Novartis receives positive CHMP opinion for Itvisma® for spinal muscular atrophy (SMA)

CHMP Recommends Itvisma for Older Children and Adults with SMA

Novartis announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion recommending marketing authorization for Itvisma (onasemnogene abeparvovec) for children two years and older, teens, and adults with 5q spinal muscular atrophy (SMA). This gene replacement therapy, designed to address the genetic root cause of SMA with a single dose, demonstrated clinically meaningful and statistically significant improvements in motor function in the registrational Phase III STEER study. If approved, Itvisma would be the first and only gene replacement therapy for this older patient population in the EU, offering the potential to reduce the need for chronically administered treatments.

• The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has issued a positive opinion for Itvisma, recommending its marketing authorization for children aged two years and older, teenagers, and adults with 5q spinal muscular atrophy (SMA) who have a bi-allelic mutation in the SMN1 gene. This recommendation marks a significant step towards expanding treatment options for an underserved older patient population in Europe.
• The positive opinion is primarily supported by data from the registrational Phase III STEER study, which showed Itvisma achieved a statistically significant 2.39-point improvement in the Hammersmith Functional Motor Scale (HFMSE) compared to a 0.51-point improvement in the sham group (p=0.0074). These effects were sustained over 52 weeks of follow-up, demonstrating clinically meaningful benefits for both treatment-naïve and pre-treated patients.
• Itvisma is an adeno-associated virus 9 (AAV9)-based gene therapy designed to deliver a functional copy of the human SMN1 gene via a single, one-time intrathecal injection. This unique approach aims to address the genetic root cause of SMA, offering the potential to improve motor function through sustained SMN protein expression and reduce the long-term burden associated with chronically administered treatments.

Why Older Children and Adults with SMA Need New Options

Recent literature reveals significant unmet needs in the SMA population, particularly among older patients who remain underserved despite therapeutic advances. Adults with SMA represent a growing population with distinct treatment priorities that differ from pediatric patients, while musculoskeletal complications continue to progress even with current disease-modifying therapies.

• Functional improvement priorities - Gaining muscle strength was the most frequently reported unmet need among adults with SMA, followed by improving daily functioning, achieving new motor function, and stabilizing motor function

• Musculoskeletal complications persist - Progressive spine deformity and hip subluxation remain significant problems in the majority of SMA type 1 cases despite disease-modifying therapy, with 93.1% having scoliosis, 69% having pelvic obliquity, and 60.7% having hip subluxation

• Underserved adult population - 21.8% of the adult SMA population remains untreated, with progressive impairment and increased sensitivity to treatment discontinuations, along with delayed or reduced access to commercialized SMA drugs and clinical trials

• Respiratory and bulbar function needs - People with more severe SMA types and lower mobility were more likely to report lung function and bulbar function as important unmet needs, with breathing function being the most important treatment attribute for caregivers

• Treatment response biomarkers - High costs and treatment burden of gene-based therapies highlight the need for biomarkers to objectify or predict treatment response, with Neuronal Pentraxin 2 (NPTX2) emerging as a potential biomarker for nusinersen response

• SMN-independent therapeutic targets - Recognition that current SMN replacement therapies have limitations has driven development of complementary targets, with Stathmin-2 (STMN2) being explored as a novel SMN-independent target showing promise in preclinical studies

Key Efficacy and Safety Outcomes from Itvisma's STEER Study

The literature reveals several landmark SMA studies demonstrating significant therapeutic advances across multiple treatment modalities. Recent investigations have provided crucial insights into both established and emerging interventions, with particular focus on long-term outcomes and comparative effectiveness. Key findings highlight the evolving treatment landscape and improved patient outcomes across different SMA subtypes.

• OFELIA Study (2025) evaluated onasemnogene abeparvovec (1·1 × 10 vg/kg) in 16 symptomatic patients ≤24 months of age across Brazil and Argentina. Safety outcomes included universal adverse events, with 11 patients experiencing serious AEs and hepatotoxicity (n=11/12), thrombocytopenia (n=5/12), and two deaths (one possibly treatment-related). Most patients maintained or improved motor milestones through 18 months, including sitting, crawling, standing, and walking abilities.

• French National SMA Registry Comparative Study (2025) compared nusinersen versus onasemnogene abeparvovec as first-line treatments in 24 children with SMA1. Gene therapy demonstrated superior supportive care outcomes at 2 years: nutritional support required in 9% versus 50% with nusinersen, nocturnal ventilation in 45% versus 80%. Unsatisfactory clinical response occurred in 25% of gene therapy patients compared to 67% receiving nusinersen, though motor outcomes remained comparable between groups.

• International 4-Year Nusinersen Study (2025) tracked 73 SMA type II and 111 type III patients, revealing mean HFMSE improvements of +4.18 points (SMA II) and +1.08 points (SMA III). Age and baseline HFMSE emerged as strongest progression predictors, with younger patients and higher baseline scores associated with superior outcomes, particularly during the initial two years of treatment.

