Intrathecal onasemnogene abeparvovec in treatment-naive patients with spinal muscular atrophy: a phase 3, randomized controlled trial

Abstract

STEER ( NCT05089656 ) was a 52-week, phase 3, multicenter, randomized, sham-controlled, double-blind trial evaluating intrathecal onasemnogene abeparvovec (OAV101 IT), a one-time gene transfer therapy, in patients with spinal muscular atrophy (SMA). Participants ranged in age from 2 years to <18 years, were treatment-naive and were able to sit but never walked independently. Primary efficacy endpoint was change from baseline in Hammersmith Functional Motor Scale-Expanded (HFMSE) score. In total, 126 patients received OAV101 IT (n = 75) or a sham procedure (n = 51). The primary endpoint was met: patients treated with OAV101 IT demonstrated a significant increase in HFMSE score compared with sham (least squares mean difference, 1.88 (95% confidence interval: 0.51-3.25); P = 0.0074). Overall incidence of adverse events (AEs), serious adverse events (SAEs) and adverse events of special interest (AESI) was similar between groups. Transaminase increases were infrequent; most were low grade and transient. Two participants in the OAV101 IT arm and one participant in the sham arm developed sensory symptoms. One-time OAV101 IT demonstrated a statistically significant improvement in motor function compared with sham control. The overall safety findings were acceptable, with similar incidences of AEs, SAEs and AESI in the OAV101 IT and sham groups. Trial registration: ClinicalTrials.gov identifier: NCT05089656 .

Fig. 1. CONSORT diagram.

CONSORT diagram and patient disposition at the end of Follow-Up Period 1.

Fig. 2. LSM with ±s.e. for change from baseline in HFMSE score by visit.

The primary efficacy endpoint was analyzed using a mixed model with repeated measurements, with the observed change from baseline in HFMSE score at all post-baseline visits (through the end of Follow-Up Period 1) as the dependent variable. The fixed effects included treatment, visit, treatment by visit interaction and the strata and baseline HFMSE score as covariates. An unstructured covariance matrix was used. LSM for each treatment group, standard errors, difference of LSM compared with the sham procedure group as well as the two-sided P values were determined by visit and treatment. OAV101 IT, n = 74; sham, n = 50. Note: End of Follow-Up Period 1 was defined as the average of the week 48 and week 52 assessments.

Fig. 3. Secondary endpoint results, 2 to <18 years.

Change from baseline in HFMSE and RULM scores was analyzed using a mixed model with repeated measurements, with the observed change from baseline in HFMSE/RULM score at all post-baseline visits (through the end of Follow-Up Period 1) as the dependent variable. The fixed effects included treatment, visit, treatment by visit interaction and the strata and baseline HFMSE/RULM score as covariates. An unstructured covariance matrix was used. LSM for each treatment group, standard errors, associated 95% CIs, difference of LSM compared to the sham procedure group and the associated 95% CIs for the difference, as well as the two-sided P values, were determined by visit and treatment. The dichotomous endpoint (percentage of responders, defined as participants who achieved at least a 3-point improvement from baseline in HFMSE score at the end of Follow-Up Period 1) was analyzed by logistic regression model with Firth correction, including treatment, strata and baseline HFMSE score as covariates. OAV101 IT, n = 74; sham, n = 50. Note: Group estimates are displayed as LSM (s.e.m.) for change from baseline endpoints and as n/m (%) for achievement of at least a 3-point improvement in HFMSE score (n = number of patients achieving at least a 3-point improvement from baseline in HFMSE score; m = total number of patients at the end of Follow-Up Period 1). Treatment effect is displayed as LSM (95% CI) for change from baseline endpoints and as log(OR) (95% CI) for achievement of at least a 3-point improvement in HFMSE score. CI, confidence interval; OR, odds ratio.

Fig. 4. Secondary endpoint results, 2 to <5 years, and exploratory and post hoc endpoint results, 5 to <18 years.

Change from baseline in HFMSE and RULM scores was analyzed using a mixed model with repeated measurements, with the observed change from baseline in HFMSE/RULM score at all post-baseline visits (through the end of Follow-Up Period 1) as the dependent variable. The fixed effects included treatment, visit, treatment by visit interaction and the strata and baseline HFMSE/RULM score as covariates. An unstructured covariance matrix was used. LSM for each treatment group, standard errors, associated 95% CIs, difference of LSM compared with the sham procedure group and the associated 95% CIs for the difference, as well as the two-sided P values, were determined by visit and treatment. a, In the 2 to <5 years age subgroup, the dichotomous endpoint was analyzed using a generalized linear mixed-effects model, including treatment, visit, treatment by visit interaction, strata and baseline HFMSE score as covariates. The model included logistics as the link function, and a compound symmetry matrix was used. b, In the 5 to <18 years age subgroup, the dichotomous endpoint was analyzed using logistic regression model with Firth correction, including treatment, strata and baseline HFMSE score as covariates. OAV101 IT, n = 41; sham, n = 29. OAV101 IT, n = 33; sham, n = 21. Note: Group estimates are displayed as LSM (s.e.m.) for change from baseline endpoints and as n/m(%) for achievement of at least a 3-point improvement in HFMSE score (n = number of patients achieving at least a 3-point improvement from baseline in HFMSE score; m = the total number of patients at the end of Follow-Up Period 1). Treatment effect is displayed as LSM (95% CI) for change from baseline endpoints and as log(OR) (95% CI) for achievement of at least a 3-point improvement in HFMSE score. CI, confidence interval; OR, odds ratio.