Continued benefit of nusinersen initiated in the presymptomatic stage of spinal muscular atrophy: 5‐year update of theNURTUREstudy

Abstract

Introduction/Aims NURTURE (NCT02386553) is an open‐label study of nusinersen in children (two SMN2 copies, n = 15; three SMN2 copies, n = 10) who initiated treatment in the presymptomatic stage of spinal muscular atrophy (SMA). A prior analysis after ~3 y showed benefits on survival, respiratory outcomes, motor milestone achievement, and a favorable safety profile. An additional 2 y of follow‐up (data cut: February 15, 2021) are reported. Methods The primary endpoint is time to death or respiratory intervention (≥6 h/day continuously for ≥7 days or tracheostomy). Secondary outcomes include overall survival, motor function, and safety. Results Median age of children was 4.9 (3.8–5.5) y at last visit. No children have discontinued the study or treatment. All were alive. No additional children utilized respiratory intervention (defined per primary endpoint) since the prior data cut. Children with three SMN2 copies achieved all World Health Organization (WHO) motor milestones, with all but one milestone in one child within normal developmental timeframes. All 15 children with two SMN2 copies achieved sitting without support, 14/15 walking with assistance, and 13/15 walking alone. Mean Hammersmith Functional Motor Scale Expanded total scores showed continued improvement. Subgroups with two SMN2 copies, minimum baseline compound muscle action potential amplitude ≥2 mV, and no baseline areflexia had better motor and nonmotor outcomes versus all children with two SMN2 copies. Discussion These results demonstrate the value of early treatment, durability of treatment effect, and favorable safety profile after ~5 y of nusinersen treatment. Inclusion/exclusion criteria and baseline characteristics should be considered when interpreting presymptomatic SMA trial data.

Molecular mechanisms and therapeutic strategies for neuromuscular diseases

“…Safety and efficacy findings were confirmed in larger cohort of patients and in real-world data [ 5 ]. Given the rapid deterioration of motor neuron, [ 1 ] it is not surprising that, in line with what observed with other compounds [ 6 ], the magnitude of the effect is greater when patients are treated in a pre-symptomatic stage [ 7 , 8 ]. The main side effects of gene therapy are related to the immune reaction against the capsid.…”

Consensus from the Brazilian Academy of Neurology for the diagnosis, genetic counseling, and use of disease-modifying therapies in 5q spinal muscular atrophy

“…A recent paper showed the continued benefit of the nusinersen in pre-symptomatic patients followed for five years of treatment (NURTURE study). 70 All patients were alive, and none discontinued the treatment or utilized respiratory intervention. Children with three SMN2 copies achieved all WHO motor milestones, and all children with two SMN2 copies achieved sitting without support, 4/15 walking with assistance, and 13/15 walking alone.…”

Gene-based therapies for neuromuscular disorders

“…Children with three SMN2 copies achieved all WHO motor milestones, and all children with two SMN2 copies achieved sitting without support, 4/15 walking with assistance, and 13/15 walking alone. 40 Risdiplam (Evrysdi®) is a small oral molecule designed to selectively modify the splicing of SMN2 pre-mRNA and promote the inclusion of exon 7 to increase levels of functional SMN protein from a complete mRNA transcript. 41 Registration approval in Brazil occurred in October 2020.…”

“…Children with three SMN2 copies achieved all WHO motor milestones, and all children with two SMN2 copies achieved sitting without support, 4/15 walking with assistance, and 13/15 walking alone. 40 …”