Aa
replicor
So what was the outcome of Replicor..Any results?
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?
Thank you again for your help!
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?
Thank you again for your help!
hope we'll get soon some good results of birinapant, study is going to finish in June.
https://clinicaltrials.gov/ct2/show/NCT02288208?term=birinapant&rank=2
Good that phase here seems to be much shorter than for example replicore one.
https://clinicaltrials.gov/ct2/show/NCT02288208?term=birinapant&rank=2
Good that phase here seems to be much shorter than for example replicore one.
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.
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.
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)?
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.
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.
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.
Your explanation about the difference in release mechanism for HBV and HDV virions is fascinating. I think it is unexpected result, even for Replicor.
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
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
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.
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.
So has it been confirmed that rep2139-ca block the release of HBsAg and HDV virions, but not HBV virions?
Thanks.
Thanks.
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.
Unfortunately it will be much harder to establish permanent immune control in e antigen negative patients.
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.
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.
btw, do you think Rep 2139-Ca may be used for HBe+ mainly or HBe status doesn't matter so much ?
exactly, fast track ! like here
http://www.healio.com/hepatology/chronic-hepatitis/news/online/%7B09e99bec-adf3-4539-9812-b30f66a3096c%7D/fda-grants-fast-track-designation-for-hdv-inhibitor
http://www.healio.com/hepatology/chronic-hepatitis/news/online/%7B09e99bec-adf3-4539-9812-b30f66a3096c%7D/fda-grants-fast-track-designation-for-hdv-inhibitor
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.
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.
Have an Answer?
You are reading content posted in the Hepatitis B Community
A list of national and international resources and hotlines to help connect you to needed health and medical services.
Herpes sores blister, then burst, scab and heal.
Herpes spreads by oral, vaginal and anal sex.
STIs are the most common cause of genital sores.
Condoms are the most effective way to prevent HIV and STDs.
PrEP is used by people with high risk to prevent HIV infection.
