Phase 1 Study of Intrathecal Administration of AVXS-101 Gene-Replacement Therapy (GRT) for Spinal Muscular Atrophy Type 2 (SMA2) (STRONG) (P1.6-059)

Objective: To describe STRONG, a multicenter, open-label, phase 1 study (NCT03381729) of the safety, tolerability, optimal dose, and efficacy of onasemnogene abeparvovec (AVXS-101) in patients with SMA2.

Background: SMA is a rapidly progressing neurodegenerative disease causing loss of motor and respiratory function. The genetic root cause is bi-allelic deletion/mutation of the survival motor neuron 1 gene (SMN1). Disease severity is modified by SMN2 copy number. AVXS-101 comprises an adeno-associated virus serotype 9-encapsulated transcript of human SMN that crosses the blood-brain barrier. In a phase 1 study (NCT02122952) in patients with SMA1, intravenous AVXS-101 demonstrated unprecedented improvements in survival, motor function, and motor milestone achievement

Design/Methods: In STRONG, SMA2 patients (bi-allelic SMN1 mutations/deletions, 3 copies of SMN2) who could sit but not stand or walk independently were enrolled in 2 cohorts by age (cohort 1: ≥6 to <24 months; cohort 2: ≥24 to <60 months), received one-time intrathecal AVXS-101 at the highest acceptably safe dose, and were followed for 12 months. Three patients in cohort 1 received dose A. Based on demonstrated acceptable safety, three additional patients in cohort 2 received dose B. Given ongoing demonstration of acceptable safety, 13 additional patients in cohort 1 and 9 in cohort 2 were treated with dose B. Primary endpoints were safety/tolerability, optimal dose, ability to stand unsupported ≥3 sec (cohort 1), and Hammersmith Functional Motor Scale-Expanded score (cohort 2).

Results: As of October 12, 2018, 28 patients have been enrolled at 11 sites. Enrollment is complete. To date, no safety or tolerability concerns have been identified. A study update will be provided.

Conclusions: Results from STRONG show intrathecal delivery of AVXS-101 in infants is feasible and well tolerated, with no safety concerns to date, and may support AVXS-101 as a promising treatment option for patients with SMA2.

Disclosure: Dr. Finkel has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Ionis Pharmaceuticals, Inc. and Biogen, AveXis, Novartis, and Roche. Dr. Finkel has received royalty, license fees, or contractual rights payments from Licensing fees from Children’s Hospital of Philadelphia for development of the CHOP-INTEND motor scale. Dr. Finkel has received research support from Ionis Pharmaceuticals, Inc. and Biogen, grants from AveXis and Cytokinetics. Dr. Day has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AMO, Audentes, AveXis, Biogen, Cytokinetics, Santhera, and Sarepta. Dr. Day has received research support from AveXis, Biogen, Cytokinetics, Genzyme, Ionis, Roche, Santhera, and Sarepta. Dr. Darras has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Biogen, Bristol-Myers Squibb, Cytokinetics, Marathon, PTC Therapeutics, Roche, Santhera, and Sarepta. Dr. Darras has received research support from the National Institutes of Health/National Institute of Neurological Disorders and Stroke, the Slaney Family Fund for SMA, Working on Walking Fund, the SMA Foundation, CureSMA, Ionis Pharmaceuticals, Inc., Biogen, AveXis, Cytokinetics, Fibrogen, PTC Therapeutics, Roche, Santhera, Sarepta, and Summit. Dr. Kuntz has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Audentes, AveXis, Catalyst, Cytokinetics, Marathon, PTC Therapeutics, and Sarepta Therapeutics. Dr. Kuntz has received research support from AveXis, Audentes, Biogen, Pfizer, Roche and Sarepta Therapeutics. Dr. Connolly has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Avexis, Sarepta, Astelles, Marathon, Accelleron, Roche, (advisory boards) and Catabasis (DMSB). Dr. Connolly has received research support from Clinical trial site PI for Avexis, Sarepta, Biogen, Cytokinetics, NS Pharma, Pfizer, Roche, Italfarmaco, Fibrogen, and Capricor. Dr. Crawford has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Biogen, Catalyst, Cure SMA, Cytokinetics, Marathon, Muscular Dystrophy Association, Novartis, Roche, Sarepta, Scholar Rock, and the Spinal Muscular Atrophy Foundation. Dr. Butterfield has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Sarepta Therapeutics and Biogen. Dr. Butterfield has received research support from PTC Therapeutics, Sarepta Therapeutics, Pfizer, and, Biogen. Dr. Shieh has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Alexion, AveXis, Inc., Biogen, Grifols, PTC Therapeutics and Sarepta. Dr. Shieh has received research support from AveXis, Inc., Audentes, Biogen, Bristol-Myers Squibb, Cytokinetics, Catalyst, Fibrogen, Ionis Pharmaceuticals, Inc., Marathon, Pfizer, PTC Therapeutics, Sarepta, Santhera, Summit, Sanofi/Genzyme and Ultragenyx. Dr. Tennekoon has received research support from Catabasis Pharmaceuticals. Dr. Iannaccone has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Avexis, Biogen, Sarepta, Capricor. Dr. Iannaccone has received research support from AveXis, Biogen, Sarepta, Capricor, Mallinckrodt, Fibrogen, Regeneron, PTC Therapeutics. Dr. Meriggioli has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc. Dr. Spector has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc. Dr. Ogrinc has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, a Novartis company. Dr. L’Italien has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc.. Dr. Wells has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, a Novartis company. Dr. Kaspar has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, a Novartis company. Dr. Sproule has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities as an employee of AveXis, a Novartis company. Dr. Sproule has received compensation for serving on the Board of Directors of AveXis, a Novartis company. Dr. Feltner has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Acadia, Embera Neurtherapeutics, AveXis, Inc. 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. Dr. Mendell has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AveXis, Inc.