Switching to Gene Therapy After Nusinersen or Risdiplam May Benefit Patients With SMA

Children with spinal muscular atrophy (SMA) who were treated with onasemnogene abeparvovec (Zolgensma; Novartis) following initial treatment with nusinersen (Spinraza; Biogen) or risdiplam (Evyrsdi; Genentech) experienced clinically meaningful motor function improvement in a real-world study published in Neuromuscular Disorders.1

The retrospective, single-center study also showed a manageable safety profile, suggesting that treatment with onasemnogene abeparvovec gene therapy in this patient population may yield benefits. However, motor function assessment scale improvements were modest compared with those seen with first-line treatment with onasemnogene abeparvovec for SMA.

Although the findings suggest that switching to onasemnogene abeparvovec after non–gene therapy treatments could be beneficial to patients with spinal muscular atrophy, it is not clear which patients may benefit the most from switching therapies. | Image credit: Rochu_2008 - stock.adobe.com

“Notably, our cohort included older and heavier children than those enrolled in most pivotal trials, aligning more closely with real-world registries such as d-A-CH and RESTORE, which included children up to 6 years of age and weighing more than 15 kg,” the authors wrote. “These findings reflect an evolving treatment landscape for spinal muscular atrophy (SMA), wherein [onasemnogene abeparvovec] therapy is increasingly initiated later due to limitations in treatment availability or delays in funding.”

In recent years, the SMA treatment landscape has shifted substantially with the introduction of disease-modifying therapies such as nusinersen and risdiplam. Both therapies modulate SMN2 pre-messenger RNA splicing to increase production of survival motor neuron (SMN) protein, which is lacking in patients with SMA due to a mutated or missing SMN1 gene. Onasemnogene abeparvovec works by delivering a functional copy of the SMN1 gene via a one-time intravenous injection. It has been approved for use in children younger than 2 years since 2019, but recent phase 3 data have shown encouraging efficacy and safety in children aged 2 to 17 years with SMA.2

Combination strategies have also emerged. These include bridging therapy with nusinersen or risdiplam for a short period followed by gene therapy, or switching to gene therapy following long-term treatment with nusinersen or risdiplam.1

“Notably, earlier intervention (younger age, lower weight) correlates with greater improvements in the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) and the Hammersmith Functional Motor Scale Expanded (HFMSE), while patients treated at older ages have more modest gains or stabilization,” the study authors wrote.

The new analysis evaluated motor and safety outcomes in children with SMA who switched to gene therapy following nusinersen or risdiplam. It included 40 children with SMA who were treated at the University Children’s Hospital at the Medical University of Lublin in Poland. The median patient age was 18 months (range, 5-107 months), and 60% of patients were female. A total of 38 patients had received nusinersen prior to gene therapy, whereas 2 received risdiplam prior to gene therapy infusion. Motor function was assessed with either the CHOP-INTEND (n = 19) or HFMSE (n = 21) at baseline, 1 month, and 6 months.

Median CHOP-INTEND scores increased from 27 at baseline to 37 at 6 months, and median HFMSE scores increased from 30 to 36 (P < .0001). At 1 month and 6 months, 67.5% ( n = 27) and 95% (n = 38) of patients showed clinically meaningful improvement.

More children with type 2 and 3 SMA (16 out of 21; 76.2 %) showed a clinical response 1 month after gene therapy administration compared with children with type 1 SMA (9 out of 17; 52.9 %), which is a more severe form. However, this difference did not reach clinical significant (P = .234).

Safety was manageable, although all patients experienced transient fever, vomiting,and weakness on the third or fourth day after infusion. All patients also experienced liver enzyme elevation and received corticosteroid therapy for at least 4 weeks. Thrombocytopenia occurred in 32.5% of patients, and there were no cases of thrombotic microangiopathy or multi-organ failure.

Although the findings suggest that switching to gene therapy after initial treatment with non–gene therapy treatments could be beneficial, the authors also noted that it is difficult to determine which patients might benefit the most from switching therapies.

“Earlier reported key predictors of therapeutic response included age at the time of gene therapy, disease severity (eg, SMA type), and possibly SMN2 copy number,” they explained. “Although prior treatment does not appear to reduce the efficacy of [onasemnogene abeparvovec], a longer duration of earlier therapies often coincides with greater patient age and more advanced motor neuron loss, potentially limiting the extent of functional improvement.”

The authors concluded that there were consistent improvements in motor function in patients who switched to gene therapy, although the patient population was heterogenous in terms of age and weight at infusion, as well as other factors that could potentially affect the impact of gene therapy.

References

1. Chrościńska-Krawczyk M, Kozioł I, Zienkiewicz E. Real-world experience with switch to onasemnogene abeparvovec after initial therapy with nusinersen or risdiplam. Neuromuscul Disord. Published online August 5, 2025. doi:10.1016/j.nmd.2025.105454

2. Mattina C. STEER data open door to SMA gene therapy for wider age range of children. AJMC®. March 19, 2025. Accessed August 14, 2025. https://www.ajmc.com/view/steer-data-open-door-to-sma-gene-therapy-for-wider-age-range-of-children