In an open-label phase 1 study and its long-term extension, nusinersen was delivered by intrathecal injection to medically stable patients aged 2 to 14 years with type 2 and type 3 spinal muscular atrophy (04). This study provided Class IV evidence that intrathecal nusinersen is not associated with safety or tolerability concerns in children with spinal muscular atrophy, and phase 2 studies are warranted.
Part 1 of an open study assessed the tolerability and pharmacokinetics of nusinersen in subjects with presymptomatic spinal muscular atrophy who were not eligible to participate in clinical trials (NCT02386553). Part 2 of this study, NURTURE, assessed the long-term safety in those who had completed part 1. The completion date was in 2015, but no updated information is available, and the current status is not known.
A phase 2, randomized, double-blind, sham-procedure controlled study, EMBRACE, is assessing the safety as well as tolerability, and exploring the efficacy, of nusinersen administered intrathecally in subjects with spinal muscular atrophy who are not eligible to participate in other clinical trials (NCT02462759).
An open-label, phase 2, escalating dose clinical study has assessed the safety and tolerability, pharmacokinetics, and clinical efficacy of multiple intrathecal doses of nusinersen (6 mg and 12 mg dose equivalents) in patients with infantile-onset spinal muscular atrophy (07). Results showed that nusinersen was well tolerated, and clinical efficacy was consistent with its intended mechanism of action. This information was used for the design of sham-controlled phase 3 clinical study, CHERISH, in infantile-onset spinal muscular atrophy (NCT02292537). Results after 15 months of treatment starting at 6 months of age showed that 57% of the children in the nusinersen group as compared with 26% in the control group had significant and clinically meaningful improvement in motor function (14).
Phase 3 studies enrolled 173 patients, of which 121 patients participated in a multicenter, randomized, double-blind, sham-controlled investigation. Interim data of the study, submitted to the FDA, formed part of the documents reviewed for the decision to approve nusinersen. Of the 82 patients who had been treated for at least 183 days, 40% of the nusinersen-treated patients achieved a motor milestone response versus none of the sham-treated patients. The study is still ongoing, and the results have not been published.
The primary objective of an ongoing phase 3 study is to evaluate the long-term safety and tolerability of nusinersen administered by intrathecal injection to participants with spinal muscular atrophy who previously participated in investigational studies of nusinersen (NCT02594124). The secondary objective of this nonrandomized study is to examine the long-term efficacy of nusinersen.
The primary end points of ENDEAR, a randomized, double-blind, sham-controlled, phase 3 efficacy and safety trial of nusinersen in infants with spinal muscular atrophy, were a motor-milestone response (defined according to results on the Hammersmith Infant Neurological Examination) and event-free survival, ie, time to death or the use of permanent assisted ventilation (NCT02193074). Interim analysis showed that a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response, and this result prompted early termination of the trial (08). Infants with spinal muscular atrophy who received nusinersen were more likely to be alive and have improvements in motor function than those in the control group. Early treatment may be necessary to maximize the benefit of the drug. A systematic review of randomized controlled trials and cohort studies concluded that nusinersen increased survival without permanent ventilatory support in children with spinal muscular atrophy type 1, whereas improvements in spinal muscular atrophy type 2 and 3 were less evident (02). Better outcomes were seen in young children with a short disease duration, particularly in children receiving nusinersen before symptom onset.
A study titled “Pre-symptomatic study of intravenous onasemnogene abeparvovec-xioi in spinal muscular atrophy (SMA) for patients with multiple copies of SMN2 (SPR1NT)” is ongoing (NCT03505099). This is an open-label, phase 3, single-arm study of a single, one-time dose of onasemnogene abeparvovec-xioi (gene replacement therapy) in patients with spinal muscular atrophy who are genetically defined by biallelic deletion of survival motor neuron 1 gene (SMN1) with 2 or 3 copies of survival motor neuron 2 gene (SMN2). Patients with survival motor neuron 1 point mutations or the survival motor neuron 2 gene modifier mutation (c.859G> C) may enroll but will not be included in the efficacy analysis sets. The study starting in infancy will have a follow-up period up to the age of 2 years.
