Zolgensma (onasemnogene abeparvovec-xioi) / Novartis, REGENXBIO - LARVOL DELTA

Nonclinical toxicity study duration in AAV gene therapy development: Evidence from industry survey supports adequacy of short-term assessments. (PubMed, Mol Ther Methods Clin Dev) - "These findings aligned with regulatory reviews of approved AAV products (e.g., Zolgensma, Luxturna, Roctavian) that consistently demonstrated the adequacy of ≤3-month studies for approved and marketed products. The outcome of this survey supports a risk-based, science-driven approach to in vivo study duration, emphasizing that shorter-term studies are generally sufficient for identifying relevant toxicities associated with AAV-based gene therapies. Embracing this approach can reduce animal use, accelerate development timelines, and support harmonized regulatory expectations for AAV gene therapy products."

Journal • Gene Therapies

Economic evaluations of disease-modifying therapies for spinal muscular atrophy: a systematic literature review. (PubMed, Orphanet J Rare Dis) - "The economic evaluation landscape for SMA treatments is evolving. However, challenges remain due to data gaps and methodological variability across studies. Future research should prioritise the integration of long-term real-world data into economic evaluations, consider the development of patient- and caregiver-derived utility values, and the use of transparent, standardised modelling approaches. These improvements will enhance the robustness, comparability, and policy relevance of economic evaluations in rare disease treatment funding."

HEOR • Journal • Review • CNS Disorders • Genetic Disorders • Movement Disorders • Muscular Atrophy • Rare Diseases

Promises past and future - Gene therapy and the actualisation of future expectations. (PubMed, Soc Sci Med) - "The advent of gene therapies such as Zolgensma, Libmeldy, and Luxturna has given rise to new treatment options for several rare conditions, drastically changing the expectations of affected patients...Similarly marginalised issues include for instance assumptions of effectiveness that do not acknowledge the long-term uncertainty of treatment outcomes; and assumptions of profitability that run counter to real-life examples of business failure. As a revolutionary future becomes reality for some patients, such questions are becoming harder to ignore - but are crucially often omitted from discussion about projected change."

Journal • Gene Therapies

Advances in SMA treatment: Lessons for ALS (ALS-MND 2025) - "Three disease modifying treatments (the IT-delivered splice switching anti-sense oligonucleotide nusinersen, the orally bioavailable splice modifying small molecule risdiplam, and the iv-administered AAV9-SMN gene therapy onasemnogene abeparvovec) increase SMN expression and can ameliorate disease features...As the experience with treated SMA patients grows, the new natural history of the disease is being defined including characterization of potential new phenotypes not previously recognized. Although SMA treatment development represents a remarkable success, it has raised multiple new questions that have relevance to ALS and other neurodegenerative disorders."

Amyotrophic Lateral Sclerosis • CNS Disorders • Gene Therapies • Genetic Disorders • Movement Disorders • Muscular Atrophy • Rare Diseases

Pharmacokinetics of therapies approved for spinal muscular atrophy: A narrative review of current evidence. (PubMed, J Int Med Res) - "Over the past decade, disease-modifying therapies targeting the survival motor neuron pathway-nusinersen, onasemnogene abeparvovec, and risdiplam-have significantly transformed the clinical landscape of spinal muscular atrophy...As the field evolves, biomarker-based monitoring and combination therapies are emerging as promising complementary approaches. With growing clinical experience and an expanding body of pharmacokinetic research on targeted therapies, there is strong potential to further refine treatment strategies-ultimately making spinal muscular atrophy care more effective, safer, and more accessible for patients worldwide."

Journal • PK/PD data • Review • CNS Disorders • Gene Therapies • Genetic Disorders • Movement Disorders • Muscular Atrophy • Rare Diseases

Gene Therapy in Rare Genetic Disorders: Current Progress and Future Perspectives. (PubMed, Curr Genomics) - "Gene therapy has achieved significant milestones, with the successful development of therapies like Zolgensma for spinal muscular atrophy and Luxturna for retinal dystrophy...Gene therapy holds transformative potential for the treatment of rare genetic disorders. While recent successes mark a new era in genetic medicine, ongoing research is required to refine delivery mechanisms, overcome immune-related barriers, and ensure ethical and safe therapeutic interventions."

