they just showed data that 7 days of slow perfusion cleared hbsag and made hbsab in all human subjects treated, immune control by 24 weeks, no sides
this is too good and i fear the same ending as alinia, no development for....they will never say it but answer is market reasons: all the other drugs (making billions now) would go directly to the bin if this compound is so strong.
another similarity nobody talks about it, on latest trails romark says alinia works for hcv and flu virus, nothing about hbv....hcv slow release will be managed/produced for romark by roche through a japanese company they own (ltd maker owns 33% of roche and make some drugs for gilead, viread producer), it's all one family
hope all this i think will not be true but until now i see this
REPLICor updates clinical results demonstrating the achievement of therapeutic vaccine-like responses in patients with chronic hepatitis B with short term exposure to immunotherapy in combination with REP 9AC’.
10 November 2012, Boston, U.S.A. and Nanjing, China.
Montreal, Quebec – Friday , November 9th, 2012 – REPLICor is currently undertaking a proof of concept trial in patients with chronic hepatitis B (HBV) undergoing treatment with its nucleic acid polymer (NAP) REP 9AC’ in combination with Zadaxin™ or Pegasys™. The hepatitis B surface antigen protein (HBsAg) is produced in large excess by the HBV infection as subviral particles (SVPs) which act to block the immune response to HBV infection. NAPs act to block the release of SVPs from infected hepatocytes, providing an effective method for clearing HBsAg from the blood. The elimination of HBsAg in the blood of HBV-infected patients is well known to be the best indicator of a curative response to treatment.
Updated interim results from REPLICor’s proof of concept trial will be disclosed simultaneously on Saturday Nov 10, 2012 at the 63rd annual meeting of the American Association for the Study of Liver Disease (AASLD) in Boston, U.S.A. and at the 10th annual meeting on International Drug Discovery Science and Technology in Nanjing, China.
Patients who had cleared HBsAg from their blood with REP 9AC’ monotherapy were subjected to combination treatment with REP 9AC’ and either Pegasys™ or Zadaxin™. Profound increases in anti-HBV antibodies or immune function were observed in all patients with as few as 6-10 weeks of combination treatment. All patients have achieved HBV antibody levels seen in healthy patients after vaccination with a total of 12 weeks of combination treatment and many patients have achieved antibody titers > 1000 mIU / ml. In 8 out of 9 patients who have achieved this therapeutic vaccine-like response, they continue to control their viral infection off treatment. REPLICor expects that short term Zadaxin™ or Pegasys™ treatment given in combination with the HBsAg release inhibitor REP 9AC’ will achieve an effective, therapeutic vaccination in patients with chronic HBV infection, resulting in the achievement of durable immunological control in most patients, regardless of viral genotype or state of their HBV infection.
For the 63rd annual meeting of the American Association for the Study of Liver Disease:
For the 10th annual meeting on International Drug Discovery Science and Technology:
I totally agree with you. I am in the US where we hbv patients have it very bad
. They dont even want to give us interferon. Incredibly hard to find a doctor that is willing to do pegasys. I am starting to think it has something to do with insurance companies. Maybe antivirals are cheaper for them to get.
Two of my university level doctors assentially have dumped me because I ask for pegasys rather then etv. They are saying that for people with undetectable vl and normal liver tests peg does not help. When I say about sequential therapy is what I want to do I am told I play doctor and that there is no proof of effectiveness what I say.
When I say antivirals cause matochondrial toxicity I am told it is low. And being thrown at a bunch of meaningless statistics. About how wonderful and safe antivirals are. Even despite articles shows as proof. So they are defending the antivirals like crazy. It is pathetic to have to sit there and listen as a patient somebody tell you that antivirals have the same affect on hbv clearance as interferon. Especially for someone wth genotype A. And when you tell them they are dead wrong and show actual facts you are told you have to find another doctor. Why is that?
When I say I take 10000 iu daily of vitamin d3 I am told there is also no proof that it helps - even though I feel better and my crashing chest pains have gone. and blood tests show improvements. Overall wbc counts are higher and afp reading is very low. Lower then it was on just etv alone.
