Aa
ARC-520 Hepatocyte Targeted Therapy / Powerful HBV Silencer by Arrowhead Reasearch
Hey everyone,
Following the press release, I took studyforhope suggestion and read the paper on this new therapy. There's a lot to read and understand but here is what I got from my first pass (below is the link for the paper).
1. The therapy interferes with the RNA of the viral proteins: HbsAg, HBV DNA, and HbeAg
2. The therapy has shown in mice and non-human primates to have a powerful effect on reducing HbsAg, HBV DNA, and HbeAg (numbers of 90%+ from a single dose)
3. More importantly Arrowhead has found a very efficient way to deliver 99% of the drug directly to Hepatocytes which was previously a big concern due to toxicity.
4. The hope of this therapy is to inhibit the viral proteins to help the immune system recover and build immunity.
5. Many safety markers had no increase for example ALT.
6. They hope to provide this as a monthly injection.
Seems very promising. Looking forward to discussion on this from the community.
http://www.nature.com/mt/journal/vaop/ncurrent/full/mt201331a.html
Following the press release, I took studyforhope suggestion and read the paper on this new therapy. There's a lot to read and understand but here is what I got from my first pass (below is the link for the paper).
1. The therapy interferes with the RNA of the viral proteins: HbsAg, HBV DNA, and HbeAg
2. The therapy has shown in mice and non-human primates to have a powerful effect on reducing HbsAg, HBV DNA, and HbeAg (numbers of 90%+ from a single dose)
3. More importantly Arrowhead has found a very efficient way to deliver 99% of the drug directly to Hepatocytes which was previously a big concern due to toxicity.
4. The hope of this therapy is to inhibit the viral proteins to help the immune system recover and build immunity.
5. Many safety markers had no increase for example ALT.
6. They hope to provide this as a monthly injection.
Seems very promising. Looking forward to discussion on this from the community.
http://www.nature.com/mt/journal/vaop/ncurrent/full/mt201331a.html
Best Answer
StudyforHope -
I tried without success to send you a p.m.
I am a compensated cirrhotic; cleared HCV virus, sustained (SVR) for several years now - but left with damaged liver. Made worse by alcohol abuse (I no longer drink alcohol, however) -
I've seen you make references to HepTech products. Do you have experience with these products? And if so, then how long did you take them?..and are you still taking them?
What improvements have you seen?...symptomatically, any blood test improvements, liver numbers improved, etc??
Many thanks!!
PD
I tried without success to send you a p.m.
I am a compensated cirrhotic; cleared HCV virus, sustained (SVR) for several years now - but left with damaged liver. Made worse by alcohol abuse (I no longer drink alcohol, however) -
I've seen you make references to HepTech products. Do you have experience with these products? And if so, then how long did you take them?..and are you still taking them?
What improvements have you seen?...symptomatically, any blood test improvements, liver numbers improved, etc??
Many thanks!!
PD
The immunomodulating effects of the surface antigen that tend to protect the existence and spread of HBV can be divided into three categories.
1. The obvious direct effect is to remove any antibody that could coat the virions and protect the liver cells from reinfection. The large amounts of antigen in comparison with the available titers of antibody are completely eliminating the effectiveness of that antibody, that might exist in many cases at substantial titers, masked and undetectable by standard assays.
Thus the surface antigen ascertains HBVs capacity to constantly reinfect the liver.
2. There are numerous reports at conferences and some published papers that show that larger concentrations of surface antigen have the effect of deactivating, reactivity, have suppressing effect on dendritic cells and macrophages, reducing cytokine output, like Il18 and Il-12 and diminish activity in several other proinflammatory signaling pathways, especially NFKappaB.
In most cases however, the concentrations to demonstrate these effects are rather high and towards the high end of HBSAg concentations found in patients plasma.
Also, if the immunosuppressive effect is real, then it should effect not just the reactivity against HBV, but against other viral diseases as well and we should see a general immune weakness of HBV patients. While there are some claims in this direction, the general impression is that HBV patients have basically, aside from their viral infection with HBV, a normally reacting immune system as it is relevant to real life clinical performance.
3.The third effect is the overwhelming presence of the surface antigen particles in high amounts distributed over the whole circulation and even in the extracellular space. Thus dendritic cells and macrophages will take them up in high numbers all the time, everywhere in the body. Consider the fact that large amounts are produced every day that also disappear in eual amounts in the steady state, thus those particles are basically phagocytosed and processed and presented in huge amounts in every dendritic cell and macrophage.
