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Replicor to present new HBV and HDV mechanistic data for its NAP technology

Replicor to present new HBV and HDV mechanistic data for its NAP technology

NEW YORK, Sept 19, 2016 – Replicor Inc., a privately held biopharmaceutical company targeting a cure for patients with chronic hepatitis B virus (HBV) and chronic HBV and hepatitis delta virus (HDV) co-infection, today announced it will disclose new mechanistic data on the activity of its NAP technology in HBV and HDV infection at the 2016 International Meeting of the Molecular Biology of Hepatitis B Viruses, to be held from Sept 21-24, 2016 in Seoul, Korea (http://www.hepb.org/research-and-programs/international-hbv-meeting/).

Studies ongoing with viral hepatitis experts in France at the Institute Nationale de la Transfusion Sanguine in Paris and the Centre de Recherche en Cancerologie de Lyon have been examining the antiviral effects of NAPs in cellular models of HBV and HDV infection.  Results of these studies will be disclosed in two separate poster presentations to be presented on Thursday, September 22
and will focus on the ability of different NAPs (including the clinically active NAPs REP 2055 and REP 2139 ) to block the entry of these viruses into cells.
4 Responses
Avatar universal
Look like a very interesting conference coming up in Seoul, Korea to-morrow. We are all very frustrated by the lack of progress in finding a cure - very many new drug candidates, but they are all in very early stages and seem to me, lack the killer punch. A lot of research literature appeared recently about the core capsid and the core protein, also about HBx protein. So I wonder whether anyone is considering using RNAi to silence the expression of the Core and HBx proteins?
I think the current Arc520 and 521 iRNA products are already interfering with all messenger RNAs, thus they silence the core and X proteins as well.

The problem seems to be the efficiency of this process, meaning the silencing is not complete enough,  thus enough messenger RNAS escape destruction to keep the HBV virion replication and helper proteins running at a lower level.
I believe you are right as Arrowhead did claim Arc520 target the 4 viral mRNAs. I guess these 4 viral mRNAs share common regions that can be matched to a single guide RNA. Why Arc520 cannot target mRNA transcribed from integrated HBV S-gene is a mystery to me. Does it mean the S gene mRNAs from cccDNA and integrated S gene are different?
The solution to this puzzle must lie in the complex way mRNAs are generated and translated. There are basically four mRNAs  read from the hbv genome, they are however translated into all 6 proteins and all have the same 3prime end point. The 520 iRNA are located close to the short x Gene and cut all messenger RNAs close to their 3 prime end, eliminating their translatability.

When the genome is integrated into chromosomal dna, a portion closer to the end of the 2.1kb RNA coding section can be cut off, resulting in a messenger RNA for the surface antigen that does not contain the section that arc 520 can attack.  But 521 is designed to cut inside the integrated sequence portion of the message,  allowing it's elimination.
Many thanks for the explanation. Make good sense to me. I hope ARC521 should then also work against S gene mRNA from cccDNA, and that it will be more efficient.
Avatar universal
when we will have some data??
Both posters with all the data are now available on the replicor website.
Any update studyforhope i would like to see your analysis
This was in vitro work by French scientists analyzing the capacity of various NAPS to inhibit entry of hbv and hdv virions into hepatocyte target cells.

It is a fascinating fact that some naps have the ability to block virus entry for hbv, HCV and hiv, probably all by a similar mechanism.

They attach to the peptide strands protruding from the virion surface,  hooked up to receptors on the surface of endosomes that have just internalized the virions.
The increasing pH in these endosomes will cause a contraction of these peptides that will pull the virion in such close proximity to the endosomes membrane that they can fuse, allowing an injection of the virions core into the cytosol of the target cell.

The NAPS block this process by inhibiting the length contraction of the mentioned peptide  by attaching to them,  blocking their pH induced bending.

Some naps , like 2055, have a high capacity to inhibit reinfection , while others,  like 2139, the one used in the current replicor trials , have lost this feature, as the experiments clearly show.

The effect on the surface antigen levels and others in the clinical setting must therefore depend on other mechanisms,  in particular, as is well known by now,  on a block of surface antigen particle secretion.

There is another fact to consider, that will make this nice entry blocking effect not very useful for the clinical, in vivo setting.
while in these in vitro experiments the cells are submersed  in a culture liquid that contains these NAPS in the chosen concentration fairly constant over time, the extracellular NAPS concentration surrounding a hepatocyte and in the endosomes uptaken from surface invaginations will rapidly fall following the end of the once weekly infusion, since the NAPS are highly water soluble and the plasma concentration will rapidly drop due to renal elimination.

