Ascletis Announces First Patient Dosed in the Phase II Clinical Trial of ASC42, An In-House Developed, Best-in-Class FXR Agonist for Chronic Hepatitis B Indication

Ascletis Pharma Inc. (HKEX: 1672) today announces the dosing of the first patient in the Phase II clinical trial of ASC42 for chronic hepatitis B (CHB) indication.

The Phase II clinical trial (ClinicalTrials.gov Identifier: NCT05107778) 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. About 45 CHB patients will be enrolled and receive ASC42 tablets (10mg or 15mg) or matching placebo orally once daily in combination with Entecavir (0.5mg, orally once daily) and PEG-IFN-α-2a (180μg, 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.

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.

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. Nucleot(s)ide analogues (NAs) inhibit only reverse transcription of HBV RNA into HBV DNA and do not inhibit the transcription of HBV cccDNA into HBV RNA, thus have no inhibitory effect on HBsAg.

"In vitro studies demonstrated that FXR agonists inhibited HBV mRNA, DNA and protein production, reduced cccDNA pool size and repressed RNA transcription and viral secretion. It is of great significance to explore an FXR agonist to achieve HBV functional cure based on the novel mechanism of action and we are expecting to see the achievement," said by Professor Jinlin Hou, MD, principal investigator of ASC42 Phase II study for CHB indication, Director of the Hepatology Unit and Department of Infectious Diseases, Nanfang Hospital, Southern Medical University.

Dr. Jinzi J. Wu, Founder, Chairman and CEO of Ascletis stated, "Ascletis is a global leading company in anti-viral drug development. In addition to ASC42 as an anti-viral candidate for HBV functional cure, we have ASC22, a subcutaneously injected PD-L1 antibody for HBV functional cure through immune modulation, which has shown promising interim data in the Phase IIb trial with 19% of patients whose baseline HBsAg≤500 IU/mL achieving HBsAg loss and no rebound after the last dosing of ASC22. ASC22 as an immunotherapy may play a fundamental role in HBV functional cure, and we are on track to advance the registration trial of ASC22 as planned. Meanwhile, the combination of ASC22 with a novel anti-viral agent such as ASC42 or siRNA may further improve the rate of functional cure."

About Ascletis

Ascletis is an innovative R&D driven biotech listed on the Hong Kong, S.A.R., China Stock Exchange (1672.HK), a global platform covering the entire value chain from discovery and development to manufacturing and commercialization. Ascletis is committed to developing and commercializing innovative drugs in the areas of viral diseases, NASH/PBC, and cancer (oral cancer metabolic checkpoint and immune checkpoint inhibitors) to address unmet medical needs both in China and globally. Led by a management team with deep expertise and a proven track record, Ascletis targets those therapeutic areas with unmet medical needs from a global perspective, and efficiently advances the developments of pipelines with an aim of leading in global competition. To date, Ascletis has three marketed products and 20 robust R&D pipelines of drug candidates with global competitiveness, and is actively exploring new therapeutic areas.

1. Viral Diseases: (1) Hepatitis B Virus (functional cure): focus on breakthrough therapies for CHB functional cure with a subcutaneously-injected PD-L1 antibody – ASC22 and Pegasys® as cornerstone drugs. (2) COVID-19 pipeline: currently includes (i) ritonavir oral tablet (100 mg), an authorized product, (ii) ASC10, an oral RNA dependent RNA polymerase (RdRp) inhibitor and (iii) ASC11, an oral 3-chymotrypsin like protease (3CLpro) inhibitor. (3) HIV/AIDS: ASC22, an immune therapy to restore HIV-specific immune responses and eventually lead to a functional cure of HIV-infected patients. (4) Hepatitis C: successfully launched an all-oral regimen of combining ASCLEVIR® and GANOVO® (RDV/DNV regimen).

2. Non-alcoholic Steatohepatitis/Primary Biliary Cholangitis: Gannex, a wholly-owned company of Ascletis, is dedicated to the R&D and commercialization of new drugs in the field of NASH. Gannex has three clinical stage drug candidates against three different targets – FASN, THRβ and FXR, three fixed-dose combinations for NASH and one PBC program targeting FXR.

3. Cancer (oral cancer metabolic checkpoint and immune checkpoint inhibitors): a pipeline of oral inhibitors targeting FASN, which plays a key role in cancer lipid metabolism, and a pipeline of oral PD-L1 small molecule next generation immune checkpoint inhibitors.

4. Exploratory Indications: Acne: Following NASH and recurrent GBM, the third indication for ASC40 has been approved to enter Phase 2 clinical trial. For more information, please visit www.ascletis.com.

Source: Ascletis Pharma Inc.