rescued by an active form of PFN1. Our data suggest a loss-of-function of PFN1 as targetable mechanism to treat these specific cases of ALS."

PFN1 • SYP • VAMP2

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 | Not yet recruiting | Sponsor: Biogen

New P4 trial • Amyotrophic Lateral Sclerosis • CNS Disorders

Effective SOD1 targeting with vMiX™, an innovative AAV-based RNA interference platform. (ESGCT 2024) - "The recent positive EMA CHMP opinion and accelerated approval from the US FDA for Qalsody (Tofersen) were based on reductions in the levels of SOD1 in cerebrospinal fluid (CSF), reduction in plasma levels of neurofilament light chain (NfL), and a numerically favourable effect on ALSFRS-R clinical scale...We have developed and demonstrated that vMiX™, a novel RNA interference platform with the capacity to efficiently silence a gene associated with both familial and sporadic ALS, has potential as a future therapeutic strategy. Furthermore, this platform shows broad adaptability for an AAV-based RNA interference approach to target a range of diseases."

Amyotrophic Lateral Sclerosis • CNS Disorders • Respiratory Diseases • NEFL • Plasma NfL • SOD1

Methotrexate therapy as a promising long-term treatment approach for immune-mediated adverse reactions of tofersen in SOD1-ALS: a case report. (PubMed, J Neurol) - No abstract available

Journal • CNS Disorders • Immunology

Antisense Oligonucleotide Therapy for Amyotrophic Lateral Sclerosis (ALS): An Umbrella Review. (PubMed, Cureus) - "Results revealed that of multiple tentative ASO treatments, for multiple specific gene mutations, only one, Tofersen, was approved for the wider population...While initially discouraging, the production of ASOs is a relatively new and advanced process, and slow progress is expected. However, there remains the problem of identifying and treating the much more prevalent sporadic ALS, which is much more common compared to familial ALS."

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

Entering the era of precision medicine to treat amyotrophic lateral sclerosis. (PubMed, Mol Neurodegener) - "With the disease modifying therapy Qalsody (tofersen) which targets the RNA product of the SOD1 gene, having been shown effective in amyotrophic lateral sclerosis (ALS), the present perspective seeks to explore progress towards the implementation of precision medicine principles in ALS drug development...We highlight the recent advances in omics-data for understanding ALS patient sub-groups and how this knowledge should be applied to pre-clinical drug development in a proposed patient profiling workflow, particularly for gene targeted therapies. Finally, we summarise key ethical considerations that are pertinent to equitable care for patients, as we enter the era of precision medicine to treat ALS."

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

Integrative treatment of the motor neuron disease amyotrophic lateral sclerosis, efficacy of pharmacotherapy, traditional Chinese medicine and importance of respiratory support, life-style, and gastrostomy-assisted nutrition: A review. (PubMed, Int J Clin Pharmacol Ther) - "Drugs such as riluzole, edaravone, dextromethorphan/quinidine combinations, and the administration of tofersen by injection are approved treatment options for ALS although a number of other agents are being examined in clinical trials. Despite these developments, the availability of effective treatment options is limited. This review summarizes the etiology and pathogenesis of ALS and describes treatments in detail as an integrative medicine approach and including traditional Chinese medicine together with the importance of the timing for interventions, precautions necessary for noninvasive ventilator and gastrostomy surgery, and precautions for dealing with respiratory issues with the overall aim of providing state-of-the-art clinical recommendations for the care and therapy of ALS patients."

Journal • Review • Amyotrophic Lateral Sclerosis • CNS Disorders • Metabolic Disorders

CASE REPORT: FAMILIAL AMYOTROPHIC LATERAL SCLEROSIS WITH L145S SOD1 MUTATION ON TWO UNRELATED FILIPINOS PRESENTING AS FLAIL LEG SYNDROME (WCN 2025) - "Case 1 was started on Riluzole, Tauroursodeoxycholic acid (TUDCA), Ultrahigh-Dose Methylcobalamin and Edaravone while Case 2 was given Riluzole and Edaravone. ALS SOD1 mutation L145S variant commonly present as flail leg syndrome with slower disease progression. Atypical presentation of ALS like this frequently results to a delay in diagnosis. Gene testing among suspected fALS SOD1 cases can help predict the disease course and potentially receive gene-targeted therapy like Tofersen."

Case report • Clinical • Amyotrophic Lateral Sclerosis • CNS Disorders • SOD1

SFDA Approves Qalsody For Treating ALS Linked To SOD1 Mutations (OneArabia) - "Qalsody is part of the Orphan Drug Program, which aims to expedite access to promising therapies for rare conditions...The approval followed a thorough evaluation of Qalsody's efficacy, safety, and quality. Clinical trials showed reduced neurofilament light chain (NfL) levels compared to placebo, indicating potential slower neurodegeneration. Additionally, there was a decrease in SOD1 protein concentrations in cerebrospinal fluid, suggesting effective molecular target engagement."

Approval • Amyotrophic Lateral Sclerosis

Tofersen in the treatment of SOD1 ALS—experience from the Polish EAP (EAN 2025) - "the data supports the clinical andë molecular response to tofersen in SOD1-ALS."

Amyotrophic Lateral Sclerosis • CNS Disorders • Musculoskeletal Pain • SOD1