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ARC-520 Hepatocyte Targeted Therapy / Powerful HBV Silencer by Arrowhea...
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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
Tags: ARC-520, Cure, Arrowhead Research
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Avatar_m_tn
The problem with unintentional silencing is going to be very real to the FDA and i think they will insist on safety studies.

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.
40 Comments Post a Comment
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Avatar_m_tn
Ok , now for starters to focus on the critical problem areas of this approach:

Look at the high specificity and sequence sensitivity of the target area sequence in these RNAs, which is discussed at a specific place in the paper. They made a strong effort to identify genotype independent sequences, so that they will have a drug that is effective across all relevant genotypes.
Also, they deselected from all mRNA sequences that can be expected in the human genome, to reduce the risk of switching off one of our own gene products. Very good and thanks to the human genome project for making that possible.

So now what major problem could occur due to the sequence sensitivity of the target sequence as it is mentioned in quite detail?

We will, after discussing this question, move on to the next problem area.
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Avatar_m_tn
Here is the sentence you need to focus on for this:

Canonical siRNAs are based on 19 nucleotides of complementary sequence, but mismatches at the terminal ends are generally well tolerated and have much less effect on the efficacy of the siRNA than internal mismatches.
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Avatar_m_tn
After reading it a few times. It seems like the major problem or challenge could be targeting HBV effectively without interfering with our own gene products.

They seemed to have narrowed it down to over 90% accuracy but not 100%. So it seems like there could be very adverse effects if it hits and silences our own genes from the mismatch at the terminal ebd but they believe that it's well tolerated?

As I was reading the paper I got the feeling that this could be a very powerful yet dangerous therapy.
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Avatar_m_tn
Another off topic thing I picked up on based on what you had brought up I believe about Myrcludex is the potential problen of developing antibodies to the therapy by our immune system. With ARC-250 they mentioned that they didn't see this or it didnt occur which is a good thing?
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Avatar_m_tn
This is not adding to the discussion, just news released by Arrowhead.

Arrowhead Receives Notice of Patent Allowance for New Protease Sensitive Masking Chemistry for DPC siRNA Delivery System


PASADENA, Calif. - February 28, 2013 - Arrowhead Research Corporation, a targeted therapeutics company, today announced that it has received a Notice of Allowance from the U.S. Patent and Trademark Office for U.S. Patent Application Number 13/336,028 entitled, "In Vivo Polynucleotide Delivery Conjugates Having Enzyme Sensitive Linkages." This new IP expands the Dynamic Polyconjugate (DPC) platform, broadly protecting Arrowhead's next generation DPC polymer masking technology. Using this masking technology, DPCs can be engineered for long circulation times and improved tissue-targeting characteristics. In addition, hepatocyte-targeted DPCs formulated using this new masking technology have shown to be highly potent upon subcutaneous administration. The company has previously reported target gene knockdown of 99% in monkeys after a single subcutaneous injection of 1 mg/kg, with >80% knockdown for 3 months. Additional data will be reported at upcoming scientific conferences and through peer-reviewed publications.



"This patent protects a new masking chemistry that broadens the reach of DPC-enabled RNAi therapeutics.  It enables efficient subcutaneous delivery of siRNA and opens up new therapeutic area targets including oncology," said Dr. Chris Anzalone, President and CEO of Arrowhead. "Arrowhead scientists continue to discover innovative solutions for siRNA delivery and we look forward to providing updates on how these technologies are being deployed to create new drug candidates."
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Avatar_m_tn
The formation of drug effect blocking antibodies is always a concern with macromolecular therapeutics. With regard to Myrcludex, the doctoral thesis of Alexa Schieck has shown that in a rat study the existing antibodies, despite a high titer against Myrcludex, did not inhibit the liver uptake and distribution of the drug. Antibodies against not structurally stable peptides without a stable folding structure are likely to be weakly binding and to only a small portion of the injected peptide. Furthermore the almost complete and tight binding to Albumin and plasma HDL particles will shield the peptide from AB attack.

The two components of the arrowhead system, the cholesterol bound iRNAs and the NAG linked bee venom peptide will also hopefully not be neutralized by AB responses on their way to the liver. I consider this a low risk concern.
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Avatar_m_tn
Thanks for explaining the antibodies.

I read the ARC-520 paper again  and also the link to "reference 16".  My current understanding is that mismatches could lead to "off-target" slicencing, this will be a challenge because the HBV geonome has overlaps with the human geonomes which they refer to as mRNA's. I believe this mismatch is at the terminal ends.

They say that even so based the article below that these are well tolerated.


