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

Real-world outcomes of spinal muscular atrophy treatment with onasemnogene abeparvovec in Croatia: a comprehensive case series and literature review. (PubMed, Front Med (Lausanne)) - "In addition, our case series emphasize the critical role of newborn screening in identifying affected individuals before the onset of irreversible motor neuron loss as well as prompt start of treatment in all patients. We hope that our findings will contribute meaningfully to the expanding body of literature and knowledge on spinal muscular atrophy, ultimately fostering better patient care and outcomes."

Journal • Real-world evidence • CNS Disorders • Developmental Disorders • Gene Therapies • Genetic Disorders • Movement Disorders • Muscular Atrophy • Pediatrics • Rare Diseases • SMA4 • SMN1

A Study to Learn About the Safety of BIIB115 Injections and How BIIB115 is Processed in the Bodies of Healthy Adult Male Volunteers and of Pediatric Participants With Spinal Muscular Atrophy Who Previously Took Onasemnogene Abeparvovec (clinicaltrials.gov) - P1 | N=62 | Active, not recruiting | Sponsor: Biogen | Trial completion date: Nov 2026 ➔ Nov 2031 | Trial primary completion date: Nov 2026 ➔ Nov 2031

Trial completion date • Trial primary completion date • Genetic Disorders • Movement Disorders • Muscular Atrophy • Pediatrics • Rare Diseases • SMN1 • SMN2

REGISTRE SMA FRANCE: A nationwide observational registry of patients with spinal muscular atrophy in France. (PubMed, J Neuromuscul Dis) - "Three innovative disease-modifying therapies (DMTs)-nusinersen, risdiplam, and onasemnogene abeparvovec-are available for treatment.ObjectiveTo provide a descriptive overview of patients enrolled in the Registre SMA France until July 22, 2024.MethodsRegistre SMA France is a multicenter, national observational registry that includes patients with SMA-children and adults, treated or untreated...Major complications included ventilatory support (SMA1: 69.9%, SMA2: 64.5%, SMA3: 18.1%), enteral feeding (SMA1: 56.2%SMA1), and spine surgery (SMA2: 24.5%). Survival was significantly higher in treated SMA1 and SMA2 cases.ConclusionThis registry serves as a key resource for understanding the clinical course and treatment outcomes of SMA in the real world, supporting future research and informing clinical and policy decisions in the era of DMTs.Trial registrationNCT04177134."

Journal • Amyotrophic Lateral Sclerosis • CNS Disorders • Gene Therapies • Genetic Disorders • Hematological Disorders • Movement Disorders • Muscular Atrophy • Orthopedics • Pediatrics • Rare Diseases • SMA4

Risdiplam treatment following onasemnogene abeparvovec in individuals with spinal muscular atrophy: a multicenter case series. (PubMed, BMC Neurol) - "Many children included in this case series had improvements in motor, respiratory and/or bulbar function after adding risdiplam following OA. No new safety concerns were observed. The real-world evidence generated from this case series provides additional information on risdiplam's risk-benefit profile after OA administration in children with SMA. Future studies with a larger cohort should be conducted."

Journal • CNS Disorders • Gastrointestinal Disorder • Gene Therapies • Genetic Disorders • Movement Disorders • Muscular Atrophy • Rare Diseases • Respiratory Diseases • SMN2

Early Intervention and Speed-to-Effect in Spinal Muscular Atrophy Type 1 Following Onasemnogene Abeparvovec Gene Replacement Therapy: Results of aPost-Hoc Analysis of Pooled Clinical Study Data. (PubMed, Neurol Ther) - "Rapid and clinically significant improvements in motor function were observed for onasemnogene abeparvovec-treated patients with symptomatic SMA type 1. Early diagnosis and treatment are essential for timely restoration and preservation of motor neurons and maximal motor function improvement."

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

Pharmacy-directed coordination of gene and high-cost therapies. (PubMed, Am J Health Syst Pharm) - "The creation of a pharmacy-directed program for coordination of gene and high-cost therapies has been crucial to the hospital's success in offering these innovative and potentially life-altering therapies."

