Final Phase 3 Data Confirms Spinraza of Benefit to Children with Later-Onset SMA

Treatment with Spinraza (nusinersen) induced significant and clinically relevant motor function improvement in children with later-onset spinal muscular atrophy (SMA), final results of a Phase 3 trial show.

The study detailing these results, “Nusinersen versus Sham Control in Later-Onset Spinal Muscular Atrophy,” appeared in The New England Journal of Medicine and was based on data from the Phase 3 CHERISH trial that concluded in February 2017.

Spinraza is a disease-modifying SMA treatment, marketed by Biogen. It became the first SMA therapy approved by the U.S. Food and Drug Administration (FDA) in December 2016, and for all disease types, after showing improvements in motor function and survival. Spinraza has since been approved for use in the E.U., Canada, and Korea.

SMA is caused by mutations in the SMN1 gene, leading to poor or no production of the SMN1 protein that is essential to motor neurons. The SMN2 gene also encodes for SMN protein, but at only 5 to 10% of the levels generated by a fully-functional SMN1. Spinraza binds to a specific sequence in the RNA of SMN2 to increase the expression of a full-length SMN protein.

SMA’s three types are classified based on age at symptom onset and motor milestones achieved. Type 1, the most severe and common type, starts between birth and 6 months of age and is characterized by serious muscle weakness, from an inability to raise heads to breath, cough or swallow well; type 2 has its onset between six and 18–24 months of age, and children are unable to walk independently; and type 3 develops after age 18 months and children are able to walk unassisted at some point.

CHERISH (NCT02292537) was a multicenter, double-blind trial that evaluated Spinraza’s efficacy and safety in children with later-onset SMA, defined as having symptom onset after six months of age and likely corresponding to types 2 and 3.

The study enrolled 126 children, ages 2-12 years, all unable to walk independently. They were randomly assigned to intrathecal (spinal canal) administration of Spinraza (12 mg) or a sham procedure (control) on days 1, 29, 85, and 274.

Investigators primarily analyzed changes in the Hammersmith Functional Motor Scale–Expanded (HFMSE) score at 15 months of treatment. Higher HFMSE scores indicate better motor function. A clinically relevant increase in the HFMSE score (equal to or higher than three points) is associated with improvement in at least two motor skills.

Preliminary results showed that Spinraza increased the HFMSE score by a mean of four points, and was statistically significant compared to the control group, which declined by a mean of 1.9 points. This positive data prompted CHERISH to close early and all patients were moved to an open-label extension trial, where all received treatment.

This final analysis confirmed those interim results. An increased score of at least three points was observed in 57% of children treated with Spinraza and in 26% of those in the control group.

Younger children and those treated within 25 months of disease onset showed the greatest improvements, which is in line with results of the ENDEAR Phase 3 trial  (NCT02193074) in children with infantile-onset SMA, most likely type 1, the researchers observed.

Spinraza and control groups showed a similar incidence of adverse events. Of note, the strict exclusion criteria in CHERISH lead to a more homogenous and younger study population than the one found in clinical practice, the investigators noted.

“Among children with later-onset SMA, those who received nusinersen [Spinraza] had significant and clinically meaningful improvement in motor function as compared with those in the control group,” the researchers wrote.

Importantly, “persons with later-onset SMA and their caregivers indicated that stabilization of their current state would meet their therapeutic expectations and represent a clinically meaningful response,” they added.