Hello, I was hoping someone could clarify the significance of these phase 1b findings:
It was in the news in August for having phase 2 results in line with phase 1b results.
If this CAM is able to clear serum HBV DNA, what does that mean for the HBV patient? Would that mean disease progression has been halted, and the patient would need to take the CAM indefinitely to keep the disease well managed and essentially without health effects? Would that be an improvement over existing treatment options?
Or, would taking this CAM over a long period of time actually result in being cured, and the patient could stop taking the drug?
Lastly, would this drug have an effect on HbsAg levels?
Thank you!
Dear @hepbmom,
Capsid assembly modulators work by interfering with the normal assembly of the capsid, athe protein shell which houses the genetic information of the virus.
Unfortunately, , while this mechanism results in the inhibition of release of virus, it does nothing to the production of subviral particles (which are where the bulk of HBsAg lies).
In this regard, CAMs as a class of compounds are not really any different in their impact on HBV infection as compared to approved NUC therapies like ETV and TDF/TAF; both result in clearance of HBV DNA from the blood but have no real impact on HBsAg or cccDNA or integrated HBV DNA. This has been demonstrated with numerous CAMs in clinical trials before GST-HG141, most already abandoned.
Like removal of NUCs, removal of CAMs leads to rapid rebound in viral replication requiring restarting treatment becuase HBsAg loss has not been achieved.
@availlant
Hi @availlant , thank you so much for the explanation! That’s disappointing. Would CAMs have fewer side effects than entecavir, tenofovir, etc.? If not, and CAMs are truly redundant with no incremental value, why would these companies put resourcing toward their development?
Dear @hepbmom,
There are no real safety differences between NUCs and CAMs and both are pills taken once a day. This is why many CAMs have been abandoned already - they cannot provide any improvement over the current standard of care.
Unfortunately, there has been a lot of “wishful” thinking behind many of the antiviral approaches for HBV. It is important to understand that the development of antiviral approaches is a moneymaking endeavor and is undertaken by many companies who are publicly traded on the stock market. Unfortunately, when this happens there are a lot of forces at work here which are not necessarily guided by science alone.
One of the reasons this forum exists is so that patients can get access to the science and understand better which`“promises” will work and which won’t.
@availlant
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Hi @availlant , I just came across this data on ALG-000184 and was wondering how you would interpret it. I believe it shows that the medication does reduce HBsAg. Is that right? In that case, what would be the gap between what the medication can do and curing HBV? Is the drug not reducing HBsAg enough?
Dear @hepbmom,
HBsAg reductions in the range of 0.5 log from baseline are routinely observed with ETV, TDF and pegIFN and are 100% predictive of futility in achieving functional cure. This reduction is quite minor and does not provide any restoration of immune function. In the case of ALG-000184, this is almost certainly coming from off target immunostimulatory functions (as is the case for ETV and TDF). For comparison, even reductions of > 3 log (1000 fold) to levels of 10 IU/mL are not sufficient for functional cure. HBsAg < 0.05 IU/mL during treatment is required for functional cure, which represents a 6 log decline from baseline (average HBsAg in HBV patients is ~ 10,000 IU/mL).
@availlant
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Wow, that’s fascinating. Thank you so much for the explanation!