Table 2
Pivotal studies of nusinersen in patients with SMA
Study Methodology/patients Treatment Primary outcomes
ENDEAR – type 1
infantile onset SMA Phase III, randomised, double blind,
13-month trial of nusinersen vs sham
procedure (< 7 months old at screening,
two copies of SMN2 gene).
121 infantile-onset children, randomised
(2:1) to nusinersen or sham procedure Dosed with nusinersen
(12mg) intrathecally or a
sham injection procedure
on days 1, 15, 29, 64, 183
and 302 Pre-planned interim analysis after
183 days.
Primary outcomes:
1 Hammersmith Infant Neurological
Examination (HINE;) responders
2 Event-free survival
CHERISH – type 2 or 3 Phase III randomised, double-blind,
sham- procedure controlled, 16 months
duration
126 children, randomised (2:1),
nusinersen vs sham procedure
Clinical signs after six months of age.
Inclusion: children 2–12 years of age Nusinersen or sham
administered on days 1,
29, 85 and 274 Change from baseline score of
Hammersmith Functional Motor Scale
Expanded (HFMSE) at 15 months
NUTURE – pre-
symptomatic infants Phase II, open-label study, patients aged
< six weeks at fi rst dose. Patients can
continue for up to 2.5 years Nusinersen administered
(dosage adjusted for age)
on days 1, 15, 29, 64, 183,
302, 421, 540, 659 and
778 Time to death or respiratory
intervention
HINE – Hammersmith Infant Neurological Examination HINE was designed to be a simple scoring method for evaluating infants from two months to two years of age. The tool
assesses the motor milestones typically expected for this age group in normal development on a 0 to 4 scale and includes eight items (for example, ability to walk, stand, craw,
ability to kick, etc). For the ENDEAR trial, a responder was defi ned when there were more HINE categories with improvement than worsening.
HFMSE – Hammersmith Functional Motor Scale Expanded This tool has 33 items that assess motor function that are scored between 0 and 2. It is used to assess the physical
abilities of type 2 and 3 SMA patients. The higher the HFMSE score, the better. A change of at least 3 points on the HFMSE scale is deemed to be clinically meaningful.
Event-free survival This was defi ned as the time to death of permanent ventilation (that is, tracheostomy or ≥ 16 hours per day ventilator support for > 21 days)
those with infantile onset SMA, due to an impaired
cough refl ex and therefore poor clearance of airway
secretions owing to weakness of the inspiratory and
expiratory muscles. Patients thus require ventilator
support, without which many would die before the
age of two years. Gastrointestinal complications
involve diffi culty in swallowing and aspiration
pneumonia. Finally, muscle weakness limits motor
function, leading to contracture formation, spinal
deformity, limited mobility (many children with
SMA are wheelchair bound) and at an increased risk
of osteopenia and fractures. of exon 7 in SMN2-derived transcripts, leading to
full length SMN protein. 8 This work formed the
basis for several clinical studies in patients either
prior to the development of SMA (NUTURE),
those with infantile onset (ENDEAR) and type 2
and 3 (CHERISH). The details of these studies are
shown in Table 2 and a brief description of the
outcome measures used in the trials, given in
the box. The results of the NUTURE trial are not
yet available but may provide important insight
into the role of nusinersen for the prevention
of SMA.
Nusinersen
Nusinersen is an antisense oligonucleotide that
contains 18 nucleotides. The drug binds to the
intron downstream of exon 7 and this attachment
modifi es the splicing of the SMN2 gene to include
exon 7, thereby producing normal length and
functional survival motor neuron protein. 8
The European Medicines Agency (EMA) granted
a marketing authorisation in the EU for the
treatment of patients with SMA in May 2017. 9
Spinraza is available as a single dose use,
intrathecal injection containing 12mg of
nusinersen. According to the Summary of Product
Characteristics, the drug should be administered
as early as possible after diagnosis with four
loading doses on days 0, 14, 28 and 63 with
a maintenance dose once every four months
thereafter. 10 Effi cacy data
ENDEAR
ENDEAR was a multicentre trial involving
13 countries and at the pre-planned interim
analysis, only the primary outcome measure,
the proportion of milestone responders (based
on HINE) was assessed.
At this time point:
• 41% of patients assigned to nusinersen were
Clinical studies
Early in vitro work and transgenic animal models
have shown that nusinersen led to the inclusion
Table 3
Event-free survival in the ENDEAR trial
Outcome Nusinersen Sham control
Death or permanent
ventilation n (%) 31 (39) 28 (68)
Alive without permanent
ventilation n (%) 49 (61) 13 (32)
132
HHE 2018 | hospitalhealthcare.com