A Phase I/II Study of BMN053 in Subjects With Duchenne Muscular Dystrophy (DMD)

NCT01957059 | Terminated Phase 1 DMC

• 1 other identifier: PRO053-CLIN-01
• Study Type: interventional
• Target: 9
• Locations: 5 countries
• Sites: 6

Brief Summary

The purpose of the study is to see whether BMN053 is safe and effective to use as medication for Duchenne muscular dystrophy (DMD) patients with a mutation around location 53 in the DNA for the dystrophin protein.

Conditions

Duchenne Muscular Dystrophy

Keywords

DMD; Duchenne muscular dystrophy; Duchenne; BMN053; BioMarin

Outcome Measures

Primary Outcomes (1)

• Change from baseline in 6 minute walk test

  after 48 weeks of treatment phase

Secondary Outcomes (10)

• Muscle function

  after 48 weeks treatment phase

• Muscle strength

  after 48 weeks treatment phase

• Pulmonary function

  after 48 weeks treatment phase

• Functional outcomes questionnaire

  after 48 weeks treatment phase

• Adverse Events

  after single intravenous and subcutaneous doses, and after 48 weeks of treatment phase

Study Arms (4)

Dose escalation phase

EXPERIMENTAL

In the dose-escalation phase, following screening assessment, two cohorts of three subjects each receive two single doses of BMN 053 in two study periods (i.e., four single doses in total per subject). In each study period they will receive BMN 053 by IV infusion and by SC injection (separated by one week). The proposed doses are 1 mg/kg (Cohort 1, study period 1), 3 mg/kg (Cohort 2, study period 1), 6 mg/kg (Cohort 1, study period 2) and 9 mg/kg (Cohort 2, study period 2). The actual doses may be amended or repeated based on emerging data from previous doses.

Drug: Regimen Selection Phase Group 1 (COMPLETED)

Regimen selection

EXPERIMENTAL

After completion of the dose-escalation period of Cohort 1, the safety data of the subjects will be reviewed by a DSMB and if no safety concerns these subjects will continue to receive 6 mg/kg BMN053 weekly by SC injection for 48 weeks. 3 more treatment-naïve subjects will be entered into this Group. These 6 subjects will form Group 1 of the Regimen Selection phase who received 6 mg/kg SC. At the time of this amendment (4) this part of the study has been completed. Following completion of the dose-escalation study period of Cohort 2 (9 mg/kg), the planned review of the preliminary plasma PK data from the dose-escalation phase showed a relative bioavailability of 50% for BMN053 with SC dosing (50% lower plasma AUC after SC dosing compared to IV dosing). Taking into consideration the risk of injection site reactions noted with similar compounds when administered SC over longer term, the planned 9 mg/kg BMN053 weekly by SC injection will be discontinued to be replaced by an IV regimen.

Drug: Regimen Selection Phase Group 2; Drug: Regimen Selection Phase Group 3

48-week Treatment Phase

EXPERIMENTAL

Thirty additional treatment-naïve subjects will be recruited for the primary evaluation and will receive treatment at the recommended regimen for a total of 48 weeks. Subjects dosed initially in the dose escalation phase and/or the regimen selection phase of the study will not be included in the primary analysis. Following completion of the 2nd study period for Cohort 2, the safety data will be reviewed by the DSMB and in the absence of safety concerns the subjects may enter the 48 week treatment phase and receive 9 mg/kg PRO053 once weekly by SC injection. Three new subjects will enter cohort 2 (i.e. 6 subjects in total at this dose level). After the initial 12 subjects have completed 12 weeks of dosing the dose for the Treatment group (30 new subjects) will be selected based on the totality of the 12-week data from those initial 12 subjects. The initial 12 subjects will also be dosed on the selected dose (i.e. continue on their dose or \[down-\]titrate).

Drug: Treatment Phase Group 4

Dosing extension

EXPERIMENTAL

All subjects who have completed the dose escalation and regimen selection phase of the study (N=15), and subjects who have complete the treatment phase of the study who have tolerated the treatment will be offered to continue dosing in the dosing extension with ongoing assessment of efficacy, safety, and tolerability of BMN 053. Safety, efficacy, PK/PD and biomarker assessments will be performed at scheduled visits; adverse events (AEs) and concomitant medications and therapies will be continuously monitored. The dose extension phase will provide BMN 053 treatment for 48 weeks.

