Duchenne muscular dystrophy resulting from a mutation correctable by PRO053-induced DMD exon 53 skipping MedDRA version: 18.1 Level: PT Classification code 10013801 Term: Duchenne muscular dystrophy System Organ Class: 10010331 - Congenital, familial and genetic disorders
Conditions
Interventions
Product Name: BMN053
Product Code: BMN053
Pharmaceutical Form: Solution for injection/infusion
INN or Proposed INN: PS524
Current Sponsor code: PS524
Concentration unit: mg/ml milligram(s)/millilitre
Sponsors
BioMarin Nederland B.V.
Eligibility
Sex/Gender
Male
Inclusion criteria
Inclusion criteria: 1. Duchenne muscular dystrophy resulting from a mutation correctable by treatment with PRO053 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 HRMCA (High-Resolution Melting Curve Analysis). 2. Ambulant boys aged at least 5 years on the day of first dosing able to walk for at least 300 metres in the 6 minute walking distance (6MWD) test at the first screeining visit and also at the baseline visit. In addition, results of 2 of any of the 3 pretreatment 6MWD test (assessed screen 1, screen 2, baseline) must be within ±30 metres of each other prior to first PRO053 administration. Subjects must also be able to rise from the floor in = 7 seconds at the first screening visit and also at the baseline visit. 3. Adequate quality for biopsy (confirmed with MRI) of the lateral head of the gastrocnemius muscle. Only under exceptional circumstances will an alternative muscle (preferably brachii) be considered for biopsy and only following discussion between the Principal Investigator and the BioMarin Medical Monitor. 4. Life expectancy of at least 3 years after inclusion in the study. 5. Glucocorticosteroid use which is stable for at least 3 months prior to first PRO053 administration. Subjects must have been receiving glucocorticosteroids for at least 6 months prior to the first PRO053 administration. 6. Willing and able to adhere to the study visit schedule and other protocol requirements. 7. Written informed consent signed (by parent(s)/legal guardian and/or the subject, according to the local regulations). 8. In France, a subject will be eligible for inclusion in this study only if either affiliated to, or a beneficiary of, a social security category. 9. Anticipated adequate vein access for intravenous (IV) infusion. Are the trial subjects under 18? yes Number of subjects for this age range: 45 F.1.2 Adults (18-64 years) no F.1.2.1 Number of subjects for this age range F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: 1. Current or history of liver disease or impairment. 2. Current or history of renal disease or impairment. 3. Screening aPTT above upper limit of normal (ULN). 4. Screening platelet count below the lower limit of normal (LLN). 5. Acute illness within 4 weeks prior to first dose of PRO053 which may interfere with the study assessments. 6. Severe mental retardation and/or behavioural problems which, in the opinion of the Investigator, prohibit participation in this study. 7. Severe cardiomyopathy which, in the opinion of the Investigator prohibits participation in this study. If a subject has a left ventricular ejection fraction <45% at screening, the Investigator should discuss inclusion of the subject with the Medical Monitor. 8. Expected need for daytime mechanical ventilation within the next year. 9. Use of anticoagulants, antithrombotics or antiplatelet agents. 10. Use of idebenone or other forms of coenzyme Q10 within 1 month prior to the start of the screening for the study. 11. Use of nutritional or herbal supplements which, in the opinion of the Investigator, may influence muscle performance within 1 month prior to first dose of PRO053. 12. Use of any other investigational product or participation in another trial with an investigational product, within 6 months prior to the start of the screening for the study.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To assess the efficacy of PRO053 at recommended dosing regimen after 48 weeks treatment in ambulant subjects with Duchenne muscular dystrophy.;Secondary Objective: To assess the safety and tolerability of PRO053 after single intravenous (IV) and subcutaneous (SC) dose and after 48 weeks of treatment in subjects with Duchenne muscular dystrophy. To investigate the pharmacokinetics PRO053 at different dosing regimens in subjects with Duchenne muscular dystrophy. To assess the safety and tolerability at different dosing regimens in subjects with Duchenne muscular dystrophy. To assess the pharmacodynamics of PRO053 at different dosing regimens in subjects with Duchenne muscular dystrophy. To assess efficacy trends and safety of PRO053 in subjects with Duchenne Muscular Dystrophy not included in the primary analysis after 48 weeks of dosing and/or dosing extension.;Primary end point(s): Change from baseline in 6MWD after 48 weeks of treatment phase for primary evaluation at recommended regimen;Timepoint(s) of evaluation of this end point: At screening, baseline, at weeks 13, 25, 37 and 49 | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Efficacy: • Muscle function (North Star Ambulatory Assessment, Timed tests, 6MWD) • Muscle strength (handheld myometry) • Pulmonary function (spirometry) • Performance of upper limb (PUL) • DMD Functional Outcomes Questionnaire (DMD-FOS) • Exploratory efficacy endpoints: - Accelerometry - Myotools (grip strength, key pinch, moviplate) Safety parameters: • Adverse events • Local tolerability • Laboratory assessments including: - Routine biochemistry and haematology - Urinalysis (routine parameters plus 1-microglobulin, microscopy) and 24-hour urine (additionally including protein electrophoresis, urine cystatin and KIM-1 and exploratory measurement of specific DMD protein biomarkers and micro RNAs) - Coagulation parameters (aPTT, PTT [INR], fibrinogen) - Complement C3 and split products (C3a, SC5b-9, Bb) - Pro-inflammatory markers (cytokines IL-6, TNF- and chemokine MCP-1) • Anti-dystrophin antibodies • ECG parameters • Vital signs (temperature, blood pressure, pulse rate, respiration rate) • Echocardiography • Physical examination • DEXA • Standard renal ultrasound Pharmacokinetic parameters: • t ½ (if reliable) • AUC: 0-24h, 0-72h, 0-7d, 0- (where applicable) • Cmax, Ctrough, 7d • tmax • Vd (for IV) or Vd/F (for SC) • CL (for IV) or CL/F (for SC) • PRO053 concentrations in urine • PRO053 concentrations in muscle tissue Pharmacodynamic parameters: • Presence of (BMD-like) dystrophin expression after treatment (in muscle biopsy) • Histological and immunological staining on cross-sections of muscle tissue • Production of exon skip 53 mRNA (in muscle biopsy) • Exploratory PD endpoints: - Nuclear Magnetic Resonance imaging and spectroscopy (MRI and MRS) - Exploratory biomarkers(e.g. MMP-9, miR-1, miR-133);Timepoint(s) of evaluation of this end point: Efficacy: at all available study visits Safety: at all time points Pharmacokinetic parameters: per protocol Pharmacodynamic parameters: per protocol | — |
Countries
Argentina, Australia, Belgium, Brazil, Bulgaria, Chile, France, Germany, Hungary, Israel, Italy, Japan, Netherlands, Poland, Turkey, United Kingdom, United States
Contacts
Public ContactClinical department
BioMarin Nederland B.V.
Outcome results
None listed