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New REP 9AC Clinical Trial,
Wednesday, October 30, 2013 New REP 9AC Clinical Trial, Adding Interferon and Antivirals, Begins in Europe, with comments by Christine. M. Kukka, Project Manager, HBV Advocate
— Christine. M. Kukka, Project Manager, HBV Advocate
For months, the hepatitis B community has been waiting for updates about the experimental drug REP 9AC that stops production of hepatitis B surface antigen (HBsAg) within weeks. There will be no news unveiled at this week's international Liver Conference in Washington D.C., but a new clinical trial is about to begin that combines REP 9AC with an immune stimulant and an antiviral.
REP 9AC, administered intravenously, uses nucleic acid-based polymers to stop HBV-infected liver cells from releasing HBsAg—an antigen critical to the production of HBV. Early clinical trials in HBV-infected animals and humans showed that within four weeks REP 9AC rapidly reduced or eliminated HBsAg in the blood.
The drug’s developers, REPLICor Inc. based in Montreal, had hoped the dramatic decline in HBsAg would enable the immune system to quickly gain the upper hand and eradicate the infection. However, patients treated with just REP 9AC didn’t clear the infection as anticipated. Despite the decline in HBsAg, in many cases viral load remained detectable and the infection remained entrenched in liver cells.
“In some patients, REP 9AC (by itself) was enough to allow their immune systems to fully recover during the course of about six months of treatment and these patients have long-term control (after four years) of their infection,” Andrew Vaillant, REPLICor’s chief scientific officer and director of operations, wrote in an email to HBVAdvocate.org. Next, developers tweaked the drug to allow it to be absorbed more easily (the second-generation drug is called REP 9AC’) and tried adding either pegylated interferon (Pegasys) or another immune stimulator, thymalfasin to the ongoing REP 9AC’ treatment to see if the drug combination would knock out the infection.
At the July 2013 meeting of the Asian Pacific Association for the Study of Liver Disease, researchers reported that the number of surface antibodies did rise rapidly in these patients and viral load continued to decline even after treatment ended, but they still were not happy with the result.
In its latest clinical trial, involving 20 patients, researchers will try a triple treatment of REP 9AC’, the immune stimulant and an antiviral (either entecavir (Baraclude) or tenofovir (Viread). “This triple combination will likely provide the most potent response in patients,” Vaillant wrote.
Many patients have been frustrated with the slow pace of REPLICor’s drug development. The company is privately-held and its development pace is so far slower than that of “big pharma companies” that are funded through publicly-traded stock sales.
“We are aware that some patients have been frustrated with the apparent ‘slow’ pace of progress with this technology,” Vaillant told the HBVadvocate, “but we have had to do many things with these initial proof of concept experiments, including optimizing the dosing regimen and tolerability for REP 9AC/REP 9AC’ and understanding how best to use REP 9AC’ in a combination regimen to achieve the best possible sustained viral response result in patients with a defined course of therapy.
“We feel that we are getting to the end of this process and we are hopeful that the European study will be the last confirmatory piece of evidence we will need to start the registration process for this treatment,” he wrote.
— Christine. M. Kukka, Project Manager, HBV Advocate
For months, the hepatitis B community has been waiting for updates about the experimental drug REP 9AC that stops production of hepatitis B surface antigen (HBsAg) within weeks. There will be no news unveiled at this week's international Liver Conference in Washington D.C., but a new clinical trial is about to begin that combines REP 9AC with an immune stimulant and an antiviral.
REP 9AC, administered intravenously, uses nucleic acid-based polymers to stop HBV-infected liver cells from releasing HBsAg—an antigen critical to the production of HBV. Early clinical trials in HBV-infected animals and humans showed that within four weeks REP 9AC rapidly reduced or eliminated HBsAg in the blood.
The drug’s developers, REPLICor Inc. based in Montreal, had hoped the dramatic decline in HBsAg would enable the immune system to quickly gain the upper hand and eradicate the infection. However, patients treated with just REP 9AC didn’t clear the infection as anticipated. Despite the decline in HBsAg, in many cases viral load remained detectable and the infection remained entrenched in liver cells.