Reference:
16.Huang, H, Qiao, R, Zhao, D, Zhang, T, Li, Y, Yi, F et al. (2009). Profiling of mismatch discrimination in RNAi enabled rational design of allele-specific siRNAs. Nucleic Acids Res 37: 7560–7569
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Avatar_m_tn
The problem with unintentional silencing is going to be very real to the FDA and i think they will insist on safety studies.

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.
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Avatar_m_tn
This is not related to ARC520, but to precore mutants. After natural HbeAg seroconversion, most patients will be in the used to be called "inactive" phase. However, some researchers argued that in this phase, the HBV is actually under intense immune control/pressure, leading finally to the immune escape phase (100% precore, no wildtype, according to Liaw). No-one actually stated what that immune pressure is. So can it be due to e-antigen specific CD8+ Tcells? Some papers described an increase in viral diversity both before and after e-antigen seroconversion. So it seems plausible that a gradual decrease in e-antigen production due to increase in precore mutants, finally leads to breaking of tolerance, some clearance of infected liver cells by e-antigen specific CD8+ Tcells? The loss of infected liver cells seems to be supported by the fact that serum HbsAg is lowest in this inactive phase. So is it true that in this phase, HBeAg is still being produced, therefore CLASS I MHC molecules with e-antigen epitopes are expressed on the surface of infected cells and  can be seen by e-antigen specific CD8+ T cells? Thereby maintaining control and keeping replication to very very low? If all this is true, why don't the e-antigen specific CD8+ T cells completely clear the infection?

Finally, ARC520 does not seem to silence the gene for HBcAg(?) and so core antigen epitopes MHC Class1 molecules should still be expressed on the cell's surface.
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Avatar_m_tn
You are raising some very important and fundamental questions, the answer to which  explains the very existence of the e antigen negative stage and the subphases of low and then higher disease activity.

A few items for introductory consideration:

The e antigen, that in the immune tolerant phase tolerizes the class1 and likely the class2 Tcells is present in absolutely substantially lower amounts than the surface antigen in the circulation.This fact makes it easier for an antibody response to neutralize it when its production is slowed down in the liver by a cytokine milieu that reduces its expression intensity from the cccDNA.

David Milich has shown, that an intense anti e antibody level is usually present even in patients whose e AB is negative by regular tests. He showed using an unusual detection antibody that it is present in high titers in the form of immune complexes. Thus if the absolute amount of e antigen produced becomes low it will also travel undetectable in the form of immune complexes, despite its ongoing production in some or all infected liver cells.
Here you have the paradox state of an e antigen neg hepatitis with ongoing low level e antigen production. In that phase you expect intense immune pressure and resulting HBV adaption over time. The immune pressure is likely resulting from the cd8+ Tcells recognizing e or core epitopes class1 on the surface of liver cells that still produce e antigen.

It is important to understand that the core protein, despite sharing the same epitopes with the e antigen DOES NOT PARTICIPATE in the proteasome processing towards class1 epitope peptides, therefore a precore mutant carrying cell shows no core/e Ag on its surface. The reason is likely that the core component polypeptides are very strongly bound to each other forming the globular core particle and the synthesis rate is also much less than the e antigen. This also points to the fact that the remaining core expression under the arrowhead iRNA treatment will not lead to epitope visibility.

The adaptive escape mutations against the e antigen recognizing class1 T cells are not limited to a shutdown of the incriminating remaining e antigen expression. There is another route of escape by mutating the single relevant class1 epitope itself, from lower proteasome processing to lower to no binding to the Tcell receptor. This is without question a critical component of the final scenarios that we see in the later stages of e antigen negative disease.

Thus the answer to the question why the class1 anti e Tcells do not typically wipe out the remaining infected cells is that too many precore mutants are already present and that in non precore mutant cells the epitopes themselves have mutated away from being recognizable.

The density of the remaining e Ag epitope class1 Tcell activation in the liver has to be high enough and the activation strong enough to produce the collateral exstinction of cccDNA by the gamma IFN bursts sufficiently for a clearance in a range that the surface antigen Tcell response can finally set in and allow permanent maintainance of the ultra low infected state.

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Avatar_m_tn
It looks like you posted a response and it was removed?
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Avatar_m_tn
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?






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Avatar_m_tn
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.

.

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Avatar_m_tn
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.
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Avatar_m_tn
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.