Journal • Gene Therapies • Pediatrics

Eculizumab for Thrombotic Microangiopathy Induced by Onasemnogene Abeparvovec in Spinal Muscular Atrophy. (PubMed, Case Rep Nephrol Dial) - "Thrombotic microangiopathy is an ultra-rare, but potentially life-threatening condition that can occur after onasemnogene abeparvovec therapy. Anticipation of these serious adverse events, its prompt recognition and treatment is crucial for a better outcome."

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

Cost-effectiveness of treatments for presymptomatic newborn patients with spinal muscular atrophy and two or three copies of the survival motor neuron 2 gene in Italy. (PubMed, Eur J Health Econ) - "OA for the treatment of presymptomatic newborns was dominant or cost effective compared with other treatments or BSC in the full patient cohort within the Italian context."

HEOR • Journal • Genetic Disorders • Movement Disorders • Muscular Atrophy • Rare Diseases • SMA4 • SMN1 • SMN2

Thrombotic microangiopathy following gene therapy for 5q-spinal muscular atrophy. (PubMed, Gene Ther) - "TMA is a rare but severe complication of OA therapy for SMA. Prompt recognition and management, often with corticosteroids, are crucial for improving outcomes."

Clinical • Journal • Gene Therapies • Genetic Disorders • Hematological Disorders • Infectious Disease • Movement Disorders • Muscular Atrophy • Rare Diseases • Thrombocytopenia

Switching disease-modifying therapies in patients with spinal muscular atrophy: A systematic review on effectiveness outcomes. (PubMed, Br J Clin Pharmacol) - "Eligible studies included clinical trials and real-world evidence (RWE) reports describing patients with genetically confirmed SMA who received nusinersen or risdiplam and subsequently switched to nusinersen, risdiplam or onasemnogene abeparvovec...However, long-term outcomes and standardized data were limited. Future research should prioritize robust RWE and post-marketing surveillance to evaluate long-term safety and effectiveness, incorporate standardized switching protocols, and account for SMA genotype-phenotype variation."

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

Costs of Treating Onasemnogene Abeparvovec-Xioi-Induced Liver Injury. (PubMed, Pharmacol Res Perspect) - "Medication costs range from €26.8 for prednisone to €695.4 for severe cases requiring additional immunosuppressive agents like tacrolimus and mycophenolate mofetil. To conclude, OA-induced liver injury, though notable, is clinically manageable with immunosuppressive therapy and rarely causes severe complications like encephalopathy or liver failure. Its modest costs do not undermine OA's cost-effectiveness, supporting its transformative role in spinal muscular atrophy treatment."

Journal • CNS Disorders • Gene Therapies • Genetic Disorders • Hepatology • Liver Failure • Movement Disorders • Muscular Atrophy • Rare Diseases

Role of External Control Arm (ECA) Derived from Real World Data (RWD) in US FDA Regulatory Approval from 2020-2024 (ISPOR 2025) - "OBJECTIVES: To analyze role of ECA in US FDA approvals ( 2020 - 2024) & summarize the key disease areas leveraging ECA. systematic literature review and analysis of all novel drug approvals including NDA (New Drug Application) and BLA (Biological License Application)submitted from 2020-2024 were analyzed. The percentage of approvals involving external control arms increased steadily, particularly in rare diseases, oncology, and conditions with small or hard-to-recruit patient populations from 2020-2024 2020: Early Exploration (5-7% of Approvals) : 1.Ibrance (palbociclib): Used retrospective RWD to support male breast cancer indication...Blincyto (blinatumomab): Supplemental approvals for rare cancers based on external data. 2021: Accelerated Adoption Amid COVID-19 (10-15% of Approvals) 1.Veklury (remdesivir): Approval supported by real-world hospital data as external comparisons...Keytruda (pembrolizumab): Label expansion for certain cancers using external control..."