“In some patients, REP 9AC (by itself) was enough to allow their immune systems to fully recover during the course of about six months of treatment and these patients have long-term control (after four years) of their infection,” Andrew Vaillant, REPLICor’s chief scientific officer and director of operations, wrote in an email to HBVAdvocate.org. Next, developers tweaked the drug to allow it to be absorbed more easily (the second-generation drug is called REP 9AC’) and tried adding either pegylated interferon (Pegasys) or another immune stimulator, thymalfasin to the ongoing REP 9AC’ treatment to see if the drug combination would knock out the infection.
At the July 2013 meeting of the Asian Pacific Association for the Study of Liver Disease, researchers reported that the number of surface antibodies did rise rapidly in these patients and viral load continued to decline even after treatment ended, but they still were not happy with the result.
In its latest clinical trial, involving 20 patients, researchers will try a triple treatment of REP 9AC’, the immune stimulant and an antiviral (either entecavir (Baraclude) or tenofovir (Viread). “This triple combination will likely provide the most potent response in patients,” Vaillant wrote.
Many patients have been frustrated with the slow pace of REPLICor’s drug development. The company is privately-held and its development pace is so far slower than that of “big pharma companies” that are funded through publicly-traded stock sales.
“We are aware that some patients have been frustrated with the apparent ‘slow’ pace of progress with this technology,” Vaillant told the HBVadvocate, “but we have had to do many things with these initial proof of concept experiments, including optimizing the dosing regimen and tolerability for REP 9AC/REP 9AC’ and understanding how best to use REP 9AC’ in a combination regimen to achieve the best possible sustained viral response result in patients with a defined course of therapy.
“We feel that we are getting to the end of this process and we are hopeful that the European study will be the last confirmatory piece of evidence we will need to start the registration process for this treatment,” he wrote.
They are in itself capable to reduce the vl by a factor of 30 after the second injection. If enough synergistic suppression of virion production is achieved, it could in theory reduce the rate of reinfection. But it does not seem a sufficiently strong effect to achieve that.
Overall the hope is that the reduction in e and hbsag expression will trigger an immune response by unblocking. It will all depend on the preset readiness of an individual patients immunity to respond in that way. Certainly the reduction in hbsag levels by a factor of over 10000 by the NAPs seems way superior in that regard.
The tolerance to repeating the injections with higher doses will likely decide if this approach will bring a useful addition to the treatment repertoire in chronic hepatitis B.
Overall the hope is that the reduction in e and hbsag expression will trigger an immune response by unblocking. It will all depend on the preset readiness of an individual patients immunity to respond in that way. Certainly the reduction in hbsag levels by a factor of over 10000 by the NAPs seems way superior in that regard.
The tolerance to repeating the injections with higher doses will likely decide if this approach will bring a useful addition to the treatment repertoire in chronic hepatitis B.
The combination with Entecavir will,lead to an additional reduction in the number of virions produced by an independent mechanism.
The ARC treatment by itself reduces the pre genomic RNA and the core protein RNA , but not very effectively. Theyybre
The ARC treatment by itself reduces the pre genomic RNA and the core protein RNA , but not very effectively. Theyybre
Many thanks for that clear and easy to understand explanation. I know you have commented on ARC520 before(the Christmas lights), can you enlighten us with your views in the light of their latest results and the proposed phase2a trial together with Entecavir.
Many thanks.
Many thanks.
Dear Studyforhope! thanks a lot for your detailed reply.
So srv to anti-hbs with low Ab titer after inf treatment is far from final point and only possible option is to artificially promote AB titer to above 200 with vaccination (if ab with titer above 200 does not occur naturally)?
So srv to anti-hbs with low Ab titer after inf treatment is far from final point and only possible option is to artificially promote AB titer to above 200 with vaccination (if ab with titer above 200 does not occur naturally)?
