Discovery of a first-in-class orally available HBV cccDNA inhibitor

  • J Hepatol. 2022 Dec 29;S0168-8278(22)03466-3. doi: 10.1016/j.jhep.2022.12.014.
Li Wang  1 ,  Qihui Zhu  2 ,  Jitao David Zhang  3 ,  Yaling Zhang  2 ,  Xiaoju Ni  2 ,  Kunlun Xiang  2 ,  Jiaxi Jiang  2 ,  Baocun Li  2 ,  Youjun Yu  2 ,  Hui Hu  2 ,  Meifang Zhang  4 ,  Waikwong Wu  4 ,  Jing Zeng  2 ,  Zhipeng Yan  2 ,  Jieyu Dai  3 ,  Kai Sun  3 ,  Xin Zhang  5 ,  Dongdong Chen  6 ,  Song Feng  6 ,  Lisa Sach-Peltason  7 ,  John A T Young  2 ,  Lu Gao  2
Affiliations
  • 1. Infectious Disease Discovery, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Shanghai, Roche Innovation Center Basel. Electronic address: [email protected].
  • 2. Infectious Disease Discovery, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Shanghai, Roche Innovation Center Basel.
  • 3. Pharmaceutical Sciences, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Shanghai, Roche Innovation Center Basel.
  • 4. Lead Discovery, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Shanghai, Roche Innovation Center Basel.
  • 5. Preclinical Chemistry Manufacturing and Controls, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Shanghai, Roche Innovation Center Basel.
  • 6. Medicinal Chemistry, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Shanghai, Roche Innovation Center Basel.
  • 7. Data & Analytics, Roche Pharmaceutical Research and Early Development, Roche Innovation Center Shanghai, Roche Innovation Center Basel.
PMID: 36587899 DOI: 10.1016/j.jhep.2022.12.014
Abstract

Background & aims: The persistence of covalently closed circular DNA (cccDNA) in infected hepatocytes is the major barrier preventing viral eradication with existing therapies in patients with chronic hepatitis B (CHB). Therapeutic agents that can eliminate cccDNA are urgently needed to achieve virus eradication and thus HBV cure.

Methods: A phenotypic assay with HBV-infected primary human hepatocytes (PHHs) was employed to screen for novel cccDNA inhibitors. A HBVcircle mouse model and a urokinase-type plasminogen activator-severe combined immunodeficiency (uPA-SCID) humanized liver mouse model were used to evaluate the anti-HBV efficacy of the discovered cccDNA inhibitors.

Results: Potent and dose-dependent reductions in extracellular HBV DNA, HBsAg, and HBeAg levels were achieved upon the initiation of ccc_R08 treatment two days after the HBV Infection of PHHs. More importantly, the level of cccDNA was specifically reduced by ccc_R08, while it did not obviously affect mitochondrial DNA. Additionally, ccc_R08 showed no significant cytotoxicity in PHHs or in multiple proliferating cell lines. The twice daily oral administration of ccc_R08 to HBVcircle model mice, which contained surrogate cccDNA molecules, significantly decreased the serum levels of HBV DNA and antigens, and these effects were sustained during the off-treatment follow-up period. Moreover, at the end of the follow-up, the levels of surrogate cccDNA molecules in the livers of ccc_R08-treated HBVcircle mice were reduced to below the lower limit of quantification (LLOQ).

Conclusions: We have discovered a small molecule cccDNA inhibitor that reduces HBV cccDNA levels. cccDNA inhibitors potentially represent a new approach to completely cure patients chronically infected with HBV. IMPACT AND IMPLICATIONS: cccDNA persistence in HBV-infected hepatocytes is the root cause of chronic hepatitis B. We discovered a novel small molecule cccDNA inhibitor that can specifically reduce cccDNA levels in HBV infected hepatocytes. This type of molecule offers a new approach to completely cure patients chronically infected with HBV.

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