Clinical • Real-world • Real-world evidence • Alzheimer's Disease • Breast Cancer • CNS Disorders • Genetic Disorders • HER2 Breast Cancer • HER2 Positive Breast Cancer • Infectious Disease • Male Breast Cancer • Movement Disorders • Muscular Atrophy • Novel Coronavirus Disease • Oncology • Rare Diseases • Solid Tumor • HER-2

Summary of Evolving Role and Impact of Real World Evidence (RWE) in US FDA Regulatory Approvals (2020-2024) (ISPOR 2025) - "Notable cases like Rozlytrek (entrectinib) for rare cancers leveraged synthetic control arms, Zolgensma (onasemnogene abeparvovec-xioi) used RWE for expanded indications...Examples include Enhertu (fam-trastuzumab deruxtecan-nxki) for HER2-low breast cancer and Evrysdi (risdiplam) for spinal muscular atrophy, supported by longitudinal real-world data. 1) 2020, RWE was primarily used in label expansions and post-marketing safety evaluations, particularly in oncology and rare diseases. Notable approvals included Ibrance (palbociclib) for male breast cancer, based on real-world data from EHRs.2) 2021, during COVID-19 pandemic, RWE played a key role in Emergency Use Authorizations (EUAs) and full approvals of treatments like Veklury (remdesivir). The % of approvals involving RWE increased to 15-20%, with RWE supporting label expansions for drugs like Keytruda (pembrolizumab).3)2022, RWE contributed to 25-30% of approvals, including initial NDAs and BLAs."

Clinical • HEOR • Real-world • Real-world evidence • Alzheimer's Disease • Breast Cancer • CNS Disorders • Genetic Disorders • HER2 Breast Cancer • HER2 Positive Breast Cancer • Infectious Disease • Male Breast Cancer • Movement Disorders • Muscular Atrophy • Novel Coronavirus Disease • Oncology • Rare Diseases • Solid Tumor • HER-2

The Role of Patient-Reported Outcomes in US FDA Novel Drug Approvals and Reimbursement Decisions (2020-2024) (ISPOR 2025) - "Rinvoq (AbbVie) - PRO data showed improved quality of life in rheumatoid arthritis, contributing to $2.3 billion...Zeposia (Bristol-Myers Squibb) - PROs on fatigue reduction generated $500 million. Imcivree (Rhythm Pharmaceuticals) - PRO data supported FDA approval 2022: FDA : 37 drugs, with 30% (11 drugs) Reimbursement : 85 total approvals, with 35% (30 approvals) Adbry (LEO Pharma) - PROs on itch reduction generated $90 million . Camzyos (Bristol-Myers Squibb) - Symptom relief PROs were key 2023: FDA : 49 drugs, with 33% (16 drugs) Reimbursement 95 total approvals, with 45% (43 approvals. Leqembi (Eisai/Biogen) - FDA approval and Medicare conditional reimbursement for Alzheimer's disease leveraged PROs on cognitive function improvements, generating $200 million/ Jaypirca (Eli Lilly) - Patient-reported symptom relief supported FDA and payer decisions for mantle cell lymphoma... The inclusion of PROs in FDA novel drug approvals increased from 18% in 2020 to 40% in..."

Clinical • Patient reported outcomes • Reimbursement • US reimbursement • Alzheimer's Disease • CNS Disorders • Fatigue • Hematological Malignancies • Immunology • Infectious Disease • Inflammatory Arthritis • Lymphoma • Mantle Cell Lymphoma • Oncology • Rheumatoid Arthritis • Rheumatology

BODY COMPOSITION AND METABOLIC IMPACT OF NEW THERAPIES IN SPINAL MUSCULAR ATROPHY PATIENTS (ESPGHAN 2025) - "Seventy percent received medication (94% nusinersen, 6% Zolgensma)...Conclusions Our findings highlight the complex challenges faced by SMA patients, including significant changes in body composition and metabolic function. Despite new therapies, nutritional issues persist, emphasizing the need for early detection and tailored interventions"