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Avatar_m_tn
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
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Avatar_m_tn
i think you got confused by posts, it is me who used heptech to regress cirrhosis, it did work very very fast, about 2 years to reduce fibrosis and a fibroscan of 4.5kpa or maybe little less dont remember now at the end of 2012

i also changed my diet but made little exsercise and used black rice and bluberries every day for a long time to clear fatty liver too, just check all my older posts so you can see all the improvments

i also used gcmaf therapy,.....activation of macrophages because of ultra high nagalase in serum and a general immune deficency.we cannot say if this worked too on liver repair process with diet and life style, it did work on nagalase and general immune system which is very very strong since it lowered nagalase
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Avatar_m_tn
Thank you so much for your response.

Ive been doing some reading on Virology and Immunology to understand more about how the immune system works so I can participate in other disucssions and prevent myself from posting elementry questions but I wanted to thank you for your answers you posted the other day.

1. I read about the two people you mentioned and they seem to be very reputable, its very encouraging to know that. The most encouraging factor is that you believe that Replicor has made a breaktrhough.

2. It seems like Replicor has a good solution that could really benefit. Have they been making waves at the conferences? (I am sure this will lead to a good partnership opportunities for them and also good offers which will help speed up the development of the drug).

3. Do you think that Arrowhead's delivery model could be used to effieciently deliver other treaments more effectively to the liver such as TDF, Replicor or TDF?

4. Have you been presented with details at conferences on how Replicor works on the Surface Antigen in detail such as to the degree of detail that Arrowhead posted. If yes, does it make sense to you as for the unintended effect of Replicor on Surface Antigen?

5. Lastly since you have more exposure to development of HBV treatments. Do you think Replicor is moving at a decent pace to bring the drug to market? (I understand this is very legnthy process)

Thank you in advance.

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Avatar_m_tn
At the conferences, the replicor presentations and posters are well attended, but clinical hepatologists have a hard time to believe the data sometimes, since the numbers are so low.
As for company personnel, I am sure they show some interest, but it is not at a stage for them to buy, I would guess, since the application per infusion is very hard to sell and they would also be afraid that unexpected side effects might pop up later, that could terminate the development as it happens so often in the world of drug development.
All in all replicor seems to move as fast as they can to arrive at the final formula and at a combo with immunmodulators that will generate a high chance of truly stable svr.

While the effect of surface antigen particle formation blockage was initially a pleasant surprise and serendipitous find, it makes sense to experts in the field of molecular morphogenesis of HBV, who understand the delicate and unique interaction of the touching points of the surface antigens transmembrane helices that lead to a closed protein sphere embedded in a membrane. This interaction is easily disturbed by mutation experiments as Volker Bruss, the worlds leading expert in this field has convincingly shown at the molecular biology meeting of hepatitis B in Orlando. Thus the disturbance of this interaction by the replicor drugs is a plausible mechanism.
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Avatar_m_tn
Thanks Stefan.  Of course I remember you, but I'm reasonably sure that Studyforhope had also made a reference to HepTech some time ago.
HT is not regressing my cirrhosis, so perhaps there is something else that I need to add.  I have been on HT for several months, and only a month ago began developing palmar erythema and joint pains..possibly signs of decompensation.  As I recall your cirrhosis was totally asymptomatic...is that correct?  If so, then perhaps it was in much earlier stage than mine.  Stefan, do you know of anyone with symptomatic cirrhosis that has benefitted from HT (HepTech) products??
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Avatar_m_tn
I have seen several people regress their cirrhosis on the HT protocol. But it might take at least two years and has to be combined with a healthy lifestyle.
It is of course possible that it does not work in your case, but you seem to be using it for only a short time. The products are unfortunately way to expensive. You also need to use a pre and probiotic.
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Avatar_m_tn
more information on HT protocol and antifibrotic study you can found on their website (was a antifibrtic study that was presented some time ago):


http://www.hepatitistechnologies.com/Posters2-4.pdf

Study was conducted at the University of Alberta under the direction of Dr. Lorne Tyrrell, (co-investigators Dr. Peter Schmid and Dr. Michael Joyce).
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Avatar_m_tn
Thanks - I appreciate your reply.  I agree w/you that the HT products are way too expensive.  I do have healthy diet and lifestyle - and also take a daily probiotic. As for HepTech (HT) efficacy, I am committed to a minimum of one year..to see if there is some benefit for me.
Stefan told me that his was fully compensated cirrhosis - no symptoms whatsoever.
Do you know of ANYone with symptomatic cirrhosis who has benefitted from the HepTech products?  If so, I would be very interested in any information or experience that you could share with me.
Again, sincere thanks for your response -
PD
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Avatar_m_tn
I am not aware of a case of decompensated cirrhosis that has tried any of the heptech products. Once a patient is at this stage, bad episodes of encephalopathy or varicosis bleeding can occur easily and any recommendation must be made very carefully and best be done by an experienced hepatologist. However, the use of regular lactulose and acetylcysteine 3 x 600mg plus about 1000mg of TMG is most likely very beneficial. As for the antioxidants and antifibrotics in the HT products, if somebody decides to use them, i would use a dosing of only one third, with food, to lower possible spikes in uptake and exposure.
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Avatar_m_tn
if somebody decides to use them, i would use a dosing of only one third, with food...

