Molecure Sa · GPW:MOC
Molecure Sa — ERS International Congress 2018
17 slides from Molecure Sa's conference presentation, September 2018
Slide 1: CHIT1 is a novel therapeutic target in IPF: anti-fibrotic efficacy of OATD-01
CHIT1 is a novel therapeutic target in IPF: anti-fibrotic efficacy of OATD-01, a potent and selective chitinase inhibitor, in the mouse model of pulmonary fibrosis Barbara Dymek P. Sklepkiewicz, M. Mlacki, A. Zagozdzon, R. Koralewski, M. Mazur, M.Paplinska-Goryca, P. Nejman-Gryz, M. Proboszcz, K. Go
Slide 2: Conflict of interest disclosure
Conflict of interest disclosure ❑ X I have no real or perceived conflicts of interest that relate to this presentation. ❑ I have the following real or perceived conflicts of interest that relate to this presentation: Affiliation / Financial interest Commercial Company Grants/research support: Honora
Slide 3: CHIT1 – structure and function
CHIT1 – structure and function Chitotriosidase (CHIT1) is a member of the GH18 family of chitinases which consists of enzymatically active hydrolases, CHIT1 and AMCase, and enzymatically non-active chitinase-like proteins (YKL-40, YKL-39, oviductin). Evolutionary CHIT1 confers protection against chi
Slide 4: Targeting CHIT1 in interstitial lung diseases: rationale
Targeting CHIT1 in interstitial lung diseases: rationale Human: • CHIT1 gene expression is significantly upregulated in lungs of IPF patients as compared to healthy subjects. Data extracted from the study GSE32537 (IPF n=119; Control n=50). (Yang IV, 2013) • CHIT1 activity is elevated in BAL and ser
Slide 5: CHIT1 activity is elevated in ILDs (IPF and sarcoidosis)
CHIT1 activity is elevated in ILDs (IPF and sarcoidosis) Serum Induced sputum BAL fluid The analysis of chitinolytic activity in samples collected from patients demonstrate significantly increased chitinolytic activity in serum and in induced sputum in patients with IPF and sarcoidosis when compared
Slide 6: CHIT1 is expressed in macrophages and lymphocytes in BALf from IPF patients
CHIT1 is expressed in macrophages and lymphocytes in BALf from IPF patients BAL fluid cells smears – anti-CHIT1 IHC 77% of all BALf cells in IPF (n=8) express CHIT1. Cytological analysis demonstrated that macrophages (83% positive) and lymphocytes (51%) are the main cell subtypes expressing CHIT1. B
Slide 7: OATD-01: the first chitinase inhibitor in clinical development
OATD-01: the first chitinase inhibitor in clinical development • OATD-01 is a highly potent, dual AMCase and CHIT1 small-molecule inhibitor with a nanomolar activity. hAMCase hCHIT1 mAMCase mCHIT1 OATD-01 IC50 [nM] 9,2 23,4 7,8 27,5 • OATD-01 demonstrated a strong anti-inflammatory and anti-remodeli
Slide 8: OATD-01: mouse PK profile
OATD-01: mouse PK profile OATD-01 Pharmacokinetic Parameters Route IV PO Dose (mg/kg) 3 10 C0 or Cmax(mg/L) 3,97 3,42 Tmax(h) n/a 2,0 CL (mL/min/kg) 5,8 n/a Vss (L/kg) 1,01 n/a T½ (h) 2,09 1,88 Bioavailability (F%) n/a 77% OATD-01 has a favorable pharmacokinetic profile in mice suitable for once- or
Slide 9: CHIT1 in upregulated mouse model
CHIT1 in upregulated in lung fibrosis mouse model C57Bl/6 Control d3 d7 d14 d21 CHIT1 PSR CHIT1 is upregulated in the lungs in the belomycin-induced pulmonary fibrosis model and localizes to fibrotic lesions. ERS 2018
Slide 10: PK/PD study of OATD-01 in lung fibrosis model
PK/PD study of OATD-01 in lung fibrosis model OATD-01 administered once or twice a day led to a siginificant inhibition of chitinolytic activity (PD marker) in lung homogenates for 24h confirming the extended pharmacodynamic activity in lungs ERS 2018
Slide 11: OATD-01 efficacy model: comparison with pirfenidone
OATD-01 efficacy in lung fibrosis model: comparison with pirfenidone C57Bl/6 • 21-day-long mouse model of pulmonary fibrosis induced by triple intranasal administrations of bleomycin • Therapeutic scheme of treatment: oral bid administration of OATD-01 and pirfenidone starting at day 7 • Lung fibros
Slide 12: OATD-01 efficacy model: comparison with pirfenidone
OATD-01 efficacy in lung fibrosis model: comparison with pirfenidone OATD-01 exhibited significant anti-fibrotic activity, comparable to pirfenidone, as assessed by the modified Ashcroft scale Control Bleomycin OATD-01 Pirfenidone ERS 2018
Slide 13: OATD-01 efficacy model: comparison with pirfenidone
OATD-01 efficacy in lung fibrosis model: comparison with pirfenidone The significant reduction in Ashcroft score and in lung weight following OATD-01 administration was associated with suppression of the bleomycin-induced chitinolytic activity in plasma (4h after last dose) confirming target engagem
Slide 14: OATD-01 efficacy model: comparison with nintedanib
OATD-01 efficacy in lung fibrosis model: comparison with nintedanib C57Bl/6 • 21-day-long mouse model of pulmonary fibrosis induced by a single intratracheal administrations of bleomycin • Therapeutic scheme of treatment starting at day 7; oral administration of OATD-01 and nintedanib once-a-day • L
Slide 15: OATD-01 efficacy model: comparison with nintedanib
OATD-01 efficacy in lung fibrosis model: comparison with nintedanib OATD-01 dosed orally at 100 mg/kg qd demonstrated strong antifibrotic efficacy comparable to nintedanib Significant, dose-dependent inhibition of chitinolytic activity in plasma was observed 24h after the last dose of OATD-01 confir
Slide 16: Summary
Summary ➢ CHIT1 activity is elevated in serum and induced sputum of IPF patients and it is a potential novel therapeutic target in IPF ➢ OATD-01 is a potent, selective, orally active small-molecule inhibitor of chitinases that is currently in the phase I clinical trials ➢ OATD-01 demonstrated strong
Slide 17: Acknowledgements
Acknowledgements Department of Medicinal Chemistry Department of Internal Medicine, Adam Golebiowski Pulmonary Diseases and Allergy, Robert Koralewski Medical University of Warsaw Marzena Mazur Michal Kowalski Prof. Rafal Krenke Magdalena Paplinska-Goryca Department of Biology Patrycja Nejman-Gryz K