Safety, efficacy, and pharmacodynamic (PD) activity of 12 weeks treatment with oral RIG-I agonist, inarigivir (IRIG), plus 48 weeks of tenofovir alafenamide in adult patients with chronic hepatitis B: a phase 2 collaboration study

Abstract

Background and aims: IRIG, RIG-I agonist, has demonstrated antiviral activity in CHB patients. The MOA of IRIG suggests a direct antiviral and an immune modulatory pathway. This study evaluated safety, efficacy, and PD activity of IRIG ≤400 mg ± TAF in CHB pts.

Method: IA CHB pts were enrolled into 4 cohorts: 48WK TAF alone or TAF+IRIG 50, 200, and 400 mg QD for 12WK; and virally suppressed (VS) cohort of 12WK IRIG 100 mg. Safety included AEs and lab abnormalities. Primary obj: %pts with HBsAg ≥-0.5 log10 IU/ml at WK12. Secondary obj: change from BL in immune PD biomarkers. Final WK48 data and immunological characterization of 400 mg cohort to be presented.

Results: 102 IA and 21 VS Asian CHB pts enrolled. Table shows BL and mean change at WK12 of viral markers. More TAF and IRIG 50 mg pts at BL had GT C (≥75%), higher HBV DNA and ALT vs IRIG 200 mg and 400 mg. No difference at WK12 in HBV DNA decline observed; TAF and IRIG 50 mg had numerically greater decline in HBsAg vs IRIG ≥200 mg. In VS pts, no change in HBsAg with IRIG 100 mg observed. Prelim WK12 safety showed, no G4 AEs; 3 IRIG and 1 TAF pts had G3 AEs. Majority of IRIG 400 mg pts had slight increase in ALT at WK16 (mean (SD) change in ALT = 9 (65) U/L); similar trends were not observed at lower doses. AEs reported by 41% (46/111) IRIG and 58% (7/12) TAF pts. Frequent (>1 pt) AE related to study drug were: ALT increase (n = 5), constipation, dizziness, and headache (n = 2 each) all in IRIG pts. PD analysis demonstrates minimal changes to ISG expression with IRIG 50 mg and 200 mg. Peripheral cytokine and HBV-specific T cell response was similar between TAF and IRIG 50 mg.

Conclusion: No dose dependent changes in HBV DNA or HBsAg were observed with IRIG ≤400 mg+NUC. IRIG was generally safe and well tolerated at doses ≤400 mg for 12WK. IRIG development has been discontinued due to IRIG-related hepatoxicity.