Journal • Review • CNS Disorders • Gene Therapies • Genetic Disorders • Inherited Retinal Dystrophy • Movement Disorders • Muscular Atrophy • Rare Diseases

Role of PROs in HTA and Reimbursement Decisions Across UK, Germany, France, Italy, and Spain (ISPOR-EU 2025) - "In Germany, crizotinib's positive benefit rating was supported by robust PRO data (EORTC QLQ-C30, EQ-5D), while regorafenib's absence of robust PRO evidence downgraded its rating from "minor added benefit" to "no proven added benefit". UK's NICE cited PROs as pivotal in positive appraisals of pemetrexed and roflumilast, referencing significant improvements in symptom scales and quality-of-life...France's HAS rejected olaratumab and avelumab due to lack of robust PROs, but supported dupilumab and onasemnogene abeparvovec, where validated PROs and caregiver-reported outcomes strengthened value claims... PROs are increasingly integrated into HTA submissions across EU4 + UK, yet their impact on reimbursement varies. Methodological rigor, validated instruments, and disease context remain critical for influencing positive decisions."

Reimbursement • US reimbursement • Rheumatology

Evaluation of the Telomere Length in Patients with Spinal Muscular Atrophy. (PubMed, Int J Mol Sci) - "These findings indicate that telomere attrition is present in SMA and may be mitigated by gene replacement. While the exact contribution of telomere biology to SMA pathogenesis remains to be clarified, telomere length may represent a biomarker for disease severity and treatment response, as well as a potential therapeutic target in this disorder."

Journal • CNS Disorders • Genetic Disorders • Movement Disorders • Muscular Atrophy • Pediatrics • Rare Diseases • SMA4 • SMN1

Onasemnogene abeparvovec gene replacement therapy for spinal muscular atrophy in children: a Moscow experience (PubMed, Zh Nevrol Psikhiatr Im S S Korsakova) - "This study presents the findings of a long-term assessment of the efficacy and safety profile of drug OA in pediatric patients across various age groups and functional ability levels, including individuals identified through expanded newborn screening. Younger patients exhibited a significantly lower incidence of adverse events and demonstrated superior therapeutic efficacy. The majority of older children experienced either positive progression or stabilization of their condition, outcomes that were largely contingent upon their initial functional status and the duration of the pre-treatment waiting period."

Journal • CNS Disorders • Genetic Disorders • Hematological Disorders • Movement Disorders • Muscular Atrophy • Pediatrics • Rare Diseases • Thrombocytopenia

Delphi consensus on gene therapy of spinal muscular atrophy with onasemnogene abeparvovec in Germany, Austria and Switzerland-part I-systematic literature review and existing evidence. (PubMed, J Neuromuscul Dis) - "(3) Earlier initiation of therapy with fewer symptoms and shorter disease duration leads to better outcomes. (4) There is no clinical evidence supporting the superiority of combining two treatments over monotherapy. The systematic literature analysis constitutes the basis for the subsequent part 2, which involves the generation of expert-based recommendations for the surveillance of SMA gene addition therapy."

Journal • Gene Therapies • Genetic Disorders • Movement Disorders • Muscular Atrophy • Rare Diseases

Treating Presymptomatic Spinal Muscular Atrophy Patients with Onasemnogene Abeparvovec in Italy: The Role of the National Health System and Drug Supply. Comment on Zaidman et al. Newborn Screening for Spinal Muscular Atrophy: Variations in Practice and Early Management of Infants with Spinal Muscular Atrophy in the United States. Int. J. Neonatal Screen. 2024, 10, 58. (PubMed, Int J Neonatal Screen) - "We read with interest the recent study by Zaidman et al [...]."

Journal • Genetic Disorders • Movement Disorders • Muscular Atrophy • Rare Diseases

Trach and treat: Safety and motor outcomes following onasemnogene abeparvovec in patients with spinal muscular atrophy and tracheostomies in the RESTORE registry. (PubMed, J Neuromuscul Dis) - P | "Overall, patients exhibited positive motor outcomes, even in cases where the need for tracheostomy emerged after treatment. These real-world data support OA treatment for patients with SMA and tracheostomies and can inform future access, treatment, and care decisions.Trial registration: Clinicaltrials.gov NCT identifier NCT04174157, registration date September 12, 2019."

