Hi All,
I was reading about the ABI-4334 Capsid inhibitors and was wondering if anyone can explain its mode of actions. I read they stop the virus replication as well as have a secondary action to affect integrated RNA. Not sure if it does affects the integrated DNA which causes cancer. If yes this would be the best because now we will have an oral medicine which will not only stop cirrhosis but also cancer. Not sure if we have to take it for life but even if it i dont mind since it is better than cancer.
Any thoughts? @availlant @john.tavis @ThomasTu
Dear @Ash_Malhotra ,
Capsid assembly modulators or CAMs alter the assembly of capsids. While this class of compounds very efficiently block the release of virons containing HBV DNA and HBV RNA, they do not target production of HBsAg or impact integrated HBV DNA or cccDNA. There is no such thing as integrated HBV RNA.
ABI-4334 is a new CAM from Assembly Biosciences which is now undergoing clinical trials in humans. It suffers from the same limitations agsinst HBsAg and integrated HBV DNA as all CAMs prior. Preliminary clinical effficacy data show this CAM has similar potent effects on HBV DNA and HBV RNA as other later generation CAMs (i.e. from Aligos) but no efficacy against cccDNA for either of these later generation CAMs has yet been reported.
Best regards,
Hi @Ash_Malhotra,
Just a bit more elaboration on Andrew’s excellent response. Capsid inhibitors (CAMs) are some of the most advanced of the new HBV treatments. They bind to a little pocked formed at the junction of the HBc proteins that form the capsid and mess up the normal pattern that the 240 copies of HBc bind to each other to make the capsid. CAMs look good for reducing HBV replication in monotherapy trials, but as Andrew points out, they are not anticipated to be curative by themselves. They are likely to be good components of an eventual combination therapy, but combination trials are just starting with them, so there are lots of unknowns about which drugs they should be combined with, how long therapy should be given, etc. They will reduce accumulation of more integrated HBV DNA because they block HBV replication that is needed for integration, but they will have no direct effect on the integrated DNAs. There is a lot of talk about them interfering with cccDNA function, but I personally think that that aspect of their mechanism of action is often greatly exaggerated.
As to integrated DNA causing cancer: Most HBV-induced liver cancers carry HBV DNA integrations, and there are documented individual tumors that appear to have required HBV integration. However, most people with HBV have integrations butnever get liver cancer, so most integrations don’t do anything really bad. Therefore, it might be a bit strong to say that they “cause cancer”. Most HBV researchers I know would rather say that the integrations help promote cancer in the presence of the long-term liver inflammation induced by chronic HBV infection and probably HBx expression. Cancer development requires multiple independent points of damage to cells, and it is probable that the integrations cause only one of the cancerous “hits” to the cell.
I hope this helps.
John.
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Dear @Ash_Malhotra,
I would add the following to John’s comments:
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The blockade of continual accumulation of integrated HBV DNA is an effect that will occur with both NUCs and CAMs as they prevent the reintroduction of HBV DNA into host cells (although this effect many be slightly stronger with CAMs). However, we know that the delayed introduction of NUCs, while effectively reducing liver inflammation and HBV replication, does not alter the rate of hepatocellular carcinoma. A beneficial impact on rates of liver cancer only occurs with early introduction of NUC therapy to block accumulation of integrated HBV DNA early on in the disease. This is one of the primary drivers of the current debate regarding the introduction of NUC therapy before the onset of detectable liver disease.
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NUCs like ETV, TDF and TAF also inactivate cccDNA, an effect driven by the immunostimulatory properties of these compounds well described in the literature since their discovery and observed in numerous clinical studies. As John has mentioned, effects of CAMs on cccDNA have been shown to be absent in numerous clinical trials to date and so it is currently unclear how CAMs will provide additional clinical benefit above and beyond NUC therapy. Several large phase II studies with long term combination therapy have shown no benefit of the addition of CAMs in a combination environment including the following regimens:
- NUCs + CAMs (Assembly Biosciences and J&J)
- CAMs + ASPINs (NUC) (Assembly Biosciences / Antios)
- NUCs + CAMs + ASPIN (NUC) (Assembly Biosciences / Antios)
- NUCs + CAMs + RNAi (Assembly Biosciences / Arbutus and J&J)
- NUCs + CAMs + pegIFN (Assembly Biosciences - this trial was completed but no data was presented prior to verbicorvir being abandoned).
Also a small but important correction to my post above. The preliminary HBV DNA responses I mentioned above for ABI-4334 are actually for ABI-H3733. There is no clinical efficacy data yet for ABI-4334.
Best regards,
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Dear @availlant
According to your mentioned:
However, we know that the delayed introduction of NUCs, while effectively reducing liver inflammation and HBV replication, does not alter the rate of hepatocellular carcinoma. A beneficial impact on rates of liver cancer only occurs with early introduction of NUC therapy to block accumulation of integrated HBV DNA early on in the disease. This is one of the primary drivers of the current debate regarding the introduction of NUC therapy before the onset of detectable liver disease
If anyone starts treatment as soon as possible, could have higher chance to control it.( if I understand it correct)
for someone has inactive HBV, Has any chance to reduce the risk more? Because the guidelines do not suggest any treatment like NUCs.
another silly question sorry, How long does someone with inactive HBV have to block the accumulation of integrated HBV DNA early? (with current guidelines?) I don’t know how much the rate of accumulation of integrated HBV DNA is in the inactive phase but I think it is possible.
do we have any chance to increase the rate of a functional cure if any new treatments such as NAPs become available and reduce the risk of the condition getting worse? ( I mean for Inactive people)
Actually I am looking for optimistic solution for such condition.
