Givinostat in Duchenne Muscular Dystrophy Paolo Bettica Italfarmaco SpA Action Duchenne, London 7° November 2015 25/04/2017

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 25/04/2017 Consalvi et al., Epigenomics (2014) 6(5). 547–560

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 25/04/2017

Givinostat Corrects Histological Defects in mdx DMD model 25/04/2017

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 25/04/2017 Confidential Data

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: 25/04/2017 Confidential Data 6

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) 25/04/2017 Confidential Data

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 25/04/2017 Confidential Data

Changes in Functional Tests * The study was not powered to evaluate effects on function 25/04/2017 Confidential Data

Givinostat Well Tolerated at 37.5/25mg BID for 12 months 25/04/2017 Confidential Data

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 25/04/2017

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) 25/04/2017 Confidential Data