Onasemnogene Abeparvovec Gene Therapy in Presymptomatic Spinal Muscular Atrophy (SMA): SPR1NT Study Update in Children with 3 Copies of SMN2
Kevin Strauss1, Francesco Muntoni2,3, Michelle Farrar4,5, Kayoko Saito6, Jerry Mendell7,8, Laurent Servais9, Hugh McMillan10, Kathryn Swoboda11, Jennifer Kwon 12, Craig Zaidman13, Claudia Chiriboga14, Susan Iannaccone15, Jena Krueger16, Julie Parsons17, Perry Shieh18, Sarah Kavanagh19, Deepa Chand13,19, Sitra Tauscher-Wisniewski19, Thomas Macek19
1Clinic for Special Children, 2The Dubowitz Neuromuscular Centre, University College London, Great Ormond Street Institute of Child Health & Great Ormond Street Hospital, 3National Institute of Health Research, Great Ormond Street Hospital Biomedical Research Centre, 4Department of Neurology, Sydney Children’s Hospital Network, 5UNSW Sydney, 6Institute of Medical Genetics, Tokyo Women's Medical University, 7Center for Gene Therapy, Nationwide Children’s Hospital, 8Department of Pediatrics and Department of Neurology, Ohio State University, 9Department of Pediatrics, MDUK Oxford Neuromuscular Center, 10Department of Pediatrics, Children's Hospital of Eastern Ontario, 11Department of Neurology, Massachusetts General Hospital, 12Department of Neurology, University of Wisconsin School of Medicine and Public Health, 13Washington University School of Medicine, 14Division of Pediatric Neurology, Columbia University Medical Center, 15Department of Pediatrics, University of Texas Southwestern Medical Center, 16Department of Neurology, Helen DeVos Children's Hospital, 17Department of Pediatrics, University of Colorado School of Medicine, 18Department of Neurology, David Geffen School of Medicine at UCLA, 19Novartis Gene Therapies, Inc.
Objective:
Evaluate the safety/efficacy of onasemnogene abeparvovec (formerly AVXS-101) in presymptomatic SMA patients with 3 copies of the survival motor neuron 2 gene (SMN2).
Background:
SMA causes loss of motor/respiratory function due to SMN1 deletion/mutation. Copies of SMN2 modify disease severity. A range of phenotypes may occur with 3SMN2 with approximately 85% developing symptoms in infancy and not being able to walk independently without intervention.
Design/Methods:

SPR1NT (NCT03505099) is an ongoing multicenter, open-label, Phase III study. Asymptomatic patients expected to develop SMA (Cohort 2: 3SMN2, ≤6 weeks) received a one-time intravenous infusion and are assessed through 24 months. Primary outcome: standing unassisted for ≥3 seconds. Secondary outcome: independent walking. Safety outcomes: incidence of adverse events (AEs)/serious AEs.

Results:
As of 11 June 2020, 15 patients in Cohort 2 were enrolled (enrollment complete). Median age (range) at last visit (months): 15.2 (3.3–21.1); median follow-up time (range) at last visit (months): 14.5 (2.0–19.9). All patients are alive and none used ventilatory or feeding tube support at any time. Eight of 15 Cohort 2 patients had achieved the primary efficacy endpoint of stands alone within the normal developmental window (16.9 months, De Onis 2006).  The remaining 7 patients were all younger than 16.9 months of age. Six patients also walked alone within the normal developmental window (17.6 months, De Onis 2006); remaining patients were younger than 17.6 months of age. Within the whole SPR1NT study population 30/30 patients (14 2SMN2, 15 3SMN2, and 1 4SMN2 patient included only in the safety population) experienced ≥1 AE; 17/30 experienced treatment-related AEs. 7/13 experienced a serious AE, but all resolved and were considered unrelated to treatment.
Conclusions:
Patients in this cohort treated with onasemnogene abeparvovec have achieved gross motor milestones similar to non-SMA, typically developing peers, demonstrating a significant therapeutic benefit.