Nusinersen versus Sham Control in Later-Onset Spinal Muscular Atrophy

Sibylle Vogt , Marcus Krueger , Astrid Pechmann , Bianca Rippberger , Matthias Eckenweiler , Ulrike Schara (1) , Heike Koelbel , Barbara Andres , Katrin Rupprich , Andrea Gangfuss , Philipp Jachertz , Adela Della Marina , Nina Sponemann , Markia Pane , Concetta Palermo , Marco Piastra , Lavinia Fanelli , Roberto de Sanctis , Orazio Genovese (2) , Laura Antonaci , Maria Carmela Pera , Priscilla Lamendola , Sonia Messina , Gianluca Vita , Vincenzo Di Bella , Maria Sframeli , Matteo La Rosa , Costanza Barcellona , Maria Grazia Distefano , Filippo Cavallaro , Antonio Versaci , Francesco de Luca , Giuseppe Vita , Andres Nacimento Osorio , Eduardo Tizzano (3) , Carlos Ignacio Ortez Gonzalez , Juan Dario Ortigoza Escobar (4) , Juame Colomer Oferil , Julita Medina Cantillo , Anna Febrer Rotger , Meritxell Vigo Morancho , Johanneh Eldblom , Niklas Darin (5) , Anna Karin Kroksmark , Asa Lindstedt , Eva Michael , Eva Kimber , Lisa Wahlgren , Sophelia Hoi-Shan Chan , Stella Chim , Joseph Chiu , Alvin Chi Chung Ho , Jing Kun Janice Ip , Wendy Wai Man Lam , Maggie Chui-San Ng , Connie Wan , Virginia Chun Nei Wong , Yvonne Yue , Reiko Arakawa , Akemi Yamauchi , Satoru Nagata , Yasushi Ito , Hidetsugu Nakatsukasa , Akiko Takeshita , Kyoko Hirasawa , Tetsuo Ikai , Kaoru Eto , Yui Otamni , Yasuhiro Takeshima , Noroki Fukuda , Yasuhiro Tanaka , Hideki Shimomura , Tomoko Lee , Takayuki Shibano , E. Mercuri , Tomohiro Tachikawa , B. T. Darras , Jong-Hee Chae (6) , C. A. Chiriboga , Byung Chan Lim , J. W. Day , Hyung-Ik Shin , C. Campbell , Soo Yeon Kim , A. M. Connolly , Sun Ah Choi , S. T. Iannaccone , Woo Sung Son , J. Kirschner (7) , Hyemi Jo , N. L. Kuntz , Seong Min Chun , K. Saito (8) , Hyuna Kim (9) , P. B. Shieh , M. Tulinius , E. S. Mazzone , J. Montes , K. M. Bishop , Q. Yang (10) , R. Foster , S. Gheuens , C. F. Bennett , W. Farwell , E. Schneider (11) , D. C. de Vivo , R. S. Finkel , Walter G. Bradley , Petra Kaufmann , Patricia I. Dickson , Stephen C. Reingold , Charles S. Davis , Kristen Arredondo , Diana Castro , Margaret Cowie , Alan Farrow-Gillespie , Andrew Hebert , Melissa Kauk , Nancy Miller , Leslie Nelson , Thomas Spain , Joshua Cappell , Andrei Constantinescu (12) , Rosangel Cruz (13) , Jahannaz Dastgir , Darryl de Vivo , Sally Dunaway , Kristin Engelstad , Alexander G. Khandji , Samantha Kramer , Jonathan Marra , Molly Popolizio , Rachel Salazar , Louis H. Weimer , Sonya Aziz-Zaman , Nicole Lamarca , Partha Ghosh , Fouad Al-Ghamdi , Wendy Liew , Robert Graham , Charles Berde (14) , Navil Sethna , Anjali Koka , Luke Wang , Regina Laine , Michelle Souris , Grace Ordonez , Timothy Harrington , Heather Szelag , Amy Pasternak , Elizabeth Mirek , Janet Quigley , Richard Finkel , Debbie Berry , Matthew Civitello , Julie Duke Endsley , Candace Eden , Wendy Leon , Kathleen O'Reardon , Laufey Sigurdardottir , Craig Johnson (15) , Jenna Turner , Melisa Vega , Fabiola Weber-Guzman , Matthias Zinn , Ana Carolina Tesi Rocha , Karolina Watson , Genevieve d'Souza , R. J. Ramamurthi , Richard Gee , Janis Kitsuwa-Lowe , Katharine Hagerman (16, 17) , Sheela Crasta , Lesly Welsh , Shirley Paulose , Danielle Mcfall , Jennifer Perez , Swetapadma Patnaik , Bharati Sanjanwala , Sarada Sakamuri , Crystal Proud , Bona Park Purse , Trinh Tina Duong , Jacinda Sampson , Gihan Tennekoon , John Brandsema , Allan Glanzman , Jean Flickinger , Michele Toms , Laura Adang , Delores Stanford , Oscar Mayer , Joshua Zigmont , Madeline Chadehumbe , Elizabeth Kichula , Erika Finanger , Barry Russman , Colin Roberts , Andrea Frank , Danielle Benjamin , Kirsten Zilke , Paul T. Golumbek , Craig M. Zaidman , Pallavi Anand (18) , Rebecca Gadeken , Catherine Siener , Nancy Kuntz (19) , Leon Epstein , Jena Krueger , Stewart Goldman , Kristin Krosschell , Colleen Blomgren , Hyoung Won Choi , Jonathan Kurz , Julie Parsons , Joanne Janas , Michele Yang , Alison Ballard , Terri Carry , Stephanie Shea , Alan Bielsky , Kaylee Booker , Alicia Camuto , Sierra Lord-Halvorson , Melissa Gibbons , Carl Zimmerman , Victoria Allen , Peter Fuhr (20) , Hannah Johnson , Vi Tran , Gina Vanderveen , Perry Shieh , Eileen Fowler , Nicholas Parziale , Lekha Rao , Christy Skura , Carolyn Kelley , Francy Shu , Maryam Oskoui , David Zielinski , Chantal Poulin , Pablo Mauricio Ingelmo , Sarah Turgeon Desilets , Pamela Dinunzio , Gonzalo Rivera , Myriam Srour (21) , Stephanie Arpin (22) , Sharan Goobie , Paul Gibson , Cheryl Scholtes , Wendy Mcdonald , Eugenio Zapata , Cam-Tu Emilie Nguyen , Laurent Servais (23) , Elena Gargaun (24) , Anne-Gaelle Le Moing (25, 26) , Teresa Gidaro (27) , Raphael Vialle (27) , Marie-Laurence Guye , Charlotte Lilien (24, 28) , Gwenn Olliver , Stephanie Gilabert , Sabine Borell , Sabine Wider , Sabine Stein

