European Commission Approves Novartis' Itvisma for Spinal Muscular Atrophy (SMA)

June 30, 2026 - The European Commission (EC) announced the approval of Itvisma® (onasemnogene abeparvovec) for the treatment of Spinal Muscular Atrophy (SMA) specifically originating from mutations of the survival motor neuron 1 (SMN1) gene.¹ The one-time fixed dose treatment option includes children two years and older, teens and adults. The EC's approval follows the U.S. FDA regulations last year in 2025.²

1. Background on Spinal Muscular Atrophy (SMA)

Spinal muscular atrophy (SMA) is a rare, autosomal recessive neuromuscular disease characterized by the loss of motor neurons in the spinal cord.³ It is caused by biallelic mutations or deletions in the SMN1 gene on chromosome 5 (5q13), leading to a deficiency of the survival motor neuron (SMN) protein and cascading to symptoms of progressive muscle weakness.

Although the endogenous existence of SMN2 gene acts as a modifier to produce few functional SMN protein, the result is predominantly truncated, non-functional variants due to an exon 7 skipping event.⁴ Consequently, the severity of SMA correlates inversely with the number of SMN2 copies (ranging from type 0, the most severe prenatal form, to type 4, a mild adult-onset form).⁵

Historically untreatable, SMA has recently become a treatable condition following the advent of three disease-modifying therapies (DMTs) approved in the last decade.

2. Development and Evolution of Onasemnogene Abeparvovec

The development of onasemnogene abeparvovec (Zolgensma for intravenous use; Itvisma for intrathecal use) represented a paradigm shift from small-molecule or oligonucleotide therapies to gene replacement therapy.⁶

Initially developed as an intravenous (IV) of onasemnogene abeparvovec, adeno-associated virus serotype 9 (AAV9) vector-based gene transfer, it was designed to deliver a functional copy of the human SMN1 cDNA to motor neurons. And while both Zolgensma and Itvisma contain this identical active ingredients and genetic payload, the Itvisma intrathecal formulation is an optimized solution for direct spinal delivery.

• Intravenous Formulation (Zolgensma): For SMA patients under 2 years of age, this formulation required weight-based dosing and systemic infusion, limiting its use to younger, lighter patients.⁷
• Intrathecal Formulation (Itvisma): To address the unmet need for older children, adolescents, and adults who are ineligible for IV gene therapy due to body weight or antibody titers, a fixed-dose intrathecal formulation was developed. This formulation allows for direct delivery of the therapeutic vector into the cerebrospinal fluid (CSF) surrounding the spinal cord, targeting motor neurons more efficiently with a lower viral load compared to systemic administration.⁸

3. Mechanism of Action

Onasemnogene abeparvovec is a non-replicating, self-complementary AAV9 vector that carries a functional copy of the human SMN1 gene. Upon intrathecal injection, the vector transduces motor neurons, where the episomal DNA integrates into the nucleus and remains stably expressed. The hybrid cytomegalovirus (CMV) enhancer/chicken-β-actin (CB) promoter drives constitutive and sustained expression of the SMN protein (Figure 1) in post-mitotic cells. This restoration of SMN protein levels promotes the survival, maintenance, and function of motor neurons, halting disease progression and enabling the achievement of motor milestones that would otherwise be unattainable.

4. Clinical Trials: Evidence for Efficacy and Safety

Two pivotal phase 3 studies have established the efficacy and safety profile of intrathecal onasemnogene abeparvovec Itvisma across a broad SMA population.

The STEER Study (NCT05089656)⁹

• Design: A 52-week, phase 3, randomized, sham-controlled, double-blind trial.
• Population: 126 patients with SMA aged 2 to <18 years who were treatment-naïve and able to sit but never walked independently.
• Primary Endpoint: Change from baseline in the Hammersmith Functional Motor Scale-Expanded (HFMSE) score at the end of follow-up.
• Results: The study met its primary endpoint, demonstrating a statistically significant increase in HFMSE scores for patients treated with onasemnogene abeparvovec compared to sham control (least squares mean difference: 1.88 points; P = 0.0074). Benefits were observed as early as week 4 and sustained throughout the follow-up period.

The STRENGTH Study (NCT05386680)¹⁰

• Design: A 52-week, phase 3b, open-label, single-arm trial.
• Population: Patients with SMA aged 2 to <18 years who had previously discontinued nusinersen or risdiplam (treatment-experienced).
• Results: The study demonstrated a safety profile consistent with findings in treatment-naïve patients. While motor function stabilization was observed, the open-label design precluded direct efficacy comparisons against sham control.

5. Safety Profile and Administration of Itvisma

• Administration: Itvisma is administered as a single fixed dose (1.2 x 10¹⁴ vector genomes (vg)) via intrathecal injection under sedation or anesthesia.^5,11 Prophylactic corticosteroids (prednisolone) are administered for 30 days post-injection to dampen the host immune response and mitigate hepatotoxicity.
• Adverse Events (AEs): The most common AEs include upper respiratory tract infections, pyrexia, vomiting, headache, and increased hepatic enzymes. Serious adverse events (SAEs) such as thrombotic microangiopathy (TMA), severe hepatotoxicity, and peripheral sensory neuropathy have been reported but are generally manageable.
• Adverse Events of Special Interest (AESI): These include hepatotoxicity (elevated transaminases), transient thrombocytopenia, cardiac AEs (e.g., elevated troponin I), and signs/symptoms suggestive of dorsal root ganglion (DRG) toxicity. All reported AESIs were mild to moderate in intensity and resolved without sequelae.

6. Market Impact and Competition

The approval of Itvisma marks a significant milestone for the SMA market, particularly in Europe where it became the first gene replacement therapy approved for patients aged 2 years and older. This expands treatment options beyond the narrow age window (<2 years) previously available for Zolgensma (IV formulation). The fixed-dose nature of intrathecal administration simplifies logistics compared to weight-based IV dosing, potentially improving access for larger children and adults who might otherwise be excluded from gene therapy due to cost or dosing limitations.

Competition remains focused on the availability and affordability of the three approved DMTs: nusinersen (antisense oligonucleotide via intrathecal), risdiplam (small molecule via oral), and Zolgensma and Itvisma (gene replacement via intravenous and intrathecal, respectively).¹² While combination therapies (e.g., onasemnogene abeparvovec plus nusinersen) are being explored in real-world settings, robust evidence for their superiority over monotherapy is still emerging.

7. Future Outlook

The successful development of intrathecal onasemnogene abeparvovec underscores the potential of gene therapy to address the genetic root cause of SMA across a broad patient spectrum.¹³ Future research directions include long-term follow-up, prenatal treatment strategies, and investigating combination therapies.

• •  Long-term Follow-up: Extended monitoring is required to assess durability of effects and long-term safety, particularly regarding potential neurotoxicity or off-target effects over decades.
• •  Prenatal Treatment: With improved understanding of the therapeutic window, there is ongoing interest in developing strategies for antenatal treatment to preserve motor neurons before disease onset.
• •  Combination Therapies: Investigating synergistic benefits of combining SMN-restoring therapies with emerging non-SMN-targeting approaches (e.g., myostatin inhibitors) could further improve outcomes for patients who do not respond adequately to single-agent therapy.

Itvisma’s innovative delivery of onasemnogene abeparvovec
represents a transformative treatment that has expanded the reach of gene
therapy for SMA, offering a one-time, fixed-dose solution that provides
sustained motor function improvement and stabilization for patients across the
disease spectrum. The lasting benefits stops disease progression but cannot
reverse existing nerve damage.

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References

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