BACKGROUND: Nusinersen is a 2'-O-methoxyethyl phosphorothioate-modified 
antisense drug being developed to treat spinal muscular atrophy. Nusinersen is 
specifically designed to alter splicing of SMN2 pre-mRNA and thus increase the 
amount of functional survival motor neuron (SMN) protein that is deficient in 
patients with spinal muscular atrophy.
METHODS: This open-label, phase 2, escalating dose clinical study 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. Eligible participants were of 
either gender aged between 3 weeks and 7 months old with onset of spinal 
muscular atrophy symptoms between 3 weeks and 6 months, who had SMN1 homozygous 
gene deletion or mutation. Safety assessments included adverse events, physical 
and neurological examinations, vital signs, clinical laboratory tests, 
cerebrospinal fluid laboratory tests, and electrocardiographs. Clinical efficacy 
assessments included event free survival, and change from baseline of two 
assessments of motor function: the motor milestones portion of the Hammersmith 
Infant Neurological Exam-Part 2 (HINE-2) and the Children's Hospital of 
Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) motor function 
test, and compound motor action potentials. Autopsy tissue was analysed for 
target engagement, drug concentrations, and pharmacological activity. HINE-2, 
CHOP-INTEND, and compound motor action potential were compared between baseline 
and last visit using the Wilcoxon signed-rank test. Age at death or permanent 
ventilation was compared with natural history using the log-rank test. The study 
is registered at ClinicalTrials.gov, number NCT01839656.
FINDINGS: 20 participants were enrolled between May 3, 2013, and July 9, 2014, 
and assessed through to an interim analysis done on Jan 26, 2016. All 
participants experienced adverse events, with 77 serious adverse events reported 
in 16 participants, all considered by study investigators not related or 
unlikely related to the study drug. In the 12 mg dose group, incremental 
achievements of motor milestones (p<0·0001), improvements in CHOP-INTEND motor 
function scores (p=0·0013), and increased compound muscle action potential 
amplitude of the ulnar nerve (p=0·0103) and peroneal nerve (p<0·0001), compared 
with baseline, were observed. Median age at death or permanent ventilation was 
not reached and the Kaplan-Meier survival curve diverged from a published 
natural history case series (p=0·0014). Analysis of autopsy tissue from patients 
exposed to nusinersen showed drug uptake into motor neurons throughout the 
spinal cord and neurons and other cell types in the brainstem and other brain 
regions, exposure at therapeutic concentrations, and increased SMN2 mRNA exon 7 
inclusion and SMN protein concentrations in the spinal cord.
INTERPRETATION: Administration of multiple intrathecal doses of nusinersen 
showed acceptable safety and tolerability, pharmacology consistent with its 
intended mechanism of action, and encouraging clinical efficacy. Results 
informed the design of an ongoing, sham-controlled, phase 3 clinical study of 
nusinersen in infantile-onset spinal muscular atrophy.
FUNDING: Ionis Pharmaceuticals, Inc and Biogen.