Ascending dose cohort study of inarigivir - A novel RIG I agonist in chronic HBV patients: Final results of the ACHIEVE trial

Abstract

Background and Aims: Inarigivir, an oral dinucleotide RIG-I agonist has demonstrated anti-viral activity against HBV via a combination of activation of innate immunity and a DAA effect as a Non Nucleotide reverse transcriptase inhibitor (NNRTI). We report here the final results of the ACHIEVE trial, an ascending dose cohort study of 12 weeks of inarigivir followed by a switch to 12 weeks of tenofovir (TDF) 300mg daily in treatment naïve HBV patients. Method: 80 patients were randomized to inarigivir (25,50,100 and 200mg) daily or placebo in a 4:1 ratio for 12 weeks and then all patients were switched to TDF. Primary endpoints were safety and efficacy measured by reduction in HBV DNA at week 12 from baseline. Secondary endpoints included HBV RNA, quantitative HBsAg, peripheral serum cytokines and change in ALT. Results: Patient demographics are given in the table. Primary endpoint of HBV DNA reduction was achieved in a dose dependent fashion for both HBeAg positive and negative patients with a maximal reduction of 3.26 log10 in the 200mg dose. HBV RNA paralleled HBV DNA reductions, with greater reduction in HBeAg negative patients. Quantitative HBsAg response with a predefined threshold of a >0.5 log10 reduction at either week 12 or week 24 was seen in 22% of patients with a mean reduction of 0.8 log10 and a maximal reduction of 1.4 log10. Unlike HBV DNA, HBsAg decline was not dose dependent and indicates the potential importance of the host response to inarigivir. Tolerability of treatment was good with 1 unrelated SAE of knee pain and 1 grade 3 non-sustained laboratory abnormality of hypertriglyceridemia. ALT flares ( > 200 IU) were seen in 6 treated patients (10%) and 4 placebo patients (25%) and 1 patient required dose discontinuation for ALT > 400 IU. No significant increases in bilirubin or INR were seen. Conclusion: The ACHIEVE trial confirms the safety and anti-viral efficacy of inarigivir up to 200mg daily and further studies at doses of up to 400mg daily in combination with TDF or added to NUC suppressed patients are underway.