HHE Neurology supplement 2018 - Page 24

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) 24 HHE 2018 | hospitalhealthcare.com