INS018-055, A Novel Traf2- and NCK-interacting Kinase (TNIK) Inhibitor, Improves Lung Function in Patients With Idiopathic Pulmonary Fibrosis: Results From a Randomized, Double-blind, Placebo-controlled Phase 2a Study

Abstract Rationale: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease carrying a poor prognosis with a median survival of 3 to 4 years. Wnt signaling is identified as a major activated signaling cascade that contributes to the pathogenesis of lung fibrosis where Traf2- and NCK-interacting kinase (TNIK) acts. INS018-055 is a first-in-class small molecule developed in-house using generative AI to target TNIK and fibrotic pathways. Method: INS018-055-003 (NCT05938920) was a randomized, double-blind, placebo-controlled Phase IIa study of INS018-055, a novel TNIK inhibitor, in patients with IPF conducted at 22 clinical sites in China. Diagnosis of IPF was confirmed by investigator according to ATS/ERS/JRS/ALAT Clinical Practice Guideline with centrally read HRCT scan. Patients with % predicted FVC > 40%, FEV1/FVC ratio >0.7 and DLCO ≥ 25% and < 80% were randomized 1:1:1:1 at baseline to receive 30 mg INS018-055 QD (n=18), 30 mg INS018-055 BID (n=18), 60 mg INS018-055 QD (n=18) or placebo (n=17) orally for 12 weeks, with or without background anti-fibrotic therapy (pirfenidone or nintedanib). The primary endpoint was the percentage of patients suffering from at least 1 TEAE with key secondary endpoint of change from baseline to Week 12 (CFB12) in forced vital capacity (FVC; mL). The safety population included subjects receiving at least 1 dose of study treatment. FVC changes from baseline were summarized with standard descriptive statistics with the intent-to-treat (ITT) population including any randomized subjects. Results: Safety: INS018-055 was well tolerated with similar rates of TEAEs in the pooled treatment and placebo groups (43/54, 79.6% and 12/17, 70.6%). Hypokalemia was the most common TEAE (11/54, 20.4%). Diarrhea (8/54, 14.8%) and hepatic enzymes elevation (8/54, 14.8%) were the most common TRAE, several of these subjects were concomitantly treated with nintedanib. Efficacy: Patients who received INS018-055 demonstrated a dose-dependent improvement in lung function by the 12 weeks of the trial, with a 98.4ml mean improvement in forced vital capacity (FVC) from baseline at the highest dose of 60mg QD (Figure 1) as compared to a mean decline in FVC change from baseline of 20.3ml for patients in the placebo group. Conclusion: These results suggested that INS018-055 is well-tolerated in IPF patients and demonstrated a dose-dependent effect in lung function improvement within 12 weeks, supporting further development of INS018-055 in larger Phase 2b trials. Figure 1: Descriptive summary of FVC change from baseline at week 12, box plot, mean (SD)