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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

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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

Givinostat Corrects Histological Defects in mdx DMD model

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Givinostat POC Study (43): Rationale

• To Prove the Concept by replicating the pre-clinical histological findings in humans

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CSA (Cross Sectional Area) and MFAF ( Muscle

Fibers Area Fraction)

Fibrosis (Perimysial & Endomysial)

Fatty replacement, Necrosis

Inflammation

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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:

Givinostat Counteracts the Histological Changes of DMD

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• 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

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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

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Givinostat Well Tolerated at 37.5/25mg BID for 12 months

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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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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)