The AASLD (American Association for the Study of Liver Diseases) 2023 conference was held in Boston, USA, from November 10th to 14th, marking a significant event in the field of hepatology. Hepatology Digest’s reporting team was fortunate to invite Dr. Zhihong Liu from the Department of Infectious Diseases and Hepatology at Southern Hospital of Southern Medical University to share insights from the AASLD and discuss the work presented by his team at the conference, along with their learning experiences.
The AASLD is one of the most prestigious academic conferences in hepatology. This year’s event was especially notable as it was the first major in-person gathering since the COVID-19 pandemic. A hot topic in recent years within the tech community has been the breakthroughs in large language models (LLMs) in artificial intelligence (AI). The potential revolutionary changes these tools can bring to the medical field are highly anticipated. At the conference, American scholars presented case studies on integrating LLMs with healthcare, and discussions on the development of related legal and regulatory frameworks were initiated. One key point highlighted was the importance of crafting prompt languages for LLMs, with top institutions like Boston Children’s Hospital advocating for the hiring of specialized prompt engineers to embrace the technological revolution of LLMs. The University of California, San Francisco showcased their approach in generating responses from LLMs based on specific literature databases. Although this topic was presented in a smaller session, the full house reflected the public’s immense enthusiasm for cutting-edge technology.
In my own field of expertise, I also paid close attention to the academic advancements in the United States regarding expanded screening and treatment of hepatitis B. In this topic, Professor Mindie Nguyen mentioned that through their efforts, the U.S. CDC has implemented a bill for universal screening for chronic Hepatitis B. Professor Norah Terrault, the principal author of the current AASLD guidelines for Hepatitis B, shared her personal opinion on simplifying indications (expanding the treatment population). Also, in this session, Professor Harry Janssen noted that the new Chinese guidelines recommend treating all patients over 30 years old who are HBV DNA positive, viewing it as an excellent precedent. The discussion on how to simplify treatment indications was also intense, with the starting age for treatment being one of the focal points of contention.
However, past research has indicated that patients in the immune-tolerant phase or the grey zone, who are included in the expanded treatment indications, might respond poorly to nucleos(t)ide analogues and become patients with low-level viremia. Therefore, in our center’s study of Tenofovir Alafenamide (TMF) phase III randomized control over 144 weeks (included in the conference’s late-breaking abstracts, NO.5034), we also reviewed different virological responses of patients between weeks 96 to 144: The results suggest that at 96 weeks, around 60% of patients in both treatment groups achieved a sustained virological response (MVR, maintaining HBV DNA below 20IU/mL since the first time), about 30% had low-level viremia (LLV, at least one instance of HBV DNA >20IU/mL after virological response), and 10% did not respond; after switching to open-label TMF treatment from 96 to 144 weeks, about 80% of LLV patients achieved MVR. The study also suggests that TMF still has a significant advantage in normalizing ALT levels in the MVR population compared to TDF, and switching to TMF treatment also significantly increased the ALT normalization rate in the TDF treatment group.
Another hot topic is the release of data on investigational new drugs for functional cure of hepatitis B. This AASLD conference presented the latest research results for several investigational new drugs for hepatitis B, especially the highly anticipated Bepirovirsen, an antisense oligonucleotide drug. Last year’s phase 2b B-Clear study data published in the New England Journal of Medicine showed that 26% of patients turned negative after 24 weeks of treatment with 300 mg Bepirovirsen once a week, but only 9% maintained HBsAg and HBV DNA negativity during the 24 weeks after stopping the drug. This year’s latest results indicate that sequential PEGylated interferon (PegIFN) treatment at the end of Bepirovirsen monotherapy did not further improve the HBsAg clearance rate but played an important role in reducing relapse and rebound in Bepirovirsen responders.
Roche’s Piranga phase 2 study is the first in hepatitis B new drug research to explore the “Mix & Match” concept. This new platform design (Adaptive design) allows for head-to-head comparisons of investigational drugs or combinations at different stages of development. At this conference, the Piranga team was invited to give an oral summary report: Patients received 48 weeks of treatment with SiRNA drug Xalnesiran and nucleos(t)ide analogues, combined or not with immune-activating drugs (Toll-like receptor 7 agonist-Ruzotolimod or Peg-IFN). The results suggest that the response rate of patients combined with immune-activating drugs was significantly higher, with 30.0% of patients in the Peg-IFN combined treatment group turning HBsAg negative at the end of treatment, and 23.3% remaining HBsAg and HBV DNA negative 24 weeks after stopping the drug; the respective proportions for the Ruzotolimod combined treatment group were 17.6% at the end of treatment and 11.8% after 24 weeks.
