HBV infection can lead to acute and chronic hepatitis, posing a global health issue. HBV capsid assembly modulators play a crucial role in multiple stages of HBV replication, such as capsid assembly and HBV DNA synthesis, making them a new focus in HBV drug development. Besides being a major threat to public health, Non-Alcoholic Fatty Liver Disease (NAFLD) is on the rise in the general population, presenting a challenging issue.
At the 58th Annual Meeting of the European Association for the Study of the Liver (EASL 2023) and the EASL Congress 2023, Dr. Yanhua Ding’s team from The First Hospital of Jilin University in China presented their latest research results on CAM new drug clinical trials and a novel NAFLD prediction model. Hepatology Digest had the privilege of inviting Dr. Yanhua Ding to discuss the details, talk about the prospects of new drugs for hepatitis B, NAFLD management strategies, and share their experiences from attending EASL. Let’s dive in together.
Hepatology Digest: Currently, the development of new drugs for hepatitis B is in full swing, and your research on the HBV capsid assembly modulator (CAM) Freethiadine has been selected for presentation at the EASL conference. Could you please discuss the antiviral mechanism, progress, and prospects of this new drug?
Dr. Yanhua Ding : Freethiadine is a capsid assembly modulator that primarily targets the core protein, serving as a core protein regulator. We conducted a Phase I clinical trial of this drug. Compared to similar drugs in the past, Freethiadine has demonstrated improved structural properties, stronger in vitro activity, and superior pharmacokinetic performance, with higher exposure. This conference mainly revealed the safety, efficacy, and clinical pharmacokinetic characteristics of this drug in chronic hepatitis B patients. We observed a dose-dependent reduction in HBV DNA levels and HBV pgRNA levels during a 28-day dosing period.
After the initial discovery that capsid assembly modulators had a certain effect in reducing hepatitis B surface antigen, many companies have actively researched compounds of this type. Recent results may not have been very promising, but at this year’s EASL Annual Conference, Aligos Therapeutics developed a Class II capsid assembly modulator, ALG-000184, which led to a continuous reduction of HBsAg by 1-2 log values within a 36-week dosing period. Therefore, for CAMs, we still need drugs with better activity and pharmacokinetics, hoping to see more advantages in terms of efficacy.
Hepatology Digest: From pre-clinical to clinical trial stages and into the real world after market approval, a new drug undergoes a long wait before it is used for clinical treatment. As a frontline clinician or from a patient’s perspective, how should we view new drug research in relation to existing medications? Could you please share some insights from your experience with new drug development clinical trials?
Dr. Yanhua Ding : Based on the results of many early clinical trials of new drugs, new drugs often have better therapeutic effects than those already on the market. Early clinical research is crucial, as it allows us to pinpoint potentially effective dosages during the initial single-dose and multiple-dose escalation stages in healthy subjects. After completing trials in healthy individuals, we can quickly recruit patient subjects to verify the drug’s efficacy, allowing for rapid proof-of-concept validation, which is essential.
Most of the early-phase clinical trials conducted at The Phase I Clinical Trial Unit of The First Hospital of Jilin University take approximately one year from the first human trial to seeing efficacy. During this time, we conduct single-dose and multiple-dose trials in healthy individuals, food-effect studies, and efficacy trials in small patient samples. Based on these trial results, we can generally determine whether the compound is worth pursuing further in clinical trials. Therefore, the speed of completion in the early clinical stages is crucial.
Hepatology Digest: Regarding further exploration of new drugs for hepatitis B, what key areas or promising directions do you see?
Dr. Yanhua Ding: Currently, in addition to core protein regulators like capsid assembly modulators, nucleoside analogs and small interfering RNAs have also shown promising results. Combining or sequencing these new drugs may yield better results than currently marketed drugs, potentially bringing us closer to functional cure goals.
Hepatology Digest: Besides your research on this hepatitis B new drug, we noticed that your study evaluating non-invasive models to predict the severity and progression of NAFLD has been selected for conference presentation. Could you tell us about the background and motivation for conducting this research?
Dr. Yanhua Ding: In addition to hepatitis B, NAFLD is a major health issue with an increasing incidence in the general population. It remains an unmet clinical need and a disease that has not been adequately addressed. Currently available drugs have limited efficacy, and NAFLD can have serious consequences.
Our center initiated a NAFLD cohort study led by researchers, and it has enrolled more than 800 NAFLD patients to date. We will conduct long-term follow-up on all patients. Some patients have already been followed up for two years, with initial biannual check-ups. Based on their disease progression, we have adjusted the follow-up to annual comprehensive examinations. These assessments include measurements of liver fat content using magnetic resonance proton density fat fraction (MRI-PDFF), transient elastography (FibroScan), as well as the testing of biomarkers and gene peptides. In addition to these non-invasive assessments, liver biopsies have also been performed, with 98 biopsy specimens collected, including over 20 cases with repeat biopsies after one year.
Through this study, we aim to understand the disease progression in Chinese NAFLD patients, identifying some unique clinical features in Chinese patients compared to those in Western countries. Furthermore, we seek to determine which NAFLD patients require treatment, and who needs immediate intervention. Our first related article has already been published in Hepatology International.
At this EASL conference, we mainly focused on patients who had a second examination after one year, showcasing our evaluation of NAFLD progression and our assessment of existing non-invasive models. Using MRI-PDFF to measure liver fat content as the evaluation index, we found that KANFLD and FAST can better predict disease progression in NAFLD patients.
Hepatology Digest: What are your future plans for this study?
Dr. Yanhua Ding: We will continue with the follow-up in this study to investigate disease progression. Currently, we are recruiting volunteers who are asymptomatic but have been identified with fatty liver through ultrasound results. From a pathological perspective, about one-third of the patients have fatty liver hepatitis, and 27% have developed liver fibrosis, primarily at the F1 stage but with some progressing to F2, F3, and F4 stages. Many NAFLD patients, even though asymptomatic, are experiencing hidden disease progression, making it urgent for China to develop new drugs for NAFLD.
Within the cohort, we are conducting a lifestyle intervention study involving 100 pairs of patients, providing detailed guidance on diet and exercise. However, in reality, lifestyle changes are seldom sustained, and few people achieve ideal results. Therefore, the control and treatment of this disease in the future will still rely on new drugs.
Hepatology Digest: Finally, could you share the topics or research that particularly interested you at this year’s EASL conference, as well as your overall impressions of attending the event?
Dr. Yanhua Ding : I am most interested in hepatitis B and NAFLD, and I have conducted extensive research in these two fields. There has been limited communication and exchange with the outside world during the three years of the pandemic. By participating in this conference, I have learned a lot about the latest developments in hepatitis B and NAFLD in foreign countries, which I find highly beneficial. It greatly contributes to our research.
