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

Abstract

Objective Strategic Targeting of Registries and International Database of Excellence (STRIDE) is an ongoing, international, multicenter registry of real-world ataluren use in individuals with nonsense mutation Duchenne muscular dystrophy (nmDMD) in clinical practice. This updated interim report (data cut-off: January 31, 2022), describes STRIDE patient characteristics and ataluren safety data, as well as the effectiveness of ataluren plus standard of care (SoC) in STRIDE versus SoC alone in the Cooperative International Neuromuscular Research Group (CINRG) Duchenne Natural History Study (DNHS). Methods Patients are followed up from enrollment for at least 5 years or until study withdrawal. Propensity score matching was performed to identify STRIDE and CINRG DNHS patients who were comparable in established predictors of disease progression. Results As of January 31, 2022, 307 patients were enrolled from 14 countries. Mean (standard deviation [SD]) ages at first symptoms and at genetic diagnosis were 2.9 (1.7) years and 4.5 (3.7) years, respectively. Mean (SD) duration of ataluren exposure was 1671 (56.8) days. Ataluren had a favorable safety profile; most treatment-emergent adverse events were mild or moderate and unrelated to ataluren. Kaplan–Meier analyses demonstrated that ataluren plus SoC significantly delayed age at loss of ambulation by 4 years (p < 0.0001) and age at decline to %-predicted forced vital capacity of < 60% and < 50% by 1.8 years (p = 0.0021) and 2.3 years (p = 0.0207), respectively, compared with SoC alone. Conclusion Long-term, real-world treatment with ataluren plus SoC delays several disease progression milestones in individuals with nmDMD. NCT02369731; registration date: February 24, 2015.

Gene-based therapies for neuromuscular disorders

“…The safety and effectiveness of ataluren in patients with nonsense mutation DMD in the STRIDE registry (real-world treatment with ataluren) were compared with the CINRG Duchenne Natural History Study. 110 Ataluren treatment significantly delayed age at loss of ambulation by 4 years and age at decline to predicted FVCof < 60% and < 50% by 1.8 years and 2.3 years, respectively. 110 However, the major limitation of this study is the fact that the comparator control group included DMD patients with different types of mutations, not just nonsense mutations, which can certainly affect the interpretation of the results.…”

“… 110 Ataluren treatment significantly delayed age at loss of ambulation by 4 years and age at decline to predicted FVCof < 60% and < 50% by 1.8 years and 2.3 years, respectively. 110 However, the major limitation of this study is the fact that the comparator control group included DMD patients with different types of mutations, not just nonsense mutations, which can certainly affect the interpretation of the results. 110 …”

“… 110 However, the major limitation of this study is the fact that the comparator control group included DMD patients with different types of mutations, not just nonsense mutations, which can certainly affect the interpretation of the results. 110 …”

“…110 However, the major limitation of this study is the fact that the comparator control group included DMD patients with different types of mutations, not just nonsense mutations, which can certainly affect the interpretation of the results. 110 Ataluren is not approved by the FDA. The Human Medicines Committee (CHMP) of the European Medicines Agency (EMA) gave conditional marketing authorization in 2014.…”

Mechanisms and Delivery of tRNA Therapeutics

“…Furthermore, the efficacy of Ataluren is still under investigation. The mechanism of action is not yet known, and characterization of ribosomal target sites is incomplete. , While successful at delaying symptoms of Duchenne’s muscular dystrophy (DMD) by up to 4 years, Ataluren has not established an ability to arrest disease progression . Considering the limitations at the clinical level, it seems that improved TRID design or alternative treatment methods such as suppressor tRNAs are needed to produce a viable PTC therapeutic.…”