Dear @IWillBeCured
Earlier start of NUCs has a better chance of preventing the development of liver cancer.
From available clinical data, rates of liver cancer are lower with inactive HBV DNA but there is still a small increased risk versus the population without HBV infection (0.06% versus 0.02%) see here. I am not aware of any data showing that NUCs influence this risk in inactive carriers.
It is important to understand that the extent of viral replication influences the rate of HBV DNA integration. In the case of inactive HBV DNA, viral replication is low (viral load in the blood is < 2000 IU/mL) so HBV DNA integration occurs more slowly (hence the reduced risk for liver cancer).
Functional cure (sustained HBsAg loss without therapy) is the best outcome for reducing the risk of liver cancer because it signals the removal of most (if not all) integrated HBV DNA. The most recent clinical trial with NAP-based combination therapy demonstrated 39% of patients achieved functional cure and an additional 39% achieved partial cure (inactive HBV). It is expected that these patients will all have a significantly reduced risk for liver cancer but this has not been experimentally confirmed. This trial was conducted in the most difficult to treat genotype of HBV (genotype D), and exluded patients with low baseline HBsAg (< 1000 IU/mL) and used an suboptimal route of administration (IV infusion).
Transitioning REP 2139-Mg to subcutaneous administration, inclusion of easier to treat HBV genotypes and patients with low baseline HBsAg are expected to significantly increase the rates of functional cure. Indications of this are already being seen in the compassionate use of REP 2139-Mg in patients with HBV / HDV co-infection recently disclosed here.
Best regards,
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Just adding some additional points to the conversation:
Various labs (including ours) did some studies on CAMs and showed high levels of CAMs prevent NEW cccDNA and probably NEW integration being formed on infection. I am not sure whether you get to these levels when actually treated with CAMs.
As mentioned above, new cccDNA and integration will probably be lowered by decreasing the viral load as well (just as they do with Nucs) but they don’t directly target the existing viral DNA.
TT
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high levels of CAMs prevent NEW cccDNA and probably NEW integration being formed on infection
So, maybe yet another option - after NUCs - promising finite therapy (for those with infinite lives, that is)?
https://onlinelibrary.wiley.com/doi/full/10.1002/kjm2.12518
A mathematical modeling study has estimated that several decades of Nuc therapy are required to achieve HBsAg loss.
Hi @mantana,
There are many groups looking at this option (withdrawal of NUCs while HBsAg is still detectable). There have been many studies which have suggested that removing NUCs in patients with very low HBsAg (< 100 IU/mL) can lead to beneficial activation of the immune system (as a result of renewed viral replication) with a resulting host mediated liver enzyme flare and ultimate achievement of functional cure (similar to what happens in the resolution of acute HBV infection).
The problems is that in this scenario, some patients following this program do achieve functional cure but many other patients have very strong re-activation of HBV infection and have “bad flares” where decompensation of liver function occurs. This is similar to the severe hepatitis which can occur during acute HBV infection which is a dangerous situation requiring careful monitoring and reintroduction of antiviral therapy. This situation occurs even in patients with HBsAg < 100 IU/mL and illustrates the importance of HBsAg loss in safely removing NUC therapy and in achieving functional cure.
The issue with NUCs is that while they effectively suppress viral replication, normalize liver function and frequently silence cccDNA, they have little to no impact on HBsAg production from integrated HBV DNA. This is the reason for the inactivity of NUCs against HBsAg (and futility for achieving functional cure). This is the reason for the “several decades” requirement for functional cure with NUCs. The integrated HBV DNA problem was very well illustrated in recent study showing minimal impact of 10 years of NUC therapy on integrated HBV DNA. Effect of Antiviral Treatment on Hepatitis B Virus Integration and Hepatocyte Clonal Expansion | Clinical Infectious Diseases | Oxford Academic
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Hi @availlant , I’m a little confused what Assembly means when they say “ABI-4334 observed to be >1000x more potent against cccDNA formation in vitro than the 1st gen CAM vebicorvir.” Does this mean they think ABI-4334 will solve the cccDNA problem, or not really because it would only stop new cccDNA from forming but leave existing cccDNA untouched?
Thanks for your explanation.
(this is from their presentation https://investor.assemblybio.com/static-files/9da006d9-32e4-4719-8ed0-55cde52c2709)
Hi @hepbmom,
These slides are mentioning how the formation of new cccDNA is inhibited at greater rates using the new drugs. That means a cure would depend getting rid of already established cccDNA (possibly with other therapeutic agents).
Hope this helps,
Thomas
Hi Thomas, thank you for the explanation! Do you know of any therapeutic agents that would get rid of already established cccDNA?
Also, do existing drugs already inhibit the formation of new cccDNA? I guess I don’t really understand what the value of these new CAM drugs is.
Great questions, @hepbmom
I’m not sure if any have shown direct and robust reduction of existing cccDNA. Interferons can (to some extent), but this problem is essentially the one the whole HBV field is working on at the moment.
Existing antivirals would limit the number of new infection events, so would inhibit the formation of cccDNA to some extent. The advantage of CAMs is that they disrupt the incoming virus (which current antivirals do not) so may have additional effect in this aspect.
Hope this helps,
Thomas