Nusinersen treatment of spinal muscular atrophy: current knowledge and existing gaps

Abstract

Spinal muscular atrophy (SMA) is a recessive disorder caused by a mutation in the survival motor neuron 1 gene (SMN1); it affects 1 in 11 000 newborn infants. The most severe and most common form, type 1 SMA, is associated with early mortality in most cases and severe disability in survivors. Nusinersen, an antisense oligonucleotide, promotes production of full-length protein from the pseudogene SMN2. Nusinersen treatment prolongs survival of patients with type 1 SMA and allows motor milestone acquisition. Patients with type 2 SMA also show progress on different motor scales after nusinersen treatment. Nusinersen was recently approved by the European Medicines Agency and the US Food and Drug Administration; it is now reimbursed in several European countries and in the USA. In Australia, the transition from expanded access programme to commercial availability is coming soon. In New Zealand, an expanded access programme is opened, and in Canada price negotiation for the treatment is in progress. In this review we exemplify the clinical benefit of nusinersen in subgroups of patients with SMA. Nusinersen represents the first efficacious marked approved drug in type 1 and type 2 SMA. Different knowledge gaps, such as results in older patients, in patients with permanent ventilation, in patients with neonatal forms, or in patients after spinal fusion, still need to be addressed. WHAT THIS PAPER ADDS: Identifies gaps in knowledge about the efficacy of nusinersen in broader populations of patients with spinal muscular atrophy. Identifies open questions in populations of patients where proof of efficacy is available.

Nusinersen in type 1 spinal muscular atrophy: Twelve‐month real‐world data

“…5 Furthermore, the possibility of administering the drug in a large number of centers in each country increases the difficulties in getting reliable assessments by trained physical therapists and sharing data. Although some have granted access to the drug only in type I infants, with the same criteria used in the ENDEAR clinical trial, others have granted a much wider label including all types of SMA at all ages.…”

“…The recently published preliminary data in an Italian cohort and in other European countries [4][5][6][7][8] showed promising results even in older infants and children. This was, however, mostly limited to the initial response in the first 6 months of treatment.…”

ACTIVE (Ability Captured Through Interactive Video Evaluation) workspace volume video game to quantify meaningful change in spinal muscular atrophy

“…Traditionally, treatment for SMA was supportive; however, with the approval of Nusinersen and other promising therapeutics on the horizon, treatment options are finally becoming available in SMA. There is a need for a valid and reliable functional outcome that assesses a broad spectrum of abilities that is easily implemented across sites for use in post‐marketing surveillance, insurance reauthorization, and current and future clinical trials …”

Video games to measure outcome for children with neuromuscular disorders

“…However, there is still a huge unmet need in SMA – and more generally in the neuromuscular field – for objective, reliable, and sensitive outcome measures. The magnitude of effect of new drugs in previously untreated patients with SMA is such that regardless of scale sensitivity, clear clinical differences between untreated and treated patients can be obvious, as it can be illustrated by patients’ videos . But more sensitivity to change will be required in add‐on therapy trials or when the goal is to demonstrate an effect on an individual basis, for instance to justify to payers the use of expensive innovative therapy in individual patients.…”