Nusinersen versus Sham Control in Later-Onset Spinal Muscular Atrophy
Open accessAbstract
BACKGROUND: Nusinersen is an antisense oligonucleotide drug that modulates pre-messenger RNA splicing of the survival motor neuron 2 ( SMN2) gene. It has been developed for the treatment of spinal muscular atrophy (SMA). METHODS: We conducted a multicenter, double-blind, sham-controlled, phase 3 trial of nusinersen in 126 children with SMA who had symptom onset after 6 months of age. The children were randomly assigned, in a 2:1 ratio, to undergo intrathecal administration of nusinersen at a dose of 12 mg (nusinersen group) or a sham procedure (control group) on days 1, 29, 85, and 274. The primary end point was the least-squares mean change from baseline in the Hammersmith Functional Motor Scale-Expanded (HFMSE) score at 15 months of treatment; HFMSE scores range from 0 to 66, with higher scores indicating better motor function. Secondary end points included the percentage of children with a clinically meaningful increase from baseline in the HFMSE score (≥3 points), an outcome that indicates improvement in at least two motor skills. RESULTS: In the prespecified interim analysis, there was a least-squares mean increase from baseline to month 15 in the HFMSE score in the nusinersen group (by 4.0 points) and a least-squares mean decrease in the control group (by -1.9 points), with a significant between-group difference favoring nusinersen (least-squares mean difference in change, 5.9 points; 95% confidence interval, 3.7 to 8.1; P<0.001). This result prompted early termination of the trial. Results of the final analysis were consistent with results of the interim analysis. In the final analysis, 57% of the children in the nusinersen group as compared with 26% in the control group had an increase from baseline to month 15 in the HFMSE score of at least 3 points (P<0.001), and the overall incidence of adverse events was similar in the nusinersen group and the control group (93% and 100%, respectively). CONCLUSIONS: Among children with later-onset SMA, those who received nusinersen had significant and clinically meaningful improvement in motor function as compared with those in the control group. (Funded by Biogen and Ionis Pharmaceuticals; CHERISH ClinicalTrials.gov number, NCT02292537 .).
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Treating FTD is likely to be most effective when started early, ideally before symptoms appear.
“Experience from Alzheimer’s disease (AD), spinal muscular atrophy (SMA),5 and amyotrophic lateral sclerosis (ALS)6 suggests treating FTD will be most successful if treatment is initiated early in the disease course, ideally prior to the onset of symptoms.”
From Temporal order of clinical and biomarker changes in familial frontotemporal dementia (2022) · cites this paper as [5]
The Discussion reports the greatest motor-function improvements in children with SMA who received nusinersen soon after symptom onset, supporting the early-treatment rationale. It does not establish a benefit from treatment before symptoms appear; applying the SMA finding to FTD is the citing authors’ inference. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAntisense oligonucleotides (ASOs) have proved effective in treating diseases such as spinal muscular atrophy (SMA) in human patients.
“Antisense oligonucleotides (ASOs) have proved effective in treating diseases such as spinal muscular atrophy (SMA) in human patients (49, 50); accordingly, the development of ASOs targeting RECK could be one possible intervention to mitigate pathologies associated with amyloidogenic APP processing (2, 51).”
From GDE2-RECK controls ADAM10 α-secretase–mediated cleavage of amyloid precursor protein (2021) · cites this paper as [50]
Structural studies including those using diffusion tensor imaging (DTI) and functional MRI (fMRI) have accelerated understanding of how altered neural circuits relate to clinical symptoms of ASD.
“structural studies including those using diffusion tensor imaging (DTI) 62 and functional MRI (fMRI) 63 have accelerated our understanding of how altered neural circuits relate to clinical symptoms of ASD 64,65”
From Autism spectrum disorder (2020) · cites this paper as [62]
The Discussion reports motor-function outcomes in children with later-onset spinal muscular atrophy, not neural circuits or ASD. Searches for altered neural circuits and for ASD, DTI, and fMRI found no passage addressing the claim. (LLM, conf=0.79)
Experimental — accuracy not yet measured
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- Authors
- Mercuri, E., Darras, B. T., Chiriboga, C. A., Day, J. W., Campbell, C., Connolly, A. M., Iannaccone, S. T., Kirschner, J., Kuntz, N. L., Saito, K., Shieh, P. B., Tulinius, M., Mazzone, E. S., Montes, J., Bishop, K. M., Yang, Q., Foster, R., Gheuens, S., Bennett, C. F., Farwell, W., Schneider, E., De Vivo, D. C., & Finkel, R. S.
- Affiliations
- Università Cattolica del Sacro Cuore (IT)
- Boston Children's Hospital (US)
- From the Department of Pediatric Neurology, Catholic University, Rome (E.M., E.S.M.); the Department of Neurology, Boston Children’s Hospital, Boston (B.T.D.), and Biogen, Cambridge (R.F., S.G., W.F.) — both in Massachusetts; the Departments of Neurology (C.A.C., J.M., D.C.D.), Pediatrics (C.A.C., D.C.D.), and Rehabilitation and Regenerative Medicine (J.M.), Columbia University Medical Center, New York; the Department of Neurology, Stanford School of Medicine, Stanford (J.W.D.), David Geffen School...
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2018-02-15
- Volume
- 378
- Issue
- 7
- Pages
- 625-635
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2789114047
- Cited by
- 1,433
- References
- 37
- Citations by year
- 2026: 102 · 2025: 137 · 2024: 200 · 2023: 151 · 2022: 175 · 2021: 230 · 2020: 199 · 2019: 155 · 2018: 79 · 2012: 1
- FWCI
- 93.73
- Type
- journal article
- Language
- en
- Open access
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion)
- HAL (submittedVersion)
- Universitätsbibliographie, Universität Duisburg-Essen (submittedVersion)
- Scholarship@Western (Western University) (submittedVersion)
- ORBi (University of Liège) (submittedVersion)
- Funders
- Biogen
- Ionis Pharmaceuticals, Inc.
- Topics
- Health Sciences › Medicine › Genetics › Neurogenetic and Muscular Disorders Research
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- nusinersen, spinal muscular atrophy, antisense oligonucleotides, SMN2 splicing, intrathecal drug delivery, motor function, Hammersmith Functional Motor Scale Expanded, children, early trial termination, adverse events, treatment efficacy and safety
- MeSH terms
- Child, Child, Preschool, Double-Blind Method, Female, Humans, Infant, Injections, Spinal, Male, Motor Skills, Oligonucleotides, Spinal Muscular Atrophies of Childhood, Least-Squares Analysis, Oligonucleotides, Antisense, Age of Onset
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