It is important at this point to consider the effect of dendritic cells phagocytosing antigens in the context of local noninflammation or non danger, as happens physiologically all the the time.
The lack of a danger signal to be recognized by the dendritic cell leads to a processing in the class1 and class II pathways with consequent engagement of the cognate Tcell receptors of patrolling naive or memory Tcells of both kinds THAT WILL BE FOLLOWED BY A LACK OF STIMULATION AND ACTIVATION, or a stimulation towards apoptosis of the engaged Tcell. This is an important way to physiologically avoid Tcell autoimmunity against "peaceful" antigens, a critical function of our immune system. What is rather stimulated are suppressor Tcells, to control the posssibly wrongly stimulated effector T cell that is CTLs or Thelper cells.
The surface antigen particle is seen as a peaceful antigen by the dendritic cells either for reasons analyzed in number 2 or because they lack the spiky ordered structure of the core and the intense danger signal that comes fromthe presence of DNA or RNA in a particle that is phagycytosed.
The HBV virions have all these features and are causing a danger signal activation.they also get caught first of all at their site of production in the liver and activate local macrophages and dentritic cells and then classII cognate T helper cells right on site, with resulting local proinflammatory cytokine production, but not of a very effective nature, hence the chronic hepatitis and hence the effectiveness of the antivirals to intensely reduce that inflammation by lowering virion production without reducing the number of infected cells, since the gamma IFN levels are typically not high enough to initiate cccDNA noncytolytic elimination.
Thus in summary, on a bodywide scale,the surface antigen eliminates Tcells principally active against its epitopes of both classes.
A further school of thought proposes that the activation away from the liver absorbs and activates surface antigen specific Tcells and that upon even stronger activation, the activated Tcell is far from the point of action and will have a limited life time as is typically the case for a stimulated cd8+ cell, since the body needs to recover from diseases quickly, they receive the order to apoptose even in the case of positive activation to a lytic, activated state with some delay after the activation took place.
All together these processes deplete the body from capable surface antigen specific Tcell activation and from accumulation and activation and action in the liver, rendering this antigen almost totally ineffective in the setting of chronic hepatitis.
It can thus easily be seen that removing the surface antigen particle from the circulation, while leaving its intrahepatocyte expression fully intact with intense epitope presentation due to the relative large intracellular amount will cause a game change in the bodys defense mechanisms against HBV.
1. The obvious direct effect is to remove any antibody that could coat the virions and protect the liver cells from reinfection. The large amounts of antigen in comparison with the available titers of antibody are completely eliminating the effectiveness of that antibody, that might exist in many cases at substantial titers, masked and undetectable by standard assays.
Thus the surface antigen ascertains HBVs capacity to constantly reinfect the liver.
2. There are numerous reports at conferences and some published papers that show that larger concentrations of surface antigen have the effect of deactivating, reactivity, have suppressing effect on dendritic cells and macrophages, reducing cytokine output, like Il18 and Il-12 and diminish activity in several other proinflammatory signaling pathways, especially NFKappaB.
In most cases however, the concentrations to demonstrate these effects are rather high and towards the high end of HBSAg concentations found in patients plasma.
Also, if the immunosuppressive effect is real, then it should effect not just the reactivity against HBV, but against other viral diseases as well and we should see a general immune weakness of HBV patients. While there are some claims in this direction, the general impression is that HBV patients have basically, aside from their viral infection with HBV, a normally reacting immune system as it is relevant to real life clinical performance.
3.The third effect is the overwhelming presence of the surface antigen particles in high amounts distributed over the whole circulation and even in the extracellular space. Thus dendritic cells and macrophages will take them up in high numbers all the time, everywhere in the body. Consider the fact that large amounts are produced every day that also disappear in eual amounts in the steady state, thus those particles are basically phagocytosed and processed and presented in huge amounts in every dendritic cell and macrophage.
It is important at this point to consider the effect of dendritic cells phagocytosing antigens in the context of local noninflammation or non danger, as happens physiologically all the the time.
