Mechanistic Effectiveness of Combined Approach With Nusinersen and Zolgensma: Crystal Proud, MD

WATCH TIME: 4 minutes

"We know that Zolgensma is delivering a functional copy of the SMN1 gene. Nusinersen is not looking to replicate that, it’s looking to build on that by leading to more SMN functional protein being produced by the SMN2 gene."

RESPOND (NCT04488133) is a phase 4, multicenter, single-arm, open-label study assessing nusinersen (Spinraza; Biogen) in individuals with spinal muscular atrophy (SMA) who have previously received onasemnogene abeparvovec (Zolgensma; Novartis) and have suboptimal clinical status as determined by an investigator. Nusinersen, an antisense oligonucleotide designed as an SMN2 mRNA splicing modifier, was the first approved therapy for SMA in 2016, while Zolgensma, a gene replacement therapy, was marketed years later in 2019. Once considered a devastating disease, the introduction of these 2 therapies has significantly improved outcomes and quality of life for this patient population.

The study featured 60 individuals with SMA who have at least 1 SMN2 copy and were less than 36 months after first nusinersen dose. Recently, investigators presented interim data from the study at the 2023 Cure SMA Clinical & Scientific Conference, with 29 children comprising the interim set and 38 who made up the safety set. At day 183 of treatment, most participants with investigator-reported suboptimal motor function showed improvements. This included 12 of 13 individuals with 2 SMN2 copies who received their first nusinersen dose less than 9 months after birth. Of note, all 3 individuals with 3 SMN2 copies showed improvements in motor function.

After 183 days, the majority of participants with suboptimal swallowing/feeding ability or respiratory function at baseline had no changes, with some showing improvements. Among the 15 individuals with data, 6 improved their swallowing or feeding ability and 9 remained stable. Following the release of these findings, lead investigator Crystal Proud, MD, a neuromuscular expert, sat down to discuss the clinical significance, and the most notable take-home points from the analysis. Proud, director of neurology and neuromuscular medicine at the Children’s Hospital of the King’s Daughters in Norfolk, Virginia, provided perspective on the reasons behind why a combination of these 2 therapies may further improve clinical outcomes for patients with SMA.

REFERENCE
1. Proud C, Parsons JA, Kuntz NL, et al. Interim results from the ongoing RESPOND study evaluating nusinersen in children with spinal muscular atrophy previously treated with onasemnogene abeparvovec. Presented at: 2023 Cure SMA Research & Clinical Care; June 28-30; Orlando, FL.