1. Givinostat in Duchenne Muscular Dystrophy
Paolo Bettica
Italfarmaco SpA
Action Duchenne, London 7° November 2015
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2. 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

3. 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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4. Givinostat Corrects Histological Defects in mdx DMD model
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5. Givinostat POC Study (43): Rationale
To Prove the Concept by replicating the pre-clinical 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

6. 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 6

7. 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< to <0.0001)
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Confidential Data

8. Givinostat Homogeneously Enlarges Muscle Fibres
No. hypercontracted fibers x field (20X)
PRE
POST
change (%)
relative change (%)
MEAN
1.98
0.77
-1.20
-60.4 SD
0.71
0.54
0.66
p-value
<.0001
p-value= <.0001
The P-value is from a pairwise t-test to test the difference between Baseline and End of Study
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Confidential Data

9. Changes in Functional Tests
* The study was not powered to evaluate effects on function
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Confidential Data

10. Givinostat Well Tolerated at 37.5/25mg BID for 12 months
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Confidential Data

11. 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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12. 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