A titer of 10 miu/ml is definitely too low to prevent spreading of infection from cell to cell in the liver. It can prevent the infection when a virion enters the body far from the liver, proceeds slowly through the lymph system and then the general circulation before it reaches the liver. At this long route a low titer has enough of a chance to grab the virion, coat it and make it impossible to attach and infect at the hepatocyte.
Titers of 200 to 500 miu however are needed to decently prevent local reinfection. Fully complexing an hbv virion from all sides takes time, a high AB concentration will drive the rate of complexion.
The space to traverse for a newly secreted virion to the next sinusoidal liver cell surface is only about 10 micrometers. Thus a newly born hbv virion can reinfect within minutes locally. Because of this, even a high titer will not completely prevent local reinfection, but it will slow it down and make the infection grow in tighly contained clusters of cells.
The critical event to occur is the reactivation of the latent memory epitope specific cd8 Tcell response, that will, after the clusters have grown to a certain size, relaunch a Tcell attack onto these clusters, with killing of a few hepatocytes, but more importantly by secreting very high ultralocal ifn gamma amounts, leading to the very high concentrations needed to stimulate the interferon response genes that will actually destroy the cccDNA noncytopathically, which will clear the cccDNAs in most of the cluster cells, cleaning out the infection again down to a very small remnant.
However this small remnant will again slowly grow into new clusters over time, that can be many month or longer and the cycle will repeat.
The Tcell response and memory titer is not easily assessable as is the ab titer, experimentally, only flow cytometry detecting and quantifying epitope specific Tcells using tetramers, pentamers or dexamers of MHC bonded epitope peptides are available to approach this most important instrument of antiviral defense. Several are now commercially available.
That is the reasons everybody is talking only about AB titers, the Tcell determination is too expensive, requires live cells on the spot and high tech instruments and unfortunately, only reflects the status in the peripheral blood, not in the liver, where the resident Tcell clones might be dramatically more abundant than in the peripheral blood, where they have no real function. Thus all these efforts might still not reflect the real Tcell defense strength in place in a patient at a given time. A workup from liver biopsies is the only method to give reliable results with respect to epitope cognate cd8 tcells in the liver.
Last not least even the flow cytometry determination only detects the epitope spefic Tcell receptor ( TCR) carrying population, but not the functional capacity of these Tcells, which can be intense killer, high or low ifn gamma producers upon Tcell receptor engagement. Those qualities require yet other assays to be combined with the flow cytometry of the epitope specific TCR.
Nevertheless this is the mechanism that truly keeps the infection under control. The antibody plays only an important helping role in reducing the speed of reinfection to a crawl and forcing the formation of slow growing clusters, that can be detected and responded to in sufficient time by the cd8 Tcell population also called CTLs. They are doing the real work. Please note that natural killer cells (NK cells) will also participate in this reaction, but only to a small degree.
Titers of 200 to 500 miu however are needed to decently prevent local reinfection. Fully complexing an hbv virion from all sides takes time, a high AB concentration will drive the rate of complexion.
The space to traverse for a newly secreted virion to the next sinusoidal liver cell surface is only about 10 micrometers. Thus a newly born hbv virion can reinfect within minutes locally. Because of this, even a high titer will not completely prevent local reinfection, but it will slow it down and make the infection grow in tighly contained clusters of cells.
The critical event to occur is the reactivation of the latent memory epitope specific cd8 Tcell response, that will, after the clusters have grown to a certain size, relaunch a Tcell attack onto these clusters, with killing of a few hepatocytes, but more importantly by secreting very high ultralocal ifn gamma amounts, leading to the very high concentrations needed to stimulate the interferon response genes that will actually destroy the cccDNA noncytopathically, which will clear the cccDNAs in most of the cluster cells, cleaning out the infection again down to a very small remnant.
However this small remnant will again slowly grow into new clusters over time, that can be many month or longer and the cycle will repeat.
The Tcell response and memory titer is not easily assessable as is the ab titer, experimentally, only flow cytometry detecting and quantifying epitope specific Tcells using tetramers, pentamers or dexamers of MHC bonded epitope peptides are available to approach this most important instrument of antiviral defense. Several are now commercially available.
