Risdiplam treatment following onasemnogene abeparvovec in individuals with spinal muscular atrophy: a multicenter case series

Abstract

Abstract Background Spinal muscular atrophy (SMA) is caused by deletions or mutations in the survival of motor neuron (SMN) 1 gene resulting in progressive motor function loss, and additional disease-related complications, including dysphagia and respiratory failure. With three US FDA–approved disease-modifying therapies (DMTs) available for SMA, patients, caregivers and healthcare providers have become increasingly interested in using a combination of DMTs to maximize clinical benefit. Current data on combination therapy are limited, and additional studies are needed. Case presentation This multicenter, retrospective case series presents real-world outcomes in children with SMA who received onasemnogene abeparvovec (OA; ZOLGENSMA®), a single-dose gene therapy, and were subsequently treated with risdiplam (EVRYSDI®), a once-daily oral DMT. Adverse events as well as motor, respiratory and swallowing outcomes were evaluated before and after risdiplam initiation. Twenty children were included, ten (50%) of whom were female. The majority had Type 1 SMA (n = 17; 85%) and two SMN2 copies (n = 16; 80%). At baseline, eight (40%) children were clinically diagnosed with severe dysphagia, and ten (50%) required either noninvasive ventilation or invasive ventilation via tracheostomy. The mean time from OA administration to risdiplam initiation was 15.2 months, and the mean age at risdiplam initiation was 24.9 months. The most common reasons (n = 15; 75%) for starting risdiplam were either a plateau or inadequate improvement in disease symptoms. After risdiplam initiation, seven (35%) and six (30%) children had improvements in swallowing and respiratory function, respectively. Of the children whose motor function was assessed with the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders and/or the Hammersmith Functional Motor Scale – Expanded after risdiplam initiation, nearly all (n = 12/13; 92%) showed stability or improvement. No serious adverse events were observed post risdiplam initiation, and one child discontinued risdiplam due to a perceived lack of effectiveness. Conclusions 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. Graphical Abstract

Keywords

• Case series
• Onasemnogene abeparvovec
• Gene therapy
• Risdiplam
• Spinal muscular atrophy