Gene-Replacement Therapy (GRT) in Spinal Muscular Atrophy Type 1 (SMA1): Long-Term Follow-Up From the Onasemnogene Abeparvovec Phase 1/2 Clinical Trial

Research Question: 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. Onasemnogene abeparvovec (AVXS-101), a one-time SMN gene-replacement therapy, addresses the genetic root cause of SMA and is designed for immediate, sustained SMN protein expression in motor neurons. In the phase 1/2a trial (CL-101; NCT02122952), 15 SMA1 patients received a one-time intravenous (IV) AVXS-101 infusion at low dose (Cohort 1, n = 3) or proposed therapeutic dose (Cohort 2, n = 12). The results of this study (published in Mendell 2017) demonstrated event-free survival, motor function, and motor milestone achievement that were significantly improved relative to natural history (Finkel 2014).

Material and Method: SMA1 patients in the phase 1/2a study could roll over into a long-term follow-up (LTFU) study (Study LT-001; NCT03421977). The primary objective is 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 to determine whether the highest achieved milestone in the parent study is maintained.

Results: As of 31 December 2018, 13 patients (3 from Cohort 1; 10 from Cohort 2) had enrolled in Study LT-001 and had a baseline visit. Seven patients had completed a 1-year post-baseline visit. All 13 (100%) of the patients were alive. There has been no loss of developmental milestones that were achieved at the end of the CL-101 study and new milestones have been achieved, further supporting the persistence of AVXS-101 efficacy. These patients ranged from 39.1–62.4 months of age (39.1–55.3 months of age for patients in Cohort 2). The time since dosing ranged from 37–56.5 months (37–49.7 months for patients in Cohort 2). LTFU data from an 8 March 2019 data cut will be presented at the congress.

Discussion: A one-time IV administration of AVXS-101 at the proposed therapeutic dose in the CL-101 study continues to provide prolonged and durable efficacy with milestone development as assessed in Study LT-001.

Conclusion: The LT-001 study investigates the long-term efficacy and safety of AVXS-101 in SMA1 patients.

References

1. Finkel RS, McDermott MP, Kaufmann P, et al. Observational study of spinal muscular atrophy type I and implications for clinical trials. Neurology 2014;83(9):810–817

2. Mendell JR, Al-Zaidy S, Shell R, et al. Single-dose gene-replacement therapy for spinal muscular atrophy. N Engl J Med 2017;377(18):1713–1722

No conflict of interest has been declared by the author(s).