Efficacy and safety of GLS4/ritonavir combined with entecavir in HBeAg-positive patients with chronic hepatitis B: interim results from phase 2b, multi-center study

Zhang, Mingyuan; Zhang, Jiming; Ya, Tan; Xin, Yongning; Gao, Haibing; Zheng, Sujun; Yue, Yi; Zhang, Jie; Wu, Chao; Zhao, Yingren; Jin, Zhenjing; Gao, Zhiliang; Mao, Xiaorong; Wang, Maorong; Hu, Ping; Rao, Huiying; Jia, Zhansheng; Hou, Jinlin; Chen, Liang; Yang, Xiangdong; Lu, Jiajie; Han, Tao; Chen, Yongping; Ning, Qin; Yang, Dongliang; Shang, Jia; Jiang, Jianning; He, Qingwei; Chen, Yunfu; Ren, Qiushi; Luo, Lin; Zhou, Qinghong; Zhang, Yingjun; Kong, Fei; Ding, Yanhua; Niu, Junqi

doi:10.1016/s0168-8278(20)32197-8

Cited by 23 publications

(21 citation statements)

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“…Similarly, the combination of NUCs with a potent CAM could provide stronger suppression of viral replication, leading to a decrease in intracellular recycling of cccDNA and its impaired formation in de novo‐infected hepatocytes, thus reducing the pool of intrahepatic cccDNA. Whether this type of approach can achieve a functional cure or high rate of virological control after cessation of therapy needs to be evaluated in clinical trials 37 …”

Section: Opening the Possibility For New Drug Combinationsmentioning

confidence: 99%

“…Whether this type of approach can achieve a functional cure or high rate of virological control after cessation of therapy needs to be evaluated in clinical trials. 37 The idea of combining drugs that target the HBV replicative cycle with compounds targeting HBV expression is based on the hypothesis that reducing not only viral replication but also expression…”

Section: Daa Combinations With or Without Inhibition Of Hbv Expressionmentioning

confidence: 99%

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HBV 2021: New therapeutic strategies against an old foe

Suarez

Testoni

Zoulim

2021

Liver International

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Hepatitis B virus (HBV) affects more than 250 million people worldwide, and is one of the major aetiologies for the development of cirrhosis and hepatocellular carcinoma (HCC). In spite of universal vaccination programs, HBV infection is still a public health problem, and the limited number of available therapeutic approaches complicates the clinical management of these patients. Thus, HBV infection remains an unmet medical need that requires a continuous effort to develop new individual molecules, treatment combinations and even completely novel therapeutic strategies to achieve the goal of HBV elimination. The following review provides an overview of the current situation in chronic HBV infection, with an analysis of the scientific rationale of certain clinical interventions and, more importantly, explores the most recent developments in the field of HBV drug discovery.

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Section: Opening the Possibility For New Drug Combinationsmentioning

confidence: 99%

Section: Daa Combinations With or Without Inhibition Of Hbv Expressionmentioning

confidence: 99%

HBV 2021: New therapeutic strategies against an old foe

Suarez

Testoni

Zoulim

2021

Liver International

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“…GLS4, a direct HAP successor of BAY41-4109, had initially shown less pronounced anti-HBV activity than other CAMs which could be related to its metabolization by CYP3A, one of the cytochrome P450 isoenzymes. Co-application of the CYP inhibitor ritonavir (RTV) enhanced GLS4 trough concentrations and boosted antiviral activity in phase 2 studies, with reported up to 4.4 log10 reductions in HBV DNA without added NUC [ 242 ]. Ongoing phase 2b studies evaluate the combination of GLS4/RTV with NUC (entecavir); interim data indicate also here superiority over NUC alone, with transient ALT flares correlating with stronger antigen declines [ 242 ].…”

Section: Targeting Hbv Capsid Dynamicsmentioning

confidence: 99%

“…Co-application of the CYP inhibitor ritonavir (RTV) enhanced GLS4 trough concentrations and boosted antiviral activity in phase 2 studies, with reported up to 4.4 log10 reductions in HBV DNA without added NUC [ 242 ]. Ongoing phase 2b studies evaluate the combination of GLS4/RTV with NUC (entecavir); interim data indicate also here superiority over NUC alone, with transient ALT flares correlating with stronger antigen declines [ 242 ]. Another CAM-A HAP compound, RO7049389, also achieved up to > 3 log10 declines in HBV DNA after 28 days of treatment in phase 1 [ 234 , 235 ], and entered phase 2 trials evaluating long-term triple combinations, including with investigational drugs.…”