Journal • Genetic Disorders • Movement Disorders • Muscular Atrophy • Rare Diseases

Hip Displacement in Spinal Muscular Atrophy in the Early Disease-Modifying Therapy Era: Association With Hip Pain and Timing of Therapy Initiation. (PubMed, J Pediatr Orthop) - "Hip displacement in SMA begins early, with progression patterns differing by disease severity. Hip displacement is also associated with pain, which was observed primarily in dislocated hips. These findings highlight the need for routine hip surveillance from early infancy and pain assessment. DMT initiation may confer only minimal benefit when instituted at a later age, but may yield more substantial benefit when administered presymptomatically soon after birth."

Journal • Genetic Disorders • Movement Disorders • Muscular Atrophy • Pain • Rare Diseases

Role of Real-World Evidence (RWE) in Pricing and Reimbursement Decisions for Rare Disease in Health Technology Assessment (HTA) Submissions Across EU4 + UK (ISPOR-EU 2025) - "Onasemnogene abeparvovec and Elosulfase alfa were reimbursed in all five markets... HTA bodies have primarily accepted RWE to provide external comparators or to supplement clinical effectiveness data in rare disease therapies, though acceptance remains variable across agencies and may become more standardized under the EU Joint Clinical Assessment (EU-JCA)."

Clinical • HEOR • Pricing • Real-world • Real-world evidence • Reimbursement • US reimbursement • CNS Disorders • Gene Therapies • Rare Diseases

Can Generative AI Deliver Patient-Friendly Summaries? A Case Study Using NICE Guidance for Spinal Muscular Atrophy (ISPOR-EU 2025) - "Generative AI shows strong potential to support PLS development, enhancing transparency, efficiency, and inclusion in HTA processes. Broader validation and integration into HTA workflows are recommended to promote consistent, scalable, and patient-centered communications."

Case study • Clinical • Genetic Disorders • Movement Disorders • Muscular Atrophy • Rare Diseases

Building the Bridge to Access: Leveraging RWE From Early Access Schemes to Reimbursement in Gene and Cell Therapies (ISPOR-EU 2025) - "Early-access programmes only bridge evidence gaps when RWE is prospectively planned, aligned with payer expectations, and tied to transparent managed-entry contracts. Harmonised data, validated controls, and clear HTA feedback are key to making early-access RWE a standard driver reimbursement."

Reimbursement • US reimbursement • Gene Therapies • Rare Diseases

Can Generative AI Deliver Patient-Friendly Summaries? A Case Study Using NICE Guidance for Spinal Muscular Atrophy (ISPOR-EU 2025) - "Generative AI shows strong potential to support PLS development, enhancing transparency, efficiency, and inclusion in HTA processes. Broader validation and integration into HTA workflows are recommended to promote consistent, scalable, and patient-centered communications."

Case study • Clinical • Genetic Disorders • Movement Disorders • Muscular Atrophy • Rare Diseases

Onasemnogene abeparvovec gene therapy for treatment of patients with spinal muscular atrophy: Updated real-world practical considerations. (PubMed, J Neuromuscul Dis) - "These include nusinersen and risdiplam, which modify splicing of the SMN2 pre-mRNA, and onasemnogene abeparvovec, a viral-mediated gene therapy...As more countries have approved onasemnogene abeparvovec and new data have emerged from clinical trials and real-world use, a similar expert panel provides updated recommendations along with additional guidance. Specific recommendations are centered around family preparation prior to and immediately following dosing to minimize risk of infectious illness, timing of anti-adeno-associated virus serotype 9 antibody titer testing for those patients with exclusionary titers, modifying immunization schedules, avoiding potential complications with long-term corticosteroid administration, safety monitoring, considerations for combination therapy, implementing newborn screening, and emphasizing the need for ongoing multidisciplinary care and adherence to standard-of-care guidelines."

Journal • Real-world evidence • Review • CNS Disorders • Gene Therapies • Genetic Disorders • Infectious Disease • Movement Disorders • Muscular Atrophy • Rare Diseases • SMA4 • SMN1 • SMN2

Incidence and Clinical Significance of Immune-mediated Myocarditis after Gene Replacement Therapy: a Systematic Reviewew and Meta-Analysis (AHA 2025) - "In VigiBase, myocarditis occurred in relation to Delandistrogene Moxeparvovec (1/16(6%)) and Onasemnogene Abeparvovec (14/217 (6%)). Six percent of patients treated with AAV gene therapy experienced immune mediated myocarditis, most of which were early onset and clinically mild... Six percent of patients treated with AAV gene therapy experienced immune mediated myocarditis, most of which were early onset and clinically mild. One death occurred in the settings of a capillary leak-syndrome and cardiac dysfunction. These findings underscore the relative rarity of clinically significant cardiac sequale."