1 University of Duisburg-Essen
2 Department of Paediatrics
3 Vall d'Hebron University Hospital [Barcelona]
4 CIBER de Enfermedades Raras (CIBERER)
5 Inserm U393 - Handicaps génétiques de l'enfant
6 Seoul National University Hospital
7 MPI-HALLE - Max-Planck-Institut für Mikrostrukturphysik
8 UTokyo - The University of Tokyo
9 ICOA - Institut de Chimie Organique et Analytique
10 ASIPP - Institute of Plasma Physics, Chinese Academy of Sciences
11 INEM - UM 111 (UMR 8253 / U1151) - Institut Necker Enfants-Malades
12 LMS - Laboratoire de mécanique des solides
13 CureSMA [Elk Grove Village, IL, USA]
14 HMS - Harvard Medical School [Boston]
15 IMAS - Institute for Marine and Antarctic Studies [Hobart]
16 SickKids - The Hospital for sick children [Toronto]
17 University of Toronto
18 OU - The Open University [Milton Keynes]
19 Department of Pediatrics
20 University Hospital Basel [Basel]
21 MUHC - McGill University Health Center [Montreal]
22 Service de génétique [Tours]
23 Service of Clinical Trials and Databases
24 Institut de Myologie
25 CHU Amiens-Picardie
26 GRAMFC - Groupe de Recherche sur l'Analyse Multimodale de la Fonction Cérébrale - UMR INSERM_S 1105
27 CHU Trousseau [APHP]
28 University of Oxford

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.)

Domaines: Sciences du Vivant [q-bio]

Sibylle Vogt, Marcus Krueger, Astrid Pechmann, Bianca Rippberger, Matthias Eckenweiler, et al.. Nusinersen versus Sham Control in Later-Onset Spinal Muscular Atrophy. New England Journal of Medicine, 2018, 378 (7), pp.625-635. ⟨10.1056/NEJMoa1710504⟩. ⟨hal-03604455⟩