An open-label extension study of the long-term safety, tolerability and efficacy of drisapersen in subjects with Duchenne Muscular Dystrophy.

Duchenne Muscular Dystrophy (DMD) is the most frequent genetic moral child
disease with an incidence of 1 in 3500 newborn boys. Due to the disease the
cells in the muscles cannot produce the protein dystrophyn. The first signs of
muscle weakness can start from the age of 2. The skeleton muscles in the arms,
legs and torso will become weaker gradualy. Most of the DMD patients are in
wheelchairs before they become 12 years old. Before mechanical ventilation was
introduced, most patients died around their twenties.

The disease leads to severe disability and morbitidy. Prednison is accepted to
decrease the progress of the disease. However, this therapie also leads to
adverse events, such as obesity, osteopenia or osteoporosis, effect on
behaviour, hypertension, cataract, disturbance in growth and hormonal
reactions.

Different other therapeutic strategies have been under research without succes,
such as muscle cell and stam cell transplants, mediations and genetic
therapies.

Antisense exon skipping is a new, promissing way to induce the amount of
dystrophyn in the muscles, similar like patients with Becker muscular
dystrophy. This would decrease the progression of DMD or maybe could even stop
the progression.

In this study, drisapersen (BMN051) will be researched, a antisense
oligonucleotide which skips exon 51. Information about earlier studies with
this medication will be available in the study protocol and in the
Investigator's Brochure.

The purpose of this study is to assess the safety, tolerability and efficacy of
long term drisapersen in subjects with DMD.

This is a phase IIIb, multi-centre, open-label, uncontrolled extension study in
male subjects with DMD who have previously been treated with drisapersen.

This study aims to enroll up to approximately 220 subjects.

The primary dosing arm is drisapersen 6 mg/kg as subcutaneous (SC) injection(s)
once a week. All subjects starting with subcutaneous injections will receive a
loading dose of twice weekly 6mg/kg drisapersen for the first three weeks of
treatment. This study does not have a minimum duration of participation.
Subjects will have varying times of study participation depending on when they
enter from one of the eligible studies and will be permitted to continue the
study until such a time that they withdraw based on protocol-defined criteria,
or BioMarin stops the study as described in Section 5.6 of the protocol.

For subjects who have previously experienced significant safety or tolerability
issues in one of the eligible studies, or who experience these during this
study, there is the potential of an alternate intermittent dosing arm. This
will be agreed in advance with the Medical Monitor.

For subjects who have previously experienced significant injection site
reactions in an earlier drisapersen study, or who experience similar
reaction(s) during this study, there is the potential to be dosed
intravenously. IV administration may also be available for subjects based on
other reasons. Studies are ongoing to determine the feasibility and safety of
intravenous administration with a maximum exposure of 6 mg/kg/week over a 2
hour infusion time. Currently data is available to support IV dosing of
3mg/kg/week over a 1 hour infusion time. A switch to intravenous
administration will be agreed in advance with the Medical Monitor.

The primary dosing arm is drisapersen 6 mg/kg as subcutaneous (SC) injection(s)
once a week. All subjects starting with subcutaneous injections will receive a
loading dose of twice weekly 6mg/kg drisapersen for the first three weeks of
treatment. This study does not have a minimum duration of participation.
Subjects will have varying times of study participation depending on when they
enter from one of the eligible studies and will be permitted to continue the
study until such a time that they withdraw based on protocol-defined criteria,
or BioMarin stops the study as described in Section 5.6 of the protocol.

For subjects who have previously experienced significant safety or tolerability
issues in one of the eligible studies, or who experience these during this
study, there is the potential of an alternate intermittent dosing arm. This
will be agreed in advance with the Medical Monitor.

For subjects who have previously experienced significant injection site
reactions in an earlier drisapersen study, or who experience similar
reaction(s) during this study, there is the potential to be dosed
intravenously. IV administration may also be available for subjects based on
other reasons. Studies are ongoing to determine the feasibility and safety of
intravenous administration with a maximum exposure of 6 mg/kg/week over a 2
hour infusion time. Currently data is available to support IV dosing of
3mg/kg/week over a 1 hour infusion time. A switch to intravenous
administration will be agreed in advance with the Medical Monitor.

The duration of the study is approximately 122 weeks. The patient will visit
the clinic every week during this period. THe patient can be admitted to the
hospital 1 time in this period for a port-a-cath(r) surgery to allow an easier
access for IV administration.
The patient will be adminsterd with study drug every week, unless the patient
is in the intermittent dosing arm. If the latter, the patient will be
adminstered with study drug 8 week (6mg/kg) and 4 weeks of treatment. Patients
on IV treatment may receive their treatment at the daycare center during the
study.

The following assessments will be performed 1 or more times during the study:

administration of drisapersen
physical examination
vital signs
ECG
Echocardiography
urine assessment
Biochemistry/hematology
bloodsamples (assessment of thrombocytes)
MRI
if necessary a skin biopt
If possible efficacy assessments: 6 minute walk test, nort start ambulatory
assessment (NSAA, lung function assessment, Performance upper limb (PUL),
Patient reported outcome measure (PODCI), EQ-5D-5L questionnaire.

For a detailed overview of the assesments, see appendix 1 of the protocol