CHERISH: Nusinersen May Improve Motor Function in SMA

Deborah Brauser

April 27, 2017

BOSTON — Use of the antisense oligonucleotide nusinersen (Spinraza, Biogen/Ionis Pharmaceuticals) appears effective and tolerable for the treatment of children with symptomatic spinal muscular atrophy (SMA), new research suggests.  

The phase 3 CHERISH trial, which included 126 participants with SMA  aged 2 to 12 years, met its primary outcome measure. It showed that those who received 4 doses of intrathecal nusinersen over 9 months had significantly greater improvement in Hammersmith Functional Motor Scale-Expanded (HFMSE) scores compared with those who received a sham procedure.

In addition, the active treatment group had more improvements in upper-limb function and a greater number of new motor milestones achieved. No child stopped treatment because of adverse events (AEs).

As reported by Medscape Medical News, the US Food and Drug Administration approved nusinersen in December 2016, marking the agency's first approval for an SMA drug. And last week, the European Medicines Agency Committee for Medicinal Products for Human Use recommended approval based on the findings from CHERISH and from the positive ENDEAR trial, which assessed infantile-onset SMA.

"Nusinersen had significant and clinically meaningful improvements compared with the sham procedure control-treated children, while demonstrating a favorable safety profile," said Eugenio Mercuri, MD, PhD, associate professor in pediatric neurology at Universita Cattolica del Sacro Cuore in Rome, Italy.

He presented the findings at an Emerging Science session here at the American Academy of Neurology 2017 Annual Meeting (AAN).

Alters Gene Splicing

Nusinersen "alters SMN2 gene splicing to promote the production of full-length SMN protein," write the investigators.

In CHERISH, they enrolled children with confirmed 5q SMA who had symptom onset after age 6 months. All were randomly assigned 2:1 to 4 doses of 12 mg nonscaled intrathecal nusinersen (n = 84) or a matching sham procedure (n = 42) over 9 months during the study's 15-month duration.

In the active treatment and sham procedure groups, 55% vs 50%, respectively, were girls; the mean age at screening was 4 vs 3 years; and the mean age at symptom onset was 10 vs 11 months.

In addition to 15-month evaluation, prespecified interim analysis for the primary endpoint was conducted.

Key secondary outcomes included percentage of children who were HFSME responders, defined as an increase of 3 or more points on the measure between baseline and month 15, and changes in scores on the revised Upper Limb Module (RULM).

Results showed that the group receiving nusinersen had highly significantly greater changes on the HFMSE and RULM than the sham procedure group, with more members becoming HFMSE responders (adjusted odds ratio for the latter outcome, 5.59; 95% confidence interval, 2.09 - 14.91).




Table. Outcomes With Nusinersen vs Placebo  




P Value

Change from baseline on HFMSE




Change on HFMSE at interim analysis




Change in RULM score




HFMSE responders (%)





Although a greater percentage of the active treatment group achieved any new World Health Organization (WHO) motor milestones (19.7% vs 5.9%), this missed statistical significance (P = .08).

However, the number of new WHO milestones achieved per child was significantly higher in those receiving nusinersen (0.2 vs –0.2; P = .0001). In addition, 1.5% were able to walk without assistance at the end of the study compared with none of the children who received the sham procedure.

Interestingly, the control group had more reports of any AE, severe AE, or serious AE than did the active treatment group (100% vs 93%, 55% vs 46%, and 17% vs 29%, respectively).

AEs possibly related to the study drug were reported by 29% of those receiving nusinersen and 10% of those receiving the sham procedure. The most frequently reported AEs were pyrexia (by 43% vs 36%), upper respiratory tract infection (30% vs 45%), headache (29% vs 7%), and vomiting (29% vs 12%).

"The majority of AEs were considered to be related to SMA disease, common events in the general population, or events related to the lumbar puncture procedure," said Dr Mercuri.

He noted that the study population will now be transitioned into the SHINE open-label extension trial.

"A New Era in SMA"

Session co-moderator Edward H. Bertram, MD, University of Virginia Health System in Charlottesville, told Medscape Medical News that the studies looking into treating SMA are "really exciting."

"I think everyone is surprised at how well [nusinersen] works, and it's making those who treat these patients very hopeful," said Dr Bertram. "What we're going to want to see now is: How well does it work over the years? But the initial assessments are very interesting."

His fellow co-moderator, Paul George, MD, assistant professor of neurology and neurologic sciences at Stanford School of Medicine, California, added that he thinks the study data "are the news of the conference," especially because it's making a difference in such a devastating disease.

"This is a new and exciting therapy that is showing great promise," said Dr George.

Vice chair of the AAN Science Committee, Natalia Sana Rost, MD, speaking at a press conference on "the most groundbreaking scientific research advances" presented at the meeting, said she chose to include the CHERISH trial to highlight that "there is significant progress being made in a disease that has previously been considered incurable."

"As a result of the trial, we saw both clinical and statistical improvements in a population that, in many cases, is never able to walk and often never able to sit up or hold their head in an upright posture," said Dr Rost, who is director of the Acute Stroke Service at Massachusetts General Hospital and associate professor of neurology at Harvard Medical School, Boston, Massachusetts.

She noted that she's optimistic that this treatment "will provide at least hope and promise to these patients who otherwise had none."

Dr Rost added that the safety profile was "fairly uneventful" except for some of the procedure-related events.

"We're entering a new era in SMA, and I feel that neuromuscular neurology is making a breakthrough, which was desperately needed."

The study was funded by Ionis Pharmaceuticals and Biogen. Dr Mercuri reported serving on advisory boards for Ionis, Biogen, AveXis, Novartis, and Roche.  Dr Betram and Dr George have disclosed no relevant financial relationships.

American Academy of Neurology 2017 Annual Meeting (AAN). Emerging Science Session, Talk 9. Presented April 25, 2017.

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