• Eugenio Mercuri, Basil T Darras, Claudia A Chiriboga, John W Day, Craig Campbell, Anne M Connolly, Susan T Iannaccone, Janbernd Kirschner, Nancy L Kuntz, Kayoko Saito, Perry B Shieh, Már Tulinius, Elena S Mazzone, Jacqueline Montes, Kathie M Bishop, Qingqing Yang, Richard Foster, Sarah Gheuens, C Frank Bennett, Wildon Farwell, Eugene Schneider, Darryl C De Vivo, Richard S Finkel, and CHERISH Study Group.
• 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 of Medicine at University of California, Los Angeles, Los Angeles (P.B.S.), and Ionis Pharmaceuticals, Carlsbad (K.M.B., Q.Y., C.F.B., E.S.) - all in California; Children's Hospital-London Health Sciences Centre, London, ON, Canada (C.C.); the Department of Neurology, Washington University School of Medicine, St. Louis (A.M.C.); the Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas (S.T.I.); the Department of Neuropediatrics and Muscle Disorders, Medical Center-University of Freiburg, Faculty of Medicine, Freiburg, Germany (J.K.); the Department of Pediatrics, Ann and Robert H. Lurie Children's Hospital, Chicago (N.L.K.); the Institute of Medical Genetics and Department of Pediatrics, Tokyo Women's Medical University, Tokyo (K.S.); the Department of Pediatrics, Gothenburg University, Queen Silvia Children's Hospital, Gothenburg, Sweden (M.T.); and the Division of Neurology, Department of Pediatrics, Nemours Children's Hospital, Orlando, FL (R.S.F.).
• N. Engl. J. Med. 2018 Feb 15; 378 (7): 625-635.

BackgroundNusinersen 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).MethodsWe 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.ResultsIn 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).ConclusionsAmong 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 .).

17 keywords...

hide…