Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterized by muscle weakness and loss of motor function.1 SMA occurs in 1 out of every 11,000 live births and approximately 60% of affected infants have type 1 SMA.1 After diagnosis, infants with type 1 SMA rarely achieve new developmental motor milestones, and median life expectancy is less than 2 years without respiratory support.
The cause of SMA is a homozygous deletion or mutation in the survival motor neuron 1 (SMN1) gene, resulting in decreased SMN protein expression in the spinal cord and brain stem. The SMN2 gene also encodes for SMN protein; however, due to aberrant splicing of SMN2, 90% to 95% of the translated protein is rendered nonfunctional. Infants with a higher copy number of SMN2 generally have milder forms of SMA; thus, modification of SMN2 splicing to increase SMN protein synthesis has been explored as a treatment strategy.
Nusinersen is an antisense oligonucleotide drug developed to promote production of SMN protein by modifying SMN2 splicing.1 After the phase 2 trial of nusinersen in infantile-onset SMA demonstrated motor function improvements and prolonged survival, a phase 3 trial (ENDEAR) was conducted to further evaluate the efficacy and safety of nusinersen.
The ENDEAR trial was a 13-month multicenter, randomized, sham-controlled trial of nusinersen in infants with infantile-onset genetic SMA. Eligible patients were 7 months of age or younger and had homozygous deletion or mutation of SMN1, 2 copies of the SMN2 gene, and an onset of symptoms at 6 months of age or earlier.1
Patients were randomized in a 2:1 ratio to receive intrathecal nusinersen or a sham procedure (placebo procedure designed to mimic nusinersen injections).1 An interim analysis showed a benefit-risk assessment in favor of nusinersen. Given the benefits observed with nusinersen and ethical consideration for patients in the control group, the trial was terminated early and patients were enrolled in the open-label extension study SHINE (NCT0294124). An end-of-trial follow-up visit was conducted at least 2 weeks after patients completed their most recent study treatment.
Primary efficacy end points were motor-milestone response, measured by the Hammersmith Infant Neurological Examination (HINE), and event-free survival, defined as time to death or use of permanent assisted ventilation. Motor-milestone response was considered to be achieved if a patient demonstrated improvement in 1 or more HINE category (ie, ≥1 point increase for head control, rolling, sitting, crawling, standing, or walking) and had more HINE categories with improvement than categories with worsening. A subgroup analysis compared the event-free survival rate among patients with disease duration of up to 13.1 weeks and those with disease duration of longer than 13.1 weeks.1
Key secondary end points included Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) response (score increase ≥4 points), survival rate, use of permanent assisted ventilation, and compound muscle action potential (CMAP) response (peroneal CMAP amplitude increase ≥1 mV).1
A total of 122 patients were enrolled and randomized; 1 patient in the nusinersen group was withdrawn prior to receiving treatment, leaving 80 in the nusinersen group and 41 in the control group.1 All patients were included in the final time-to-event analyses (n = 121). Other analyses included only patients enrolled for at least 6 months before the last infant’s last visit (n = 110; 73 in the nusinersen group and 37 in the control group).
Baseline characteristics between groups were similar except that patients in the nusinersen group had earlier onset of symptoms and greater disease burden compared with patients in the control group. All patients had symptoms consistent with a classification of SMA type 1.1
Primary End Points
The interim analysis showed that patients in the nusinersen group had a significantly higher rate of motor-milestone response compared with the control group (41% vs 0%, respectively; P <.001), which prompted early termination of the trial. The final analysis showed that among patients in the nusinersen group, 51% had a motor-milestone response, compared with no patients in the control group. The most common motor milestone reached was achievement of full head control (22%), followed by ability to roll over (10%), ability to sit independently (8%), and ability to stand (1%).
With regard to event-free survival, patients in the nusinersen group had a 47% lower risk of death or use of permanent assisted ventilation compared with the control group (hazard ratio [HR], 0.53; 95% CI, 0.32-0.89; P = .005).1 In the subgroup analysis, patients with shorter duration of disease (≤13.1 weeks) had a greater likelihood of event-free survival than those with longer duration of disease (>13.1 weeks).
Secondary End Points
A significantly greater proportion of patients in the nusinersen group achieved a CHOP INTEND response (score increase ≥4 points from baseline) compared with control (71% vs 3%; P <.001). Patients in the nusinersen group also had a 63% lower risk of death compared with the control group (HR, 0.37; 95% CI, 0.18-0.77; P = .004).
The overall rate of permanent assisted ventilation use was lower in the nusinersen group, but the between-group difference was not significant (HR, 0.66; P = .13). However, patients who died were not included in the analysis. As the proportion of patient deaths in the control group was more than 2 times the proportion in the nusinersen group, the true treatment effect of nusinersen on use of permanent assisted ventilation may have been masked.
A greater proportion of patients in the nusinersen group achieved CMAP response (peroneal CMAP amplitude increase ≥1 mV) compared with control (36% vs 5%; P value not reported).[p1727,col1,para4,ln9-15]
Adverse events (AEs) occurred at a similar rate in both groups. Most of the reported AEs were consistent with those seen in infants with SMA and similar to those reported in a previous study of nusinersen. No serious safety concerns regarding intrathecal injections were flagged; however, AEs associated with post-lumbar puncture syndrome are less common in children than adults.
The authors concluded that nusinersen was effective at improving motor function in infants with SMA, as demonstrated by the achievement of motor-function response and increases in CHOP INTEND score and CMAP amplitude.1 Furthermore, nusinersen significantly increased the likelihood of event-free (P = .005) and overall survival (P = .004), which is notable given that there were more patients on ventilator support in the nusinersen group than the control group at baseline.1 The results of the subgroup analysis based upon duration of disease (≤13.1 weeks vs >13.1 weeks) suggest that early initiation of nusinersen may maximize its efficacy.1 The long-term effects of nusinersen are being evaluated in an extension study (SHINE).1
1. Finkel RS, Mercuri E, Darras BT, et al; ENDEAR Study Group. Nusinersen versus sham control in infantile-onset spinal muscular atrophy. N Engl J Med. 2017;377(18):1723-1732. doi: 10.1056/NEJMoa1702752.