Do you mean one third of the dose three times a day with food or one third once a day?

Do you think it is a good idea to take HT for inactive carrier without cirrhosis or fibrosis just as a supplement against oxidative stress and as a supply of vitamins and antioxidants? In what dosing?

If ALT is a bit elevated (around 40) and HbsAg slowly goes down, can HT's anti-inflamatory agents(milk thistle, PPC) interfere with the immune response?

Many thanks for your comments!
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Avatar_m_tn
The one third reduction is best applied evenly over the day.

The use of the fibrosis protective HT  protocol in carriers is very likely important to counteract any fibrosis progression. It is unclear if it would dampen the intrahepatic inflammation to the extent that immune mediated clearance could be negatively affected. However this spontaneous surface antigen clearance in e ag neg patients is so rare that a liver protective regimen seems to be more important. This is not to say that the ht protocol is truly immunosuppressive, it might even be immunoenhancing when it comes to lymphocyte and other functions, but the answer to this question is simply not known.
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Avatar_m_tn

it is kind of strange how decompensation occurs on cirrhosis, i ve heard from the clinical researchers in pisa that some livers are able to keep function despite advanced damage and nodules while others go into decompensation very early even with much less liver damage.i dont know how the liver damage on cirrhosis is linked to decompensation, of course i do know that fibroscan values higher than 20kpa start to be in the danger zone for decompensation

i guess studyforhope knows more about decompensation and level of liver damage in cirrhosis

as to my degree of damage i had no signs in blood tests except a lowering of pltlets to 138 while on an alt flare at 600, all the rest was normal range.but as the antiviral lowered hbvdna, alt got to about 70 and plts increased immedialetly to 170-180
on US the liver was full of nodules, now nodules are much smaller but this takes decades to clear in the most lucky ones

this is a sum of my values and how long it took to see results.losing weight, HT protocol and healthy diet did the big jump on the reduction of kpa.hope this can help to get an idea of a fast response i think we need at least 2years to see if you are improving

nov 2009 fibroscan 15.9kpa, started etv
dec 2009 started vit d3 5000iu daily, blueberries daily
march 2010  16.3kpa
july 2010       13.9kpa
started HT protocol but no healthy diet yet, i still had fatty liver
oct 2010           9kpa
jan 2011           9.2kpa
started healthy diet with black rice and some simming to clear fatty liver, lost about 10kg
may 2011            6.3kpa
dec 2011            6.1kpa
feb 2012             5.6kpa
oct 2012             4.5kpa

cirrhosis values over about 12.5kpa, normal liver less than 6kpa but in case of cirrhosis a true regression is for very low values like around 4-5kpa
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Avatar_m_tn
Many thanks!
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Avatar_m_tn
Thanks.  To clarify - I am compensated in the sense that all liver functions are still good.  Platelets approx 180K (low end of normal).  I have no debilitating fatigue - indeed no debilitating symptoms of any kind.  I have, however, developed palmar erythema and other skin stigmata - and have mild anemia.  Also mild muscle loss - so obviously I am at least beginning to decompensate.  Naturally I am wanting to do everything possible to stop progression (if possible...or at the very least, slow it down).  Thankfully I am long-term SVR so I have no HCV virus.
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Avatar_m_tn

in my case i  just noticed effect on brain (confusion, difficulty in concentration....), i think this is the main effect you can feel on early decompensation.if all paramenters of liver function are good i think it is just a matter of time for heptech to work, remember you ll see an effect on yearly base not few months

do youalso have nodules on US image?
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Avatar_m_tn
Stefan, I appreciate you - thanks.  My last u/s was nearly a year ago -and no, there were no visible nodules then.  I am having another u/s done this month...and will let you know the results. However also I have been told that often cirrhosis will not be visible on u/s until it is advanced.  I am encouraged by the fact that my platelets are still approx 180K....so perhaps my disease is not as advanced as I fear -    
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Avatar_m_tn
if it is not visible by ultrasound you are eraly cirrhosis, dont worry

mine was extremely easy to see on US and all full of nodules, small but full of it
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Avatar_f_tn
Hi,
Stef2011, what do you think about this new drug? DOes it appear to be as effective as REP 9AC or MYcludex?

thanks
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Avatar_m_tn
They cant sell that heptech  here without prescription. What is the alternative brand called? I lost my bookmarks.

