AVXS-101 Phase 1 Gene Replacement Therapy Clinical Trial in SMA Type 1: Patients Treated Early with the Proposed Therapeutic Dose Were Able to Sit Unassisted at a Younger Age (S29.002)

Objective: This trial explored safety and efficacy one-time intravenous administration of gene replacement therapy (AVXS-101) in Spinal Muscular Atrophy Type 1 (SMA1). Background: Spinal Muscular Atrophy (SMA) is a devastating monogenic neurodegenerative disease. Children with SMA1 will never sit unassisted. By 6 months, almost no children with SMA1 achieve a score >40 points (maximum 64). Design/Methods: In this study, 15 patients with SMA1 confirmed by genetic testing (with 2x SMN2 copies) were enrolled; all patients had bi-allelic Exon 7 deletions of SMN1 and no SMN2 disease modifying mutation. Patients received an intravenous dose of AVXS-101 at low dose (Cohort1, n=3) or proposed therapeutic dose (Cohort2, n=12). The primary objective was safety and secondary objectives included survival (avoidance of death/permanent-ventilation) and sitting unassisted (video confirmed by external reviewer). CHOP-INTEND scores and motor milestones were evaluated. Results: The vast majority of patients in Cohort 2 demonstrated improvements in motor function superior to the natural history (20 January 2017). 11 of 12 patients achieved CHOP-INTEND scores ≥40, and 10 of 12 achieved scores ≥50, both significantly superior to the published natural history (Exact Binomial test; both p 3 months of age (median 22.2 months of age) (Wilcoxon non-parametric two-sample test, p=0.0159). Conclusions: The vast majority of patients in Cohort 2 achieved levels of motor function never seen in SMA1 patients. The majority of Cohort 2 patients achieved sitting unassisted regardless of age at dosing; however, those dosed early achieved this milestone more quickly, emphasizing the need for newborn screening for SMA. Additional children have achieved sitting unassisted since January 20, 2017; an update to the data described here will be given at the time of presentation. Study Supported by: This study was supported by Avexis, Inc. Disclosure: Dr. Alfano has nothing to disclose. Dr. Lowes has nothing to disclose. Dr. Al-Zaidy has nothing to disclose. Dr. Shell has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Advisory Committee for Avexis Pharmaceuticals. Dr. Arnold has nothing to disclose. Dr. Rodino-Klapac has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Myonexus Therapeutics, Inc - Consulting. Dr. Rodino-Klapac has received compensation for serving on the Board of Directors of Myonexus Therapeutics, Inc — Founders Stock. Dr. Rodino-Klapac has received royalty, license fees, or contractual rights payments from License Option Fee Payments from Myonexus Therapeutics, Inc. and Sarepta Therapeutics. Dr. Rodino-Klapac holds stock and/or stock options in Hold Stock in Myonexus Therapeutics, Inc., which sponsored research in which Dr. Rodino-Klapac was involved as an investigator. Dr. Rodino-Klapac has received research support from Sarepta Therapeutics. Dr. Prior has nothing to disclose. Dr. Berry has nothing to disclose. Dr. Church has nothing to disclose. Dr. Kissel has received research support from Novartis, Biomarin, Cytokinetics, CSL Behring, Avexis, Ionis Pharmaceuticals, Quintiles, Axelacare. Dr. Nagendran has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc. Dr. L’Italien has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc. Dr. Sproule has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc. Dr. Wells has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc. Dr. Burghes has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Consultant to AveXis and Guide point. Dr. Burghes has received research support from AveXis for development and assay of AAV-SMN by digital droplet PCR, Development of a potency assay for scAAV-SMN and testing of scAAV9-SMN in SMA mice. Dr. Foust has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc. Dr. Meyer has nothing to disclose. Dr. Likhite has nothing to disclose. Dr. Kaspar has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc. Dr. Mendell has received research support from Investigator in clinical studies funded by AveXis, Inc.