AVXS-101 Phase 1 Gene Therapy Clinical Trial in SMA Type 1: Experience with pre-existing anti-AAV9 antibody in the SMA1 population (S13.001)

Objective: Spinal muscular atrophy is a devastating, monogenic neurodegenerative disease that in its most severe form, SMA Type 1 (SMA1), afflicted children die or require permanent-ventilation by 2 years of age. In this study, SMA1 infants were treated with a gene therapy, AVXS-101, designed to deliver a human transgene via an AAV9 viral vector to replace the missing or defective SMN1 gene. Population studies have suggested low-seropositivity to AAV9 in pediatric/young adult populations with increasing sero-positivity to AAV9 >age 40. Here we report our experience with anti-AAV9 antibodies in the SMA1 infant population. Background: This is the first-ever gene therapy (AVXS-101) trial in SMA1, a rapidly lethal neurologic disease. 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). Key exclusion criteria include patients with anti-AAV9 titers >1:50 as determined by ELISA. Results: Sixteen infants were screened, and one was excluded on the basis of anti-AAV9 antibody titer of >1:50. Two infants and their mothers had anti-AAV9 titers of >1:50 on initial testing. After allowing some time, infants were retested and confirmed with ≤1:50 anti-AAV9 titers, thus allowing dosing. Conclusions: A potential obstacle to safe dosing of AVXS-101 is thought to be the existence of anti-AAV9 antibodies in the SMA1 infant population. Our study is consistent with lower sero-positivity in the pediatric/young adult population. Two patients with modestly elevated anti-AAV9 titers, presumably resulting from maternal antibody transfer through breast-feeding or placental-transfer, showed resolution at retesting that enabled dosing. These results suggest that pre-existing antibodies to AAV9 will not impact use of gene therapy for the vast majority of SMA1 patients. Study Supported by: AveXis, Inc. Disclosure: 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. 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. Lowes has received personal compensation for activities with AveXis, Inc., Bristol-Myers Squibb, Sarepta Therapeutics, and Pfizer as a consultant. 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. Dr. L9Italien holds stock and/or stock options in 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 AveXis, Inc. and Sarepta Therapeutics as a consultant. Dr. Mendell has received research support from Sarepta Therapeutics Inc. and AveXis, Inc.