Onasemnogene abeparvovec for presymptomatic infants with two copies of SMN2 at risk for spinal muscular atrophy type 1: the Phase III SPR1NT trial

Abstract

SPR1NT ( NCT03505099 ) was a Phase III, multicenter, single-arm study to investigate the efficacy and safety of onasemnogene abeparvovec for presymptomatic children with biallelic SMN1 mutations treated at ≤6 weeks of life. Here, we report final results for 14 children with two copies of SMN2, expected to develop spinal muscular atrophy (SMA) type 1. Efficacy was compared with a matched Pediatric Neuromuscular Clinical Research natural-history cohort (n = 23). All 14 enrolled infants sat independently for ≥30 seconds at any visit ≤18 months (Bayley-III item #26; P < 0.001; 11 within the normal developmental window). All survived without permanent ventilation at 14 months as per protocol; 13 maintained body weight (≥3rd WHO percentile) through 18 months. No child used nutritional or respiratory support. No serious adverse events were considered related to treatment by the investigator. Onasemnogene abeparvovec was effective and well-tolerated for children expected to develop SMA type 1, highlighting the urgency for universal newborn screening.

Fig. 1. Survival and achieved video-confirmed developmental motor milestones.

a, Milestones achieved (visit month identified). Months calculated as days/30. Only the first observed instance of a milestone is included in this figure. ^aBayley Scales gross motor subtest item #26: child sits alone without support for at least 30 seconds. ^bBayley Scales gross motor subtest item #40: child stands alone. Child stands alone for at least 3 seconds after you release his or her hands. ^cBayley Scales gross motor subtest item #43: child walks alone. Child takes at least five steps independently, displaying coordination and balance. According to the WHO-MGRS windows for normal development, the 99th percentile (that is, upper bound of normal development) of sitting and walking without support was 279 days and 534 days, respectively. b, Kaplan–Meier plot for event-free survival in the SPR1NT two-copy (blue line) and PNCR (red line) cohorts. n = 4 males and n = 10 females; mean (s.d.) age at dosing, 20.6 (7.9) days.

Fig. 2. Body weight over time.

Children achieved the ability to maintain weight at or greater than the 3rd percentile, without the need for non-oral or mechanical feeding support at any visit up to 18 months of age for female (a) and male (b) individuals, according to the WHO child growth standards. Gray shading represents WHO growth standards for the 3rd through 97th percentiles. n = 4 males and n = 10 females; mean (s.d.) age at dosing, 20.6 (7.9) days.

Fig. 3. Patient-level motor function as assessed by CHOP INTEND and Bayley gross and fine motor scores.

a, The dashed straight line represents a CHOP INTEND score of 40, which is a score that untreated patients with SMA type 1 rarely achieve in the natural history of the disease. Shading represents the CHOP INTEND values obtained from normal healthy control infants in the NeuroNEXT study with the mean values presented as a solid purple line. NeuroNext infants were 6 months of age or younger and born between 36–42 weeks gestation and were evaluated using the Test of Infant Motor Performance Screening Items (TIMPSI) and CHOP INTEND (for children who scored <41 on TIMPSI). The dashed gray line represents the mean change in CHOP INTEND score observed in the NeuroNEXT study of children with SMA type 1 who did not receive disease-modifying treatments. Children who achieved three consecutive CHOP INTEND scores ≥58 were not tested further. Bayley scales gross motor (b) and fine motor (c) subtests. The Bayley scales gross and fine motor normal ranges (±2 s.d.) are presented in gray highlights. n = 4 males and n = 10 females; mean (s.d.) age at dosing, 20.6 (7.9) days.