P07 Onasemnogene abeparvovec gene-replacement therapy (GRT) for spinal muscular atrophy (SMA): from bench to bedside

Aims Report onasemnogene abeparvovec (formerly AVXS-101) GRT development for SMA. Onasemnogene abeparvovec is a one-time, intravenous GRT that addresses the genetic root cause of SMA, a progressive neurological disease. Onasemnogene abeparvovec delivers the survival motor neuron gene (SMN) via a self-complementary adeno-associated serotype 9 viral vector (scAAV9) that crosses the blood-brain barrier. Onasemnogene abeparvovec is designed for immediate and sustained expression of SMN protein in non-dividing neurons, allowing for rapid onset and durable therapeutic effect. Methods SMA mice (SMN2+/+; SMNΔ7+/+; Smn-/-) received intravenous scAAV9-SMN or scAAV9-GFP at post-natal day 1; survival and motor function were assessed. Non-human primates (NHPs) received intravenous scAAV9-GFP; transduced cell types were assessed. A phase 1/2a study (START; NCT02122952) evaluated onasemnogene abeparvovec infused at low (Cohort 1, n=3) or high (Cohort 2, n=12) doses in symptomatic SMA type 1 (SMA1) infants; patients were followed for 2 years for safety/tolerability and efficacy and could enroll in a long-term follow-up (LTFU) study to assess long-term safety. Results In SMA mice, scAAV9-SMN improved survival (>200 versus 15 days in controls), and increased motor function. In NHPs, scAAV9-GFP efficiently targeted motor neurons throughout the central nervous system. In the phase 1/2a START trial, all patients survived free of permanent ventilation at 24 months. In the high-dose cohort, 11/12 patients reached CHOP INTEND >40; 11 sat unassisted ≥5s, 10 for ≥10s, 9 for ≥30s. Two patients crawled, stood, and walked. No patient received nusinersen during the 24-month study period. In the LTFU study, 2 more patients in Cohort 2 have gained the motor milestone of standing with assistance (as of 31 Dec 2019); neither patient has ever received nusinersen. No new treatment-related serious adverse events or adverse events of special interest have occurred in LTFU (as of 31 Dec 2019). The oldest patient in Cohort 2 is aged 5.6 years, with 5.2 years of follow-up since onasemnogene abeparvovec dosing. Conclusion Onasemnogene abeparvovec has demonstrated unprecedented outcomes in patients with SMA compared with untreated natural history. Phase 3 trials of onasemnogene abeparvovec in SMA1 are ongoing (US, EU, Asia-Pacific); additional trials are investigating presymptomatic SMA and intrathecal administration in older patients.