A new and currently experimental approach in the development of effective therapies for chronic hepatitis B is the inhibition of the HBV core protein. A study presented at ILC 2019 demonstrated the strong antiviral efficacy of this approach.
Among the many different new strategies currently being investigated in studies in the treatment of chronic hepatitis B are combination therapies of the nucleotide/nucleoside analogues (NUC) currently used in this indication with new substances designed to improve response to NUC. NUC is now the standard therapy for chronic HBV infection and generally provide satisfactory suppression of viral replication, but do not provide sustained control beyond discontinuation.
In Phase I, ABI-H0731 was well tolerated and showed dose-dependent activity against HBV (source 1) in patients with chronic hepatitis B over 28 days. Phase II data on the combination of the experimental core inhibitor ABI-H0731 with approved NUC were presented at the ILC 2019. ABI-H0731 belongs to a new class of "small molecules" that are directed against the HBV core protein, which is important for several steps of the virus life cycle.
In Phase II, the core inhibitor was now tested in the two double-blind, placebo-controlled studies ABI-H0731-201 and ABI-H0731-202, in a collective of HBV patients with fibrosis stages F0 to F2. Study 201 included 47 HBeAg-positive and 26 HBeAg-negative patients who had already achieved virus suppression under NUC-therapy. Patients were randomized to receive either ABI-H0731 or placebo in addition to their ongoing antiviral therapy. Primary efficacy endpoint of this study is a decrease of HBsAg/HBeAg by log10 after 24 weeks.
In Study 202, 25 therapy naive, HBeAg-positive, viral patients were randomly treated with either Entecavir and ABI-H0731 or Entecavir and placebo. Here, the primary efficacy endpoint is the reduction of HBV DNA by log10 at weeks 12/24. Controls were carried out in weeks 2 and 4 and then monthly for up to 24 weeks. Patients were then given the opportunity to be enrolled in an extension study, which is scheduled to run for one year.
Dr. Jacob Lalezari, Quest Clinical Research, San Francisco, presented the results of an interim analysis of the two studies after 12 weeks at the ILC 2019. In both studies, they show a significant decrease in HBV DNA. In the viremic patients, the combination showed a clearer reduction in viremia compared to entecavir monotherapy, which was -4.54 log10 IU/ml after 12 weeks; in the few patients for whom 24-week data could already be evaluated, a further decrease in HBV DNA levels was observed in weeks 12 to 24. In the combination arm, there was also a faster normalization of transaminases. The combination also showed a significantly more pronounced reduction in HBV RNA from week 2 onwards.
A more difficult result to interpret was that of Study 201 showing a further reduction of residual viremia by the core inhibitor, observed despite the low baseline levels. An assay specially developed for this study was used to detect viral DNA up to 2-5 IU/ml, i.e. far below the conventional detection limit. Especially in those patients for whom 24-week data are already available, the virus titer also moved in the direction of this detection limit. Virus RNA dropped below the detection limit in nearly half of the patients. However, the primary endpoint was not met in Study 201. Of the six patients who had already completed 24 weeks of therapy, only one had a decrease in HBeAg to the required extent, and none had a loss of HBsAg. Lalezari: "The patients will continue to be treated with ABI-H0731 and we are convinced that the HB antigens will follow after the elimination of the virus".
ABI-H0731 was well tolerated. Dr. Lalezari explained: "There were no serious adverse events and no abortions due to side effects, no interruptions, and no flares." Three patients developed rashes without systemic symptoms. The therapy did not have to be interrupted and only one of the patients needed an antihistamine preparation (source 2).
Sources:
1. Yuen M-F et al.: Final results of a Phase 1b 28-day study of ABI-H0731, a novel core inhibitor, in non-cirrhotic viremic subjects with chronic hepatitis B. 2018; 68(S1): 47A
2. Lalezari J et al.: Interim safety and efficacy results of the ABI-H0731 phase 2a program exploring the combination of ABI-H0731 with Nuc therapy in treatment-naive and treatment-suppressed chronic hepatitis B patients. ILC 2019, LB-0
3. International Liver Congress (ILC) of the European Association for the Study of the Liver (EASL), 13 April 2019, Vienna