So yes it is all business doctors treat how drug and insurance companies tell them. These profound arguments in favor of antivirals over interferon do not make sense. Indefinite hbv therapy with nucs also makes no sense. Without rescuing the immune system nothing can be achieved.
So yes lets hope a Canadian company hears our pain. And makes a difference for the better of humanity. Why wait 3-5 years when the process of curing hbv can begin now.
Regarding alinia we the patients need to get active. Criticizing the corporate system that took over the western world will do no good. We have to take action exposing this what is going or become of hbv treatment that it became an industry. That drugs that work for us better are not being used.
We need to stand up there is 300 million of us and that is a voice.
That timeline seems fairly optimistic based on their progress the last two years, but if it is then great. More interesting questions would be whether they have made any progress in making the formulation in a subcutaneous injection form? That would be important in terms of worldwide marketability.
And the other is what happened with the 9th patient? If they developed antibodies similar to those in healthy levels and were unable to control the infection, did mutation in surface antigen occur? Based on reading studyforhope excellent posts on how HBV works and adaptability, this is very important question that needs to be answered thru the trials. Hopefully if someone attends the conference, they can get information on these issues.
From the news article " Treatment was once daily via 2 hour IV infusion. Researchers measured viremia, hepatitis B surface antigen (HBsAg) and anti-HBs every 2 weeks using standard assays."
Very incorrect information. The treatment is once weekly, not daily.
Interesting to see that hausecker, who reacted silly and naive a few month ago, when I alerted him to the impact of replicors data on his iRNA predictions is now changing course.
The real big news is the dramatic reduction in HDV viremia in all patients who reduced hbsag. This points to a fundamentally different mechanism of Hdv virion reduction compared with HBV, more profound and more direct acting, with huge consequences for a disease that is rapidly progressing and currently almost untreatable. It will clearly be of great help to replicor to move forward.
No the key mechanism new here is the reduction in HDV virions, that operates in the same fashion as the blockage of HBsAg release. Thus it is not the reduction of HBsAg that drives indirectly the viral load reduction as in hbv, but the delta virions themselves are retained and thus HDV virions drop in parallel with hbsag, but NOT because of it.
Thus the HDV vl reduction is much more profound than the hbv virion reduction in serum. HDV reinfection will be dramatically reduced and then consequently the immune attack against the delta antigen, which causes the severity of this disease.
The dramatic effect on HDV gives replicor a much better chance for further development and ultimately approval. BUT the longer term outcome of this even on hdv has to be awaited, viruses bounce back if even a tiny trace is left in the liver. Since almost a year of interferon add on is planned, there is a chance, however, of good SVR rates. It remains to be seen, if due to the high instability of the HDV RNA genome, a selective eradication or control of HDV is possible. And how high the hbv svr rate will be. We will have to wait for a long time to know the answers to these critical questions.
This is the same drug that was used in the second Bangladesh trial on hbv mono e ag positiv patients. The differences are a much longer planned immunotherapy add on, in the hope also to improve hbv svr rates.
For good and valid reasons, like the size and protein composition of HDV virions vs hbv virions, hdv is presumed to be treated like a surface antigen particle in the formation and release pathway. HBV virion morphogenesis and secretion is different and not directly controlled by the replicor compounds. Additionally, The almost perfect parallelism in hbsag and hdv serum reduction, much much more profound than hbv vl reductions, lends strong support to this theory.
what about the patients with low hbsag less than 1000iu/ml naturally or by peginterferon/longterm nucs treatments.
is there any data on replicor for these cases where some immune control over hbv is already weakly present?
i guess these cases are much easier to reach svr and high hbsab
As can be seen by looking at the OTS presentation from last fall, recently presented here also, the patients had all high , some very very high, hbsag levels.
It can be assumed, that patients that have spontaneously low hbsag levels, likely as a results of a fortunate constellation of epitopes, T cell clones and cytokine milieu, will respond better and more stable to the additional artificial lowering of the hbsag that the treatment provides.
It is a big difference if hbsag is low as a symptom of improving Tcell immunity or is pushed down by interfering RNA or the replicor compound ( much much lower however). Failure to see that clearly is the reason for all these IMO naive predictions like for arrowhead etc, that the lowering by blockade will typically lead to a spontaneous self stabilization of the infection status.
