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Eteplirsen Treatment Attenuates Respiratory Decline in Ambulatory and Non-Ambulatory Patients with Duchenne Muscular Dystrophy.
Full text linkBACKGROUND: Duchenne muscular dystrophy (DMD) patients experience skeletal muscle degeneration, including respiratory muscles. Respiratory decline in glucocorticoid-treated DMD patients, measured by percent predicted forced vital capacity (FVC% p), is typically 5% annually in patients aged 10 to 18 years. OBJECTIVE: Evaluate the effects of eteplirsen on FVC% p annual change in 3 trials versus matched Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG DNHS) controls. METHODS: Eteplirsen studies 201/202 evaluated eligible ambulatory DMD patients for at least 4 years, study 204 evaluated primarily non-ambulatory DMD patients for 2 years, and ongoing study 301 is evaluating ambulatory DMD patients for 2 years (interim analysis is included). Eteplirsen-treated patients (n = 74) were amenable to exon 51 skipping and were receiving glucocorticoids. Three CINRG DNHS cohorts included: glucocorticoid-treated patients amenable to exon 51 skipping (Exon 51 CINRG DNHS; n = 20), all glucocorticoid-treated CINRG patients (All CINRG DNHS; n = 172), and all glucocorticoid-treated genotyped CINRG DNHS patients (Genotyped CINRG DNHS; n = 148). FVC% p assessments between ages 10 and <18 years were included for all patients; mixed-model analyses characterized FVC% p annual change. RESULTS: FVC% p annual change was greater for CINRG DNHS Exon 51 controls (- 6.00) versus patients in studies 201/202, study 204, and study 301 (- 2.19, P < 0.001; - 3.66, P 0.004; and - 3.79, P 0.017, respectively). FVC% p annual change in all eteplirsen studies suggested treatment benefit compared with the Genotyped CINRG DNHS (- 5.67) and All CINRG DNHS (- 5.56) cohorts (P < 0.05, all comparisons). CONCLUSIONS: Significant, clinically meaningful attenuation of FVC%p decline was observed in eteplirsen-treated patients versus CINRG DNHS controls
Efficacy and Safety of Viltolarsen in Boys With Duchenne Muscular Dystrophy: Results From the Phase 2, Open-Label, 4-Year Extension Study
Full text linkBackground: Duchenne muscular dystrophy (DMD) is caused by DMD gene mutations, resulting in absence of functional dystrophin protein. Viltolarsen, an exon 53 skipping therapy, significantly increased dystrophin levels in patients with DMD. Presented here are completed study results of \u3e 4 years of functional outcomes in viltolarsen-treated patients compared to a historical control group (Cooperative International Neuromuscular Research Group Duchenne Natural History Study [CINRG DNHS]). Objective: To evaluate the efficacy and safety of viltolarsen for an additional 192 weeks in boys with DMD. Methods: This phase 2, open-label, 192-week long-term extension (LTE) study (NCT03167255) evaluated the efficacy and safety of viltolarsen in participants aged 4 to \u3c 10 years at baseline with DMD amenable to exon 53 skipping. All 16 participants from the initial 24-week study enrolled into this LTE. Timed function tests were compared to the CINRG DNHS group. All participants received glucocorticoid treatment. The primary efficacy outcome was time to stand from supine (TTSTAND). Secondary efficacy outcomes included additional timed function tests. Safety was continuously assessed. Results: For the primary efficacy outcome (TTSTAND), viltolarsen-treated patients showed stabilization of motor function over the first two years and significant slowing of disease progression over the following two years compared with the CINRG DNHS control group which declined. Viltolarsen was well tolerated, with most reported treatment-emergent adverse events being mild or moderate. No participants discontinued drug during the study. Conclusions: Based on the results of this 4-year LTE, viltolarsen can be an important treatment strategy for DMD patients amenable to exon 53 skipping
Treatment with Ataluren for Duchene Muscular Dystrophy
No full textInvestigators from Europe and the USA, representing the STRIDE Registry and Cooperative International Neuromuscular Research Group (CINRG) Duchenne Natural History Study (DNHS), examined the effectiveness of ataluren and standard of care in the Registry versus stand of care alone in the CINRG DNHS
Efficacy and Safety of Viltolarsen in Boys With Duchenne Muscular Dystrophy: Results From the Phase 2, Open-Label, 4-Year Extension Study
Full text linkBackground: Duchenne muscular dystrophy (DMD) is caused by DMD gene mutations, resulting in absence of functional dystrophin protein. Viltolarsen, an exon 53 skipping therapy, significantly increased dystrophin levels in patients with DMD. Presented here are completed study results of >4 years of functional outcomes in viltolarsen-treated patients compared to a historical control group (Cooperative International Neuromuscular Research Group Duchenne Natural History Study [CINRG DNHS]). Objective: To evaluate the efficacy and safety of viltolarsen for an additional 192 weeks in boys with DMD. Methods: This phase 2, open-label, 192-week long-term extension (LTE) study (NCT03167255) evaluated the efficacy and safety of viltolarsen in participants aged 4 to <10 years at baseline with DMD amenable to exon 53 skipping. All 16 participants from the initial 24-week study enrolled into this LTE. Timed function tests were compared to the CINRG DNHS group. All participants received glucocorticoid treatment. The primary efficacy outcome was time to stand from supine (TTSTAND). Secondary efficacy outcomes included additional timed function tests. Safety was continuously assessed. Results: For the primary efficacy outcome (TTSTAND), viltolarsen-treated patients showed stabilization of motor function over the first two years and significant slowing of disease progression over the following two years compared with the CINRG DNHS control group which declined. Viltolarsen was well tolerated, with most reported treatment-emergent adverse events being mild or moderate. No participants discontinued drug during the study. Conclusions: Based on the results of this 4-year LTE, viltolarsen can be an important treatment strategy for DMD patients amenable to exon 53 skipping.</jats:p
