Randomised, double blind, placebo controlled, multicentre study to evaluate the efficacy and safety of givinostat in ambulant patients with Duchenne Muscular Dystrophy EPIDYS (Epigenetic Rescue of Dystrophin Dysfunction)

There are still no curative treatments for Duchenne muscular dystrophy and the
current management of the disease is based on prevention and management of
complications. Therefore, there is an unmet therapeutic need exists for the
treatment of this disabling and fatal condition. The risk/benefit ratio of
this study is postulated to be favorable for the clinical safety for the
efficacy based in the preclinical and the human Phase 2 study. This
randomised, double blind, placebo controlled, multicentre study is aimed to
evaluate the efficacy and safety of givinostat in ambulant patients with
Duchenne Muscular Dystrophy (DMD). The main objective is to establish the
effects of givinostat versus placebo administered chronically over 18 months to
slow disease progression in ambulant DMD subjects. Ambulant male paediatric
subjects aged *6 years at baseline affected by DMD will be included.

Primary objective:
* To establish the effects of givinostat versus placebo administered
chronically over 18 months to slow disease progression in ambulant DMD subjects.

Secondary objectives:
* To assess the safety and tolerability of givinostat versus placebo
administered chronically in DMD subjects.
* To evaluate the pharmacokinetic (PK) profile of givinostat administered
chronically in the target population;
* To evaluate the impact on quality of life and activities of daily living of
givinostat versus placebo administered chronically.

Secondary exploratory objectives:
* To evaluate the correlation between PK profile of givinostat and
pharmacodynamics (PD) data;
* To explore whether the effects of givinostat versus placebo administered
chronically may be related to the type of DMD mutation or to the biomarkers.

This is a Phase 3, randomised, double blind, placebo controlled, multicentre
study to evaluate the efficacy and safety of givinostat in ambulant subjects
with DMD. This study will include ambulant male paediatric subjects aged *6
years at baseline affected by DMD. Approximately 213 subjects will be
randomised in order to have 192 fully evaluable subjects (10% of drop out).
Subjects who assent to participate in this study (if capable of doing so) and
whose parent/legal guardian sign the Informed Consent Form (ICF) to participate
will undergo pre-study screening assessments up to 4 weeks before the first
scheduled dose of study drug.

At the randomisation visit, in addition to the continued standard of care
corticosteroids regimen, DMD subjects will be randomised (2:1 ratio) to receive
givinostat oral suspension 10 mg/mL or placebo oral suspension bid (in a fed
state).
At randomisation, subjects will be stratified for their concomitant use of
steroids in 2 strata:
1. Daily regimen
2. Intermittent regimen

The study duration is planned for 19 months and comprises 2 phases:
1. Screening period: starting 4 weeks (± 2 weeks) before randomisation
2. Treatment period: 18 months of treatment

There will be a total of 15 visits, including the Screening and the
Randomisation Visits and excluding the Follow up Visit. Subjects may be
evaluated more often if necessary for safety reasons. Subjects who discontinue
the study drug early will be asked to come in for an EOS
Visit within 2 weeks after the last dose of study drug. Subjects who have
ongoing AEs at discontinuation will be followed until resolution or
stabilization. In order to guarantee the continuation of treatment with
givinostat, the Sponsor has planned a long-term safety study which will start
when the first subject enrolled in this study has attended his last visit. As a
consequence, at the end of the treatment, parent/ legal guardian
will be asked to consent and subject will be asked to assent/consent to his
participation to the long-term safety study. In case the subject will not
assent/consent and/or the parent/ legal guardian will not consent it, a final
follow up visit will be performed 4 weeks after last dose
administration.

A total of 213 male ambulant subjects will be randomised to provide 192 fully
evaluable subjects (10% of drop-out subjects is foreseen).
Subjects will be stratified for their concomitant use of steroids in 4 strata:
1. Deflazacort Daily regimen
2. Deflazacort Intermittent regimen
3. Other steroids Daily regimen
4. Other steroids Intermittent regimen

Randomisation ratio:
2:1 (about 142 subjects in givinostat arm and 71 in placebo arm to give 128 and
64 evaluable subjects respectively)

Concerning the clinical experience in DMD, the aforementioned histological
results observed in the mdx mouse model were replicated in a Phase 2 study of
givinostat (Study DSC/11/2357/43, EudraCT n. 2012-002566-12) in 20 ambulant DMD
subjects (from 7 to 10 years of age at study start, on stable steroid
treatment) where, after one year of treatment, the muscle biopsy analysis
showed a significant increase in muscle fibers area fraction (MFAF) and a
significant reduction of muscle necrosis, fatty replacement and fibrosis.
Analysis of the effect on CSA of the muscle fibers showed that givinostat
significantly increases CSA of all type of fibers (small, medium, large) in a
similar manner and that such effect on CSA predicts the increase in MFAF and
the reduction of fibrosis. In addition, an increase in the number of
regenerating fibers and satellite cells was observed. Moreover, descriptive
analysis conducted on the secondary efficacy endpoints on muscle function
(i.e., six-minute walking test [6MWT], North Star Ambulatory Assessment [NSAA],
time function tests and pulmonary function tests) showed an overall stability
after 1 year of treatment in this population.
The most common AEs observed were thrombocytopenia, as well as gastrointestinal
toxicities. Adverse events were generally mild to moderate and reversible upon
discontinuation of study drug. Moreover, dose-dependent asymptomatic and
reversible platelets count reductions were observed both in healthy volunteers
and subjects treated with givinostat. These decreases typically occurred
within the first week after treatment initiation. The majority of
thrombocytopenic events were mild in severity with fewer than 10% of subjects
developing platelets count below 75 x 109/L. All occurrences resolved
completely within 2 to 3 weeks of discontinuation of treatment, suggesting a
rapidly reversible effect. No hemorrhagic episodes were observed. In addition,
during the study particular attention will be paid in monitoring possible
effects on QTc (see Table 4 for details), since some episodes (20 episodes in
14 subjects) of Corrected QT interval (QTc) prolongation have been recorded
during the clinical studies performed so far. It is worth noting that 90% of
the recorded events were reported in oncological studies in subjects treated at
highest doses (e.g., *100 mg/daily) and no events were recorded during the
previous study in DMD subjects.
The risk/benefit ratio of the proposed study is postulated to be favorable for
both the results of the clinical safety and pre-clinical toxicology studies and
for the efficacy results in the previous Phase 2 DMD study.

(for more information see section 4.2.2 and 4.2.3 of the protocol; Clinical
Experience with Givinostat Including Risks and Benefits, pages 33-38)