approved for the treatment of SMA in pediatric and
adult patients by the FDA on December 23, 2016.
Symptomatic infants diagnosed with SMA (with clinical features consistent with type 1 SMA) were randomized (2: 1) to receive intrathecal nusinersen (12-mg
scaled equivalent dose) or sham procedure. For both
groups, four doses were given over two months, on
days 1, 15, 29, and 64. This was followed by a maintenance phase, with dosing every four months.
Key eligibility criteria included 5q SMN1 homozygous gene deletion or mutation, two SMN2 gene copies,
onset of SMA symptoms at younger than 6 months, and
no hypoxemia at baseline screening at age 7 months or
younger. A total of 122 infants were enrolled.
Primary end points included proportion of modified
section 2 Hammersmith Infant Neurological Examination (HINE) motor milestone responders (ie, more categories improving [≥ 2-point increase or maximal score
in kicking ability, or ≥ 1-point increase in head control,
rolling, sitting, crawling, standing, or walking] than
worsening) and event-free survival (time to death or
permanent ventilation). Secondary end points included
percentage of Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND)
responders (≥ 4-point increase), overall survival, and
percentage of peroneal nerve compound muscle action
potential (CMAP) responders (amplitude ≥ 1 mV).
The preplanned interim efficacy analysis was triggered
when two-thirds of the infants reached day 183 involvement in the study. Because the primary end point—motor
milestone response—was positive, the study was ended,
and all of the infants were transferred into the open-label
extension study, which is called SHINE. Event-free survival and all of the secondary end points were not assessed
at the ENDEAR interim analysis. With further analysis now
complete, Dr. Kuntz presented the end-of-study data set.
ENDEAR Final Results
At the end of the study, there was a significantly great-
er proportion of nusinersen-treated motor milestone
responders versus sham-
control responders (51% vs
0%), demonstrating con-
tinued improvement over
the previous interim anal-
ysis (41% vs 0%). In the
22% of infants developed
full head control, 10% of
the infants developed the
ability to independently
roll from supine to prone
positions, 8% developed independent sitting, with half
of those being able to sit and pivot, and one infant was
able to stand with minimal to moderate support.
Looking at change over time, the improvement in
HINE motor milestone scores seen in ENDEAR match-es the trajectory seen in a previous open-label trial.
Patients in the previous trial have now been followed
for another year or so, and they slowly continue to attain their motor milestones. Additionally, infants with
presymptomatic SMA who were identified and treated
within the first six weeks of life showed improvements
in the rate and the range of their motor skills that were
much greater than those in the other groups, suggesting that early treatment makes a difference.
Additional analyses included event-free survival,
overall survival, CHOP INTEND score, peroneal nerve
CMAP response, and need for mechanical ventilation. A
significant nusinersen treatment benefit was seen with
regard to event-free survival (hazard ratio = 0.530) and
overall survival (hazard ratio = 0.372). Dr. Kuntz reported that 61% of the nusinersen-treated infants were alive
at the end of the study, compared with 32% of controls.
For nusinersen versus sham-control infants, 71% versus 3% were CHOP INTEND responders, and 36%
versus 5% were CMAP responders. The risk of
permanent ventilation was 34% lower in the
Nusinersen Provides Clinically
Significant Gains to Patients
With Spinal Muscular Atrophy
The drug costs approximately
$120,000 per dose, which raises
concerns about insurance
approval and reimbursement, as
well as questions about delays to
Nancy L. Kuntz, MD