About Hepatitis B Virus
Hepatitis B virus (HBV) is a global public health threat and the world’s most common serious liver infection. It is 50 – 100 times more infectious than the HIV/AIDS virus.1 It is also the primary cause of liver cancer (also known as hepatocellular carcinoma, or HCC), which is the second leading cause of cancer deaths in the world. 2
Worldwide, 2 billion people have been infected with HBV (one out of three people), and of those almost 300 million are chronically infected. Each year, approximately 1.5 million become newly infected and an estimated 820,000 people die from the virus and related diseases. Testing is important as only about 10% of infected people are diagnosed.2
Current approaches to treatment include interferon therapy and/or inhibitors of HBV reverse transcriptase. Treatment with interferon offers poor cure rates and is accompanied by serious side effects.3 Reverse transcriptase inhibitors can be very effective at suppressing the virus but rarely result in full eradication of the virus from the liver.4 The failure to eradicate the virus necessitates chronic treatment and leaves patients at increased risk for continued disease progression.5 New treatments that can provide functional cures to chronically infected patients are urgently needed.
It is 50 – 100 times more infectious than the HIV/AIDS virus.
Worldwide, 2 billion people have been infected with HBV (one out of three people), and of those almost 300 million are chronically infected.
= 100 million people
Enanta’s Approach to Treating HBV
Enanta is developing EDP-514, a novel core inhibitor. Core inhibitors, sometimes referred to as capsid assembly modulators, are a class of HBV antivirals that can disrupt the assembly and replication of the virus at multiple steps in the viral life cycle. Targeting the viral core protein has been shown to reduce viral replication in infected patients. EDP-514’s strong antiviral activity in preclinical animal models of HBV supported its progression into clinical studies.
EDP-514, which has Fast Track designation from the FDA, is being evaluated in a comprehensive clinical development program. In Part 1 of a Phase 1a/1b study, EDP-514 was studied in healthy subjects who received single or multiple doses for up to 14 days. EDP-514 was well-tolerated and demonstrated a favorable safety profile. Treatment-emergent adverse events (AEs) were infrequent and mild in intensity. No patients discontinued EDP-514 due to an AE. Additionally, the pharmacokinetic profile was supportive of once-daily dosing.
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In Part 2 of the Phase 1a/1b randomized, double-blind, placebo-controlled study, the safety, tolerability, pharmacokinetics, and antiviral activity of three doses of EDP-514 were evaluated in 24 chronic HBV patients already being treated with a nucleoside reverse transcriptase inhibitor (NUC) who were either HBeAg-positive or HBeAg-negative. Patients were randomized to receive 200 mg (n=6), 400 mg (n=6), 800 mg (n=6) of EDP-514 or placebo (n=6) daily for 28 days.
Overall, EDP-514 was generally safe and well-tolerated at 200, 400 and 800 mg doses for 28 days. EDP-514 was rapidly absorbed and its exposure increased with increasing multiple doses. EDP-514 exhibited PK suitable for once daily oral dosing, with Ctrough concentrations reaching up to ~20-fold above the protein-adjusted EC50. At Day 28, mean HBV RNA changes of -0.81, -1.12, 0.10, and -0.19 logs were observed in the 200 mg, 400 mg, 800 mg and placebo groups, respectively. EDP-514 led to a maximum HBV RNA reduction of 2.3 log in HBeAg-negative and 2.8 log in HBeAg-positive subjects in EDP-514 arms compared to 1.2 log in placebo. In the EDP-514 800 mg arm, five of six subjects had either non-detectable or very low levels of HBV RNA at baseline. Consequently, the effect of EDP-514 on HBV RNA could not be assessed in these subjects. As expected in this NUC-suppressed patient population, there were no discernible changes in HBV DNA, HBeAg, HBcrAg, and HBsAg, and no instances of virologic failure were reported.
EDP-514 was also evaluated in a randomized, double-blind, placebo-controlled Phase 1b study assessing the safety, pharmacokinetics, and antiviral activity of three doses of EDP-514 in 24 viremic chronic HBV patients, either HBeAg-positive or HBeAg-negative, and without cirrhosis. Patients were randomized to receive 200 mg (n=6), 400 mg (n=6), or 800 mg (n=6) of EDP-514 or placebo (n=6) daily for 28 days with an 8-week follow-up period.
Results demonstrated that EDP-514 was safe and well-tolerated through 28 days of treatment, displayed pharmacokinetics supportive of once-daily dosing, and resulted in mean HBV DNA reductions of 2.9, 3.3, and 3.5 logs at 28 days for the 200 mg, 400 mg, and 800 mg cohorts, respectively, compared to 0.2 log in placebo. HBV RNA was undetectable at Day 28 in 11 patients in the three EDP-514 cohorts as compared to none in placebo. Mean HBV RNA reductions were 2.9, 2.4, and 2.0 logs for the 200 mg, 400 mg, and 800 mg cohorts, respectively, compared to 0.02 log in placebo.
We believe that achieving a functional cure for hepatitis B will likely require a multi-drug approach, potentially involving one or more mechanisms to stop viral replication and others to inhibit HBV surface antigen. NUCs are the current standard of care, and they are reasonably effective at suppressing HBV replication.5 EDP-514, a core inhibitor, affects several stages of HBV replication, from uncoating and nuclear import of the virus, to capsid assembly and recycling. With EDP-514 as a foundation, we will look to advance our HBV program with additional mechanisms from internal discovery efforts, external opportunities or both.
- Centers for Disease Control and Prevention: Hepatitis B and Sexual Health
- Hepatitis B Foundation Facts and Figures
- Woo ASJ, et. al. Alpha-Interferon Treatment in Hepatitis B. Ann Transl Med. 2017;5(7):159. doi:10.21037/atm.2017.03.69
- Yeo YH, et. al. Factors Associated With Rates of HBsAg Seroclearance in Adults With Chronic HBV Infection: A Systematic Review and Meta-analysis. Gastroenterology. 2019 Feb;156(3):635-646.e9. doi: 10.1053/j.gastro.2018.10.027. Epub 2018 Oct 17. PMID: 30342034.
- Cho JY, et. al. Patients with Chronic Hepatitis B Treated With Oral Antiviral Therapy Retain a Higher Risk for HCC Compared with Patients With Inactive Stage Disease. Gut. 2014 Dec;63(12):1943-50. doi: 10.1136/gutjnl-2013-306409. Epub 2014 Mar 10. PMID: 24615378.