Clinical • Dyslipidemia • Genetic Disorders • Metabolic Disorders • Movement Disorders • Muscular Atrophy • Otorhinolaryngology • Pediatrics • Rare Diseases

DIFFICULTIES OF EATING AND MASTICATING SOLID FOOD IN CHIDREN WITH SPINAL MUSCULAR ATROPHY – PRELIMINARY STUDY (ESPGHAN 2025) - "Methods We investigated 17 children with SMA (aged 7; 5 ± 2; 11), treated with various medications: nusinersen (n=13), risdiplam (n=4), branaplam (n=2), and onasemnogene (n=5)...Conclusions Difficulties with oral feeding still can affect patients with SMA, despite the treatment. Weakened tongue muscle strength can results in reduce effectiveness in eating solid foods."

Genetic Disorders • Infectious Disease • Movement Disorders • Muscular Atrophy • Pneumonia • Rare Diseases • Respiratory Diseases

Next-Generation AAV-Based Gene Therapy for Spinal Muscular Atrophy: Safety and Efficacy of EXG001-307 in Clinical Trials (ASGCT 2025) - "Two patients in High-dose Cohort experienced thrombotic microangiopathy (TMA), which resolved following treatment with eculizumab (anti-C5 antibody)... EXG001-307 demonstrated remarkable efficacy, enabling Type 1 SMA patients to achieve critical motor milestones, such as sitting and standing, which are unattainable in the natural history of the disease. This novel therapy offers a promising, targeted approach to SMA treatment, advancing the standard of care for patients with this devastating condition. Disease Focus of Abstract:Neuromuscular Disorders"

Clinical • Gene therapy • Gene Therapies • Genetic Disorders • Hepatology • Infectious Disease • Liver Failure • Movement Disorders • Muscular Atrophy • Novel Coronavirus Disease • Rare Diseases

Hemophagocytic Lymphohistiocytosis (HLH)/hyperinflammatory syndrome following high dose AAV9 therapy (ASGCT 2025) - "Byrne et al noted HLH cases, with a systemically administered AAV9 product at a similar dose, resolving with anakinra, an IL-1 receptor antagonist...Case summary: A 7-year-old female with classic RTT was treated with 3E15 vg (1.5E14 vg/kg) of NGN-401 via ICV administration with no procedure-related complications. Prophylactic immunosuppression included rituximab, sirolimus, and corticosteroids...A single dose of eculizumab was given as a precaution, without signs of thrombotic microangiopathy based on negative blood smear... High dose AAV has been linked to rare cases of HLH. Monitoring ferritin, complete blood count, and liver function frequently in the early post-dose period is warranted. Prompt treatment for suspected HLH should include high-dose corticosteroids, immunomodulation, and management by a multidisiplinary team."

IO biomarker • Acute Kidney Injury • CNS Disorders • Developmental Disorders • Gene Therapies • Genetic Disorders • Hematological Disorders • Hemophagocytic lymphohistiocytosis • Hepatology • Hypotension • Immunology • Infectious Disease • Liver Failure • Movement Disorders • Nephrology • Oncology • Psychiatry • Rare Diseases • Renal Disease • Respiratory Diseases • Thrombocytopenia

Assessing Risdiplam Cost-Effectiveness for Spinal Muscular Atrophy Types I, II, and III in Chile (ISPOR 2025) - "OBJECTIVES: This study evaluates the cost-effectiveness of risdiplam compared to nusinersen and onasemnogene abeparvovec (AVXS-101) in patients with Spinal Muscular Atrophy (SMA) types I, II, & III over a 10-year horizon from a societal perspective in Chile, incorporating both direct healthcare costs and indirect costs related to productivity loss... In conclusion, risdiplam emerges as the preferred option for SMA patients, demonstrating superior effectiveness and cost advantages over alternative treatments. Sensitivity analyses confirm the robustness of the base case findings, reinforcing risdiplam's dominance. From a cost-effectiveness perspective, risdiplam offers the most convenient alternative for the Chilean public health system in all SMA types."