That is the reasons everybody is talking only about AB titers, the Tcell determination is too expensive, requires live cells on the spot and high tech instruments and unfortunately, only reflects the status in the peripheral blood, not in the liver, where the resident Tcell clones might be dramatically more abundant than in the peripheral blood, where they have no real function. Thus all these efforts might still not reflect the real Tcell defense strength in place in a patient at a given time. A workup from liver biopsies is the only method to give reliable results with respect to epitope cognate cd8 tcells in the liver.
Last not least even the flow cytometry determination only detects the epitope spefic Tcell receptor ( TCR) carrying population, but not the functional capacity of these Tcells, which can be intense killer, high or low ifn gamma producers upon Tcell receptor engagement. Those qualities require yet other assays to be combined with the flow cytometry of the epitope specific TCR.
Nevertheless this is the mechanism that truly keeps the infection under control. The antibody plays only an important helping role in reducing the speed of reinfection to a crawl and forcing the formation of slow growing clusters, that can be detected and responded to in sufficient time by the cd8 Tcell population also called CTLs. They are doing the real work. Please note that natural killer cells (NK cells) will also participate in this reaction, but only to a small degree.
"if an antibody of high titer occurs after ifn therapy, it means that most cccDNA has been lost, although the low hbsag level can be partially caused by suppression of expression, rather elimination of.cccDNA."
what titer of hbsab can be considered as high after inf theraphy? Is 10 mIu/ml of hbsab like after vaccination enough?
what titer of hbsab can be considered as high after inf theraphy? Is 10 mIu/ml of hbsab like after vaccination enough?
Well with as much money they get for clinical trials, and the amount of people envolved in this "industry" I think HBV will be eradicated rather long. But maybe we are in luck because NUCs patents are running out. And people are getting educated..
So the conclusion is to keep sufficient ab level by vaccination for all healthy individuals until hbv is not eradicated from the earth completely.
CccDNA remains after the resolution of acute infection as well. It can be considered a chronic hbv infection under excellent TCell and antibody control. Under intense immune suppression it often causes a flare of acute hepatitis.
Thanks for the explanation.
Does cccDNA remain after the resolution of the acute infection too?
Does cccDNA remain after the resolution of the acute infection too?
No data re intestinal absorption are available for the large NAPs. Smaller phospothioate antisense polymers have been found to have about ten percent absorption from the jejunum. liposomal encapsulation might enhance that further. The idea to have the liver extract most of the NAP at the first pass from the portal vein is interesting , since it could further reduce systemic, toxic exposure from the compound. But at the current high price for these substances when produced at a trial scale such a low absorption would be quite a waste of money.
This is very good news. Lets hope we will all make it there to see this drug help us.
For Replicor all I can say. Folks if you are not big pharma and do understand what is going on. Approving these drugs can be very easily done. Just treat patients that will sign special concent waiver forms stating that basically that we want to fly. Cure 20 or more people - for a proof and seek public media exposure as well as here on these hbv forums.
And nobody will be able to stop or slow down a cure. On your web site you can also accept public donations. If 300 million of us donate $1 or 2 that goes along way.
Otherwise big pharma with their resources who monitor what you are doing will beat you folks to a cure. Truth is that HBV can be cured in many ways indirecty by influencing the immune system. And researchers know it.
But in any case we hbv infected will.wait as long as we can for your drug. Hope is all we have.
For Replicor all I can say. Folks if you are not big pharma and do understand what is going on. Approving these drugs can be very easily done. Just treat patients that will sign special concent waiver forms stating that basically that we want to fly. Cure 20 or more people - for a proof and seek public media exposure as well as here on these hbv forums.
And nobody will be able to stop or slow down a cure. On your web site you can also accept public donations. If 300 million of us donate $1 or 2 that goes along way.
Otherwise big pharma with their resources who monitor what you are doing will beat you folks to a cure. Truth is that HBV can be cured in many ways indirecty by influencing the immune system. And researchers know it.
But in any case we hbv infected will.wait as long as we can for your drug. Hope is all we have.
Thank you for your valuable contribution to this community!
