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.

Keywords: Ataluren; Effectiveness; Nonsense mutation Duchenne muscular dystrophy; STRIDE Registry; Safety.

Fig. 1

Patient disposition in the STRIDE Registry analysis populations. DMD Duchenne muscular dystrophy, NBS newborn screening, PND prenatal diagnosis, STRIDE Strategic Targeting of Registries and International Database of Excellence. ^aPatients may have been grouped in more than one category. ^bScreening failure owing to a frameshift mutation. ^cAtaluren is not indicated in these patients; ataluren is indicated for the treatment of ambulatory patients with DMD resulting from a nonsense mutation in the dystrophin gene. Patients who do not have a nonsense mutation should not receive ataluren [6]. ^dData were missing for age at loss of ambulation or age at first symptoms. ^eNon-ambulatory patients were defined as such if using a wheelchair full-time or bedridden; patients who were non-ambulatory prior to study start were all ambulatory at ataluren initiation in previous clinical trials. Patient disposition for patients aged ≥ 2 to < 5 years of age and ≥ 5 year of age are included in Supplementary Figs. 5 and 6, respectively

Fig. 2

Age at loss of ambulation^b for propensity-score matched patients from the STRIDE Registry and CINRG DNHS. Propensity-score model covariates include age at first symptoms, age at first corticosteroid use, duration of deflazacort use and duration of use of corticosteroids other than deflazacort. Censor dates for censored patients in the STRIDE Registry were derived from the last assessment date across treatment, physical examination, vital signs, 6-min walk distance, timed function tests, North Star Ambulatory Assessments, percentage of predicted FVC and upper limb function tests. ‘+’ indicates a censored observation. Corticosteroid duration is calculated from the date at which corticosteroid use was started to the date of loss of ambulation or the date of the last assessment. CINRG DNHS Cooperative International Neuromuscular Research Group Duchenne Natural History Study, NC not calculable, STRIDE Strategic Targeting of Registries and International Database of Excellence. ^aNumber of patients at risk of having the event (loss of ambulation). ^bLoss of ambulation was defined as full-time wheelchair use. ^cp value is from a log-rank test stratified by deflazacort and other corticosteroid usage durations. ^dHazard ratio is from stratified (by durations of deflazacort and other corticosteroid use), Cox regression with study, age at first symptoms and age at first corticosteroid use as covariates. The hazard ratio is STRIDE Registry versus CINRG DNHS

Fig. 3

Age at predicted FVC of a < 60%, b < 50% and c < 30%, and at d FVC < 1 L for propensity-score matched patients from the STRIDE Registry and CINRG DNHS. Propensity-score model covariates include age at first symptoms, age at first corticosteroid use, duration of deflazacort use and duration of use of corticosteroids other than deflazacort. Censor dates for censored patients in the STRIDE Registry were derived from the last assessment date across treatment, physical examination, vital signs, 6-min walk distance, timed function tests, North Star Ambulatory Assessments, percentage of predicted FVC and upper limb function tests. ‘+’ indicates a censored observation. Corticosteroid duration is calculated from the date at which corticosteroid use was started to the date of the last assessment. The hazard ratio is STRIDE Registry versus CINRG DNHS. CINRG DNHS Cooperative International Neuromuscular Research Group Duchenne Natural History Study, FVC forced vital capacity, NC not calculable, STRIDE Strategic Targeting of Registries and International Database of Excellence. ^aNumber of patients at risk of having the event. ^bEvent = %-predicted FVC < 60%, < 50% or < 30% or FVC < 1 L. ^cp value is from a log-rank test stratified by deflazacort and other corticosteroid usage durations. ^dHazard ratio is from stratified (by durations of deflazacort and other corticosteroid use) Cox regression with study, age at first symptoms and age at first corticosteroid use as covariates

Fig. 4

Annual rate of predicted FVC decline for propensity-score matched STRIDE Registry and CINRG DNHS non-ambulatory patients^a with a baseline-predicted FVC ≥ 30% and ≤ 80% at first assessment. To be eligible for propensity score matching in these analyses, patients from both the STRIDE Registry and CINRG DNHS must have been non-ambulatory at their last assessment (but can be ambulatory or non-ambulatory at first assessment), the duration between their first and last assessments must be ≥ 48 weeks and they must have a predicted FVC ≥ 30% and ≤ 80% at first assessment. STRIDE patients must have received ataluren for ≥ 12 months on their first assessment. Propensity score matching was performed to identify non-ambulatory CINRG DNHS patients who were comparable to STRIDE patients in the effectiveness population using the following five covariates: age at first symptom onset; age at first corticosteroid use; duration of deflazacort use to the last assessment (i.e., with a predicted FVC ≥ 30%); duration of other steroid use to the last assessment (i.e., with a predicted FVC ≥ 30%); and time from loss of ambulation to the last assessment. CINRG DNHS Cooperative International Neuromuscular Research Group Duchenne Natural History Study, FVC forced vital capacity, STRIDE Strategic Targeting of Registries and International Database of Excellence. ^aThe non-ambulatory STRIDE population is defined as the subset of the effectiveness population who were full-time wheelchair users or bedridden on or before first recorded commercial or early-access program ataluren use or anytime during the study