Drug: Dosing Extension

Interventions

Regimen Selection Phase Group 2 DRUG

All doses of BMN053 will be administered as IV infusions. The proposed doses are as follows: • 3 mg/kg

Regimen selection

Regimen Selection Phase Group 3 DRUG

All doses of BMN053 will be administered as IV infusions. The proposed doses are as follows: • 4-6 mg/kg

Regimen selection

Treatment Phase Group 4 DRUG

All doses of PRO053 will be administered as IV infusions. The proposed doses will be decided upon completion of the Regimen Selection Phase of Groups 2 and 3

48-week Treatment Phase

Regimen Selection Phase Group 1 (COMPLETED) DRUG

All doses of BMN053 have been administered as subcutaneous injections.

Dose escalation phase

Dosing Extension DRUG

All doses of PRO053 will be administered as IV infusions. The proposed doses will be decided upon completion of the Regimen Selection Phase of Groups 2 and 3 and the Treatment Phase Group 4.

Dosing extension

Eligibility Criteria

• Age: 5 Years - 18 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Duchenne muscular dystrophy resulting from a mutation correctable by treatment with BMN053 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).
• 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. In addition, results of the 6MWD test must be within ±30 metres of each other at 2 of 3 pre-treatment visits (screen 1, 2 and baseline) prior to first BMN053 administration.
• 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.
• Glucocorticosteroid use which is stable for at least 3 months prior to first BMN053 administration. Subjects must have been receiving glucocorticosteroids for at least 6 months prior to the first BMN053 administration.
• Willing and able to adhere to the study visit schedule and other protocol requirements.
• Written informed consent signed (by parent(s)/legal guardian and/or the subject, according to the local regulations).
• Anticipated adequate vein access for intravenous (IV) infusion.

You may not qualify if:

• Current or history of liver disease or impairment.
• Current or history of renal disease or impairment.
• At least two aPTT above upper limit of normal (ULN) within the last month prior to first dose of BMN053.
• Screening platelet count below the lower limit of normal (LLN).
• Acute illness within 4 weeks prior to first dose of BMN053 which may interfere with the study assessments.
• Severe mental retardation and/or behavioural problems which, in the opinion of the Investigator, prohibit participation in this study.
• Expected need for daytime mechanical ventilation within the next year.
• Use of anticoagulants, antithrombotics or antiplatelet agents.
• Use of idebenone or other forms of coenzyme Q10 within 1 month prior to the start of the screening for the study.
• 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 BMN053.
• 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.

Sponsors & Collaborators

• BioMarin Pharmaceutical: lead

Study Sites (6)

UZ Leuven, Campus Gasthuisberg

Leuven, 3000, Belgium

Location

Institut de Myologie

Paris, 75651, France

Location

Policlinico Universitario Agostino Gemelli

Rome, 00168, Italy

Location

Leids Universitair Medisch Centrum

Leiden, 2333ZA, Netherlands

Location

Great Ormond Street Hospital for Children

London, WC1N 3JH, United Kingdom

Location

Institute of Genetic Medicine International Centre for Life

Newcastle, NE1 3BZ, United Kingdom

Location

Related Links

• BioMarin website

MeSH Terms

Conditions

Muscular Dystrophy, Duchenne

Condition Hierarchy (Ancestors)

Muscular Dystrophies; Muscular Disorders, Atrophic; Muscular Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases; Genetic Diseases, X-Linked; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities

Study Officials

• V. Straub, Prof.

  Institute of Genetic Medicine, Newcastle University, UK

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 2, 2013
• First Posted: October 8, 2013
• Study Start: June 1, 2013
• Primary Completion: August 3, 2016
• Study Completion: August 3, 2016
• Last Updated: December 8, 2017

Record last verified: 2017-12

Locations

FR (1); IT (1); BE (1); NL (1); GB (2)