PT  - JOURNAL ARTICLE
AU  - Jerry Mendell
AU  - Samiah A. Al-Zaidy
AU  - Richard Shell
AU  - W. David Arnold
AU  - Louise R. Rodino-Klapac
AU  - Thomas W. Prior
AU  - Linda Lowes
AU  - Lindsay N. Alfano
AU  - Katherine Berry
AU  - Kathleen Church
AU  - John Kissel
AU  - Sukumar Nagendran
AU  - James L’Italien
AU  - Doug M. Sproule
AU  - Minna Du
AU  - Jessica A. Cardenas
AU  - Arthur Burghes
AU  - Kevin D. Foust
AU  - Kathrin Meyer
AU  - Shibi Likhite
AU  - Brian K. Kaspar
TI  - AVXS-101 Phase 1 Gene Therapy Clinical Trial in SMA Type 1: Event Free Survival and Achievement of developmental milestones (CT.003)
DP  - 2017 Apr 18
TA  - Neurology
PG  - CT.003
VI  - 88
IP  - 16 Supplement
4099  - http://n.neurology.org/content/88/16_Supplement/CT.003.short
4100  - http://n.neurology.org/content/88/16_Supplement/CT.003.full
SO  - Neurology2017 Apr 18; 88
AB  - 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, roll over or maintain head control. A natural history study of SMA1 children reported that none achieved a CHOP-INTEND score of ≥40 (with one transient exception at ~41) and 75% died or required permanent-ventilation by 13.6 months. This trial explores safety and efficacy of a single intravenous administration of gene therapy in SMA1.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 2xSMN2 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: AVXS-101 appears safe and to improve survival (15Sept16 cut-off). All patients are alive and only 1 patient, from Cohort 1, reached the pulmonary endpoint at 28.8 months of age. All patients reaching 13.6 months did so free of permanent ventilation. Patients in Cohort 2 demonstrated improvements in motor function: 11/12 have CHOP-INTEND scores >40 points, 11/12 have head control, and 8/12 sit unassisted. Two patients can crawl, stand and walk independently.Conclusions: In contrast with the published natural history, a single intravenous administration of AVXS-101 appears to demonstrate a positive impact on the survival of both dosing cohorts and a dramatic, sustained impact on motor function in Cohort-2: 11/12 patients achieved CHOP-INTEND scores and motor milestones rarely or never seen in this population.Study Supported by: AveXis, Inc.Disclosure: 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. 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. L'Italien has received personal compensation for activities with AveXis, Inc. Dr. L'Italien holds stock and/or stock options in 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.