Genetic modifiers of upper limb function in Duchenne muscular dystrophy
No full textGenetic modifiers of Duchenne muscular dystrophy (DMD) are variants located in genes different from the disease-causing gene DMD, but associated with differences in disease onset, progression, or response to treatment. Modifiers described so far have been tested mainly for associations with ambulatory function, while their effect on upper limb function, which is especially relevant for quality of life and independence in non-ambulatory patients, is unknown. We tested genotypes at several known modifier loci (SPP1, LTBP4, CD40, ACTN3) for association with Performance Upper Limb version 1.2 score in an Italian multicenter cohort, and with Brooke scale score in the Cooperative International Neuromuscular Group Duchenne Natural History Study (CINRG-DNHS), using generalized estimating equation (GEE) models of longitudinally collected data, with age and glucocorticoid treatment as covariates. CD40 rs1883832, previously linked to earlier loss of ambulation, emerged as a modifier of upper limb function, negatively affecting shoulder and distal domains of PUL (p = 0.023 and 0.018, respectively) in the Italian cohort, as well as of Brooke score (p = 0.018) in the CINRG-DNHS. These findings will be useful for the design and interpretation of clinical trials in DMD, especially for non-ambulatory populations
Genetic modifiers of upper limb function in Duchenne muscular dystrophy
Full text linkGenetic modifiers of Duchenne muscular dystrophy (DMD) are variants located in genes different from the disease-causing gene DMD, but associated with differences in disease onset, progression, or response to treatment. Modifiers described so far have been tested mainly for associations with ambulatory function, while their effect on upper limb function, which is especially relevant for quality of life and independence in non-ambulatory patients, is unknown. We tested genotypes at several known modifier loci (SPP1, LTBP4, CD40, ACTN3) for association with Performance Upper Limb version 1.2 score in an Italian multicenter cohort, and with Brooke scale score in the Cooperative International Neuromuscular Group Duchenne Natural History Study (CINRG-DNHS), using generalized estimating equation (GEE) models of longitudinally collected data, with age and glucocorticoid treatment as covariates. CD40 rs1883832, previously linked to earlier loss of ambulation, emerged as a modifier of upper limb function, negatively affecting shoulder and distal domains of PUL (p = 0.023 and 0.018, respectively) in the Italian cohort, as well as of Brooke score (p = 0.018) in the CINRG-DNHS. These findings will be useful for the design and interpretation of clinical trials in DMD, especially for non-ambulatory populations
Genetic modifiers of respiratory function in Duchenne muscular dystrophy.
Full text linkRespiratory insufficiency is a major complication of Duchenne muscular dystrophy (DMD). Its progression shows considerable interindividual variability, which has been less thoroughly characterized and understood than in skeletal muscle. We collected pulmonary function testing (PFT) data from a large retrospective cohort followed at Centers collaborating in the Italian DMD Network. Furthermore, we analyzed PFT associations with different DMD mutation types, and with genetic variants in SPP1, LTBP4, CD40, and ACTN3, known to modify skeletal muscle weakness in DMD. Genetic association findings were independently validated in the Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG-DNHS)
Genetic modifiers of upper limb function in Duchenne muscular dystrophy
Full text linkGenetic modifiers of Duchenne muscular dystrophy (DMD) are variants located in genes different from the disease-causing gene DMD, but associated with differences in disease onset, progression, or response to treatment. Modifiers described so far have been tested mainly for associations with ambulatory function, while their effect on upper limb function, which is especially relevant for quality of life and independence in non-ambulatory patients, is unknown. We tested genotypes at several known modifier loci (SPP1, LTBP4, CD40, ACTN3) for association with Performance Upper Limb version 1.2 score in an Italian multicenter cohort, and with Brooke scale score in the Cooperative International Neuromuscular Group Duchenne Natural History Study (CINRG-DNHS), using generalized estimating equation (GEE) models of longitudinally collected data, with age and glucocorticoid treatment as covariates. CD40 rs1883832, previously linked to earlier loss of ambulation, emerged as a modifier of upper limb function, negatively affecting shoulder and distal domains of PUL (p = 0.023 and 0.018, respectively) in the Italian cohort, as well as of Brooke score (p = 0.018) in the CINRG-DNHS. These findings will be useful for the design and interpretation of clinical trials in DMD, especially for non-ambulatory populations
Genetic modifiers of ambulation in the CINRG duchenne natural history study.
