Nucleic acid polymers (NAPs): targeting subviral particles to achieve HBV functional cure

Tamron · 20 February 2023 12:56

Dear Mr Avvailant,

I have read the relevant research you have guided, gained a lot of knowledge, and have a better understanding of the principle of REP 2139-Mg, and I have read the time information of the drug research and development pipeline on your company’s official website. You are expected to carry out a new round of research on REP 2139-Mg in 2024, but only in France and the United States. I would like to ask whether you consider joining Asian countries, such as China, because I am from China, There are many people with hepatitis B in China, and the medical needs are very large. Maybe it can meet your research needs. At the same time, I am very looking forward to using your medicine to restore my health.

Best regards,

availlant · 20 February 2023 14:57

Dear @Tamron ,

Thank you for your comments. China is a VERY important consideration and we are very mindful of the large unmet medical need there. As I have mentioned in other posts, I cannot comment on clinical development activities beyond what is in the public domain.

Best regards,

Nass · 21 February 2023 04:42

@availlant
The greater Singer…Bob Marley once said……” Though the road’s been rocky it sure feels good to me”
Due to all hassles and the long process, I believe that is the case for you and your organization…

We appreciate the effort and looking forward to its arrival!!! Thanks for what you do!!
Nass

availlant · 21 February 2023 06:28

Very much appreciated @Nass !

sorte · 21 February 2023 11:15

@availlant are you planning any clinical trials in Europe in close future, especially Poland would be most interesting for me

availlant · 21 February 2023 11:35

Hi @sorte ,

The latest clinical development plans can be found here.

Best regards,

availlant · 21 February 2023 11:54

Hi @Tamron ,

I have never said that clinical trial planning has anything to do with trade secrets. As with the development of any drug for approval, clinical trial planning always has as its first goal the most efficient pathway to approval and giving access to the drug to patients.

I appreciate your enthusiasm but please be careful with your comments.

Best regards,

sorte · 21 February 2023 12:02

@availlant those upcoming in Q1/2024 phases are p2 or p3 ? If it’s p2 do you think there’s some decent chance that regulatory bodies could approve it conditionally like covid vaccines if the results (what I wish) would be impressive and no sides ? Of maybe some fast-track route. I dont know exact details and conditions of those 2 approval paths,

Tamron · 21 February 2023 12:08

Dear Mr Avvailant,

Thank you for your correction and tolerance. I have deleted my reply with questions, and I will be careful with my comments in the future.

Best regards,

availlant · 21 February 2023 12:13

Hi @sorte ,

This is a good question.

Accelerated conditional approval for bulevirtide was given in Europe on the basis of a phase IIB study.

The next planned studies are phase IIA to confirm the results seen in the compassionate access program with SC administration of REP 2139-Mg. These should streamline initiation of a phase IIB study.

Best regards,

sorte · 21 February 2023 20:50

@availlant yep, but progress in hdv is usually faster thus more damaging than hbv thus I have doubts about some condtional approval
Other question, you’ve mentioned a few technologies which did not succeed with hbv approach like CAMs / RNAi/ siRNA / ASO how about core inhibitors, entry inhibitors, monoclonal antibodies ?
As I remember you’v commented here already why therapeutic vaccines dont work well, but correct me if I’m wrong.
Is there any approach against hbv, which is not better but at least decent and promising in compare with NAPs at the moment ?

availlant · 21 February 2023 21:13

HI @sorte ,

Given the Global priority for elimination of viral hepatitis and the utility of HBsAg loss for reducing HCC risk (something that is not achieved with existing therapies), there is certainly reason to expect conditional approval for a breakthrough technology which can achieve this result.

Core inhibitors are the same as CAMs (capsid assembly modulators).
Monoclonal antibodies have the same limitations as therapeutic vaccines (immune escape mutants present in the quasispecies pool prior to therapy). This already has been demonstrated clinically with VIR-3434.
Entry inhibitors will never target HBsAg from integrated HBV DNA and an already excellent viral entry inhibitor (bulevirtide) has shown little to no effect on HBsAg overall in HBV infection in clinical studies. Other entry inhibitors are very unlikely be any more effective than bulevirtide.