I looked at.heptech http://www.hepatitistechnologies.com/store/product/68408/HepTech  good list of ingredients mainly as was explained to me good to fight oxydative stress, but silicon dioxide  use is no good i think.
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Avatar_m_tn
http://www.advanceliferesearch.com/
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Avatar_m_tn
Thanks. Reservatrol they offer is also good to take to prevent cancer.

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Avatar_m_tn
I wish this company would come here and give us more feedback. There is absolutely no interaction between developers and us patients.

That is why all this takes so long to "find hbv cure"  lots of things are known that can help us and only a few things are used.

Very upsetting. But I hope arrowhead succeeds.  
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Avatar_m_tn
Here we discuss the paper that you just posted in fine detail.
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Avatar_m_tn
Latest news from arc-520

http://www.arrowheadresearch.com/press-releases/arrowhead-induces-90-reduction-hepatitis-b-antigens-chimpanzee-chronic-infection-data

-   Through 29 days after initial treatment, maximal knock down of HBV DNA, e-antigen, and s-antigen were approximately 95%, 90%, and 90%, respectively
-   Results discussed today at an analyst event and webcast from 12:30 to 2:00 p.m. EDT
-   Panel members for the event include Dr. Robert Gish, noted hepatologist and Arrowhead Clinical Advisory Board Chairman, and Joan Block, Executive Director and Co-founder of Hepatitis B Foundation
PASADENA, Calif. — March 25, 2013 — Arrowhead Research Corporation (NASDAQ: ARWR), a targeted therapeutics company, will host an analyst event today in New York City to discuss ARC-520, its RNAi-based candidate designed to treat chronic hepatitis B virus infection. The company will discuss the program and describe new preclinical data showing that a low dose of ARC-520 induced rapid and deep reductions in viral particles and key viral antigens in a chimpanzee chronically infected with hepatitis B virus. Arrowhead identified a well-tolerated dose of ARC-520 that lead to a 95% reduction in circulating viral DNA, and approximately 90% reductions in hepatitis e-antigen (HBeAg) and s-antigen (HBsAg), which are thought to be important in establishing a functional cure. These data support previous findings in rodent models and may be predictive of a therapeutic dose range to be identified in upcoming clinical trials expected to start in the middle of this year.
“This is the first time I have tested an siRNA therapy that was efficiently delivered to the liver and suppressed HBV infection including serum levels of HBsAg, a marker that is not suppressed effectively using current therapies,” said Dr. Robert Lanford of the Texas Biomedical Research Institute where the study was conducted. “This was a proof-of-concept study with a novel approach for curing HBV infection and this therapy provided highly promising results in a very short trial.”
The study was designed to test tolerability of a low dose of ARC-520 and its ability to reduce viral load and the key viral proteins, HBsAg and HBeAg, after intravenous administration in a chimpanzee with chronic hepatitis B infection. The animal being treated had exceptionally high titers of circulating HBV DNA and HBsAg that measured 1,000 to 10,000-fold higher than the average chronic hepatitis B patient. The HBV infection has been chronic for over thirty years and has persisted despite prior therapy with multiple anti-viral drugs and therapeutic vaccine exposures.
“Treating this animal represented a very difficult challenge,” said Dr. Chris Anzalone, President and CEO of Arrowhead. “It was the first large primate to be treated with ARC-520, and its viral and s-antigen loads were many orders of magnitude higher than what we expect to see in humans. Even with this high bar, we showed that a low dose was effective and extremely well tolerated. There is currently no way to reliably knock down key HBV antigens, thought to be critical to achieving a functional cure of the disease. Our data in multiple rodent models and now in a chimpanzee with chronic HBV infection suggest that ARC-520 may be able to provide this. We believe this is very important and positions us well for our planned clinical trials this year.”
The company will host an analyst event today in New York City to discuss ARC-520 in more detail. Panel members for the event include: Dr. Robert Gish, noted hepatologist and Arrowhead Clinical Advisory Board Chairman; Joan Block, Executive Director and Co-founder of the Hepatitis B Foundation; Dr. Bruce Given, Arrowhead COO and Head of R&D; and, Dr. Chris Anzalone, Arrowhead President and CEO. Investors and analysts may access the live presentation from 12:30 to 2:00 p.m. EDT on the Arrowhead Research website at www.arrowheadresearch.com or by calling 1.888.771.4371 (US toll free) or 1.847.585.4405 (US toll) and using the confirmation number: 34474854. The webcast will also be available for 90 days following the event.
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Avatar_m_tn
This sounds like realy good news and a definite light at the end of the tunnel for all HBV carriers. Fingers crossed
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