Onasemnogene Abeparvovec Gene Therapy in Presymptomatic Spinal Muscular Atrophy (SMA): SPR1NT Study Update in Children with 2 Copies of SMN2

Clinical Trials
67
Kevin Strauss MD, Francesco Muntoni MD, Michelle A. Farrar , Kayoko Saito , Jerry R. Mendell , Laurent Servais MD, PhD, Hugh McMillan , Kathryn J. Swoboda MD, Jennifer M. Kwon , Craig M. Zaidman , Claudia Chiriboga MD, MPH, Susan Iannaccone , Jena M. Krueger , Julie Parsons MD, Perry Shieh MD, PhD, Sarah Kavanagh , Deepa Chand , Sitra Tauscher-Wisniewski , Thomas A. Macek
1. Clinic for Special Children, 2. Dubowitz Neuromuscular Centre, UCL Institute of Child Health, London, UK, 3. Sydney Children’s Hospital and UNSW Sydney, Sydney, New South Wales, Australia, 4. Institute of Medical Genetics, Tokyo Women's Medical University, Tokyo, Japan, 5. Center for Gene Therapy, The Research Institute at Nationwide Children’s Hospital, Columbus, Ohio, 6. MDUK Oxford Neuromuscular Centre, 7. Department of Pediatrics, Children’s Hospital of Eastern Ontario, Ottawa, ON, Canada, 8. Department of Neurology, Massachusetts General Hospital, Boston, MA, USA, 9. Dept. of Neurology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA, 10. Washington University School of Medicine, St. Louis, MO, USA, 11. Columbia University Medical Center, 12. Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA, 13. Department of Neurology, Helen DeVos Children's Hospital, Grand Rapids, MI, USA, 14. Children Hospital-Colorado, 15. University of California, Los Angeles, 16. Novartis Gene Therapies, Bannockburn, IL, USA, 17. Novartis Gene Therapies, Bannockburn, IL, USA, 18. Novartis Gene Therapies, Bannockburn, IL, USA, 19. Novartis Gene Therapies, Bannockburn, IL, USA

Background:
SMA causes loss of motor/respiratory function due to survival motor neuron 1 (SMN1) deletion/mutation. Copies of SMN2 modify disease severity. Approximately 97% of patients born with 2 copies of SMN2 develop infantile-onset SMA type 1. If untreated, median survival is 13.6 months and patients do not sit without support.

Objective:
Evaluate the safety/efficacy of onasemnogene abeparvovec (formerly AVXS-101) in presymptomatic SMA patients with 2 copies of the SMN2 gene.

Design/Methods:
SPR1NT (NCT03505099) is an ongoing multicenter, open-label, Phase III study. Asymptomatic patients expected to develop SMA (Cohort 1: 2SMN2, ≤6 weeks) received a one-time intravenous infusion and are assessed through 18 months. Primary outcomes: sitting for ≥30 seconds. Secondary outcomes: survival and independent feeding with normal weight. Exploratory outcome: motor function improvement (CHOP INTEND). Safety outcomes: incidence of adverse events (AEs)/serious AEs.

Results:
As of 11 June 2020, 14 patients in Cohort 1 (2SMN2) were enrolled (enrollment complete). Median age (range) at last visit (months): 15.60 (8.8–18.8); median follow-up time (range) at last visit (months): 14.85 (8.0–18.4). All patients are alive and did not use ventilatory or feeding tube support as of last visit. 11 patients had achieved the primary endpoint of sitting without support for ≥30 seconds; 10/11 were within the normal development window (9.2 months, De Onis 2006) and similar to non-SMA, typically-developing peers; all achieved CHOP INTEND scores of ≥50. 14/14 patients experienced ≥1 AE (131 total AEs); 10/14 experienced treatment-related AEs (22 total AEs). 5/14 experienced a serious AE (7 total AEs) but all serious AEs resolved and were treatment-unrelated. No AEs caused study discontinuation/death.

Conclusions:
Overall, 79% of patients in this cohort achieved the primary endpoint as of the data-cut, at an age similar to non-SMA typically developing children, and children with some delay, demonstrating a significant therapeutic benefit. Study is ongoing.