Cost effectiveness • HEOR • Genetic Disorders • Movement Disorders • Muscular Atrophy • Rare Diseases

Supraphysiological expression of SMN1 protein leads to compromised heart function improvement and cardiac thrombosis in mice (ASGCT 2025) - "These data suggest that supraphysiological SMN expressions in the heart are detrimental to cardiac function and safety. Disease Focus of Abstract:Neuromuscular Disorders"

Preclinical • Cardiovascular • CNS Disorders • Gene Therapies • Genetic Disorders • Hematological Disorders • Movement Disorders • Muscular Atrophy • Rare Diseases • Thrombosis • SMA4 • SMN1

A Targeted Literature Review of Value-Based Agreements (VBAs) for Cell and Gene Therapies in the United States (ISPOR 2025) - "The therapies with VBAs in place included: Beqvez, Casgevy, Hemgenix, Kymriah, Luxturna, Lyfgenia, Roctavian, Vyjuvek, Zolgensma, and Zynteglo... In this review, multiple VBAs for CGTs were identified across multiple disease areas. Most payers did not publicly disclose which outcomes measures the VBAs were assessing. Of those that did, outcomes assessed could be sourced from routine patient visits and/or adjudicated claims, placing no additional burden on providers to collect data for the sole purpose of the VBA."

Gene therapy • Review • Gene Therapies

Understanding and characterizing the immune response to adeno-associated virus (AAV) in the central nervous system (CNS) (ASGCT 2025) - "Future work will include testing the role of Tregs in transgene expression through Treg depletion and further elucidating the mechanism of T cell recruitment to the brain for the creation of safer and more effective AAV gene therapies. Disease Focus of Abstract:Central Nervous System Disorders"

Gene Therapies • Hepatology • Liver Failure • CD4 • CXCL10 • FOXP3 • IFNG • IL2RA • ISG20

Evaluation of cardiac function in patients with SMA after treatment with onasemnogene abeparvovec. (PubMed, Pediatr Int) - "Subclinical myocardial dysfunction after infusion of onasemnogene abeparvovec was suggested by careful investigation of cardiac function. Cardiac toxicity may correlate with liver impairment following gene replacement therapy. Long-term studies that allow for a higher number of patients and more extended observation periods should be conducted to confirm the cardiac toxicity of onasemnogene abeparvovec."

Journal • Amyotrophic Lateral Sclerosis • Cardiovascular • CNS Disorders • Genetic Disorders • Movement Disorders • Muscular Atrophy • Rare Diseases • TNNI3

Post-Marketing Safety of Spinal Muscular Atrophy Therapies: Analysis of Spontaneous Adverse Drug Reactions from EudraVigilance. (PubMed, J Clin Med) - "Background/Objectives: Spinal muscular atrophy (SMA) treatment has evolved with the approval of nusinersen, onasemnogene abeparvovec, and risdiplam...ADRs related to SMA complications require careful differentiation from true drug-related effects. Future pharmacovigilance efforts should focus on long-term safety assessments and real-world evidence to optimize treatment strategies."

Adverse drug reaction • Journal • P4 data • Genetic Disorders • Infectious Disease • Movement Disorders • Muscular Atrophy • Pneumonia • Rare Diseases • Respiratory Diseases

The Kids Advanced Therapeutics Program – Responding to the Need for Systems Readiness in the Gene Therapy Translation Pathway (ASGCT 2025) - "(1) Australia's vast geographic landscape position it to be an exemplar for delivering specialised therapies despite physical distance, with an emphasis on agile clinical systems and equity of access. Learnings from the KAT program remain relevant beyond Australia and discussion of these experiences and insights may provide opportunities for partnership and planning across broader jurisdictions and sectors."

Gene therapy • Metastases • Developmental Disorders • Duchenne Muscular Dystrophy • Gene Therapies • Genetic Disorders • Hematological Disorders • Hemophilia • Immunology • Movement Disorders • Muscular Atrophy • Muscular Dystrophy • Myositis • Otorhinolaryngology • Pediatrics • Rare Diseases