Ascletis Pharma Inc. announced the completion of patient enrollment in the Phase II clinical trial of ASC42 for chronic hepatitis B (CHB) indication.
The Phase II clinical trial is a multi-center, randomized, single-blind, placebo-controlled study in China to evaluate safety and efficacy of ASC42 tablets in combination with Entecavir and pegylated interferon-α-2a (PEG-IFN-α-2a) in subjects with CHB. 43 CHB patients were enrolled in three cohorts of 10 mg or 15 mg ASC42 tablets or matching placebo orally once daily in combination with Entecavir (0.5 mg, orally once daily) and PEG-IFN-α-2a (180 μg, subcutaneous injection once a week) for 12 weeks, and serum hepatitis B surface antigen (HBsAg) and hepatitis B virus (HBV) pregenomic RNA (pgRNA) change from baseline will be measured during 12-week intervention period and 24-week follow-up period.
Compared to the placebo cohort, both 10 mg and 15 mg ASC42 cohorts were safe and well tolerated to date. Most adverse events (AEs) were grade 1 or 2 and there were no severe adverse events (SAEs).
ASC42 is an in-house developed, selective, potent farnesoid X receptor (FXR) agonist with best-in-class potential. The U.S. Phase I trial (ClinicalTrials.gov Identifier: NCT04679129) of ASC42 indicated that there was no pruritus observed and LDC-C values remained within normal range during 14-day treatment of the once-daily human therapeutic dose of 15 mg while FXR target engagement biomarker Fibroblast Growth Factor 19 (FGF19) increased 1,780% and 7α-hydroxy-4-cholesten-3-one (C4) decreased 91% on Day 14.
As an FXR agonist, ASC42 has unique mechanism of action against HBV: ASC42 inhibits the transcription of HBV covalently closed circular DNA (cccDNA) into HBV RNA, which in turn inhibits the translation of HBV RNA into HBsAg. ASC42 may also reduce HBV cccDNA stability. Both in vitro primary human hepatocyte (PHH) cells and in vivo AAV/HBV mouse studies demonstrated that ASC42 significantly inhibited serum HBsAg and pgRNA, indicating that ASC42 has therapeutic potential to functionally cure CHB. Combination of anti-viral candidate ASC42 with immunotherapy such as ASC22 (subcutaneously injected PD-L1 antibody) may offer an opportunity for synergistic effect, leading to high rate of HBV functional cure. CHB remains to be a significant worldwide unmet medical need, with approximately 86 million persons in China and 1.59 million persons in the U.S. infected with HBV.