Section: Targeting Hbv Capsid Dynamicsmentioning

confidence: 99%

The Hepatitis B Virus Nucleocapsid—Dynamic Compartment for Infectious Virus Production and New Antiviral Target

2021

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Hepatitis B virus (HBV) is a small enveloped DNA virus which replicates its tiny 3.2 kb genome by reverse transcription inside an icosahedral nucleocapsid, formed by a single ~180 amino acid capsid, or core, protein (Cp). HBV causes chronic hepatitis B (CHB), a severe liver disease responsible for nearly a million deaths each year. Most of HBV’s only seven primary gene products are multifunctional. Though less obvious than for the multi-domain polymerase, P protein, this is equally crucial for Cp with its multiple roles in the viral life-cycle. Cp provides a stable genome container during extracellular phases, allows for directed intracellular genome transport and timely release from the capsid, and subsequent assembly of new nucleocapsids around P protein and the pregenomic (pg) RNA, forming a distinct compartment for reverse transcription. These opposing features are enabled by dynamic post-transcriptional modifications of Cp which result in dynamic structural alterations. Their perturbation by capsid assembly modulators (CAMs) is a promising new antiviral concept. CAMs inappropriately accelerate assembly and/or distort the capsid shell. We summarize the functional, biochemical, and structural dynamics of Cp, and discuss the therapeutic potential of CAMs based on clinical data. Presently, CAMs appear as a valuable addition but not a substitute for existing therapies. However, as part of rational combination therapies CAMs may bring the ambitious goal of a cure for CHB closer to reality.

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“…No patients in the ETV group achieved ≥1.5 log HBsAg decline at week 24 compared to 12.5% patients in the GLS4/ritonavir group. In addition, GLS4/ritonavir was more effective than ETV in suppression of HBV RNA (3.53 vs. 0.73 logs, respectively) and HBcrAg (1.32 vs. 0.65 logs, respectively) in previously treatment-naïve patients at week 24 [ 56 ].…”

Section: Novel Therapeutic Approachesmentioning

confidence: 99%

Novel Antivirals in Clinical Development for Chronic Hepatitis B Infection

Mak

Seto

Yuen

2021

Viruses

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Globally, chronic hepatitis B (CHB) infection is one of the leading causes of liver failure, decompensated cirrhosis, and hepatocellular carcinoma. Existing antiviral therapy can suppress viral replication but not fully eradicate the virus nor the risk of liver-related complications. Novel treatments targeting alternative steps of the viral cycle or to intensify/restore the host’s immunity are being developed. We discuss novel drugs that have already entered clinical phases of development. Agents that interfere with specific steps of HBV replication include RNA interference, core protein allosteric modulation, and inhibition of viral entry or viral protein excretion (NAPs and STOPS). Agents that target the host’s immunity include toll-like receptor agonists, therapeutic vaccines, immune checkpoint modulators, soluble T-cell receptors, and monoclonal antibodies. Most have demonstrated favorable results in suppression of viral proteins and genomic materials (i.e., HBV DNA and/or pre-genomic RNA), and/or evidence on host-immunity restoration including cytokine responses and T-cell activation. Given the abundant clinical experience and real-world safety data with the currently existing therapy, any novel agent for CHB should be accompanied by convincing safety data. Combination therapy of nucleos(t)ide analogue, a novel virus-directing agent, and/or an immunomodulatory agent will be the likely approach to optimize the chance of a functional cure in CHB.

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Efficacy and safety of GLS4/ritonavir combined with entecavir in HBeAg-positive patients with chronic hepatitis B: interim results from phase 2b, multi-center study

Cited by 23 publications

References 0 publications

HBV 2021: New therapeutic strategies against an old foe

HBV 2021: New therapeutic strategies against an old foe

The Hepatitis B Virus Nucleocapsid—Dynamic Compartment for Infectious Virus Production and New Antiviral Target

Novel Antivirals in Clinical Development for Chronic Hepatitis B Infection

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