Another new drug that garnered significant attention is the capsid assembly modulator (CAM-E) ALG-000184. Previously, the industry believed that such drugs might have limited impact on patients’ HBsAg levels. However, the latest data released at this AASLD shows that ALG-000184, when initially combined with entecavir treatment, can significantly and persistently reduce HBsAg levels. Moreover, the treatment group that initially received a placebo for 12 weeks and then switched to ALG-000184 also showed further decreases in HBsAg levels.
The conference featured numerous abstracts and oral reports on new curative drugs for hepatitis B, each filled with fascinating content, too extensive to detail individually. Being present at AASLD and experiencing its vibrant academic atmosphere was incredibly inspiring. I am hopeful that in the future, we will collectively witness humanity curing HBV, this ancient virus, with the aid of modern technology.
Study Overview
Long-Term (>24 Weeks) Oral Administration of New Hepatitis B Drug ALG-000184 in HBeAg-Positive Patients: Efficacy and Safety (Abstract No.: 1483-C)
First Author: Jinlin Hou
Research Background:
ALG-000184 is a prodrug of ALG-001075 and represents a novel, pan-genotypic capsid assembly modulator (CAM-E) with picomolar potency in vitro.
Research Method:
ALG-000184-201 is a multi-part, multi-center, double-blind, randomized, placebo-controlled phase 1b clinical study (NCT04536337). Its aim is to evaluate the safety, pharmacokinetics, and antiviral activity of daily oral administration of ALG-000184 in both healthy volunteers (≤7 days) and patients with chronic Hepatitis B (≤48 weeks). Previous reports indicated good outcomes for these characteristics within ≤24 weeks of medication. This study reports new safety and efficacy data observed after >24 weeks of medication in the ongoing fourth part of the cohort, assessing the antiviral activity of ALG-000184 (300 mg) in untreated HBeAg-positive chronic Hepatitis B subjects. Other obtained data will also be disclosed at the conference.
Study Results:
To date, five untreated HBeAg-positive subjects have been treated with 300mg ALG-000184 in combination with entecavir for over 24 weeks, reaching up to 32 weeks. All subjects are Asian, with genotype B or C, and are undergoing entecavir-based baseline treatment. The average baseline levels of the subjects include ALT at 29.2U/L, HBV DNA at 8.1 log10 IU/mL, HBV RNA at 6.9 log10 copies/mL, and HBsAg at 4.3 log10 IU/mL. The data shows good tolerance to long-term ALG-000184 administration, with no serious adverse events (AE) reported and no treatment discontinuations due to AE. All treatment-emergent adverse events (TEAEs) were grade 1 or 2, except for one subject who experienced a grade 4 TEAE, namely elevated ALT, which peaked at 416 U/L (10.1xULN) on day 171. Despite continuing ALG-000184, this condition is currently improving; thus, the study’s safety monitoring board considers this TEAE unrelated to drug toxicity. Additionally, no abnormal results or trends related to laboratory tests, electrocardiograms, vital signs, or physical examinations were found.
Among these five subjects, four showed a decrease in HBsAg levels exceeding 1.1 log10 IU/mL, with the greatest reduction being 1.9 log10 IU/mL (Figure 3). The HBV DNA levels in all patients decreased by ≥5 log10 IU/mL, with one case below the detection limit; all patients’ HBV RNA levels also fell by ≥2 log10 IU/mL and were below the detection limit.
Study Conclusion:
The results indicate that treatment with 300 mg ALG-000184 in combination with entecavir for over 24 weeks is well-tolerated in untreated HBeAg-positive chronic Hepatitis B patients and leads to a multilogarithmic reduction in HBsAg, HBV DNA, and HBV RNA levels. The associated decline in HBsAg levels suggests a potential auxiliary mechanism of action for CAM-Es. Researchers are currently conducting further studies with more subjects and longer medication durations to better understand the risk-benefit profile of ALG-000184.
Reference : [1] Hou JL, DING YH, LIANG XE, et al. PROLONGED (> 24 WEEK) DOSING WITH THE ORAL CAM-E COMPOUND ALG-000184 RESULTS IN MULTI-LOG REDUCTIONS IN HEPATITIS B SURFACE ANTIGEN, HBV DNA, AND HBV RNA LEVELS IN UNTREATED E ANTIGEN POSITIVE SUBJECTS WITH CHRONIC HEPATITIS. AASLD 2023, Poster 1483-C.