To date, only NAPs have achieved a high rate of HBsAg loss during therapy (regardless of baseline HBsAg levels) and a high rate of functional cure after therapy.

Best regards,

sorte · 21 February 2023 21:27

@availlant thanks for detailed answer, bitter sweet situation, but at least sth is going on and I hope for conditional approval

bob · 23 February 2023 01:34

Everyone who has chronic hepatitis b and has done their homework has known for a long time that replicor are the only company very likely to have a real cure.

Having said that can some of the other verified science experts on this forum provide the community with your honest thoughts? We have a company here who seem to be legitimately claiming that they have the cure and the only holdup is regulatory so it would be good to have some third party perspectives on this.

Two questions please @availlant:

What can the hepatitis b community do to help?
Do you have a pitch deck to distribute to get funding? This seems like a clear cut case or requiring funding for some clinical trials for what would be a blockbuster drug in investor terms.
The other companies pumping to billion dollar valuations with drugs that were clearly never going to work just had better communications (as is frequently the case in organizations with bad technology - their strengths tend to lie elsewhere).
So communications appear to be the bottleneck for you now. If you do have any material I would be interested is seeing it, and if it’s appropriate I’ll send it to some of my contacts for potential funding.

availlant · 23 February 2023 02:07

Hi @bob ,

Your sentiments and comments are appreciated.

One correction here for the community, there is no regulatory “hold-up” with the technology. This should be clear from the conduct of the ongoing compassionate use studies under approval of the French National Regulatory Agency (ANSM).

This is posted publicly on their website. ATU/RTU - REP 2139-Mg - ANSM.

Best regards,

stef2011 · 26 February 2023 15:45

dear mr @availlant

in 2012/2013 (under medical supervision and on nucs monotherapy since 2010) i used an experimental protocol to lower hbsag.

sequential treatment of imiquimod suppository+nucs, then stopped it to change to ezetimibe+nucs.i was able to lower hbsag for the first time from a steady 4500iu/ml to 1400iu/ml.i always used extremely high dose vitamin d3 while on these drugs and pegintf.

when i reached hbsag 1400iu/ml i stopped ezetimibe and started pegintf+tdf, it was a trial so i felt not confortable using ezetimibe although it would have been appropriate.EOT hbsag 699iu/ml that relapsed to 1300iu/ml to slowly go down again to 800iu/ml in 2018/2019.

today hbsag is around 600-700iu/ml but it has a very slow decline 50-100iu/ml per year max

imiquimod had little effect on hbsag, it moved it from 4300iu/ml to 3600iu/ml to go back to 4200iu/ml during 3months of treatment.i had flu like symptoms and low fever 37.5.dosing was weekly (daily not tollerable, heavy flu like symptoms) and then stopped it because hbsag was not going down

ezetimibe 50mg daily moved hbsag from 4200iu/ml to 1400iu/ml in 9months then i stopped it to start peg+tdf.it moved hbsag very fast

do you have any idea if ezetimibe monotherapy could have such results?my hbsag kinetics have always been big up and down on all of these drugs, peg included.small up and down on nucs too, never steady continuous decline

all blood tests normal and no sides from ezetimibe except Tsh moving from 2.35 to 4.9 but then stable on normal range until 5th month of pegintf+tdf when it moved to 7-8 but today it is all normal.i never had autoantibodies

do you have any idea if ezetimibe monotherapy can have such results on hbv?i have seen many interesting studies on this drug for hdv, hcv, ebola and other viruses.or you think ezetimibe effect might be the combined result from previous immune activation by imiquimod?

