BY JAMIE TALAN
KANSAS CITY, MO—Data from several ongoing clinical trials, presented here last week at the Child Neurology Society annual meeting, show that nusinersen (Spinraza) is safe and effective for spinal muscular atrophy (SMA). The treatment, which was approved by the US Food and Drug Administration last December, is significantly changing the disease trajectory for infants identified before any clinical symptoms emerge and treated with the anti-oligonucleotide, investigators reported.
“It is clear that the sooner you treat these children, the better the outcome,” said Darryl C. De Vivo, MD, FAAN, the Sidney Carter professor of neurology, professor of pediatrics, and director of the pediatric neuromuscular disease center at Columbia University Medical Center, who reported on the interim results from the NURTURE study of pre-symptomatic infants with genetically-identified SMA treated preventively with nusinersen.
SMA is caused by homozygous deletions/mutations in the survival motor neuron 1 (SMN1) gene. Humans have a backup copy, the SMN2 gene, but in the absence of the normal SMN1 gene the babies are dependent on the SMN2 gene. The two genes differ in one critical place: a single nucleotide substitution that alters splicing and usually excludes exon 7 in the mRNA. The result: There isn't enough normal SMN protein produced by the SMN2 gene.
The NURTURE study recruited 20 newborns identified through screening and family history and then tested to confirm an SMN disease-causing mutation. Treatment began before they were 6 weeks old. Children received the same regimen as those with symptomatic SMA. Four doses were delivered into the cerebrospinal fluid within a two-month period and then once every four months.
To date, nine of these children have had at least a year of treatment and follow-up. Many are now toddlers, and the phase 2 open label, single-arm study continues. The primary endpoint is time to death or respiratory intervention, but the investigators are also closely following the children's developmental trajectories.
Dr. De Vivo said that there have been no deaths and no respiratory complications. All of the children are achieving milestones that would not have been expected by the natural history of the disease: Of the nine children, seven were rolling, six were sitting, and five were crawling. Two were walking without assistance. Three of the children reached all normal developmental milestones.
The infants treated earliest in life seem to be developing milestones more normally, said Dr. De Vivo.
For the CHERISH study, Nancy L. Kuntz, MD, professor of pediatrics and neurology at Northwestern Medicine, and her colleagues reported on the efficacy and safety of nusinersen in 126 children who developed symptoms after 6 months old. The children, who were enrolled in the study when they were between 2 years old and 12 years old, were randomized to receive the active drug or a sham dose. The primary endpoint was a change from baseline to 15 months on the Hammersmith Function Motor Scale-Expanded. Secondary endpoints included improvements on other motor scales.
The investigators said that the motor function score on the Hammersmith was 5.9 points higher in the treated children than the sham-treated controls. The scores increased three or more points in 57.3 percent of the nusinersen-treated children compared to 20.5 percent of the sham-treated children. The secondary measures were also improved in the treated children.
"Nusinersen is the first truly effective drug for our profoundly weak SMA patients," said Kathryn J. Swoboda, MD, director of the neurogenetics unit in the Center for Human Genetics Research at Massachusetts General Hospital, who was not involved with the studies. "Even five years ago, none of us would have predicted that these children would have such a positive response."
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Finkel RS, Chiriboga CA, Vajsar J, et al. Treatment of infantile-onset spinal muscular atrophy with nusinersen: A phase 2, open-label, dose-escalation study. Lancet 2016;388(10063):3017-3026.