C103-02 Inhaled Rentosertib (ISM018_055), a Selective TNIK Inhibitor, Improves Lung Function and Reduces Fibrosis and Inflammation in Animal Models of Pulmonary Fibrosis

Rationale Rentosertib (INS018_055) is a novel, potent inhibitor of Traf2- and Nck-interacting kinase (TNIK) in clinical testing for the treatment of idiopathic pulmonary fibrosis (IPF). Rentosertib is the first drug molecule designed using AI-based algorithms against an AI-identified target. In a Phase 2a trial, oral rentosertib was generally safe, well-tolerated, and demonstrated improvement of lung function in IPF patients. To achieve optimal therapeutic exposure in the lung while reducing systemic exposure, we developed an inhalation formulation of rentosertib. Here, preclinical testing of inhaled rentosertib in a bleomycin-induced lung fibrosis rat model found dose-dependent improvement of lung function and amelioration of lung fibrosis. Methods Lung fibrosis was induced in 8-9 week-old male Sprague-Dawley rats via intratracheal administration of bleomycin hydrochloride (n = 72) or saline (n = 12). Starting on day 7, animals in the bleomycin group were administered aerosolized rentosertib at actual delivered dose of 0.040±0.008 mg/kg, 0.136±0.017 mg/kg, 0.485±0.081 mg/kg, or 2.575±0.242 mg/kg, vehicle-only control, or oral pirfenidone at 350 mg/kg daily for 21 days (n = 12/group). Lung function was assessed by measuring forced vital capacity (FVC), pulmonary compliance (Cdyn), and airway resistance (RL). Bronchoalveolar lavage fluid (BALF) was collected for leukocyte analysis. Lung tissues were collected for hydroxyproline content, and histopathological evaluation. A separate pharmacokinetic cohort (n = 3/group) were analyzed for compound exposure in lung and plasma. Results Across all dose groups, rentosertib concentration immediately after dosing was ∼50-70-fold greater in lung tissue compared to plasma. Rats receiving inhaled Rentosertib at all dose groups experienced significantly improved lung function indicated by increased FVC, Cdyn, and decreased RL compared to vehicle controls. Compared to model controls, rats in all rentosertib dosing groups had fewer white blood cells in BALF. In addition, all rentosertib groups had significantly lower hydroxyproline in lung tissue. Pathology results revealed that the highest and second-highest dose level groups had significantly reduced fibrosis severity and inflammatory cell infiltration in lung tissue compared to model controls. Conclusions In animal models of pulmonary fibrosis, inhaled rentosertib leads to greater drug exposure in lung tissue compared to systemically and demonstrates a significant reduction in pulmonary fibrosis and inflammation. Treatment for 21 days resulted in marked therapeutic effects on lung function even in the lowest dose group; higher dose levels significantly ameliorated fibrosis pathology, supporting the potential of inhaled rentosertib as a treatment for fibrotic lung diseases. This abstract is funded by: Insilico Medicine