A phase II, double blind, exploratory, parallel-group, placebo-controlled clinical study to assess two dosing regimens of GSK2402968 for efficacy, safety, tolerability and pharmacokinetics in ambulant subjects with Duchenne muscular dystrophy

At the moment, there is no treatment available to prevent the progression of
DMD. Glucocorticosteroids are used as the current standard of care but they do
not alter the fundamental course of this seriously disabling and ultimately
fatal disease. New treatments are needed that can help to relieve the symptoms
of this disease and prolong the lifespan and quality of life of affected
individuals.

GSK2402968 has been explored at doses up to 6 mg/kg subcutaneous weekly
initially for 5 weeks in ambulant subjects with DMD. An open-label extension
protocol is ongoing, and to date subjects have received GSK2402968 6 mg/kg/week
for at least 3 months. GSK2402968 appears to be well tolerated and has the
potential to be effective however, more information is needed to determine
dosing regimens for to ensure an effective dose with minimal side effects for
the subject.

Primary objective:
• To assess the efficacy of 2 different dosing regimens of subcutaneous
GSK2402968 administered over 24 weeks in ambulant subjects with DMD.

Secondary objectives:
• To assess the safety and tolerability of 2 different dosing regimens of
subcutaneous GSK2402968 administered over 48 weeks in ambulant subjects with
DMD.
• To assess the PK of 2 different dosing regimens of subcutaneous GSK2402968
administered over 48 weeks in ambulant subjects with DMD.
• To assess long term efficacy of 2 different dosing regimens of subcutaneous
GSK2402968 administered over 48 weeks in ambulant subjects with DMD.

This is a phase II, double-blind, exploratory, parallel-group,
placebo-controlled clinical study in ambulant subjects with DMD resulting from
a mutation that can be corrected by exon skipping induced by GSK2402968.

The study aims to randomise 54 subjects, which assuming a drop-out rate of
approximately 10%, should provide 48 evaluable subjects. There will be 2
parallel cohorts. Each cohort will include 16 subjects on GSK2402968 and 8
subjects on matched placebo (2:1 ratio).

The active doses will be:
• Continuous regimen; 6mg/kg GSK2402968 once weekly
• Intermittent regimen; 6mg/kg GSK2402968 twice weekly on 1st, 3rd and 5th
weeks, once weekly on 2nd, 4th and 6th weeks, and no active drug on 7th to 10th
week of each 10 week cycle

All subjects will receive a loading dosing regimen of twice weekly dosing with
6 mg/kg GSK2402968 or placebo for the first 3 weeks of treatment. The
intermittent regimen cycles will start after completion of the loading dosing
regimen (i.e. from Week 4).
The study will be fully blinded with respect to active and placebo in each
cohort, however the different regimens will not be fully blinded. Subjects
allocated to the continuous dosing regimen will receive a total of 51 doses of
GSK2402968 or placebo, whereas subjects allocated to the intermittent regimen
will receive a total of 50 doses of GSK2402968 or placebo.

Prior to randomisation, subjects will have two screening visits. At the first
screening visit (2-4 weeks prior to the first dose) full safety and efficacy
measurements will be undertaken to evaluate eligibility. At the second
screening visit (up to 2 weeks prior to the first dose), two of the efficacy
assessments (6-Minutes Walking Distance [6MWD] and *rise-from-floor*) will be
conducted as well as laboratory safety assessments. Results from both screening
visits must be available prior to randomisation.

Subjects will be treated for 48 weeks (including the loading dose period)
following a 2 to 4 week screening period. At the end of the treatment period,
subjects who have completed the study may be entered into an extension study.
Subjects who withdraw from the study for any reason will not be eligible for an
extension study. Any subjects who do not enter the extension study, for
whatever reason, will be monitored as clinically indicated but for a minimum of
20 weeks after the last dose of GSK2402968/placebo. A formal follow-up visit
will be conducted 20 weeks after the last dose of GSK2402968/placebo.

If a subject withdraws from the study (but does not withdraw consent), he will
have an Early Termination Visit as soon as possible after withdrawal, and will
then be followed up for safety and progress as clinically indicated, but for no
less than 20 weeks after the last dose of study treatment. A formal follow-up
visit will be conducted 20 weeks after the last dose of GSK2402968/placebo. If
subjects withdraw, they will not be replaced.

Safety and efficacy will be measured at intervals throughout the study. An
Independent Data Monitoring Committee (IDMC) will oversee the study and will
regularly evaluate safety and tolerability, according to the IDMC charter.

The primary efficacy analysis for this study will be conducted when all
subjects have completed 24 weeks of dosing. All subjects will remain on study
until the final efficacy evaluations after 48 weeks of dosing.

Selected investigational sites will be involved in the collection of
exploratory accelerometry data for gait characterisation. It is expected that
20 subjects from these sites will enter the accelerometry ancillary part of the
protocol.

Study Drug
*All patients will received 2 doses of the study drug per week for the first 3
weeks administered by subcutaneous injection.
*Patients will then follow one of two regimens:
- The continuous regimen group will receive the study drug administered by
subcutaneous injection weekly
- intermittent regimen group will receive the study drug administered by
subcutaneous injection at the following timepoints: : twice weekly on 1st, 3rd
and 5th weeks, once weekly on 2nd, 4th and 6th weeks, and no active drug on 7th
to 10th week of each 10 week cycle

Muscle Biopsy
Both groups will undergo 3 muscle biopsies during their participation in the
study

DEXA Scan
Both groups will undergo 3 DEXA scans during their participation in the study

Venipuncture
26 blood samples will be taken from each patient during their participation in
the study

Because GSK2402968 is an experimental drug and there might be risks that are
unknown or unforeseen at the moment. The following side effects have been
reported in patients who received GSK2402968 and these side effects can cause a
risk for patients participating in the study:

•Skin reactions at the injection site* the study medication may cause all, some
or none of the following at the site of the injection:
- redness,
- swelling,
- hardening of skin
- itching,
- irritation,
- pain.

•At the site of injection, the subject may experience minor bleeding, causing a
bruise in the skin.

Blood Tests:
•A number of blood samples will be taken during the course of the study. There
is a chance of a minor bleeding when taking blood as well as bruising at the
site of needle insertion.

Muscle Biopsy:
•After the muscle biopsy the subject may feel pain at the place of the biopsy.
Patients usually find the pain easy to tolerate and they rarely need to take a
painkiller. The muscle biopsy may leave a small scar and it is possible that
the strength of that muscle might be slightly reduced in the short term.

DEXA Scan:
•There is a very low radiation risk from the DEXA body scan. The level of
radiation that the subject will be exposed to each scan is the same as
radiation from watching television.

All measures will be taken by the study team to ensure the subject is as
comfortable as possible during the above mentioned procedures. The subjects
health and well being will be monitored closely throughout the study by the
study team and adverse events will be treated and follwed up as clinically
indicated.