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Background: Nusinersen showed a favourable benefit-risk profile in participants with infantile-onset spinal muscular atrophy at the interim analysis of a phase 2 clinical study. We present the study's final analysis, assessing the efficacy and safety of nusinersen over 3 years., Methods: This phase 2, open-label, multicentre, dose-escalation study was done in three university hospital sites in the USA and one in Canada. Infants aged between 3 weeks and 6 months with two or three SMN2 gene copies and infantile-onset spinal muscular atrophy were eligible for inclusion. Eligible participants received multiple intrathecal loading doses of 6 mg equivalent nusinersen (cohort 1) or 12 mg dose equivalent (cohort 2), followed by maintenance doses of 12 mg equivalent nusinersen. The protocol amendment on Jan 25, 2016, changed the primary efficacy endpoint from safety and tolerability to reaching motor milestones, assessed using the Hammersmith Infant Neurological Examination section 2 (HINE-2) at the last study visit, in all participants who successfully completed the loading dose period and day 92 assessment. The statistical analysis plan was amended on Feb 10, 2016, to include additional analyses of the subgroup of participants with two SMN2 copies. Adverse events were assessed in all participants who received at least one dose of study treatment. The study is registered at ClinicalTrials.gov (NCT01839656)., Findings: Between May 3, 2013, and July 9, 2014, 20 symptomatic participants with infantile-onset spinal muscular atrophy (12 boys and 8 girls; median age at diagnosis 78 days [range 0-154]) were enrolled. Median time on study was 36·2 months (IQR 20·6-41·3). The primary endpoint of an incremental improvement in HINE-2 developmental motor milestones was reached by 12 (63%) of 19 evaluable participants. In the 13 participants with two SMN2 copies treated with 12 mg nusinersen, the HINE-2 motor milestone total score increased steadily from a baseline mean of 1·46 (SD 0·52) to 11·86 (6·18) at day 1135, representing a clinically significant change of 10·43 (6·05). At study closure (Aug 21, 2017), 15 (75%) of 20 participants were alive. 101 serious adverse events were reported in 16 (80%) of 20 participants; all five deaths (one in cohort 1 and four in cohort 2) were likely to be related to spinal muscular atrophy disease progression., Interpretation: Our findings are consistent with other trials of nusinersen and show improved survival and attainment of motor milestones over 3 years in patients with infantile-onset spinal muscular atrophy, with a favourable safety profile., Funding: Biogen and Ionis Pharmaceuticals., Competing Interests: Declaration of interests RSF reports grants and advisor fees from Biogen and Ionis Pharmaceuticals during CS3A, ENDEAR and CHERISH; grants from AveXis, Cytokinetics, Roche, and Scholar Rock; and royalty payments from Children's Hospital of Philadelphia for licensing fees obtained for use of the CHOP INTEND motor function scale. RSF is also advisor to AveXis, Novartis, and Genentech–Roche, on the data safety monitoring board for the AveXis AVXS-101 phase 1 gene transfer study and Roche Moonfish phase 1b study, and is an advisor for non-profit organisations: CureSMA, EveryLife Foundation, n-Lorem Foundation, SMA Europe, SMA Foundation, and SMA Reach. CAC reports grants from AveXis, Biogen, Ionis Pharmaceuticals, Roche, and National Institutes of Health and is on advisory boards of spinal muscular atrophy studies for AveXis, Biogen, Cytokinetics, Genentech, Ionis Pharmaceuticals, and Roche. JV reports grants and advisor fees from Biogen and Ionis Pharmaceuticals during CS3A and ENDEAR, and a grant from CSL Behring. JWD reports grants from AMO Pharma, Audentes, Biogen, Ionis Pharmaceuticals, Novartis Gene Therapies, Pfizer, Roche–Genentech, Sanofi–Genzyme, Sarepta, and Scholar Rock, and is a consultant for Affinia, AMO Pharma, Avidity, Biogen, Ionis Pharmaceuticals, Kate Therapeutics, Novartis Gene Therapies, Pfizer, Roche–Genentech, Sarepta, Scholar Rock, and Shift Pharmaceuticals; and has patents licensed to Athena Diagnostics for genetic testing of myotonic dystrophy type 2 (US patent 7442782) and spinocerebellar ataxia type 5 (US patent 7527931). JM reports research support from Eunice Kennedy Shriver National Institute for Child Health and Human Development (1K01HD084690-01A1) and Muscular Dystrophy Association (575870 and 629259), is on advisory boards for Biogen, Cytokinetics, Roche, Scholar Rock, and SMA Foundation, and is a consultant for Biogen and Ionis Pharmaceuticals. DCD reports clinical trial funding from Biogen, Mallinckrodt, PTC, Sarepta, Scholar Rock, and Ultragenyx and grants from Hope for Children Research Foundation, National Institutes of Health, SMA Foundation, and US Department of Defense. DCD is also an advisor for AveXis, Biogen, Cytokinetics, Ionis Pharmaceuticals, Metafora, Roche, Sanofi, Sarepta, and SMA Foundation. KMB was an employee of Ionis Pharmaceuticals during the design and conduct of this study and is currently an employee of Locana. KMB is an advisor to Myotonic Dystrophy Foundation and SMA Foundation and has issued patents (US patents 9926559 and 8980853) concerning nusinersen. RF, YL, and JW are employees of and hold stock options in Biogen. DR-S and WF are former employees of and held stock options in Biogen. ES is an employee of Ionis Pharmaceuticals. CFB is an employee of Ionis Pharmaceuticals and has issued patents (US patents 9926559 and 8980853) concerning nusinersen., (Copyright © 2021 Elsevier Ltd. 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