Thus even if a nap has the hbv or hdv  entry blocking quality it will not likely have any effect in the clinical setting.
and your short opinion about this ? it is a good news or ?
The entry blocking effect of 2139 is non existent and even if it would be as strong as 2055 it would not make any clinical difference. Thus this effect of some naps  is interesting but of no therapeutic value.
Studyforhope thank you so much for your explanation
so which nap has therapeutic potential ?
This study does not impact the general outlook for 2139 or 2165 which are currently tested. They have therapeutic potential independent of the lack of entry inhibition.  The final efficacy in combo with ifn or thymosin alpha and antiviral pre and cotreatment will be of extreme interest, but the definite result is more than 2 years away, since the long term stability of the seroconversion has to be awaited. After this a phase 3 trial will still be necessary before an approval in europe and the USA can be expected.
Avatar universal
As far as i can understand it from the poster, i don't see this latest in vitro experiment encouraging. This is a setback, once more, this time from Replicor which we placed great hope.
I cannot see why this is a setback to replicors outlook. It is simply of no relevance. The overall chances of the nap therapy are still quite good and the best in sight at this time. The capacity to extremely effective suppress hbsag levels with almost no side effects is unique and dramatic and can be used in combo with other approaches due to its lack of relevant toxicity.
Thanks for your comment; but i found the following conclusions from the study not much encouraging and in contradiction with previous clinical reports about replicor:

*Hbsag reductions were not observed with RNA based phosphorothioated NAPs (eg. REP 2139)or non-phosphorothioated NAPs
*When added to the cells after the viral inoculation NAP's did not alter the secretion of Hbsag
*RNA NAP's are uniquely inactive in blocking HBV entry including the clinically active REP 2139
Avatar universal
For me birinapant seems an easy way of fighting the hbv theoretically. Kill all infected hepatocytes, while at the same time using antivirals to suppress circulating vrions in the bloodstream. Absence of infected hepatocytes would mean no production of the viral protiens such as hbsag and hbeag, while reduction of hbv dna to undetectable levels would mean minimal re-infection; a situation that would eventually lead to  the waking up of the innate immune system.
The potential of birinapant to selectively remove infected and  maybe also  hbv integrated  cells is also unique and fascinating and should be  carefully developed to become part of a comprehensive strategy to induce stable hbsag seroconversion.
unfortunately  tetralogic seems to be on its knees at this time with little power to invest and pursue this potential breakthrough strategy.
while the problem of bell's palsy can be overcome,  there are other dangers in the long term use of an apoptosis enhancer, that need to be carefully assessed in trials increasing dose and duration to the level needed for hbv therapy.
So there may be a danger that apostosis may be triggered in other liver cells also the healthy ones ? I hope someone will just buy Tetralogic and will continue those studies, birinapant seemed like total cure, not functional one.
what is the difference between hbv infected call and hbv integrated ? First is only cccDNA and second one is hbv dna integrated into cell dna ?
Birinapant will enhance apoptosis rates in all tissues where it has access to. The brain is fortunately excluded. But where cells are partially damaged or under stress and try to rescue themselves with the help of the antiapoptotic proteins, then birinapant will tilt the rate towards eliminating these cells.

Thus there is little danger of birinapant pushing healthy liver cells into apoptosis, but it will act on the pankreas, kidney and endocrine organs and enhance apoptosis rates for cells in trouble in these sites.

This could indeed be a very positive effect in many ways, eliminating incident cancers or otherwise damaged cells, eg from the prostate.  After all birinapant is in trials against various cancers, for exactly that reason.

But in some cases, like the beta cells of the islet system, or the podocytes in the glomeruli the need to defend against loss of precious and hard to replace cells by anti apoptosis is also likley to be important and loss of function effects could occur in those organs.

And cells of organs which are already fighting hard to defend against autoimmunity like endocrine tissues might encounter too high cell losses, since they are already in a state of mild but persistent immune attack, with initiation of apoptosis pathways, that are normally successfully avoided using the antiapoptotic machinery.
In hbv integrated cells a portion - and may be sometimes all of the hbv genome -  became integrated into the liver cells own chromosomes, at various sites, some transcriptionally active and others not.
these cells can also still carry cccDNA or might have lost it, but they do not loose their integrated hbv sequences, which for example can produce surface antigen from a host chromosomal site, instead the cccDNA.  
This is particularly important when mechanisms eliminating cccDNA are present, which can clear a cell from the non integrated hbv genome, but will not touch the integrated hbv genome portions.
This way a relatively high portion  of the circulating surface antigen can be made from the integrated source, making a seroconversion impossible, even if the hbv genome is successfully reduced to minute remnant amounts.

Thus a mechanism, that could eliminate these cells with chromosomally integrated hbv genomic portions would be of enormous importance. Birinapant might provide such a mechanism.
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