AVXS-101 Phase 1 Gene Replacement Therapy Clinical Trial in SMA Type 1: Continued Event Free Survival and Achievement of Developmental Milestones (S29.001)

Objective: This trial explores safety and efficacy of a one-time administration of gene replacement therapy. AVXS-101 delivers the SMN gene in a one-time dose via the AAV9 viral vector, which crosses the blood-brain barrier. Background: Spinal muscular atrophy (SMA) is a devastating, monogenic neurodegenerative disease. Children with SMA Type 1 (SMA1) will never sit unassisted or maintain head control. A natural history study of this patient population reported that none achieved a CHOP-INTEND score of ≥40 by 6 months of age (one transient exception) and 75% died or required permanent ventilation by 13.6 months. Design/Methods: In this Phase 1 trial, 15 patients with SMA1 confirmed by genetic testing (with 2x SMN2 copies) were enrolled. Patients received an intravenous dose of low dose AVXS-101 (Cohort 1, n=3) or proposed therapeutic dose (Cohort 2, n=12). The primary objective was safety and secondary objectives included survival (avoidance of death/permanent ventilation) and ability to sit unassisted (video confirmed by external independent reviewer). CHOP-INTEND scores and other motor milestones were additional objectives. Results: AVXS-101 appeared to have a favorable safety profile and to improve survival at data cut-off (20 January 2017). All patients reached 13.6 months free of permanent ventilation and none have died (3 live >30 months). Cohort 2 patients demonstrated improvement in motor function: 11/12 achieved head control and sat with support, and 9/12 sat unassisted. Two patients stood and walked independently. Conclusions: In contrast with the natural history, a one-time intravenous administration of AVXS-101 appeared to demonstrate a positive impact on the survival of both cohorts and a dramatic, sustained impact on motor function of Cohort 2: 11/12 patients achieved CHOP-INTEND scores and motor milestones rarely or never seen in this population. A clinical update will be given at the time of presentation demonstrating continued improvements in patients. Study Supported by: This study was supported by Avexis, Inc. Disclosure: Dr. Mendell has received research support from Investigator in clinical studies funded by AveXis, Inc. 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. Lowes has nothing to disclose. Dr. Alfano 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.