New Drugs to cure Hep B?

Hi Professor Tavis,

You have very modestly omitted your own research on RNaseH, I wonder whether you have an update on your research?
It seems to me, all the immune stimulators, such as TLR agonists and therapeutic vaccines, do not do as well in human studies. Other than the complexity of the human immune system, do you think it can be due to the dosage of the agonists or the timing of the vaccinations?

Many thanks,

Stephen in Sydney

Dear Stephen,

I am very proud of and happy with the status of my lab’s drug discovery efforts—they were omitted not due to modesty (which I’ve never been accused of having an excess!) but because they are not as advanced as the types of compounds I mentioned. The RNaseH inhibitors would be in a 2nd or 3rd wave of drugs if we can push them that far forward. Our current progress is that we have 3 major chemical families that are performing well. The best of them have effects in tissue culture cells better than that of Lamivudine, but they are just inhibitors rather than drugs because we have not yet built in the pharmacological properties needed for a compound to perform well in a human body. That is one of the main things we’re working on now.

I suspect the disappointing results with the TRL agonists and therapeutic vaccines you mention are primarily due to the extreme complexity of the mammalian immune system. There are some fairly big differences in the immune systems between the preclinical animals in which the drugs were tested (such as mice) and humans. The compounds looked great in animals, but not so good in humans. This is a constant problem in drug discovery: the animal models we have at our disposal are only imperfect mimics of human biology. This problem is probably worse with immune-targeting drugs, but it is also present with small-molecule drugs due to differences in how they distribute in the body, rate of degradation, etc.

I hope this helps.

John

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Thank you, Professor Tavis for the very useful information, much appreciated.

Stephen in Sydney

came across this ;
The newly developed vaccine , called TherVacB , will be tested as immunotherapy in a two-year clinical trial starting in 2021. It is designed to cover the majority of all hepatitis B viruses and can therefore be used worldwide for infected people.TherVacB is an EU-funded project lasting five years from January 2020 to December 2024.

What does theraputic vaccine mean and is this real?

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Dear @kevin ,

Great questions.

First, the majority of the vaccines that are used are prophylactic or preventative vaccines. These are basically a weakened version or fragment of the virus or bacteria. The idea is that they teach your immune system to recognise the virus or bacteria, so that when you see the real thing, you can deal with it more effectively. They stop you from being infected. Some examples are the covid vaccines, measles mumps rubella, chickenpox, etc.

The idea behind a therapeutic vaccine is similar, but instead you already have the infection. For hep b infections, much of the time your immune system doesn’t readily recognise the virus or only is partially activated. This means you get small flares, but don’t completely clear the virus. This approach presents bits of the virus to your immune system in such a way that it says “yes, you really should get rid of all cells that express this”. The hope is that this will be enough to clear the infection.

The science has been carried out by some very experienced and reputable scientists in the field, so i believe that this is a legitimate approach. The preclinical data has been promising too. I am definitely interested in the results that come out of the clinical trials.

Hope this clarifies things.

Cheers,
Thomas

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@ThomasTu Thanks for the info , very helpful.

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I agree with Thomas about TherVacB. This was developed by one of the leading HBV virologists, and the animal data are quite promising. Of course, good preclinical data does not in any way guarantee success in a clinical trial in people, but this approach is certainly worth trying. I’m excited to see the results of the study!

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@ThomasTu @john.tavis what do you think of this?

Antios Therapeutics and Assembly Biosciences Announce Clinical Collaboration Agreement to Evaluate the Combination of ATI-2173 and Vebicorvir in Patients with Chronic Hepatitis B Virus Infection

This is a trial using a nucleotide analogue (very similar to entecavir and tenofovir) and a capsid inhibitor. Just from what I understand from first principles, this would not be necessarily aiming for a functional cure because neither of these drugs target cccDNA directly.

But this trial may be designed to find out if there a much greater suppressive effect of the virus (given they target different steps of virus production) compared to ETV/TDF by itself.

Hope this makes sense,
Thomas

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Thanks Thomas for the reply🙏
I forgot to ask about how you felt about this drug it’s coming to the United States soon I hope. it’s called - myrcludex b - bulevirtide - that’s being used already showing promising results.

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Hi Eddie,

Yeah, up until a couple of years ago I was working the lab of Prof Stephan Urban (the inventor of Myrcludex B). For people with Hepatitis D and Hepatitis B co-infections, Myrcludex B/bulevertide/hepcludex is one of the only treatments out there and it works well. For Hepatitis B infection alone, they are still testing it and working out which combinations might be best (this might include the addition of interferon).

