One strategy that has proven promising in Phase II is the activation of the intracellular receptor RIG-I to improve the immune response to the virus and to eliminate HBsAg in combination with antiviral therapy.
The disappearance of the surface antigen HBsAg, preferably in combination with the occurrence of antibodies against HBsAg, i.e. HBs seroconversion, is a therapeutic goal in the treatment of chronic hepatitis B that is rarely achieved with currently available strategies. With interferon therapy, the chances are somewhat better than with antiviral substances, but with the price of considerable side effects that cannot be expected of every patient. The restoration of an intact immune response to HBV corresponds to a functional cure, as Prof. Dr. Man-Fung Yuen from the University of Hong Kong explained.
New strategies are therefore urgently needed. One such strategy is the dinucleotide RIG-I agonist inarigivir, which is currently under development. The oral substance will combine two mechanisms of action: the direct antiviral effect of a non-nucleotide reverse transcriptase inhibitor (NNRTI) and activation of the innate immune system by activation of the intracellular receptor RIG-I (retinoic acid-inducible gene I), which is inactivated during chronic HBV infection. RIG-I plays an important role in the recognition of viral RNA and the subsequent interferon production with an intact immune response. Inarigivir enters the liver cells where it binds to RIG-I and activates the interferon signaling cascade. Dr. Yuen pointed to the high liver affinity of inarigivir with a liver to plasma ratio of 30:1. In addition, inarigivir is directly active against HBV.
At the ILC 2019, Dr. Yuen presented the results of the Phase II study ACHIEVE on inarigivir in the indication of chronic hepatitis B (see source 2). In the study, 80 patients with chronic HBV infection without cirrhosis were treated with different doses of inarigivir for 12 weeks. Primary endpoints were safety and reduction of HBV DNA after 12 weeks. After the first 12 weeks, all patients were switched to Tenofovir (TDF). The included patients had been infected for more than six months, without treatment for more than six months, and could be HBeAg positive or negative. Patients with fibrosis stage 3 or higher were excluded. As the study was conducted in Asia, the majority of patients were infected with HBV genotypes B and C. The majority of patients were infected with HBV genotypes B and C.
The primary endpoint was met and the study showed a significant dose-dependent reduction of HBV DNA under inarigivir. With the maximum dose of 200mg/d, an HBV reduction of 3.26 log10 was achieved. In parallel, a corresponding reduction in HBV-RNA was observed, which was more pronounced in HBeAg-negative patients. At the higher doses, HBV DNA had dropped below the detection limit in all patients after 12 weeks. In addition, HBsAg reduction was also observed. At a threshold of >0.5 log10 after week 12 or 24, 22% of patients reached this endpoint, with a mean reduction at 0.8 log10 and maximum reduction at 1.4 log10. In contrast to HBV DNA, the reduction of HBsAg was not dose-dependent. The tolerability was good. One patient experienced pain in the knee that was not related to the therapy, one patient showed a transient increase in triglycerides. ALT flares (>200 IU) were observed in six verum and four placebo patients. In one patient, the therapy was discontinued at an ALT >400IU. There were no significant increases in bilirubin. In view of this excellent tolerability, a dosage of 400mg per day will now also be investigated.
Sources:
1. International Liver Congress (ILC) of the European Association for the Study of the Liver (EASL), 12 April 2019, Vienna
2. Yuen MF et al.: Ascending dose cohort study of inarigivir - a novel RIG I agonist in chronic HBV patients: final results of the ACHIEVE trial. ILC 2019, GS-12