Efficacy and Safety of Viltolarsen in Boys With Duchenne Muscular Dystrophy: Results From the Phase 2, Open-Label, 4-Year Extension Study

Background: 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

Cooperative international neuromuscular research group duchenne natural history study demonstrates insufficient diagnosis and treatment of cardiomyopathy in duchenne muscular dystrophy

IntroductionCardiomyopathy is a common cause of morbidity and death in patients with Duchenne muscular dystrophy (DMD).MethodsThis investigation was a cross-sectional cross-sectional analysis of clinical data from the multi-institutional Cooperative International Neuromuscular Research Group (CINRG) DMD Natural History Study of 340 DMD patients aged 2-28 years. Cardiomyopathy was defined as shortening fraction (SF) <28% or ejection fraction (EF) <55%.ResultsTwo hundred thirty-one participants reported a prior clinical echocardiogram study, and 174 had data for SF or EF. The prevalence of cardiomyopathy was 27% (47 of 174), and it was associated significantly with age and clinical stage. The association of cardiomyopathy with age and clinical stage was not changed by glucocorticoid use as a covariate (P > 0.68). In patients with cardiomyopathy, 57% (27 of 47) reported not taking any cardiac medications. Cardiac medications were used in 12% (15 of 127) of patients without cardiomyopathy.ConclusionsWe found that echocardiograms were underutilized, and cardiomyopathy was undertreated in this DMD natural history cohort

Duchenne Regulatory Science Consortium Meeting on Disease Progression Modeling for Duchenne Muscular Dystrophy.

INTRODUCTION: The Duchenne Regulatory Science Consortium (D-RSC) was established to develop tools to accelerate drug development for DMD. The resulting tools are anticipated to meet validity requirements outlined by qualification/endorsement pathways at both the U.S. Food and Drug Administration (FDA) and European Medicines Administration (EMA), and will be made available to the drug development community. The initial goals of the consortium include the development of a disease progression model, with the goal of creating a model that would be used to forecast changes in clinically meaningful endpoints, which would inform clinical trial protocol development and data analysis. Methods: In April of 2016 the consortium and other experts met to formulate plans for the development of the model. Conclusions: Here we report the results of the meeting, and discussion as to the form of the model that we plan to move forward to develop, after input from the regulatory authorities

Genetic modifiers of ambulation in the CINRG duchenne natural history study.

We 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

The cooperative international neuromuscular research group Duchenne natural history study-a longitudinal investigation in the era of glucocorticoid therapy: Design of protocol and the methods used

Contemporary natural history data in Duchenne muscular dystrophy (DMD) is needed to assess care recommendations and aid in planning future trials. METHODS: The Cooperative International Neuromuscular Research Group (CINRG) DMD Natural History Study (DMD-NHS) enrolled 340 individuals, aged 2–28 years, with DMD in a longitudinal, observational study at 20 centers. Assessments obtained every 3 months for 1 year, at 18 months, and annually thereafter included: clinical history; anthropometrics; goniometry; manual muscle testing; quantitative muscle strength; timed function tests; pulmonary function; and patient-reported outcomes/ health-related quality-of-life instruments. RESULTS: Glucocorticoid (GC) use at baseline was 62% present, 14% past, and 24% GC-naive. In those ≥6 years of age, 16% lost ambulation over the first 12 months (mean age 10.8 years). CONCLUSIONS: Detailed information on the study methodology of the CINRG DMD-NHS lays the groundwork for future analyses of prospective longitudinal natural history data. These data will assist investigators in designing clinical trials of novel therapeutics