• Korean Adult Nusinersen Study (2026) demonstrated significant HFMSE improvements of 2.28 points at 12 months (p=0.0002) in 19 adult patients, with sustained gains of 4.55 and 6.57 points at 24 and 36 months respectively. Type 2 SMA patients exhibited faster drug response compared to type 3a patients, with 86% achieving clinically meaningful improvements by 36 months.

• Czech and Slovak Risdiplam Study (2025) in 59 adults showed motor stability over 3 years with sustained upper-limb improvements and favorable respiratory trajectories. RULM improved during the first 6 months and remained stable through 24-36 months, with no patients requiring new ventilation support during follow-up.

• Systematic Review of Combination Therapies (2025) analyzed 29 patients receiving dual (n=26) or triple (n=3) therapy regimens, demonstrating general tolerability without consistent additive toxicity. Some patients showed improved motor milestones and respiratory function with early intervention, though switching therapies (particularly from nusinersen or risdiplam to onasemnogene abeparvovec) were most common.

How Itvisma Redefines Gene Therapy for Older SMA Patients

The treatment landscape for spinal muscular atrophy has undergone a revolutionary transformation over the past five years, fundamentally changing SMA from a uniformly fatal condition to a treatable disease. Three disease-modifying therapies have become available through accelerated approval programs: nusinersen (Spinraza®), onasemnogene abeparvovec (Zolgensma), and risdiplam (Evrysdi). These therapies work through distinct mechanisms - nusinersen and risdiplam function at the pre-mRNA level to increase SMN protein production, while onasemnogene abeparvovec provides gene replacement therapy at the DNA level. Prior to these breakthrough treatments, children with SMA type 1 typically did not survive beyond age two, with management being primarily palliative.

Real-world evidence accumulated over the past five years demonstrates significant clinical improvements across all three therapeutic approaches, though with important limitations. Nusinersen studies involving over 400 patients have shown that 72% experience improved motor function and 18% achieve stabilization, with optimal outcomes observed when treatment begins within the first two years of life. The RESTORE registry data for onasemnogene abeparvovec reveals that patients identified through newborn screening achieve superior outcomes compared to those diagnosed clinically, with all treated patients maintaining or achieving motor milestones. Risdiplam has demonstrated effectiveness across the broadest age range and SMA subtypes, with systematic reviews supporting motor function improvements sustained for up to 48 months of treatment.

A critical evolution in clinical understanding has emerged regarding the differential treatment effects across organ systems. While motor function improvements have been consistently documented across all therapies, respiratory and nutritional outcomes show minimal improvement, and progressive spine deformity remains problematic in the majority of patients. Recent studies indicate that 60-93% of treated SMA type 1 patients still develop scoliosis, and many continue to require ventilatory and nutritional support despite motor gains. This has led to recognition that these therapies change the disease phenotype rather than providing complete cures, necessitating multidisciplinary care approaches that address the persistent multisystem manifestations of SMA even in the era of disease-modifying therapy.

Gene Therapy for Older SMA Patients: A New Frontier

The recent positive CHMP opinion for Itvisma (onasemnogene abeparvovec) in older spinal muscular atrophy (SMA) patients marks a significant step forward, extending the promise of gene therapy beyond the infant population. This recommendation, if it leads to full marketing authorization, would introduce the first and only gene replacement therapy for children two years and older, teens, and adults with 5q SMA in the European Union. The registrational Phase III STEER study, alongside growing real-world evidence, indicates that Itvisma can deliver clinically meaningful improvements in motor function for this broader patient group, offering a single-dose alternative to chronically administered treatments.

However, this expansion into an older, more diverse patient population also brings important considerations. Studies suggest that while efficacy is observed, the magnitude or speed of motor function improvement may differ compared to treatment in infants. Furthermore, the safety profile in older and heavier patients warrants careful attention. Evidence indicates a higher incidence, severity, and prolonged duration of adverse events, particularly hepatotoxicity and thrombocytopenia, in these groups. This often necessitates more intensive and extended corticosteroid regimens, highlighting the need for robust monitoring protocols and potentially more tailored management strategies.

From a strategic standpoint, this move significantly broadens Itvisma's market potential, positioning Novartis to compete more directly with existing chronic therapies across a wider age range. Yet, the high acquisition cost of gene therapies remains a critical hurdle. Prior analyses have questioned the cost-effectiveness of onasemnogene abeparvovec in some healthcare systems, and these challenges will likely intensify as the indication expands to a larger, potentially more heterogeneous patient cohort. Demonstrating long-term durability and sustained clinical benefit will be crucial for securing favorable reimbursement and ensuring equitable access. The evolving landscape of SMA treatment, including the potential for sequential or combination therapies, as suggested by studies evaluating nusinersen after onasemnogene abeparvovec, underscores the dynamic nature of patient care and the ongoing need for comprehensive real-world data to guide optimal treatment pathways.