A phase II, open-label, extension study to assess the effect of PRO044 in patients with Duchenne muscular dystrophy

Duchenne mucular dystrophy (DMD) is the most frequent genetic childhood*s
disease, affecting 1 in 3500 new-born boys. Due to the disease, the muscle
cells cannot produce the protein dystrophin. Patients begin to show the first
signs of muscle weakness as early as the age of 2. The skeleton muscles in the
arms, legs and trunk become gradually weaker. Also, the respiratory muscles and
the hart become weaker from early adolescence on. Most DMD patients are often
wheelchair bound before the age of 12. Before the introduction of assisted
ventilation, patients died around the age of 20. The disease causes serious
constrictions and morbidity. Currently, only prednisone is accepted to slow
down the disease progression.
However, side effects such as overweight, osteopenia or osteoporosis, effect on
behaviour, hypertension, cataract, growth retardation and hormonal problems are
associated with this therapy. Other therapies have been investigated already,
such as muscle cell, stem cell transplantation, drugs and gene therapy. None of
these strategies seemed to be applicable in clinic.
Antisense-induced exon skipping is a new and promising approach to induce
production of novel dystrophin like patients with Becker Muscular Dystrophy.
This approach could strongly slow down or even stop the progression of DMD.
In this study, PRO044, an antisense oligonucleotide inducing exon 44 skipping,
will be investigated. PRO044 has been shown to be effective in cultured muscle
cells of DMD patients with gen deletions of exon 45 and 45-54.
The information gained from this trial (PRO044-CLIN-02) is expected to be
further characterize the efficacy and safety of PRO044 over a longer treatment
period of 48 weeks.

The objective of the study is to assess the safety, tolerability and efficacy
of PRO044.

Phase II, Open label extension study
2 doses (6 or 9 mg/kg); subcutaneous or intravenous

If patient and parents consented to participate to the clinical trial, the
patient will be allocated to one of the following arms:
- Weekly subcutaneous dosing with PRO044 6mg/kg
- Weekly intraveneous dosing with PRO044 6mg/kg
- Weekly intraveneous dosing with PRO044 9mg/kg

The study will last 69 weeks in total and in this period, the patient will
visit the hospital 52 times. Of those 52 times, the patient will need to stay
in the hospital 4 times; during these visit, PRO044 will be injected and the
patients will be followed up during 24 hours.

The following treatments will be done once or several times during the study:
PRO044 administration
Physical examination
Vital signs
ECG
Echocardiography
Renal ultrasound
Urinalysis
Biochemistry/haematology
Blood drawn
MRI and MRS
Muscle biopsy
If necessary: dermatology consultation

If possible efficacy parameters: 6 minute walking distance, timed function
tests, handheld myometry, North Star Ambulatory Assessment (NSAA), spirometry,
performance of upper limb (PUL), Patient Reported Outcome Measure (PROM), DMD
functioning and activity survey, and Egen Klassification for non-ambulant
subjects.
For a more detailed overview, see Appendix 1 of the protocol (p. 68 onward)