Safety and effectiveness of ataluren in patients with nonsense mutation DMD in the STRIDE Registry compared with the CINRG Duchenne Natural History Study (2015–2022): 2022 interim analysis

**Background:** Duchenne muscular dystrophy (DMD) is a rare, progressive, X-linked neuromuscular disorder caused by mutations in the dystrophin gene, affecting approximately 1 in 3500–5000 live male births. In 10–15% of cases, a nonsense mutation leads to truncated, non-functional dystrophin. Ataluren is a first-in-class oral treatment designed to promote ribosomal readthrough of premature stop codons in nonsense mutation DMD (nmDMD). The STRIDE Registry is an ongoing, international, observational, post-approval safety study evaluating long-term real-world ataluren use. This 2022 interim analysis (data cut-off January 31, 2022) updates previous findings from the 2018 data cut-off with 3.5 additional years of follow-up.

**Methods:** The STRIDE Registry enrolls patients receiving ataluren (40 mg/kg/day) through commercial supply or early-access programs, with confirmed nmDMD. Patients are followed for at least 5 years from enrollment. As of January 31, 2022, 307 patients were enrolled from 14 countries with 66 active study sites. The as-treated population (n=284 aged ≥5 years) was used for safety analyses; the evaluable population (n=268 aged ≥5 years) for demographics; and the effectiveness population (n=261) excluded those with missing data, newborn screening/prenatal diagnosis as first symptom, or ataluren initiation after loss of ambulation. Propensity score matching was performed to compare STRIDE patients with participants from the CINRG Duchenne Natural History Study (CINRG DNHS; n=398 available, n=261 matched) using covariates: age at first symptoms, age at first corticosteroid use, duration of deflazacort use, and duration of other corticosteroid use. Kaplan–Meier analyses and Cox regression were used to estimate age-at-event endpoints. Safety was assessed via treatment-emergent adverse events (TEAEs) coded using MedDRA version 20.1.

**Key Results:** Mean (SD) age at first symptoms was 2.9 (1.7) years; mean age at genetic diagnosis was 5.4 (3.1) years. Mean (SD) ataluren exposure was 1671 (566.8) days (4.6 years), equivalent to 1226 patient-years. TEAEs occurred in 131/284 patients (46.1%); most were mild (15.8%) or moderate (18.0%), and only 3.2% were considered related to ataluren. No deaths or life-threatening TEAEs occurred. The most common TEAEs (>5% of patients) were gait inability (11.6%), fall (5.6%), and headache (4.6%). Serious AEs occurred in 27 patients (9.5%). Clinically significant laboratory abnormalities were infrequent. For effectiveness, ataluren plus standard of care significantly delayed median age at loss of ambulation by 4 years compared with standard of care alone (17.0 years vs 13.0 years; p<0.0001; hazard ratio 0.377, 95% CI 0.276–0.515). Ataluren also delayed age at decline to %-predicted FVC <60% by 1.8 years (17.7 vs 15.9 years; p=0.0021) and to <50% by 2.3 years (20.1 vs 17.8 years; p=0.0207). Median ages at decline to %-predicted FVC <30% and FVC <1 L were not estimable for STRIDE patients, while CINRG DNHS patients reached these at 22.5 years and 24.9 years, respectively. Among non-ambulatory patients with baseline predicted FVC 30–80%, the annual rate of FVC decline was −3.07% in STRIDE vs −3.95% in CINRG DNHS (p=0.0854), a numerical but not statistically significant difference. BMI shifts from normal to obese were similar between groups (5.2% vs 6.0%).

**Clinical Implications:** This updated analysis provides robust real-world evidence that long-term ataluren treatment (mean 4.6 years) delays key disease progression milestones in nmDMD, including a 4-year delay in loss of ambulation and significant delays in pulmonary function decline. The safety profile remains favorable, consistent with prior reports. These findings support the continued use of ataluren as a disease-modifying therapy for nmDMD. Limitations include the observational design, potential for unknown confounders despite propensity score matching, and lack of matching by mutation type or location. The STRIDE Registry continues to collect data, with the next interim analysis planned for 2023 and final data cut-off in 2025.