Full text linkWe studied the effects of LTBP4 and SPP1 polymorphisms on age at loss of ambulation (LoA) in a multiethnic Duchenne muscular dystrophy cohort (DMD). We genotyped SPP1 rs28357094 and LTBP4 haplotype in 283/340 participants in the Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG-DNHS). Median ages at LoA were compared by Kaplan-Meier analysis and log-rank test. We controlled polymorphism analyses for concurrent effects of glucocorticoid corticosteroid (GC) treatment (time-varying Cox regression), and for population stratification (multidimensional scaling of genome-wide markers). Hispanic and South Asian participants (n = 18, 41) lost ambulation 2.7 and 2 years earlier than Caucasian (p = 0.003, <0.001). The TG/GG genotype at SPP1 rs28357094 was associated to 1.2-year earlier median LoA (p = 0.048). This difference was greater (1.9 years, p = 0.038) in GC-treated participants, whereas no difference was observed in untreated. Cox regression confirmed a significant effect of SPP1 genotype in GC-treated participants (HR 1.61, p = 0.016). LTBP4 genotype showed a direction of association with age at LoA as previously reported, but not statistically significant. After controlling for population stratification, we confirmed a strong effect of LTBP4 genotype in Caucasians (2.4 years, p = 0.024). Median age at LoA with the protective LTBP4 genotype in this cohort was 15.0 years, 16.0 if GC-treated. In conclusion, SPP1 rs28357094 acts as a pharmacodynamic biomarker of GC response, and LTBP4 haplotype modifies age at LoA in the CINRG-DNHS cohort. Adjustment for GC treatment and population stratification appears crucial in assessing genetic modifiers in DMD
Supplementary tables: Ataluren delays loss of ambulation and respiratory decline in nonsense mutation Duchenne muscular dystrophy patients
No full textThese are peer-reviewed supplementary tables for the article 'Ataluren delays loss of ambulation and respiratory decline in nonsense mutation Duchenne muscular dystrophy patients' published in the Journal of Comparative Effectiveness Research. Supplementary Table 1. Baseline demographics and disease characteristics for Study 019 patients with nmDMD who received ataluren (40 mg/kg/day) plus SoC in at least Study 019 (N = 59) and for propensity-score matched patients with DMD receiving SoC alone in the CINRG DNHS (N = 59), using age at diagnosis for both datasets as the fourth covariate for matching, for the sensitivity analysis of age at LoA. Supplementary Table 2. Baseline demographics and disease characteristics for non-ambulatory Study 019 patients with nmDMD who received ataluren 40 mg/kg/day plus SoC in at least this study (N = 45) and propensity-score matched patients with DMD who received SoC alone in the CINRG DNHS (N = 45), using age at diagnosis for both datasets as the fourth covariate for matching, for the sensitivity analysis of age at decline in respiratory function. Supplementary Table 3. Treatment-emergent adverse events† experienced by patients in the as-treated population of Study 019 (N = 94). Supplementary Table 4. Lipid profile of patients in the as-treated population of Study 019 (N = 94) at baseline and Week 240. Supplementary Table 5. Hypertensive status of patients in the as-treated population of Study 019 (N = 94) from baseline to Week 240. Supplementary Table 6. ECG results of patients of patients in the as-treated population of Study 019 (N = 94) from screening to post-treatment. Supplementary Table 7. Hepatic and renal abnormalities in patients in the as-treated population of Study 019 (N = 94) from screening to post-treatment. Summary: Aim: We investigated the effect of ataluren plus standard of care (SoC) on age at loss of ambulation (LoA) and respiratory decline in patients with nonsense mutation Duchenne muscular dystrophy (nmDMD) versus patients with DMD on SoC alone. Patients & methods: Study 019 was a long-term Phase III study of ataluren safety in nmDMD patients with a history of ataluren exposure. Propensity score matching identified Study 019 and CINRG DNHS patients similar in disease progression predictors. Results & conclusion: Ataluren plus SoC was associated with a 2.2-year delay in age at LoA (p = 0.0006), and a 3.0-year delay in decline of predicted forced vital capacity to <60% in nonambulatory patients (p = 0.0004), versus SoC. Ataluren plus SoC delays disease progression and benefits ambulatory and nonambulatory patients with nmDMD. ClinicalTrials.gov registration: NCT01557400.</p
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