a clinical study to assess two doses of gsk2402968 in subjects with duchenne muscular dystrophy (dmd)

Conditions: Muscular Dystrophies

Summary: the purpose of this study is to determine if gsk2402968 is effective in the treatment of ambulant boys with duchenne muscular dystrophy resulting from a mutation thought to be corrected by exon 51 skipping. two doses of gsk2402968 and placebo will be used in this study.

boys with duchenne muscular dystrophy (dmd) suffer from a relentless, progressive and fatal disease due to lack of dystrophin, a critical muscle protein. there is currently no known cure for the disease. gsk2402968 is thought to correct several genetic mutations through skipping of exon 51 and therefore targets only those boys with these mutations. a reasonable hypothesis is that increasing dystrophin will result in clinical improvement, and that the amount of dystrophin expressed will correlate with clinical improvement above a threshold level (e.g. around 30% of control). the initial limited efficacy data from completed and ongoing unblinded studies with gsk2402968 are encouraging as they have demonstrated de novo production of dystrophin and improved walking ability (primary efficacy endpoint) after 48 weeks of treatment which has been generally well tolerated. this study is designed to explore the efficacy, safety and pharmacokinetics of two doses of gsk2402968 given over 24 weeks. the two doses to be assessed are 6mg/kg/week and 3mg/kg/week. based on pharmacokinetic and pharmacodynamic modeling, it is predicted at steady-state that the 6 mg/kg/week dose will induce dystrophin expression greater than 30% of control. the 3 mg/kg/week dose was chosen as modeling predicts 3 mg/kg/week of gsk2402968 will produce dystrophin expression in the range of 18-22%. potential variability between subjects could theoretically produce higher expression and lead to a dystrophin level correlated with clinical improvement. following the treatment period, the study has a 24 week post-treatment phase. the purpose of the post-treatment phase is to model the half-life of dystrophin, assess maintenance of response, and provide information about resolution of adverse event and laboratory abnormalities following cessation of treatment.

Eligibility criteria:
inclusion criteria: * ambulant subjects with duchenne muscular dystrophy (dmd) resulting from a mutation/deletion within the dmd gene, confirmed by a state-of-the-art dna diagnostic technique covering all dmd gene exons, including but not limited to mlpa (multiplex ligation-dependent probe amplification), cgh (comparative genomic hybridisation), scaip (single condition amplification/internal primer) or h-rmca (high-resolution melting curve analysis), and correctable by gsk2402968-induced dmd exon 51 skipping * males, aged at least 5 years, * life expectancy of at least 1 year, * able to rise from floor in \< or =15 seconds (without aids/orthoses) at screening visit 1 and screening visit 2, * able to complete 6 minute walk distance (6mwd) test with minimal distance of at least 75 meters, with reproducible results (within 20% of each other) at screening visit 1, screening visit 2 and at the baseline visit prior to randomization, * receiving oral glucocorticoids for a minimum of 6 months immediately prior to screening, with no significant change in total daily dosage or dosing regimen for a minimum of 3 months immediately prior to screening and a reasonable expectation that total daily dosage and dosing regimen will not change significantly for the 48 week duration of the study (dose adjustments that are based on weight changes are permitted), * qtc \<450msec (based on single or average qtc value of triplicate ecgs obtained over a brief recording period), or \<480 msec for subjects with bundle branch block. note: qtc may be either qtcb or qtcf, and machine read or manual overread * willing and able to comply with all protocol requirements and procedures, * able to give informed assent and/or consent in writing signed by the subject and/or parent(s)/legal guardian (according to local regulations). exclusion criteria: * any additional missing exon for dmd that cannot be treated with gsk2402968, * current or history of liver disease or impairment including : 1. an inr vaue above 1.5 is in and of itself exclusionary 2. a total bilirubin greater than 2 times the upper limit of normal is in and of itself exclusionary 3. a ggt greater than 2 times the upper limit of normal is in and of itself exclusionary * current or history of renal disease or impairment, * baseline platelet count below the lower limit of normal, * appt above the upper limit of normal, * history of significant medical disorder which may confound the interpretation of either efficacy or safety data e.g. inflammatory disease * acute illness within 4 weeks of the first anticipated administration of study medication which may interfere with study assessments, * use of anticoagulants, antithrombotics or antiplatelet agents, previous treatment with investigational drugs, idebenone or other forms of coenzyme q10 within 1 month of the first administration of study medication, * current or anticipated participation in any investigational clinical studies, * positive hepatitis b surface antigen, hepatitis c antibody test (if verified via riba or pca testing), or human immunodeficiency virus (hiv) test at screening, * symptomatic cardiomyopathy. if subject has a left ventricular ejection fraction \<45% at screening, the investigator should discuss inclusion of subject in the study with the medical monitor, * children in care. the definition of a child in care is a child who has been placed under the control or protection of an agency, organisation, institution or entity by the courts, the government or a government body, acting in accordance with powers conferred on them by law or regulation. the definition of a child in care can include a child cared for by foster parents or living in a care home or institution, provided that the arrangement falls within the definition above. the definition of a child in care does not include a child who is adopted or has an appointed legal guardian

Keywords: 968 duchenne muscular dystrophy gsk2402968 dmd duchenne gsk