Aa
Tekmira
http://www.streetinsider.com/Corporate+News/Tekmira+Pharma+(TKMR)+Presents+TKM-HBV+Preclinical+Study+Data/9913680.html
You must know I am not a doctor or researcher, so your question is too hard for me to answer. I think the reduction of 50% of cccDNA was observed in a mouse model. It is my understanding that mouse cannot be naturally infected with HBV, and so the mouse is genetically modified. I have no idea how HBV develops and progresses (pathogenesis) in this kind of mice. Maybe it is natural for them to clear the infection eventually, or what their immune system is like.
However, in the case of human HBV, according to research studies, cccDNA can be lost during natural liver cells (both infected and uninfected) turnover. That is one liver cell dies, another liver cell divides, so the totoal number of liver cells remains constant. cccDNA can be lost during liver cell division. Equally, cells can be infected or re-infected. Of course, cccDNA can be inactivated or degraded by the immune system.
I agree with you that we don't know what these treatments may lead, science is serendipity and we wait to be surprised. You must realize by now that we hear very little from HBV doctors and researchers regarding the potential of this type of treatments, instead we hear a lot from bloggers and investors (and here too, LOL), most of them however never heard of HBV before.
Just my opinion.
However, in the case of human HBV, according to research studies, cccDNA can be lost during natural liver cells (both infected and uninfected) turnover. That is one liver cell dies, another liver cell divides, so the totoal number of liver cells remains constant. cccDNA can be lost during liver cell division. Equally, cells can be infected or re-infected. Of course, cccDNA can be inactivated or degraded by the immune system.
I agree with you that we don't know what these treatments may lead, science is serendipity and we wait to be surprised. You must realize by now that we hear very little from HBV doctors and researchers regarding the potential of this type of treatments, instead we hear a lot from bloggers and investors (and here too, LOL), most of them however never heard of HBV before.
Just my opinion.
Durability is a pleasant surprise and hope it may be significant. As I remarked before, we have heard of instances of patients with very low level of serum HBsAg in the so called truly inactive carrier phase, yet they do not s-seroconvert and can remain in this state for several years. Of course, research studies indicate they have a higher chance of s-serconversion in the future. On the forum here, some wouldl encourage these people to try Interferon in order to bring this about quicker.
What do you think would account for the 50% reduction in cccDNA over 42 days them? Is it some kind of immune stimulation? Or is there another mechanism not yet understood
My thoughts are it is way too early to make a determination of the end game for these treatments. Too early to dismiss them as ineffective and too early to hail them as breakthroughs. What they do represent is a greater awareness of HBV and demonstrate a greater focus on finding a cure. The fact that so many companies are actively engaging in finding a cure should be welcome news to all who are affected by this scourge
(this comment is for your Arrowhead's quotations)
The following statements was also interesting in Arrowhead's open letter to shareholders:
" Interestingly, we have seen unexpectedly durable knockdown in patients, even though the low doses provided relatively shallow depth of HBsAg reductions. At the final time points studied, nearly 3 months after a single injection, we continue to see knockdown. We believe that this is important and quite unique. We expect that it will provide significant advantages, particularly as we increase dose and initiate planned multi-dose studies."
The following statements was also interesting in Arrowhead's open letter to shareholders:
" Interestingly, we have seen unexpectedly durable knockdown in patients, even though the low doses provided relatively shallow depth of HBsAg reductions. At the final time points studied, nearly 3 months after a single injection, we continue to see knockdown. We believe that this is important and quite unique. We expect that it will provide significant advantages, particularly as we increase dose and initiate planned multi-dose studies."
The main objections we have to ARC520, TMK-HBV, ALN-HBV are the impressions that a significant reduction of serum HBsAg for a period of time(single or multiple mono injections or in combination with antivirals) can lead to a functional cure. If you read carefully, the rationale for this method of achieving a cure is the assumption that a period of low level of serum HBsAg will lead to the re-establishment of immune functions that will then clear the virus. In a recent open letter to shareholders, Arrowhead stated this very clearly:
"Let us begin with our goal. We have said for some time that our goal was to identify a dose of ARC-520 capable of achieving HBsAg reduction of around 1 log (corresponding with 90% knockdown) after a single administration. This was a somewhat arbitrary goal since it is unknown what level of HBsAg reduction is necessary to de-repress the immune system and potentially enable a functional cure. Indeed, the entire CONCEPT of enabling a functional cure by suppressing HBsAg release remains an UNTESTED theory, but that is one of the challenges of being a pioneer in the field. We chose 1 log as a goal because, according to the scientific literature, the small number of patients who achieve functional cure from Interferon therapy demonstrate ½ log reduction in HBsAg (approximately 70% knockdown) after 12 weeks and 1 log (90% knockdown) after 24 weeks. We expected that if ARC-520 is active it should lead to more rapid reduction, particularly on repeat dosing, so a full log might not be needed after a single administration. Even so, we believed that a 1 log goal is intellectually honest and we wanted to share our thinking publicly rather than establish an artificially low goal just so we could beat it. "
Those of us on the forum for a long period of time, knew that a profound reduction(up to 5 log) of serum HBsAg can indeed lead to loss of HBsAg, loss of hbvdna, and appearance of HBsAb in some patients as shown by the results of REP9AC in the clinical trial of 8 patients. HOWEVER, we have also since learned that these responses are NOT SUSTAINABLE once treatment is stopped. According to REPLICor, "that prolonged elimination of viral antigens is insufficient to elicit SVR in most patients with chronic HBV infection and that concomitant immunotherapy is required to re-establish immune control in the absence of viral antigens in most patients.".