The lack of a danger signal to be recognized by the dendritic cell leads to a processing in the class1 and class II pathways with consequent engagement of the cognate Tcell receptors of patrolling naive or memory Tcells of both kinds THAT WILL BE FOLLOWED BY A LACK OF STIMULATION AND ACTIVATION, or a stimulation towards apoptosis of the engaged Tcell. This is an important way to physiologically avoid Tcell autoimmunity against "peaceful" antigens, a critical function of our immune system. What is rather stimulated are suppressor Tcells, to control the posssibly wrongly stimulated effector T cell that is CTLs or Thelper cells.
The surface antigen particle is seen as a peaceful antigen by the dendritic cells either for reasons analyzed in number 2 or because they lack the spiky ordered structure of the core and the intense danger signal that comes fromthe presence of DNA or RNA in a particle that is phagycytosed.
The HBV virions have all these features and are causing a danger signal activation.they also get caught first of all at their site of production in the liver and activate local macrophages and dentritic cells and then classII cognate T helper cells right on site, with resulting local proinflammatory cytokine production, but not of a very effective nature, hence the chronic hepatitis and hence the effectiveness of the antivirals to intensely reduce that inflammation by lowering virion production without reducing the number of infected cells, since the gamma IFN levels are typically not high enough to initiate cccDNA noncytolytic elimination.
Thus in summary, on a bodywide scale,the surface antigen eliminates Tcells principally active against its epitopes of both classes.
A further school of thought proposes that the activation away from the liver absorbs and activates surface antigen specific Tcells and that upon even stronger activation, the activated Tcell is far from the point of action and will have a limited life time as is typically the case for a stimulated cd8+ cell, since the body needs to recover from diseases quickly, they receive the order to apoptose even in the case of positive activation to a lytic, activated state with some delay after the activation took place.
All together these processes deplete the body from capable surface antigen specific Tcell activation and from accumulation and activation and action in the liver, rendering this antigen almost totally ineffective in the setting of chronic hepatitis.
It can thus easily be seen that removing the surface antigen particle from the circulation, while leaving its intrahepatocyte expression fully intact with intense epitope presentation due to the relative large intracellular amount will cause a game change in the bodys defense mechanisms against HBV.
Thanks for the reply concerning e-antigen. It is certainly food for thought. Now I want to ask about how HBsAg inhibits the immune response. I have read articles by Locarnini that "circulating HBsAg subviral particles were shown to repress TLR9 signalling by enhancing SOCS expression in dendritic cells (pDCs)". I understand pDC to be a significant source of INF-alpha. On Replicor website, the Chinese page states that these SVP inhibits the proliferation of Tcells (my translation). I wonder can you explain how SVP actually inhibits our immune response to HBV.
Many thanks in advance.
Many thanks in advance.
Here is to your questions:
1. Would it make sense for them to limit mismatches by possibly coming up with Genotype dependent RNA's
2. Forgive me for sounding so naive, but in the likely hood of mutations being developed, can message RNA's be developed to rescue viral breakthrough?
A genotype specific siRNA would be better functionally and less mismatches would be present. But it would be too expensive and they might need a trial for every genotype.
Viral breakthrough during therapy will occur, if a preexisting or de novo produced mutant has even a single internal difference in one nucleotide, for which a high chance exists. Remember that the hybridization sequence is only 19 nucleotides long, the match internally has to be perfect or it will fall off. That mutant virus will be unaffected by the siRNA therapy and start growing to the foreground, making the treatment ineffective.
A rescue siRNA could theoretically be developed, but it is not a feasable option.
I've read about Surface Antigen mutations, maybe some of these drugs can make things worse by forcing the virus to mutate where it doesnt release surface antigen at all, or is this absolutely required for the virus to survive?
A loss of suface antigen expression happens rarely or an invisibility on regular test platforms by mutations in detection Bcell epitopes. This situation, when combined with measurable HBV DNA and elevated liver enzymes is called occult Hepatitis B. It is remarkable, that the DNA never seems to rise high in these cases and normally the disease is mild.
Some remnant surface antigen expression is obviously needed to produce the viral envelope, but it is a comparably very small amount.
The hope of the company it seems is to suppress the virus production almost completely with monthly shots, realizing that it will not eliminate the cccDNA, but removes the disease symptoms. They carefully call it a "functional cure".
The expectation that the surface antigen specific Tcell response will be rekindled and a true elimination by CTLs will ensue is similar to the effects that the Replicor treatment has provided. But the limited diminishment of the surface antigen levels and the possible removal of cellular epitope targets by placing the block on the level of the messenger RNA might become a double stumbling block for that approach.
