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A4346 - OATD-01, a Dual Chitinase Inhibitor, Significantly Ameliorates Pulmonary Fibrosis in the Bleomycin-Induced Mouse Model
Author Block: B. Dymek1, P. Sklepkiewicz1, M. Mlacki1, A. Zagozdzon1, R. Koralewski1, M. Mazur1, M. Paplinska-Goryca2, P. Nejman-Gryz2, M. Proboszcz2, K. Gorska2, M. Maskey-Warzechowska2, N. Przysucha2, R. Krenke2, P. Dobrzanski1, A. Golebiowski1, K. Dzwonek1; 1OncoArendi Therapeutics SA, Warsaw, Poland, 2Department of Internal Medicine, Pulmonary Diseases and Allergy, Medical University of Warsaw, Warsaw, Poland.
Rationale
Acidic mammalian chitinase (AMCase) and chitotriosidase (CHIT1) are the enzymatically active chitinases, which have been implicated in the pathophysiology of obstructive and interstitial lung diseases. The CHIT1 activity is elevated in bronchoalveolar lavage fluid (BALF) from patients with interstitial lung diseases such as sarcoidosis and idiopathic pulmonary fibrosis (IPF). Moreover, in sarcoidosis patients serum chitinolytic activity is significantly elevated (5- to 100-fold), correlates with the disease stage and severity and was shown to be the best biomarker of disease progression identified thus far. These data suggest that inhibition of chitinolytic activity might represent a novel therapeutic approach for interstitial lung diseases.
Methods
The enzymatic inhibitory potency of OATD-01 (OAT-889) was determined using human and mouse recombinant AMCase and CHIT1. Additionally, OATD-01 activity against human chitinases was assessed in vitro in serum, BALF and induced sputum collected from patients with interstitial lung diseases (sarcoidosis and IPF). The therapeutic efficacy of OATD-01 in vivo was evaluated in the mouse model of bleomycin-induced pulmonary fibrosis. Mice were treated with OATD-01 (30 mg/kg, po, bid) or pirfenidone (250 mg/kg, po, bid) for two weeks from day 7 after the first intranasal dose of bleomycin (a therapeutic regimen).
Results
OATD-01 is a selective, dual AMCase and CHIT1 inhibitor (hAMCase IC50 = 9nM, hCHIT1 IC50 = 26nM, mAMCase IC50 = 8nM, mCHIT1 IC50 = 29nM). Additionally, OATD-01 potently inhibited elevated chitinolytic activity in serum, induced sputum and BALF collected from patients with sarcoidosis and IPF (IC50s = 10-20 nM). In the bleomycin-induced pulmonary fibrosis mouse model, OATD-01 significantly reduced lung fibrosis, comparable to pirfenidone, as assessed by the modified Ashcroft scoring system. The anti-fibrotic effects of OATD-01 correlated with a significant reduction of the increased wet lung weight and lung index (wet lung weight/body weight), observed in the bleomycin-treated control group. The anti-fibrotic activity of OATD-01 was associated with a strong pharmacodynamic effects: plasma chitinolytic activity in animals dosed with OATD-01 was significantly reduced in comparison to control mice, confirming the target engagement; there was no effect of pirfenidone.
Conclusions
We have demonstrated that suppression of the chitinase activity with OATD-01 provided a significant therapeutic efficacy, comparable to pirfenidone, in the bleomycin-induced pulmonary fibrosis model. These data support further investigation of OATD-01 as a first-in-class therapy for interstitial lung diseases such as sarcoidosis and IPF.