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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
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
This sounds like realy good news and a definite light at the end of the tunnel for all HBV carriers. Fingers crossed
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.
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.
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.
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.
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.
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.
Hi,
Stef2011, what do you think about this new drug? DOes it appear to be as effective as REP 9AC or MYcludex?
thanks
Stef2011, what do you think about this new drug? DOes it appear to be as effective as REP 9AC or MYcludex?
thanks
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
mine was extremely easy to see on US and all full of nodules, small but full of it
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 -
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?
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.
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
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.
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.
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!
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!
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.
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
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
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).
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).
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.
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.
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??
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??
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.
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.
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.
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.
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
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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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.