Abstract Details

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

Topic Child Neurology and Developmental Neurology

Presentation(s) S27 - Child Neurology and Developmental Neurology: Neurogenetics: Translating Knowledge to Therapy (1:12 PM-1:24 PM)

Poster/Presentation
Number 002

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.

Authors/Disclosures
Jerry R. Mendell, MD, FAAN (The Research Institute at Nationwide Children's Hospital) PRESENTER	Dr. Mendell has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Vertex. Dr. Mendell has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Novartis. Dr. Mendell has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Sarepta Therapeutics . The institution of Dr. Mendell has received research support from Sarepta.
Richard Shell	No disclosure on file
Kelly Lehman, MSN, CNP (Nationwide Children's Hospital- The Research Institute)	Ms. Lehman has nothing to disclose.
Markus McColly	No disclosure on file
Linda P. Lowes, PT PhD	The institution of Ms. Lowes has received research support from Sarepta Therapeutics.
Lindsay N. Alfano, PT (Nationwide Children'S Hospital)	Ms. Alfano has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for ATOM International, Ltd (Amicus Therapeutics, Catabasis, Genethon, Italfarmaco, NS Pharma, Pfizer, PTC Therapeutics). Ms. Alfano has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sarepta Therapeutics. The institution of Ms. Alfano has received research support from Novartis Gene Therapies. The institution of Ms. Alfano has received research support from Sarepta Therapeutics. The institution of Ms. Alfano has received research support from Audentes Therapeutics/Astellas Gene Therapies. Ms. Alfano has received intellectual property interests from a discovery or technology relating to health care.
Natalie F. Miller, PT	Dr. Miller has received personal compensation for serving as an employee of ATOM International. Dr. Miller has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Casimir.
Megan Iammarino, PT (Nationwide Children'S Hospital)	Dr. Iammarino has nothing to disclose.
Kathleen Church	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
	No disclosure on file
Matthew N. Meriggioli, MD, FAAN (Novartis Biomedical Research)	Dr. Meriggioli has received personal compensation for serving as an employee of Novartis Gene Therapies. Dr. Meriggioli has received stock or an ownership interest from Novartis.
Douglas Feltner	No disclosure on file
Samiah A. Al-Zaidy, MD	Dr. Al-Zaidy has received personal compensation in the range of $500-$4,999 for serving as a Consultant for AveXis Inc.

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