Nusinersen: A Review in 5q Spinal Muscular Atrophy.

Spinal muscular atrophy (SMA) is a rare autosomal recessive neuromuscular disorder most commonly caused by a deletion or mutation in the survival motor neuron 1 (SMN1) gene, which leads to insufficient levels of survival motor neuron (SMN) protein. In such patients, SMN protein production relies on the SMN2 gene. Nusinersen (Spinraza®) is a modified antisense oligonucleotide (ASO) approved in several countries worldwide, including the USA, Japan and those of the EU, for the treatment of 5q SMA. It binds to a specific site in the intron downstream of exon 7 on the SMN2 pre-messenger ribonucleic acid (pre-mRNA), modulating the splicing of SMN2 mRNA and thus increasing the production of SMN protein. In multinational phase III studies, nusinersen (administered intrathecally) provided significant improvements in motor function in patients with infantile- and later-onset 5q SMA compared with a sham procedure. It was also associated with significant improvements in event-free survival and overall survival in patients with infantile-onset 5q SMA, with preliminary data from an ongoing multinational phase II study suggesting a potential clinical benefit with early intervention (i.e. before symptom onset) with nusinersen. Preliminary subgroup data from a phase III extension study suggested continued improvements in motor function with longer-term therapy. Nusinersen demonstrated a favourable safety profile in clinical studies in symptomatic and presymptomatic patients, with no safety concerns due to nusinersen exposure. In conclusion, although studies in presymptomatic patients and over the long term in symptomatic patients are ongoing, current evidence indicates that nusinersen modifies 5q SMA and has a favourable safety profile and, thus, is a valuable treatment for this patient population.