A multi center, multi national, open label, extension study to evaluate the long-term efficacy and safety of BMN 044 (PRO044) in subjects with Duchenne muscular dystrophy

This research study is being conducted to find out whether an experimental
treatment, BMN 044, is safe and could improve or stabilise muscle strength for
patients with DMD who have mutations correctable by skipping exon 44.
The experimental treatment that will be used in this research study is an
"antisense oligoribonucleotide" (AON for short). When the instructions in the
gene are read, BMN 044 will SKIP over the faulty portion of the gene, exon 44,
and fit the pieces back together again. This produces a shorter but working
dystrophin protein, and it is hoped that this protein may help to prevent
muscles getting weaker over time. This experimental treatment is not a cure
for DMD.
This research study will allow people that have previously received BMN 044 in
studies that have closed, to continue treatment with BMN 044. Research so far
has assessed different BMN 044 doses and regimens, and one of the aims of this
research study is to review this information and decide what is the best dose
and regimen of BMN 044 for patients to receive.
BMN 044 is currently in the Phase 2 stage of clinical development, which means
that patients can only receive this treatment by participating in research
studies. It is made by BioMarin, a biopharmaceutical company in the United
States.

The aim of this study is to provide continuing access to BMN 044 treatment for
subjects previously treated with the study drug. The information gained from
this study is expected to further characterize the efficacy and safety of BMN
044 over a longer treatment period.

The primary objective of the study is:
* To evaluate the long-term safety of BMN 044 in subjects with DMD correctable
by BMN 044-induced DMD exon 44 skipping who have previously participated in an
eligible study

The secondary objectives of the study are:
Treatment Period 1:
* To evaluate the long-term efficacy of the dosing regimens used in prior BMN
044 studies.
* To evaluate the long-term safety and tolerability of the dosing regimens used
in prior BMN 044 studies.
Treatment Period 2:
* To evaluate the long-term efficacy of a selected dosing regimen(s) for BMN
044.
* To evaluate the long-term safety and tolerability of a selected dosing
regimen(s) for BMN 044.
* To evaluate the long-term impact on functional outcomes of continued
treatment with BMN 044.

This is a phase 2 multi-center, multi-national, open-label, extension study
aiming to enroll up to approximately 50 male subjects with DMD who have
previously been treated with BMN 044.
This study will be split into 2 dosing periods; Treatment Period 1 (where
subjects continue on their existing regimen) and Treatment Period 2 (a selected
regimen for all subjects). This 2 stage design will allow subjects to continue
treatment with BMN 044 following completion of existing protocols, receiving
their existing regimen, whilst the BMN 044 data from completed studies are
reviewed to determine if further dose exploration is required or a recommended
regimen is agreed for all subjects. As a result, subjects will have varying
times of study participation depending on their date of enrolment. Subjects
will be permitted to continue in this study until the subject meets any of the
defined withdrawal criteria, BioMarin decides to halt the clinical development
of BMN 044, or BMN 044 receives marketing authorization.

Screening
At enrolment all subjects will be required to attend a "Re-start Visit" to
record assessment prior to switching treatment regimens; this will be known as
the "baseline" assessments. Boys who have not switched directly from a parent
study and who have had more than 4 weeks off BMN 044 treatment will be required
to have their active baseline assessments performed within 28 days prior to the
Day 0 dosing visit for Treatment Period 1. Assessments performed during the
parent study final visit can be used as the active baseline assessments, only
if this visit has been performed within 28 days prior to Day 0.

Treatment Period 1
Subjects will continue to receive their existing dosing regimens (dose, route
and frequency) from the parent study (including both subcutaneous and
intravenous administrations), provided no dose-limiting toxicities were
observed. If required, subjects may have their dose regimens changed to one of
the regimens being used in Treatment Period 1, following consultation with the
Medical Monitor. Subjects previously randomized to receive placebo will be
treated with BMN 044 in Treatment Period 1 at 9.0 mg/kg intravenous dose.
Once all BMN 044 parent studies have completed and all eligible subjects have
been enrolled in to this extension study, all existing data for the BMN 044
studies will be reviewed by BioMarin and Data Monitoring Committee (DMC).
Following review of the BMN 044 data, a program decision will be made regarding
the ongoing regimen(s) to be used in all subjects for Treatment Period 2.

