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Paolo Bettica - Action Duchenne
Givinostat in Duchenne Muscular Dystrophy Paolo Bettica Italfarmaco SpA Action Duchenne, London 7° November 2015 16/07/2016 1 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 16/07/2016 Consalvi et al., Epigenomics (2014) 6(5). 547–560 2 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 16/07/2016 3 Givinostat Corrects Histological Defects in mdx DMD model 16/07/2016 4 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 16/07/2016 Confidential Data 5 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: 16/07/2016 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) 16/07/2016 Confidential Data 7 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 16/07/2016 Confidential Data The P-value is from a pairwise t-test to test the difference between Baseline and End of Study 8 Changes in Functional Tests * The study was not powered to evaluate effects on function 16/07/2016 Confidential Data 9 Givinostat Well Tolerated at 37.5/25mg BID for 12 months 16/07/2016 Confidential Data 10 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 16/07/2016 11 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) 16/07/2016 Confidential Data 12