Replicors trials have made that painfully clear.
Immune stimulation in addition to hbsag lowering works much better, but the correct epitopes are still needed ( Not just activated T and B cells) and the cells with integrated full genomes can also lead to a respreading of the virus after therapy has ended, even if this might take a long time.
a key problem is, that even a high titer anti hbsag antibody is not long term sufficient to keep the regrowth of the virus completely in check. Its reinfection blocking effect is never perfect on a microscopic local scale in the liver. Growing clusters of reinfected cells need to be destroyed from time to time by a localized T cell attack, that responds to the growing of this cluster.
While the inside forces of Tcell immunity will be helped by lowering hbsag, a tolerizing agent with some unspecific immune blocking activity in addition, epitope availability and intactness are still critical to switch on the permanent inside t cell maintenance "therapy" that is the heart of the "cure' in chronic HBV.
Yes, this was a very lucky turn of events for Replicor. It gives it a break and momentum to overcome the still existing obstacles. Unfortunately, it takes such a long time, even after the end of a trial to see if a true svr stability was achieved. So it will take years.
In regards to your statement of "Unfortunately it will be much harder to establish permanent immune control in e antigen negative patients"......Is there anything that looks up and coming/promising for those of us with HbeAg negative/hbsag positive only (no co infection with c or d)?
The biggest promise at this time IMO lies in the use of birinapant, an apoptosis inducer/sensitizer, whose human trial has just begun a few month ago.
The mouse research on birinapant, just published in PNAS has clearly determined that its mode of action is class I CTL ( cd8 tcell) independent, while being totally dependent on class II helper Tcell TNf alpha producing activity.
This is very important, because it holds the fascinating promise that class II epitopes only are required to stimulate the initiation of TNf alpha induced cell killing by these cd4 cells.
class ii epitopes are quite mutated as well in long standing e antigen neg patients, but they are much more abundant and never completely absent as class i epitopes.
furthermore, no cytosolic processing is required, such that eg surface antigen epitopes can contribute in the production initiation of the TNF alpha production by responding helper cells, presented by dendritic cells close to a dying hepatocyte or a macrophage and maybe most important, by a sinusoidal endothelial cell ( these can act effectively as antigen presenting cells, surprisingly) , that is always close by, to stimulate these helper cells to produce the TNf that will passively diffuse to the infected cells under birinapant influence, killing it, just cccDNA or integrated genome, without any need for direct physical contact with the T cell, and with the additional promise that an individual cell will be killed even if it has mutated all its epitopes due to the proximity to those who have not.
in other words cluster killing is possible and likely with all the promise that holds to deeply eradicate infected hepatocytes. there will be centers of TNFalpha producing activity in the liver parenchyma, where the cd4 cells are activated, with a limited radius of effectivness. Those centers will redistribute within a week or so, allowing a new cleaning attack and so on.
Thus many rounds of birinapant infusions are likely needed to eradicate infected hepatocytes to enough completion.
co-treatment with thymosin alpha might be necessary to stimulate the helper population enough and to give it a clean TH1 attitude.
It might also be necessary, to use a pretreatment with a NAP, to reduce hbsag to minute levels, to contribute to the stimulation of immune capacity, that is quite suppressed by the presence of even fairly small quantities of hbsag.
at the end of the treatment - with a high surface antibody and und hbv dna and of course a neg surface antigen, monitoring at least monthly for indicators of hbv regrowth will be necessary, with a readiness to hit it again, at an early stage, before it has overpowered the surface antibody defense.
Wow. Great information studyforhope! This might be a very naive question, but say the clinical trials go great, how long could it take to get FDA approved (fast track or regular FDA), and then prescribed by doctor, and approved by insurance company? It seems like a very long time, but can things happen pretty quickly if all goes as great as the information they have given so far?
Another question that you may not know since we are not HCV. It seems like the cure for HCV came really fast, was that so (like could we possibly be that lucky if Birinapant goes well) or did the cure for C take a really long time?
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