Treatment Period 2
Once a program level decision is made, all subjects will switch to Treatment
Period 2 and receive the selected regimen(s). Treatment Period 2 will become
active at individual sites as soon as the protocol amendment, detailing the
selected regimen(s), is approved. In the event of more than one dosing regimen
being selected for Treatment Period 2, the dosing regimen for an individual
subject will be decided by the Medical Monitor in conjunction with the treating
Investigator. Assessments pre-dose this Treatment Period 2 will be referred to
as "active baseline".

For the first 4 weeks of Treatment Period 1 dosing (Day 0 * Week 3) subjects
will visit the clinic at least once every week for BMN 044 dosing and basic
safety assessments. For subjects receiving subcutaneous BMN 044 on a frequency
higher than once weekly (e.g. daily), subjects may receive injections at home
(*home* includes a local setting agreed with BioMarin, the nursing organization
and the family, this includes satellite sites), administered by a home nurse.

From Week 5, provided there are no medical concerns, subjects may become
eligible to receivesubcutaneous injections or intravenous infusions at home,
administered by a home nurse. Home nurse support is limited and will be decided
by the Medical Monitor in conjunction with the treating Investigator. If the
subject receives home treatment, the subject will be required to visit the
clinic once every 4 weeks.

Following the transition of subjects to Treatment Period 2, all subjects will
attend clinic once a week for the first 4 weeks, to monitor the subjects during
this regimen transition period. Provided there are no medical concerns,
subjects may be offered treatment through nurse-led home dosing. This will be
decided by the Medical Monitor in conjunction with the treating Investigator.
If the subject receives home treatment, the subject will be required to visit
the clinic once every 4 weeks.

Subjects will be evaluated for safety throughout the study, using well
established safety monitoring criteria, including stopping criteria for adverse
events of special interest. Severity of adverse events will be measured
according to the National Cancer Institute (NCI) Common Terminology Criteria
for Adverse Events (CTCAE), Version 4.03.

In addition to BioMarin, a DMC will monitor the safety of subjects in the
study. The DMC is an independent committee that will act in an advisory
capacity to BioMarin.

INVESTIGATIONAL PRODUCT(S), DOSE, ROUTE AND REGIMEN:
Name: BMN 044 (previously called PRO044)
Product: Active ingredient is PS188 which is the sodium salt of a 20-mer 2*-
O-methyl-phosphorothioate oligoribonucleotide with a sequence optimized to skip
exon 44 in the human dystrophin pre-mRNA.
Formulation: Solution of the active ingredient PS188 in 20 mM phosphate buffer,
pH 7 solution for injection (200 mg/ml)
Strength: 200 mg/mL
Vial content: 0.7 mL or 1.0 mL in a 2R glass type I vial.

During treatment period 1 as well as during treatment period 2, the patient
will be asked to visit the investigator weekly, unless het receives BMN 044 on
a daily basis.

Following assessments will be done:

BMN 044 administration: weekly or daily
Physical examination: baseline, then every 12 weeks
Vital signs - injections: baseline, then every 12 weeks
Vital signs - infusions: weekly
Height/BMI: baseline
Weight: baseline, then every 4 weeks
Electrocardiogram: baseline, week 2, 3, 4, week 13, week 25, then every 12
weeks for period 1; week 1, 2, 3, 4, 13, 25, then every 12 weeks for period 2;
withdrawal visit.
Echocardiography: screening, baseline, withdrawal visit
Dermatology Assessment: baseline, then every 24 weeks
Skin Assessment: weekly
Urine testing: screening, baseline; Period 1: week 5, 9, 13, 17, 21, 25, as
from week 26 every 4 weeks; Period 2: Week 1, 3, 5, 7, 9, 13, 17, 21, 25, as
from week 26 every 4 weeks; EOT, FU.
Blood sampling: baseline, then every 4 weeks (Assuming that Treatment Period 1
of this study will be active for at least one year, the total blood taken from
patients in the first year of study participation is 349,0 ml. The first year
of Treatment Period 2 will require a total volume of 391,3 ml. Any following
year of either Treatment Period 1 or 2 will require 321,1 ml of blood.)
Additional blood sample: only for patients receiving IV infusions
Muscle tests: baseline, week 25, then every 24 weeks during period 1; week 1,
week 25, then every 24 weeks during period 2; withdrawal visit
Questionnaires: baseline, week 25, then every 24 weeks during period 1; week
1, week 25, then every 24 weeks during period 2; withdrawal visit.
Adverse events: weekly
Concomitant medications: weekly

Treatment with BMN 044 will continue until the patient no longer wishes to
participate in this research study, or if treatment results in side-effects
that requires him to stop receiving BMN 044, or if the research study is
stopped or if BMN 044 is available as prescribed medication in The Netherlands.