Do these companies consult viral experts?
Of course they do, but there is always healthy optimism present and the hope that things might work in spite of all the stumbling blocks ahead.
Replicor also cooperates with experts in molecular Biology of Hepatitis B, for example Jake Liang from NIH and Allyson Jilbert from Adelaide, Australia for their preclinical duck studies with the compound.
But their find of the particle secretion suppression in HBV is also an example of incredible good luck and great fortune, since they developed this class of compounds originally to treat influenca, HIV, HCV and other viral diseases under the concept of entry inhibitors. The effect on HBV surface antigen is kind of out of line and could not have been originally expected. But here it is and it represents a truly historical step forward in the possibility to fight and permanently suppress the HBV virus, even if this has to be achieved in combination with other treatment strategies in combination.
.
1. Would it make sense for them to limit mismatches by possibly coming up with Genotype dependent RNA's
2. Forgive me for sounding so naive, but in the likely hood of mutations being developed, can message RNA's be developed to rescue viral breakthrough?
A genotype specific siRNA would be better functionally and less mismatches would be present. But it would be too expensive and they might need a trial for every genotype.
Viral breakthrough during therapy will occur, if a preexisting or de novo produced mutant has even a single internal difference in one nucleotide, for which a high chance exists. Remember that the hybridization sequence is only 19 nucleotides long, the match internally has to be perfect or it will fall off. That mutant virus will be unaffected by the siRNA therapy and start growing to the foreground, making the treatment ineffective.
A rescue siRNA could theoretically be developed, but it is not a feasable option.
I've read about Surface Antigen mutations, maybe some of these drugs can make things worse by forcing the virus to mutate where it doesnt release surface antigen at all, or is this absolutely required for the virus to survive?
A loss of suface antigen expression happens rarely or an invisibility on regular test platforms by mutations in detection Bcell epitopes. This situation, when combined with measurable HBV DNA and elevated liver enzymes is called occult Hepatitis B. It is remarkable, that the DNA never seems to rise high in these cases and normally the disease is mild.
Some remnant surface antigen expression is obviously needed to produce the viral envelope, but it is a comparably very small amount.
The hope of the company it seems is to suppress the virus production almost completely with monthly shots, realizing that it will not eliminate the cccDNA, but removes the disease symptoms. They carefully call it a "functional cure".
The expectation that the surface antigen specific Tcell response will be rekindled and a true elimination by CTLs will ensue is similar to the effects that the Replicor treatment has provided. But the limited diminishment of the surface antigen levels and the possible removal of cellular epitope targets by placing the block on the level of the messenger RNA might become a double stumbling block for that approach.
Do these companies consult viral experts?
Of course they do, but there is always healthy optimism present and the hope that things might work in spite of all the stumbling blocks ahead.
Replicor also cooperates with experts in molecular Biology of Hepatitis B, for example Jake Liang from NIH and Allyson Jilbert from Adelaide, Australia for their preclinical duck studies with the compound.
But their find of the particle secretion suppression in HBV is also an example of incredible good luck and great fortune, since they developed this class of compounds originally to treat influenca, HIV, HCV and other viral diseases under the concept of entry inhibitors. The effect on HBV surface antigen is kind of out of line and could not have been originally expected. But here it is and it represents a truly historical step forward in the possibility to fight and permanently suppress the HBV virus, even if this has to be achieved in combination with other treatment strategies in combination.
.
No idea why my response was removed?
I wanted to ask...
TARGET MESSAGE RNA:
So the concern with this is two fold, 1 being the efficacy on mutated HBV geonomes, and 2. the inhibition resulting in mutations of the HBV geonome. Are the mismatches mainly due to their goal of a genotype independent therapy.
1. Would it make sense for them to limit mismatches by possibly coming up with Genotype dependent RNA's
2. Forgive me for sounding so naive, but in the likely hood of mutations being developed, can message RNA's be developed to rescue viral breakthrough?
REDUCTION IN SURFACE ANTIGEN:
It seems from what your saying blocking would be better than inhibition for the purpose of Immune Response. Arrowhead didn't mention or show any effect on immune recovery which is very important for the overall goal of the therapy. I hope Replicor continues to make progress, since they have even presented results on immune reocvery.