TT

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I was reading About it. It seems to do the same thing for hep b. like you said in your speech it Keeps the roots from getting into the cells

Yep, that’s how it works. But some work from our lab shows that Hep B doesn’t set up new roots very often because the roots already there are very stable. This is part of why it is not as effective against Hep B itself. But there is a thought that with combination with other drugs, it could be part of a cure treatment.

Thomas

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Sorry for the late response—I was traveling for work and had a nasty confluence of deadlines.

Disclosure: I’m an advisor to Antios.

I’m quite supportive of this combination. The Antios drug is a promising new prodrug form of Clevudine that looks like it may have solved the muscle toxicity associated with the earlier version of Clevudine, and Vebicorvir is a first-generation capsid assembly modifier. Their mechanisms of action are complementary and both seem to be performing well so far in the early clinical trials.

John.

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In looking at the responses regarding this I am wondering what the scientists on here think about the initiative that is behind the work on ThervacB. It seems there has been funding allocated specifically for finding a cure and providing ground treatment.
As with many people, the first I ever heard of hepatitis B was in my own diagnosis a few months ago.

Hi @Bonzai123,

I’ve just moved your post into a more on-topic thread. If you see above (New Drugs to cure Hep B? - #25 by ThomasTu), there is a bit of discussion about ThervacB.

Cheers,
Thomas

Hi @john.tavis and @ThomasTu
I want to say first and foremost this website is a lucky find amongst the uncertainty of a new diagnosis. Thank you Thomas for creating this community and all the verified scientists that take the time to answer our questions.

I wanted to touch on a continuing subject here which is potential cures that will rid us of this constant worry and bi-annual or annual tests. Being that a cure was found for Hepatitis C and really not that long ago, do we know why pushes for Hep B cures have only been ramped up in the past 5-8 years? This is such a dangerous disease I can’t imagine that the research into a cure for Hep C didn’t overlap with research and cures for Hep B as well? I confess I don’t know much and am hoping for clarity. I am very much hoping and looking forward to the day we can move on from this awful disease and celebrate a cure much like Hep C patients and am hopeful it will be sooner rather than later.

Dear @Bonzai123,

This is an interesting question with multiple answers.

HBV cure research never really stopped, but it slowed to just a trickle for a long time. The slowdown started in the late 80’s or early 90s after the wonderful vaccine was approved. There became an assumption at the US NIH (and presumably other major funders too) and the biotech/pharmaceutical companies that the disease would just fade away with time, so research funding got very difficult to obtain in many places. About the same time HCV was discovered and a lot of money was poured into understanding it, so many HBV researchers shifted all or part of their focus to HCV (I worked on both HBV and HCV for most of the time between 2000 and 2012). Thankfully, that effort vs. HCV was stunningly successful. So the core of the problem was that shade was thrown on HBV research by the vaccine and the urgency to address HCV. The final issue is that HBV is going to be harder to cure than HCV was due to its replication mechanism (the nuclear “cccDNA” form of the HBV genome needs to be eliminated, but that is a really hard target). The experimental systems for HBV were (and still are) quite limited in some aspects of what we need to study to develop a cure, and that makes everything even harder.

The very good news is that there is a massive, world-wide academic, biotech, and major pharma effort ongoing to develop a cure for HBV. The number of scientists pursuing cure projects is very large, and good progress is being made. Part of the credit for the very rapid scale-up vs. HBV ironically comes from HCV research. Major pharma had developed truly impressive research capacity for hepatic virology, and so they just refocused a large number of talented people and funding towards HBV. The shift in industrial resources towards HBV was really quite breathtaking in its scale and how fast it occurred!

I’ll end with this note of optimism: We cannot tell when cure(s) will become available because it is impossible to predict the pace of scientific research. However, there are so many cool projects being pursued that some of them will certainly succeed. I feeling is that cure rates will start rising from their current ~5-7% rate within a few years, and that probably within a decade or so we will be routinely curing at least half of the patients entering treatment–maybe more!!! Rest assured, the HBV research community won’t rest till cure rates for HBV match those for HCV.

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Hi John,
Thank you for your comprehensive response. When you mention current cure rates of 5-7% currently is this based on the viral load number or are people truly being cured of the virus and able to lead healthy lives without concerns of liver disease?

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That is the number reported in clinical trials of people who meet the current definition of a “functional cure” following treatment with pegylated interferon alpha (usually determined after 1 year of therapy) or nucleoside analog drugs (usually determined after many years of therapy).

John.

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