Making hepatitis B surface antigens (HBsAg) disappear is the goal of many clinical and non-clinical researchers for an effective cure for chronic hepatitis B. Because monotherapy or current drug combinations are still difficult to achieve this goal, there is still a lot of room for improvement in drug development in the HBV field.
Hepatitis B capsid assembly regulator, according to Dr. Vaillant, the field expects more effective results
So far, researchers have argued that getting all traces of HBV gone from the liver is the real cure for HBV, but that's more difficult because of the need to overcome cccDNA and integrated HBVDNA. A growing number of global hepatitis B candidates are targeting the functional cure of HBV, i.e. loss of HBsAg (ideally accompanied by anti-HBs). Partial cure of HBV means that it is possible to achieve unreceptible HBV DNA, normalization of ALT, and so on without the loss of HBsAg.
Just concluded in Singapore at a scientific conference on the theme of "Curing HBV" (held at the end of May this year), Dr Andrew Vaillant of biopharmaceutical company Replic presented a presentation entitled: Targeting Subviral Particles: Key Steps to Achieving a Functional Cure for HBV, Where are the hepatitis B drug candidates currently in clinical development?
Replicor's primary hepatitis B drug candidate is REP2139, a nucleic acid polymer (NAP) that has transitioned to subcutaneous administration, showing potential in lowering hepatitis B surface antigen levels and targeting HBV/HDV co-infection, and is often compared with other newly developed mechanisms of action, such as capsid assembly regulators, RNA interference, and antisense oligonucleotides.
According to Dr. Andrew Wilant, a recent study demonstrated that cccDNA can establish and maintain a stable cccDNA copy number without the hepatitis B core antigen, which questions the potential clinical impact of hepatitis B virus capsid assembly regulators (CAM) in chronic HBV infection. Although a variety of Class I and II HBV capsid assembly regulators are currently in clinical trials, their monotherapy can cause significant declines in HBVDNA and HBVRNA levels, but have not shown any effect on hepatitis B surface antigens.
In addition, despite the rapid renewal of cccDNA actives, CAMs monotherapy has a deficient effect on cccDNA activity (HBeAg and HBcrAg), which is consistent with the previously described requirements for the maintenance of cccDNA by lack of HBcrAg. On the other hand, all approved or under development nucleoside (acid) analogues (NUCs) (entecavir, tenofovir fumarate, tenofovir fumarate, tenofovir fumarate, or improved ATI-2173 clavudine), they have a well-described secondary effect in stimulating innate immunity.
In addition, clinically, NUC monotherapy is accompanied by a mild decline in HBsAg and a stronger decline and/or clearance of HBeAg, HBVRNA, and HBcrAg. Thus, long-term combination therapy with NUC and vebicorvir, accompanied by a general rebound and subsequent cessation of development of related drug candidates, raises questions about the contribution of CAMs in the pursuit of a functional cure for HBV. Dr. Andrew Wilant believes that the field is looking forward to the publication of more effective capsid assembly regulator development results.
Dr. Andrew Wilant argues that it should be noted that nucleic acid polymer (NAPs)-associated hepatitis B drug candidates can be accompanied by a decrease in HBsAg in clinical development, contributing much more than the typical baseline 2-3 log10 IU/mL observed when used in combination with NUCs +RNAi and CAMs+RNAi. NAPs can lower HBsAg from baseline by up to 8 log10 IU/mL, of which 70% of subjects have HBsAg < 1 IU/mL and 60% of subjects achieve HBsAg disappearance (<0.005 IU/mL).
Xiaofan Health Conclusion: At a scientific conference in Singapore in 2022, Dr. Andrew Willant of Replicor analyzed previously approved hepatitis B antiviral drugs and current hepatitis B drug candidates, focusing on the drug development prospects of pipeline core acid polymers for hepatitis B and hepatitis D sympathetics, and also recognized the new mechanism of action of HBV capsid assembly regulators in significantly reducing HBV DNA and RNA levels. However, these capsid assembly regulators have not yet been able to have an impact on the level of hepatitis B surface antigen in single-agent clinical development, and more effective HBV capsid assembly regulators need to be developed and translated into clinical studies.
Dr. Andrew Willant of Replicor will elaborate on the development and application of antisense oligonucleotides, RNAi and other cutting-edge drugs to HBV in the next chapter.