1. I've read about Surface Antigen mutations, maybe some of these drugs can make things worse by forcing the virus to mutate where it doesnt release surface antigen at all, or is this absolutely required for the virus to survive?
IN-VIVO TESTING:
1. Can some of these problems be predicted well in non-human vivo trials?
2. Do these companies consult viral experts. I am sure they do, but some of these things should be of a big concern in therapy development and resources used. Or should we expect to see these type of things from drug ccompanies to boost stock values?
Forgive my ignorance, but I am still stunned that Replicor has come up with such an efficient method of fighting HBV ahead of other companies. I haven't seen any public papers, but do you know if they have any known viral experts working with them contributing to thier success?
I wanted to ask...
TARGET MESSAGE RNA:
So the concern with this is two fold, 1 being the efficacy on mutated HBV geonomes, and 2. the inhibition resulting in mutations of the HBV geonome. Are the mismatches mainly due to their goal of a genotype independent therapy.
1. Would it make sense for them to limit mismatches by possibly coming up with Genotype dependent RNA's
2. Forgive me for sounding so naive, but in the likely hood of mutations being developed, can message RNA's be developed to rescue viral breakthrough?
REDUCTION IN SURFACE ANTIGEN:
It seems from what your saying blocking would be better than inhibition for the purpose of Immune Response. Arrowhead didn't mention or show any effect on immune recovery which is very important for the overall goal of the therapy. I hope Replicor continues to make progress, since they have even presented results on immune reocvery.
1. I've read about Surface Antigen mutations, maybe some of these drugs can make things worse by forcing the virus to mutate where it doesnt release surface antigen at all, or is this absolutely required for the virus to survive?
IN-VIVO TESTING:
1. Can some of these problems be predicted well in non-human vivo trials?
2. Do these companies consult viral experts. I am sure they do, but some of these things should be of a big concern in therapy development and resources used. Or should we expect to see these type of things from drug ccompanies to boost stock values?
Forgive my ignorance, but I am still stunned that Replicor has come up with such an efficient method of fighting HBV ahead of other companies. I haven't seen any public papers, but do you know if they have any known viral experts working with them contributing to thier success?
Have an Answer?
You are reading content posted in the Hepatitis B Community
A list of national and international resources and hotlines to help connect you to needed health and medical services.
Herpes sores blister, then burst, scab and heal.
Herpes spreads by oral, vaginal and anal sex.
STIs are the most common cause of genital sores.
Condoms are the most effective way to prevent HIV and STDs.
PrEP is used by people with high risk to prevent HIV infection.
But the sentence that i outlined from the paper holds a much more likely pitfall to this therapy.
The target message RNA has to be a very precise sequence for the silencing to work. Thus any mutation in this sequence will tender the drug ineffective and unresponsive in the cell containing the mutated cccDNA. We must assume such mutations preexist and will give the respective HBV genome a selective advantage. It will spread quickly and repopulate the liver with therapy resistent progeny. No more supression, a happy virus and a drop in stock prices. Since there are so many places where it can mutate it will likely do so.
To see problem number 2 you need to go the place where they discuss the magnitude of the surface antigen suppression that can be expected.
In this context it needs to be mentioned that the replicor drug suppresses the antigen particle production by a factor better than 10000! fold. It is likely that a very high degree of surface antigen removal is necessary to remove the tcell tolerizing effect.
The famous idea, that a reduction under 500 units is sufficient to rekindle very likely does NOT apply in this setting. But this is complicated topic in itself.
The next problem that looms is not so apparent.
Consider the reason, why the precore mutant with elimination of the e antigen reduces the chance that the infected cell can be eliminated dramatically. It is the lack of the cytosolic processing of the e antigen carrying also the class I core epitopes through the proteasome to the MHC CLASS I presenting molecules on the hepatocte surface where the cd8+ CTL engage with their Cognate T cell receptors.
What would happen if the surface antigen production is shut down due to messenger RNA silencing? How can the now available surface antigen epitope specific cd8+ T cells come and recognize the infected cell? It is as if the critical markers of infection are now turned off.
The Replicor drug does not touch the primary sythesis of the surface antigen, it only blocks the formation of the globular structure on the ER membrane. Thus proteasome processing remains fully intact and effective. All the lights are on and the infected cell is visible to the searching cd8+ Tcells, resulting in targeted lysis and hyperintensive localized IFN gamma bursts, that clean up the neigborhood by noncytolytic cccDNA elimination.