All three companies, REPLICor, TKM, and ALN were at the same recent conference, so they should all be acquainted with all the results. I think it is right to sound caution.
It would be nice if TKM-HBV can lead to a direct reduction of cccDNA. There is no reason why RNAi can affect the cccDNA within the nucleus, since the action of interference is in the cytoplasm, outside the nucleus. The effect was observed by TKM, but only in a MOUSE model. So again, caution is prudent.
BTW, you can see the full presentations on TKM website. It has much more details.
Just my understanding.
"Let us begin with our goal. We have said for some time that our goal was to identify a dose of ARC-520 capable of achieving HBsAg reduction of around 1 log (corresponding with 90% knockdown) after a single administration. This was a somewhat arbitrary goal since it is unknown what level of HBsAg reduction is necessary to de-repress the immune system and potentially enable a functional cure. Indeed, the entire CONCEPT of enabling a functional cure by suppressing HBsAg release remains an UNTESTED theory, but that is one of the challenges of being a pioneer in the field. We chose 1 log as a goal because, according to the scientific literature, the small number of patients who achieve functional cure from Interferon therapy demonstrate ½ log reduction in HBsAg (approximately 70% knockdown) after 12 weeks and 1 log (90% knockdown) after 24 weeks. We expected that if ARC-520 is active it should lead to more rapid reduction, particularly on repeat dosing, so a full log might not be needed after a single administration. Even so, we believed that a 1 log goal is intellectually honest and we wanted to share our thinking publicly rather than establish an artificially low goal just so we could beat it. "
Those of us on the forum for a long period of time, knew that a profound reduction(up to 5 log) of serum HBsAg can indeed lead to loss of HBsAg, loss of hbvdna, and appearance of HBsAb in some patients as shown by the results of REP9AC in the clinical trial of 8 patients. HOWEVER, we have also since learned that these responses are NOT SUSTAINABLE once treatment is stopped. According to REPLICor, "that prolonged elimination of viral antigens is insufficient to elicit SVR in most patients with chronic HBV infection and that concomitant immunotherapy is required to re-establish immune control in the absence of viral antigens in most patients.".
All three companies, REPLICor, TKM, and ALN were at the same recent conference, so they should all be acquainted with all the results. I think it is right to sound caution.
It would be nice if TKM-HBV can lead to a direct reduction of cccDNA. There is no reason why RNAi can affect the cccDNA within the nucleus, since the action of interference is in the cytoplasm, outside the nucleus. The effect was observed by TKM, but only in a MOUSE model. So again, caution is prudent.
BTW, you can see the full presentations on TKM website. It has much more details.
Just my understanding.
More info on the cccDNA reduction from TKM-HBV
https://propthink.com/tekmiras-ebola-first-hepatitis-b-data-encouraging/
https://propthink.com/tekmiras-ebola-first-hepatitis-b-data-encouraging/
I think all results are relevant in one way or another. I agree with Seattle in the way that I don't honk they are trying to fool anyone. I believe the race is on to find the "cure" for HBV now that HCV has been slayn. If thy have found a way I reduce cccdna in animal trials it's only so long before they do the same in humans... Hopefully In my lifetime
50% reduction in cccDNA after 42 days monotherapy is a pretty big deal
http://files.shareholder.com/downloads/ABEA-50QJTB/3544267189x0x786669/647cc552-6286-433c-b857-332a71f277e8/OTS2014Final.pdf
http://files.shareholder.com/downloads/ABEA-50QJTB/3544267189x0x786669/647cc552-6286-433c-b857-332a71f277e8/OTS2014Final.pdf
Fooling investors only works for a short period of time, I don't think that the 4 companies workings on this kind of treatment are willing to lose there companies for a short term fleeting gain.
You do realize this is just an animal study and they are just getting started. This technology is the first to demonstrate statistically significant Hbsag knockdown. Let's wait for higher doses,humans and more than one treatment before declaring this useless
you do nothing with hbsag detectable because all cccdna is still ininfected cells, 2log hbsag reduction is ridiculous, maybe trying to fool investors who dont know hbv
hbsag decline after cccdna reduction like in peginterferon or decades of nucs is one thing, blocking hbsag release without no change in its producer (cccdna and integrated hbvdna) is complitely different all by itself has no effect
yes they posted already, ridiculous results and useless, hbsag must be undetectable like for replicor for peginterferon add on to rescue immune system and clear cccdna
you do nothing with hbsag undetectable because all cccdna is still ininfected cells, 2log hbsag reduction is ridiculous, maybe trying to fool investors who dont know hbv
you do nothing with hbsag undetectable because all cccdna is still ininfected cells, 2log hbsag reduction is ridiculous, maybe trying to fool investors who dont know hbv
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