Givinostat in Duchenne
Muscular Dystrophy
Paolo Bettica
Italfarmaco SpA
Action Duchenne, London 7° November 2015
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Role of HDAC in DMD
• Histone acetylation/deacetylation
regulates DNA transcription
– HDAC Inhibition  Histones more
acetylated   DNA Transcription
• HDACs part of the Dystrophin
complex. Lack of Dystrophin 
HDAC overactive   transcription
of myogenic factors
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Consalvi et al., Epigenomics (2014) 6(5). 547–560
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Givinostat
• Potent Histone Deacetylase (HDAC) inhibitor in development for
different indications
– Duchenne Muscular Dystrophy, Polycythemia Vera
• >450 subjects treated
– Up to more than 12 months of treatment in clinical trials
– Thirty-one children/adolescents with Juvenile Arthritis treated for 6
months. Nineteen children with DMD treated for more than 28 months
• Givinostat well tolerated. Most frequent AEs:
– Platelet reduction
• Appears within few days at the non tolerated doses. Fully reversible
– Nausea, vomiting e diarrhoea
• Transient
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Givinostat Corrects Histological
Defects in mdx DMD model
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Givinostat POC Study (43): Rationale
• To Prove the Concept by replicating the preclinical histological findings in humans
CSA (Cross Sectional Area) and MFAF ( Muscle
Fibers Area Fraction)
Fibrosis (Perimysial & Endomysial)
Fatty replacement, Necrosis
Inflammation
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Confidential Data
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Study 43: Design
• 20 ambulant children (7-10 yrs old) affected by DMD all on steroid
treatment for at least 6 months
• The study is an open label, 2-part study + extension:
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Confidential Data
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Givinostat Counteracts
the Histological Changes of DMD
• Givinostat histological effect is consistent in all children
Muscle Fibre
Area Fraction
Total
Fibrosis
Total
Necrosis
Fatty
Replacement
*All changes are highly significant (p<0.0005 to <0.0001)
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Confidential Data
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Givinostat Homogeneously
Enlarges Muscle Fibres
No. hypercontracted
fibers x field (20X)
PRE
MEAN
SD
p-value
1.98
0.71
POST
relative
change
change
(%)
(%)
0.77 -1.20 -60.4
0.54 0.66
<.0001
p-value= <.0001
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Confidential Data
The P-value is from a pairwise t-test to test the difference
between Baseline and End of Study
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Changes in Functional Tests
* The study was not powered to evaluate effects on function
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Confidential Data
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Givinostat Well Tolerated
at 37.5/25mg BID for 12 months
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Confidential Data
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What’s next?
• Italfarmaco met with the EMA (Scientific Advice)
and with the FDA (preIND meeting) to define the
path to registration
• Next clinical studies (EU and USA) are being
designed
• Enrollment expected for Q3 2016
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Acknowledgements
Clinical study
•
Bertini E., D’Amico A. (Ospedale Pediatrico Bambin Gesù. Roma). Mercuri E., Pane M. Sivo S.
(Policlinico Gemelli, Roma), Comi G., Magri F. (Policlinico, Milano), Vita G., Messina S., Vita G.
(Policlinico, Messina).
Biopsy
•
Petrini S., D’Oria V. (Ospedale Pediatrico Bambin Gesù, Roma), Moggio M. (Policlinico, Milano)
Functional Tests
•
Mazzone E. (Policlinico Gemelli, Roma)
Practical and psychological support to the families
Buccella F., Ceradini F., De Angelis F. (Parent Project. Roma)
Preclinical Experiments, biopsy and pk/pd analysis
•
Consalvi S., Mozzetta C., Puri P.L.*, Saccone V. (Fondazione S. Lucia, Roma)
* also Sanford-Burnham Medical Research Institute, Sanford Children’s Health Research Center, La Jolla, CA. USA
•
Germani M., Del Bene F., Fiorentini F. (Accelera, Nerviano)
•
Rocchetti M. (Consultant)
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Confidential Data
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