AVXS-101 Phase 1 Gene Therapy Clinical Trial in SMA Type 1: Correlation between CHOP-INTEND and Motor Milestone achievements (S13.002)

Objective: Spinal muscular atrophy is a devastating, monogenic neurodegenerative disease that in its most severe form, SMA Type 1 (SMA1), afflicted children never sit unassisted, this inability being the hallmark of SMA1. Natural history studies of SMA1 children reported that almost none achieved a CHOP-INTEND score of >40. Here we report the apparent correlation between achievement of CHOP-INTEND scores ≥50 and sitting unassisted. Background: This is the first-ever gene therapy (AVXS-101) trial in SMA1. AVXS-101 delivers the SMN gene in a single-dose via the AAV9 viral vector, which crosses the blood-brain-barrier. Design/Methods: In this ongoing Phase 1 trial, 15 patients with SMA1 confirmed by genetic testing (with 2x SMN2 copies) were enrolled. Patients received an intravenous dose of AVXS-101 at 6.7e13 vg/kg (Cohort-1;n=3) or 2.0e14vg/kg (Cohort-2;n=12). The primary objective is safety and secondary objectives include survival (avoidance of death/permanent-ventilation) and ability to sit unassisted. CHOP-INTEND scores and motor milestones are additional objectives. Results: Patients receiving the proposed therapeutic dose have demonstrated improvements in motor function: 9/12 achieved CHOP-INTEND scores ≥50 and 8/12 can sit unassisted (15Sept2016). The proportion of patients sitting unassisted is significantly higher with CHOP-INTEND scores ≥50 (Fisher’s Exact Test, p= 0.018). Conclusions: SMA1 children typically do not achieve CHOP-INTEND scores >40 and the inability to sit unassisted is the hallmark of the disease. We observed the correlation between the achievement of CHOP-INTEND scores ≥50 and sitting unassisted. It appears children treated with the proposed therapeutic dose early in age and early in disease course gain motor milestones more quickly, emphasizing the need for newborn screening in SMA1 when treatments become available. The inability to sit unassisted is one of the defining characteristics of SMA1, the achievement of this milestone signifies a change in the disease phenotype in SMA1 children treated with 2.0e14vg/kg of AVXS-101. A clinical update will be given at the presentation. Study Supported by: AveXis, Inc. Disclosure: Dr. Lowes has received personal compensation for activities with AveXis, Inc., Bristol-Myers Squibb, Sarepta Therapeutics, and Pfizer as a consultant. Dr. Al-Zaidy has nothing to disclose. Dr. Shell has receivd personal compensation for activities AveXis, Inc. as an advisory board member. Dr. Arnold has received research support from Gilead Sciences. Dr. Rodino-Klapac has nothing to disclose. Dr. Prior 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 personal compensation for activities with AveXis, Inc. Dr. Nagendran has received personal compensation for activities with AveXis, Inc. Dr. Nagendran holds stock and/or stock options in AveXis, Inc. Dr. L9Italien has received personal compensation for activities with AveXis, Inc. as an employee. Dr. L9Italien holds stock and/or stock options with AveXis, Inc. Dr. Sproule has received personal compensation for activities with AveXis, Inc. as an employee. Dr. Sproule holds stock and/or stock options with AveXis, Inc. Dr. Du has received personal compensation for activities with AveXis, Inc. as an employee. Dr. Du hold stock and/or stock options with AveXis, Inc. Dr. Cardenas has received personal compensation for activities with AveXis, Inc. as an employee. Dr. Cardenas holds stock and/or stock options in AveXis, Inc. Dr. Burghes has received personal compensation for activities with AveXis, Inc., Novartis and Guide Point as a consultant, or member of the advisory board. Dr. Foust has received personal compensation for activities with AveXis, Inc. as an employee. Dr. Foust has received licensing fees from AveXis, Inc. Dr. Foust has received stock and/or stock options with AveXis, Inc. Dr. Meyer has nothing to disclose. Dr. Likhite has nothing to disclose. Dr. Kaspar has received personal compensation for activities with AveXis, Inc. as employee. Dr. Mendell has received personal compensation for activities with Sarepta Therapeutics, Inc.