i am thinking to try ezetimibe monotherapy plus extremely high dose vitamin d3 (weekly thyroid monitoring to stop if there is any effect on its function/tsh) and if i get any immune activation/hbsag lowering i am thinking to add zadaxin too

at the moment i am supplementing high dose spiruline 12g daily, i found a study reporting small hbsag decline by 6 months and intf gamma increase.i almost reached 6 months and i will be checking hbsag soon.i dont think i’m going to have big results from this so i am thinking to use ezetimbe again

thank you for your thoughts on this

availlant · 26 February 2023 18:01

Dear @stef2011 ,

I very interesting situation Stef. Factors affecting HBsAg levels are complex. Lets start with some facts to give some context to your experience:

HBV infection is genetically diverse with thousands of quasispecies. These can rapidly change in response to selection pressures like the immune response and antiviral medications.
Different HBV genotypes and even different quasispeces can have different efficiencies of HBsAg secretion.
HBsAg itself has important immunosuppressive properties which inhibit immune function and the function of immunotherapies for HBV.
Almost all HBsAg is secreted as non-infectious subviral particles (SVP). These are HDL-like and involve at least some of the pathways involved in host HDL (lipid) metabolism.

Imiquimod stimulates TLR7 (a sensor of the innate immune response) - stimulation of this TLR with other agents has had little to no impact on HBsAg levels. So you experience is in line with this.

Ezetimibe alters lipid metabolism so the mild reduction of HBsAg (SVP production) is not surprising and this has been observed with statins as well.

Optimizing vitamin D is important for over all immune health but in the case of HBV infection, persistent SVP will always prevent functional cure. It will be difficult to achieve functional cure, even with pegIFN, unless HBsAg is < 500 IU/mL (functional cure rate with pegIFN when HBsAg < 500 IU/mL is ~30%).

Best regards,

stef2011 · 26 February 2023 20:27

thank you very much

i had some mutation tests by dr.brunetto hospital in pisa when i started nucs but these quasispecies might be different today.baseline more than 20% was rtQ215Q/S and the usual A1762T+G1764A+G1899A for genotype D hbeag negative

infection from mother at birth, very aggresive immune system with alt similar to acute hbv.i had alt 1400 for 6 months when 19yo due to hbvdna detectable and later on with hbeag mutants alt flares 500-1000 as long as hbvdna more than 7000iu/ml, so compensated cirrhosis but regressed fast by nucs to 5.1kpa already in 2012

i’ll go for ezetimibe and if hbsag less than 500iu/ml zadaxin.pegintf is the last resort although response might be good with very low hbsag by my polymorphism IL28B917 (rs8099917)TT, IL28B CC

thank you very much

availlant · 27 February 2023 00:27

HI @stef2011 ,

You are in no better hands than with Dr. Brunetto.

This is the terrible problem with maternal transfer - the transfer of numerous quasispecies in your initial infection in utero.

The RT mutation (Q215/S) is well managed by NUCs (best with TDF or TAF) and the presence of core promoter / precore mutations (A1762T+G1764A+G1899A) simply means that HBeAg negativity cannot be used to stage your disease. I would not worry so much about these.

Unlike HCV, there is no good relationship shown between IL28 polymorphism and response to therapy.

So now we come to your “last resort” comment…it is impossible to put myself in your shoes as an infected person but I would like to point out that you are been very effectively managed by NUC therapy with reversal of liver disease. This is the best place you can be with currently approved therapies. Its not a position of last resort!

But yes HBsAg loss is the ultimate goal. If you are able to get a pattern of HBsAg decline again, the lower the HBsAg before you begin pegIFN, the better. You can alternatively try thymosin alpha as this also works much better with low HBsAg at the baseline.

Good luck!

.

sorte · 27 February 2023 21:17

@availlant how about spiruline part? The study Stef has mentioned is that one https://www.mdpi.com/2072-6643/14/14/2790/pdf Do you think it’s worth to lower HBsAg even if decline is slow but consistent ? Is it possible that it just lowers “free” HbsAg and doent not touch at all production of viral particles ? But anyway, what level of HBsAg gives decent chance “wake up” immune system and do spontaneous clearence, we know that happen rarely.