Primary objective: To assess the efficacy of BMN 053 at recommended dosing regimen after 48 weeks treatment in ambulant subjects with Duchenne muscular dystrophy.Secondary objectives: - To assess the safety and tolerability of BMN 053 after single…
ID
Source
Brief title
Condition
- Muscle disorders
- Neuromuscular disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Change from baseline in 6MWD after 48 weeks of treatment phase for primary
evaluation at recommended regimen
Secondary outcome
Efficacy (at all available study visits):
• 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 α1-microglobulin, microscopy) and 24-hour
urine (additionally including protein electrophoresis, urine cystatin and KIM
1)
• Coagulation parameters (aPTT, PTT [INR], fibrinogen)
• Complement C3 and split products (C3a, SC5b-9, Bb)
• Pro inflammatory markers (cytokines IL-6, TNF-α 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 * (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)
• BMN 053 concentrations in urine
• BMN 053 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)
Background summary
Duchenne muscular dystrophy (DMD) is a chromosome X-linked recessive muscle
disorder, affecting 1/3500 newborn boys. Patients experience severe progressive
muscle weakness and wasting, leading to early morbidity and mortality. DMD is
caused by alterations in the gene coding for the protein dystrophin which leads
to little or no dystrophin being produced. Dystrophin is essential for the
integrity and functioning of muscle fibres. Becker muscular dystrophy is also
caused by mutations in the DMD gene, but these maintain the open reading frame,
yield semi-functional dystrophin proteins, and result in a typically much
milder phenotype and longer lifespan.
First signs of muscle weakness typically occur before the age of 4 years and
gradually progress to include skeletal muscles in the arms, legs and trunk.
Over time, heart muscle and respiratory muscles are affected. Even with more
recent clinical interventions, such as glucocorticosteroid treatment and
ventilatory support, DMD patients are usually wheelchair-bound by their
mid-teens and generally die in their twenties/early thirties. Although
glucocort/costeroids and assisted ventilation have altered the natural course
of DMD, there is still no effective
treatment for the primary cause of the disease. A promising therapeutic
strategy is treatment with antisense oligonucleotides that induce specific exon
skipping during pre-mRNA splicing, aimed at reading frame correction and
production of a Becker-like transcript. Although the functionality of the
resulting protein may vary, this treatment could delay or even stop disease
progression and improve remaining muscle function.
Exon skipping provides a mutation-specific, and thus personalized, therapeutic
approach for DMD patients. As mutations cluster around exons 45 to 55, the
skipping of one specific exon may be therapeutic for many patients with
different mutations. The skipping of exon 53 applies to a subset of patients
(~8%). Non-clinical studies on BMN053 have shown its skipping efficiency,
safety and favourable PK profile, and proof-of-concept for therapeutic exon 53
skipping therapy; inducing novel dystrophin production in cultured muscle cells
from a DMD patient with a relevant mutation.
The aim of BioMarin's therapeutic strategy is to use RNA modulation (exon
skipping) to change the severe form of the disease (DMD) into a milder form
(BMD), in the expectation of a much improved outcome. The clinical phenotype of
BMD is variable and depends on the resulting levels of dystrophin and/or the
functionality of the truncated protein. Cases have been described that are very
severe and similar to DMD, others can be very mild (muscle cramps only) or even
asymptomatic. Remarkably, very mild BMD patients have been described, who lack
up to 67% of the central rod domain. This suggests, that despite large
deletions, a partially functional dystrophin can be generated.
Study objective
Primary objective:
To assess the efficacy of BMN 053 at recommended dosing regimen after 48 weeks
treatment in ambulant subjects with Duchenne muscular dystrophy.
Secondary objectives:
- To assess the safety and tolerability of BMN 053 after single intravenous
(IV) and subcutaneous (SC) dose in subjects with Duchenne muscular
dystrophy.
- To investigate the pharmacokinetics BMN 053 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 BMN 053 at different dosing regimens in
subjects with Duchenne muscular dystrophy.
- To assess efficacy trends and safety of BMN 053 in subjects with Duchenne
Muscular Dystrophy not included in the primary analysis after
48 weeks of dosing and/or dosing extension.
Study design
A Phase I/II, open-label study. The study consists of four phases; a
dose-escalation phase, a regimen selection phase, a treatment phase and a dose
extension phase.
Intervention
Doses with the IP, BMN 053, will be administered intravenously weeklyto study
subjects in the regimen selection phase of the study.
The proposed starting doses in each regimen selecition group are
as follows:
Group 1: 6 mg/kg/week sc voor 48 weken. Dit gedeelte is afgerond
Group 2: 3 mg/kg via IV infuus voor 48 weken.
Group 3: Potentieel varierend van 4-6 mg/kg/week IV infuus
Treatment phase:
BMN 053 will be given to 30 treatment naïve subjects at the recommended regimen
for 48 weeks based upon data from the dose escalation and regimen selection
phases of the study.
Dose extension phase:
Subjects who have completed the dose escalation and regimen selection phases of
the study, and subjects who have completed the treatment phase will continue
BMN 053 treatment in this extension phase.impact the available subject numbers
for the treatment phase. All Subjects from the dose-escalation phase will
continue into the treatment phase for safety and secondary efficacy analysis.
The expected duration of the study is in total:
Regimen selection phase: 48 weeks
Treatment phase: 48 weeks
Dose Extension phase: 48 weeks
Follow-up period: 24 week
Study burden and risks
DMD is a lethal disease for which at present no effective treatment is
available. In view of the observed toxicity profile in non-clinical studies and
the experience obtained with compounds with similar chemistry in clinical
studies, as well as the proposed safety management in the study, it is
considered acceptable to initiate the clinical development of BMN 053.
This is the first time that BMN 053 is studied in humans. The most common side
effects reported with similar oligonucleotides are: injection site reactions,
changes in hepatic and renal protein levels and decrease of platelets in the
blood. Furthermore pro-inflammatory effects have been observed. Other risks are
as follows: a small bleeding at the place of injection or at the place where
the blood is drawn, pain at the place where the biopsies are taken, the site of
the biopsy may feel numb or become infected, a scar at the place of biopsy and
it is possible that the strenght of the muscle may be slightly reduced in the
short term, and a reaction to the general anaesthesia.
Patients will receive standard treatment, in addition patients will receive an
injection every week with the study drug.
There are risks involved in joining this study and also the burden is
increased, as patients need an injection every week
and blood is drawn regularly. However, if this treatment is a succes in these
patients, there will be a change in the
severity of their disease and it is expected that this will lead to an improved
outcome.
Digital Drive 105
Novato CA94949
US
Digital Drive 105
Novato CA94949
US
Listed location countries
Age
Inclusion criteria
1. 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).
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 screening visit and also at the baseline visit. In addition, results of 2 of any of the 3 pre-treatment 6MWD tests (assessed screen
1, screen 2, baseline) must be within ±30 metres of each other prior to first BMN053 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
BMN053 administration. Subjects must have been receiving glucocorticosteroids
for at least 6 months prior to the first BMN053 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.
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 BMN053 which may interferewith 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 BMN053.
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
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2011-005042-35-NL |
| CCMO | NL43736.000.13 |