Gene-Replacement Therapy in Spinal Muscular Atrophy Type 1: Long-Term Follow-Up From the Onasemnogene Abeparvovec-xioi Phase 1/2a Clinical Trial (1808)

Objective: To evaluate long-term safety and efficacy of onasemnogene abeparvovec-xioi (formerly AVXS-101). Background: Spinal muscular atrophy type 1 (SMA1) is a rapidly progressing disease caused by biallelic survival motor neuron 1 gene (SMN1) deletion/mutation, resulting in death/permanent ventilation by 2 years of age if untreated. Onasemnogene abeparvovec, an SMN gene-replacement therapy, addresses the genetic root cause of SMA. In the phase 1/2a trial (START; NCT02122952), SMA1 patients who received a one-time intravenous (IV) infusion of onasemnogene abeparvovec at high dose (Cohort 2, n=12) demonstrated significantly improved outcomes relative to untreated natural history. Design/Methods: Patients in START could rollover into a long-term follow-up (LTFU) study (Study LT-001; NCT03421977). Primary objective: long-term safety. Patients have annual visits (5 years) followed by annual phone contact (additional 10 years). Patient record transfers from local physicians and/or neurologists are requested. Safety assessments include medical history and record review, physical examination, clinical laboratory evaluation, and pulmonary assessments. Efficacy assessments include evaluation of developmental milestones maintenance. Results: As of 31 May 2019, 13 patients (Cohort 1, n=3; Cohort 2, n=10) enrolled in Study LT-001 and had a baseline visit. For patients in Cohort 2, the mean (range) age and time since dosing were 4.2 (3.7–5.0) years and 3.9 (3.5–4.6) years, respectively. All patients in Cohort 2 were alive and free of permanent ventilation. No developmental milestones achieved at the end of START were lost; 2 patients have gained the standing with assistance milestone during LTFU (video-confirmed; neither patient has received nusinersen), further supporting the durability of onasemnogene abeparvovec. No new treatment-related serious adverse events or adverse events of special interest have occurred in LTFU (as of 8 March 2019). Conclusions: One-time IV administration of onasemnogene abeparvovec at the high dose in START continues to provide prolonged and durable efficacy with milestone development in Study LT-001. Disclosure: Dr. Mendell has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with For clinical trial consulting and serving on scientific advisory boards from AveXis, Inc.. Dr. Mendell has received research support from AveXis, Inc.. Dr. Shell has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc.. Dr. Lehman has nothing to disclose. Dr. McColly has nothing to disclose. Dr. Lowes has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with ATOM International. Dr. Lowes has received royalty, license fees, or contractual rights payments from Nationwide Children’s Hospital. Dr. Alfano has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Acceleron Pharma. Dr. Alfano has received research support from Sarepta Therapeutics. Dr. Miller has nothing to disclose. Dr. Iammarino has nothing to disclose. Dr. Church has nothing to disclose. Dr. Ogrinc has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of AveXis, Inc., a Novartis company, and may own Novartis stock or other equities. Dr. Ouyang has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of AveXis, Inc., a Novartis company, and may own Novartis stock or other equities. Dr. Kernbauer has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of AveXis, Inc., a Novartis company, and may own Novartis stock or other equities. Dr. Joshi 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 Employee of AveXis, Inc., a Novartis company, and may own Novartis stock or other equities. Dr. Sproule has received compensation for serving on the Board of Directors of AveXis, a Novartis company. Dr. Meriggioli has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Employee of AveXis, Inc., a Novartis company, and may own Novartis stock or other equities. Dr. Feltner has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Acadia Pharmaceuticals, AveXis, Inc., Embera Neurotherapeutics. Dr. Feltner has received compensation for serving on the Board of Directors of Embera Neurotherapeutics. Dr. Feltner holds stock and/or stock options in AveXis, Inc. which sponsored research in which Dr. Feltner was involved as an investigator. Dr. Feltner holds stock and/or stock options in AveXis, Inc.. Dr. Al-Zaidy has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc. Dr. Al-Zaidy has received royalty, license fees, or contractual rights payments from Mile Biotech. Dr. Al-Zaidy has received research support from AveXis, Inc., and Catalyst.