Upload
adela-stanley
View
215
Download
1
Tags:
Embed Size (px)
Citation preview
21/04/23 1
Givinostat in Duchenne Muscular Dystrophy
Paolo Bettica
Italfarmaco SpA
Action Duchenne, London 7° November 2015
Role of HDAC in DMD
• Histone acetylation/deacetylation regulates DNA transcription– HDAC Inhibition Histones more
acetylated DNA Transcription
21/04/23 2Consalvi et al., Epigenomics (2014) 6(5). 547–560
• HDACs part of the Dystrophin complex. Lack of Dystrophin HDAC overactive transcription of myogenic factors
21/04/23 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
Givinostat Corrects Histological Defects in mdx DMD model
21/04/23 4
Givinostat POC Study (43): Rationale
• To Prove the Concept by replicating the pre-clinical histological findings in humans
21/04/23Confidential Data
5
CSA (Cross Sectional Area) and MFAF ( Muscle
Fibers Area Fraction)
Fibrosis (Perimysial & Endomysial)
Fatty replacement, Necrosis
Inflammation
21/04/23Confidential 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:
Givinostat Counteracts the Histological Changes of DMD
21/04/23Confidential Data
7
• Givinostat histological effect is consistent in all children
*All changes are highly significant (p<0.0005 to <0.0001)
Muscle Fibre Area Fraction
Total Fibrosis
TotalNecrosis
FattyReplacement
Givinostat Homogeneously Enlarges Muscle Fibres
21/04/23Confidential Data
8
p-value= <.0001
The P-value is from a pairwise t-test to test the difference between Baseline and End of Study
No. hypercontracted fibers x field (20X)
PRE POST change (%)
relative change
(%)
MEAN 1.98 0.77 -1.20 -60.4SD 0.71 0.54 0.66
p-value <.0001
Changes in Functional Tests
* The study was not powered to evaluate effects on function
21/04/23Confidential Data
9
Givinostat Well Tolerated at 37.5/25mg BID for 12 months
21/04/23Confidential Data
10
21/04/23 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
21/04/23Confidential Data
12
AcknowledgementsClinical 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 familiesBuccella 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)