Treatment with Spinraza (nusinersen) was found to reduce the use of ventilation support and to improve motor function in symptomatic infants and children with infantile‐ or later‐onset spinal muscular atrophy (SMA), according to 2.5-year data from the Phase 2 EMBRACE trial.
These infants and children had been ineligible to participate in other Spinraza trials. Yet, the findings are consistent with those reported for the ENDEAR trial (NCT02193074), involving patients with infantile-onset SMA, and the CHERISH trial (NCT02292537) for children with later-onset disease.
Together, these results support Spinraza’s use for all infants and children with SMA, investigators say.
The study, “Safety and efficacy of nusinersen in spinal muscular atrophy: the EMBRACE study,” was published in the journal Muscle & Nerve.
SMA is caused by the deficient production of SMN — a protein essential for motor neuron and muscle health — due to mutations in the SMN1 gene.
It is divided into five main types, from 0 to 4, based on the age of symptom onset and disease severity. Disease severity is mostly influenced by a patient’s copy number of SMN2, a backup gene that can partially compensate for the loss of SMN1-derived SMN.
Patients showing an earlier disease onset and carrying fewer SMN2 gene copies show a more severe disease than those with a later onset and more SMN2 copies.
Biogen’s Spinraza, the first disease-modifying therapy to be approved in the U.S. for children and adults with all types of SMA, works by increasing SMN2’s ability to produce the SMN protein.
The therapy is given via injections into the spinal canal (intrathecal) at a recommended regimen of four 12 mg doses in the first two months, followed by maintenance treatment at the same dose every four months. Intrathecal injections are those administered directly into the cerebrospinal fluid (CSF), the liquid that surrounds the brain and spinal cord.
Spinraza’s approval was based on data from several clinical trials, such as the Phase 3 ENDEAR and CHERISH trials, which showed that the therapy was generally safe and led to significant and clinically meaningful motor function improvements in infants and children with SMA.
ENDEAR included infants, ages 7 months or younger, with SMA type 1 based on symptom onset at 6 months of age or younger (infantile-onset) and two SMN2 gene copies. CHERISH included children ages 2–12 years, predicted to have type 2 or 3 disease based on symptom onset at more than 6 months of age (later-onset).
The international Phase 2 EMBRACE trial (NCT02462759), completed in 2018, was designed to evaluate Spinraza’s safety and exploratory effectiveness in 21 infants and children with infantile- or later-onset SMA who did not meet the age and other criteria of the then-ongoing ENDEAR and CHERISH studies.
The participants were randomly assigned to receive Spinraza injections (nine with infantile-onset and five with later-onset) or, for the control group, a sham procedure (four infantile-onset patients and three with later-onset). The trial continued for about 14 months for Part 1, though it ended earlier than prespecified due to strong positive results from ENDEAR.
All but one patient in the EMBRACE control group completed the first randomized part and entered the second part of the trial. In that part, all participants received the therapy for about 24 months (two years), and then underwent a last assessment four months after the final dose.
The trial’s main goals were to assess Spinraza’s safety and tolerability, with secondary goals to measure Spinraza levels in the blood and CSF. Exploratory effectiveness goals included changes in ventilator use, achievement of motor milestones assessed by the Hammersmith Infant Neurological Examination Section 2, and changes in growth parameters.
Patients initially assigned to Spinraza were treated for a median of 995 days (nearly three years), while those in the control group stayed in Part 1 for a median of 302 days (about 9 months); in Part 2, the patients in the control group were treated with Spinraza for a median of 656 days (over 1.5 years).
The results showed that Spinraza’s safety profile was consistent with that reported in previous studies. There were no new Spinraza-related side effects (adverse events) and no treatment discontinuations due to Spinraza-related adverse events over a mean of 2.4 years.
The most common side effects included fever, cough, pneumonia, and upper respiratory tract infections, “consistent with events typically observed in children with SMA,” the researchers wrote.
In addition, a smaller proportion of patients receiving Spinraza throughout the study (11.3%) required ventilator support, compared with those in the control group in Part 1 (29.8%) and those initiating Spinraza treatment in Part 2 (28.6%).
However, at the study’s start, the group initially assigned to Spinraza also required less ventilator support than those in the control group, the team noted.
Motor milestone responder rates were higher in those initially assigned to Spinraza (93%) at the last available assessment as compared with those receiving the sham procedure in Part 1 (29%) or those switching to Spinraza in Part 2 (83%).
“This functional improvement was observed despite the small sample size and shortened Part 1 trial duration that undermined the power of the study to demonstrate such treatment effects at a significant level,” the researchers wrote.
In agreement with the data on participants with greater disease severity, patients with infantile-onset disease were more likely to require greater ventilator use and less likely to achieve motor milestones than those with later disease onset.
No differences in weight gain and body length were found between the two groups.
These findings highlighted that Spinraza had “a favorable benefit-risk profile in the unique population of symptomatic infants and children who were ineligible for participation in ENDEAR and CHERISH,” the researchers wrote.
The data also support the use of Spinraza among a broad population of infants and children with SMA, the team noted.
Of the 20 participants who completed EMBRACE, all have enrolled in the open-label, Phase 3 SHINE extension study (NCT02594124), in which all participants from earlier Spinraza trials are receiving the therapy for long-term follow-up.
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