AVXS-101 Phase 1 Gene Replacement Therapy Clinical Trial in SMA Type 1: Continued Independence from Nutritional and Ventilatory Support in Patients Dosed Early in Disease Progression (S29.003)

Objective: Here we report clinical data of Spinal muscular atrophy Type 1 (SMA1) infants treated with a one-time intravenous dose of the proposed therapeutic dose of AVXS-101, a gene replacement therapy that crosses the blood-brain-barrier. Background: Spinal muscular atrophy (SMA) is devastating monogenic neurodegenerative disease characterized by lower motor neuron loss. Children with SMA1 experience severe swallowing and breathing dysfunction that, without nutritional/ventilatory support, leads to malnutrition, chronic aspiration, and ultimately death via respiratory failure. Natural history studies have shown that SMA1 patients will require nutritional and ventilatory support by 12 months of age. Design/Methods: In this study, 15 patients with SMA with 2x SMN2 copies confirmed by genetic testing were enrolled; all patients had bi-allelic Exon 7 deletions of SMN1 and no SMN2 disease modifying mutation (mutation predicts a milder phenotype). Cohort 2 (n=12) received the proposed therapeutic dose of AVXS-101. Results: By Jan 20, 2017, all patients in Cohort2 were ≥13.6 months and free of permanent-ventilation. At study enrollment, 10 patients did not require ventilatory support; at end-of-study, 7/10 remained free of ventilatory support. At baseline, 7 patients did not require nutritional support at baseline; at end-of-study, 6/7 remained free of nutritional support. At baseline, 7 patients were able to feed orally; at end-of-study 11 were able to feed orally; no patient lost the ability to feed orally following dosing. Conclusions: In contrast to natural history, the majority of patients in this Phase 1 trial who did not require nutritional or ventilatory support at baseline did not require either at end-of-study. Moreover, 4 patients acquired the ability to feed orally, suggesting the potential of AVXS-101 to improve swallowing function. Patients treated early in age and early in disease course have continued to avoid the need for ventilatory and/or nutritional support. A clinical update will be given at the time of presentation demonstrating continued independence. Study Supported by: This study was supported by Avexis, Inc. Disclosure: 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. Al-Zaidy has nothing to disclose. 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. Kotha 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.