Nusinersen versus Sham Control in Infantile-Onset Spinal Muscular Atrophy

BackgroundSpinal muscular atrophy is an autosomal recessive neuromuscular disorder that is caused by an insufficient level of survival motor neuron (SMN) protein. Nusinersenis an antisense oligonucleotide drug that modifies pre– messenger RNAsplicing of the SMN2 gene and thus promotes increased production of full-length SMN protein. MethodsWe conducted a randomized, double-blind, sham-controlled, phase 3 efficacy and safety trial of nusinersenin infants with spinal muscular atrophy. The primary end points were a motor-milestone response (defined according to results on the Hammersmith Infant Neurological Examination) and event-free survival (time to death or the use of permanent assisted ventilation). Secondary end points included overall survival and subgroup analyses of event-free survival according to disease duration at screening. Only the first primary end point was tested in a prespecified interim analysis. To control the overall type I error rate at 0.05, a hierarchical testing strategywas used ...