Linda P Lowes1, Lindsay N Alfano2, W David Arnold3, Richard Shell4, Thomas W Prior5, Markus McColly2, Kelly J Lehman2, Kathleen Church2, Douglas M Sproule6, Sukumar Nagendran6, Melissa Menier6, Douglas E Feltner6, Courtney Wells6, John T Kissel4, Samiah Al-Zaidy7, Jerry Mendell8. 1. Center for Gene Therapy at the Research Institute at Nationwide Children's Hospital, Columbus, Ohio; Department of Pediatrics, Ohio State University, Columbus, Ohio. Electronic address: linda.lowes@nationwidechildrens.org. 2. Center for Gene Therapy at the Research Institute at Nationwide Children's Hospital, Columbus, Ohio. 3. Department of Neurology, Ohio State University, Columbus, Ohio. 4. Department of Pediatrics, Ohio State University, Columbus, Ohio. 5. Department of Pathology, Ohio State University, Columbus, Ohio. 6. AveXis, Inc., Bannockburn, Illinois. 7. Center for Gene Therapy at the Research Institute at Nationwide Children's Hospital, Columbus, Ohio; Department of Pediatrics, Ohio State University, Columbus, Ohio. 8. Center for Gene Therapy at the Research Institute at Nationwide Children's Hospital, Columbus, Ohio; Department of Pediatrics, Ohio State University, Columbus, Ohio; Department of Neurology, Ohio State University, Columbus, Ohio.
Abstract
BACKGROUND: This study characterizes motor function responses after early dosing of AVXS-101 (onasemnogene abeparvovec) in gene replacement therapy in infants with severe spinal muscular atrophy type 1 (SMA1). METHODS: This study is a follow-up analysis of 12 infants with SMA1 who received the proposed therapeutic dose of AVXS-101 in a Phase 1 open-label study (NCT02122952). Infants were grouped according to age at dosing and baseline Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders scores: (1) early dosing/low motor, dosed age less than three months with scores <20 (n = 3), (2) late dosing, dosed at age three months or greater (n = 6), and (3) early dosing/high motor, dosed age less than three months with scores ≥20 (n = 3). RESULTS: Early dosing/low motor group demonstrated a mean gain of 35.0 points from a mean baseline of 15.7, whereas the late dosing group had a mean gain of 23.3 from a mean baseline of 26.5. The early dosing/high motor group quickly reached a mean score of 60.3, near the scale maximum (64), from a mean baseline of 44.0. Despite a lower baseline motor score, the early dosing/low motor group achieved sitting unassisted earlier than the late dosing group (mean age: 17.0 vs 22.0 months). The early dosing/high motor group reached this milestone earliest (mean age: 9.4 months). CONCLUSIONS: The rapid, significant motor improvements among infants with severe SMA1 treated with AVXS-101 at an early age highlight the importance of newborn screening and early treatment and demonstrate the therapeutic potential of AVXS-101 regardless of baseline motor function.
BACKGROUND: This study characterizes motor function responses after early dosing of AVXS-101 (onasemnogene abeparvovec) in gene replacement therapy in infants with severe spinal muscular atrophy type 1 (SMA1). METHODS: This study is a follow-up analysis of 12 infants with SMA1 who received the proposed therapeutic dose of AVXS-101 in a Phase 1 open-label study (NCT02122952). Infants were grouped according to age at dosing and baseline Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders scores: (1) early dosing/low motor, dosed age less than three months with scores <20 (n = 3), (2) late dosing, dosed at age three months or greater (n = 6), and (3) early dosing/high motor, dosed age less than three months with scores ≥20 (n = 3). RESULTS: Early dosing/low motor group demonstrated a mean gain of 35.0 points from a mean baseline of 15.7, whereas the late dosing group had a mean gain of 23.3 from a mean baseline of 26.5. The early dosing/high motor group quickly reached a mean score of 60.3, near the scale maximum (64), from a mean baseline of 44.0. Despite a lower baseline motor score, the early dosing/low motor group achieved sitting unassisted earlier than the late dosing group (mean age: 17.0 vs 22.0 months). The early dosing/high motor group reached this milestone earliest (mean age: 9.4 months). CONCLUSIONS: The rapid, significant motor improvements among infants with severe SMA1 treated with AVXS-101 at an early age highlight the importance of newborn screening and early treatment and demonstrate the therapeutic potential of AVXS-101 regardless of baseline motor function.
Authors: Jerry R Mendell; Samiah A Al-Zaidy; Kelly J Lehman; Markus McColly; Linda P Lowes; Lindsay N Alfano; Natalie F Reash; Megan A Iammarino; Kathleen R Church; Aaron Kleyn; Matthew N Meriggioli; Richard Shell Journal: JAMA Neurol Date: 2021-07-01 Impact factor: 18.302