Retrospective data • Cardiovascular • Duchenne Muscular Dystrophy • Gene Therapies • Genetic Disorders • Hepatology • Inflammation • Movement Disorders • Muscular Atrophy • Muscular Dystrophy • Myositis • Rare Diseases

Ex vivo investigation of AAV vector-specific adaptive immunogenicity in healthy volunteers (ESGCT 2024) - "Collectively these data demonstrate the presence of pre-existing immunogenicity towards the AAV VP1 protein in certain healthy volunteers. Further research is required to explore how this translates into adverse events in patients exposed to Zolgensma."

Preclinical • Amyotrophic Lateral Sclerosis • Gene Therapies • Genetic Disorders • Infectious Disease • Movement Disorders • Muscular Atrophy • Rare Diseases • CD8 • GZMB • IL10 • IL17A • IL6 • KLRB1 • SMA4 • SMN1 • TNFA

Quebec Spinal Muscular Atrophy Newborn Screening Program: The First Year Experience. (PubMed, Int J Neonatal Screen) - "Surviving newborns initiated treatment at a median age of 30 days (range: 9-103 days), with four receiving onasemnogene abeparvovec and one nusinersen...Overall, the Quebec SMA NBS pilot program successfully identified affected newborns, facilitated early access to therapy, and provided the first provincial estimate of SMA birth prevalence. Improved sample shipping and processing times are needed to maximize the program's impact, which is expected with full automation."

Journal • Genetic Disorders • Movement Disorders • Muscular Atrophy • Palliative care • Pediatrics • Rare Diseases • SMN2

Q3 priority brands..Underpinning our financial results in the quarter is a continued focus on key growth drivers (Novartis Press Release) - "Cosentyx (USD 1698 million, -1% cc) sales were broadly stable, as strong volume growth in the US was partially offset by higher revenue deductions, and ex-US declined due to a one-time price effect in the prior year. Novartis remains confident in Cosentyx USD 8 billion+ peak sales guidance; Zolgensma (USD 301 million, -5% cc) sales declined reflecting a lower incidence of SMA compared to prior year."

Commercial • Ankylosing Spondylitis • Atopic Dermatitis • Colorectal Cancer • Hidradenitis Suppurativa • Inflammatory Bowel Disease • Lupus • Multiple Sclerosis • Muscular Atrophy • Rheumatoid Arthritis

Diverging Safety Signals: A Trend Analysis of Suspected Adverse Drug Reactions Reporting for Spinal Muscular Atrophy Therapies in the European Union. (PubMed, Neurol Int) - "Onasemnogene abeparvovec exhibited a continued but decelerating increase in suspected ADRs, while risdiplam demonstrated a consistent upward trend across all reported reactions. Diverging patterns in adverse reaction reporting suggest a stabilizing safety profile for nusinersen and potential emerging safety signals for risdiplam and onasemnogene abeparvovec, underscoring the need for ongoing continued pharmacovigilance (e.g., post-authorization studies and spontaneous reporting)."

Adverse drug reaction • Journal • Genetic Disorders • Movement Disorders • Muscular Atrophy • Rare Diseases

Characterizing the tissue specific regulation and epigenetic response to AAV9-SMN1 gene therapy for Spinal Muscular Atrophy (SMA). (ESGCT 2024) - "By 6 months, these changes were not detected, confirming that AAV9-PGK-SMN1 gene therapy restores the 5hmC landscape in adult mice, despite transient changes at P14. We now aim to understand the parameters that control the efficiency of the AAV mediated gene therapy in this system and to use this as a base to rationally design new gene therapies."

Gene therapy • Gene Therapies • Genetic Disorders • Movement Disorders • Muscular Atrophy • Rare Diseases • SMA4 • SMN1

Administration of Onasemnogene Abeparvovec in an Infant With Spinal Muscular Atrophy and PCR-Confirmed SARS-CoV-2 Infection. (PubMed, Cureus) - "This case suggests that OA administration may be safe in asymptomatic SARS-CoV-2-positive patients with low viral loads, allowing timely therapy to preserve motor function. Further studies are needed to establish evidence-based guidelines for the optimal timing of OA administration."

Journal • Gene Therapies • Genetic Disorders • Infectious Disease • Movement Disorders • Muscular Atrophy • Novel Coronavirus Disease • Rare Diseases • Respiratory Diseases