Overviewing Phase 4 RESPOND Trial of Nusinersen and Zolgensma in SMA: Crystal Proud, MD

“We know gene therapy does not reach every motor neuron, and once those neurons are lost, they cannot be replaced. The goal with additional nusinersen is to protect what remains and improve outcomes over time.”

The treatment landscape for spinal muscular atrophy (SMA) has undergone a major transformation over the past decade, with the introduction of disease-modifying therapies such as nusinersen (Spinraza; Biogen) and onasemnogene abeparvovec (Zolgensma; Novartis) significantly altering disease trajectory. These therapies, which target survival motor neuron (SMN) protein deficiency through distinct mechanisms, have improved survival and motor outcomes, particularly when administered early.¹ However, accumulating clinical experience has shown that many patients continue to exhibit residual weakness, motor delays, or evidence of ongoing neurodegeneration despite treatment.

In response to these unmet needs, the phase 4 RESPOND trial (NCT04488133) evaluated the impact of adding nusinersen following prior gene transfer therapy in young children with SMA who demonstrated suboptimal clinical response. The open-label study included symptomatic patients aged 36 months or younger who had previously received onasemnogene abeparvovec. Interim findings at day 302 showed improvements across multiple domains, including motor function (HINE-2, CHOP-INTEND), electrophysiologic measures such as compound muscle action potential (CMAP), and biomarker outcomes, including reductions in neurofilament light chain (NfL), a marker of active neurodegeneration.

Notably, the study population largely consisted of patients with 2 SMN2 gene copies, a group known to have more severe disease and higher risk of progression. Across the cohort, reductions in NfL levels and increases in CMAP amplitudes suggested both biologic and functional benefit with sequential therapy. These findings support the hypothesis that targeting motor neurons not effectively reached by gene therapy may help optimize long-term outcomes in SMA, particularly in patients with persistent disease activity

Following the publication of these findings, Crystal Proud, MD, chief of neurology and director of Neuromuscular Medicine at Children’s Hospital of The King’s Daughters, spoke with NeurologyLive® about the rationale and results of the RESPOND trial. In the discussion, she outlined the biological basis for combination or sequential therapy, key clinical and biomarker findings, and how these data may influence future treatment strategies in SMA.

REFERENCE
1. Proud CM, Finkel RS, Parsons JA, et al. Open-label phase IV trial evaluating nusinersen after onasemnogene abeparvovec in children with spinal muscular atrophy. Journal of Clin Invest. 2025;135(22). Doi:2025;135(22):e193956