Would oral delivery of NAP with liposomial embedment be an efficient way of administration? It would go stright into the liver from the intestine, or liposomial technology is too expensive for the trials?
Would oral delivery of NAP with liposomial embedment be an efficient way of administration? It would go stright into the liver from the intestine, or liposomial technology is too expensive for the trials?
one cannot easily compare the safety of these approaches. during treatment, the side effects of the NAPs are less intense than ifn.
if an antibody of high titer occurs after ifn therapy, it means that most cccDNA has been lost, although the low hbsag level can be partially caused by suppression of expression, rather elimination of.cccDNA.
if an antibody of high titer occurs after ifn therapy, it means that most cccDNA has been lost, although the low hbsag level can be partially caused by suppression of expression, rather elimination of.cccDNA.
thank you for your clear explanation, so a slow clearance by long-term tenofovir which lowers hbsag and then peginterferon add-on for hbsag clearance and hbsab>250miu/ml by peginterferon are safer?
i guess this method has an almost comlete clearance of cccdna before hbsab are formed?
the effects of ifn on immune clearance of cccDNA are not affected by the NAPs. this immune clearance is obviously positively activated by the enforced removal of hbsag. but as long as there are any remnants of cccDNA a respreading can and will occur, hence the failure of long term svr. a permanent watchdog system needs to monitor and prevent that respreading.
high antibody levels will reduce the spreading to a local event, but cannot completely prevent localized reinfection, due to the slow kinetics of immune complexing. effective cd8 tcells need to be in standby to detect the slowly regrowing foci of reinfected cells and reengage with high local levels of ifn gamma production, to clear the liver ongoingly of most of these foci. thats how the long term cure very likely works.
high antibody levels will reduce the spreading to a local event, but cannot completely prevent localized reinfection, due to the slow kinetics of immune complexing. effective cd8 tcells need to be in standby to detect the slowly regrowing foci of reinfected cells and reengage with high local levels of ifn gamma production, to clear the liver ongoingly of most of these foci. thats how the long term cure very likely works.
Daily bid iv injections are possible without side effects. it just has not been tested yet in a trial, there is too much variation here to quickly test them all.
this mode might harness the entry blocking effect, since uptake from plasma is rapid and leads to irreversible accumulation inside the hepatocyte cytosol,
thus an almost continuous renewal of the drug level in the space outside the liver cell is needed to supply drug to the endocytosed vesicles interior where the blocking action on the second, critical entry step has to happen, whereby the envelope of hbv virions is fused to the vesicle membrane and the core is then injected into the cytosol.
the NAPs block the membrane fusion step, but are needed inside the vesicle fluid to be able to do so.
this mode might harness the entry blocking effect, since uptake from plasma is rapid and leads to irreversible accumulation inside the hepatocyte cytosol,
thus an almost continuous renewal of the drug level in the space outside the liver cell is needed to supply drug to the endocytosed vesicles interior where the blocking action on the second, critical entry step has to happen, whereby the envelope of hbv virions is fused to the vesicle membrane and the core is then injected into the cytosol.
the NAPs block the membrane fusion step, but are needed inside the vesicle fluid to be able to do so.
can there be any side effect or dangerous mutation by this combo?will cccdna be cleared by pegintf add-on?
Thank you for that wonderful piece of news and comment. It is amazing how NAPs can both block entry and release. As you say, it will be wonderful if both effects can be achieved with the one method of delivery.
I agree delivery of REP9AC by repeated infusions will be problematic. Hopefully an alternative can be found.
I agree delivery of REP9AC by repeated infusions will be problematic. Hopefully an alternative can be found.
a recently published study from allyson Jilbert in Australia using ducks infected with a higj starting dose of DHBV that tested three nucleic acid polymers, including rep9ac to block the initiation of the infection, combined with an in vitro study to further elicidate the mechanisms involved in the compounds antiviral activities revealed with great clarity that the prevailing mechanism was blocking of entry into hepatocytes.
two independent mechanisms of blocking entry were also revealed. The first involved binding to the cell surface and the second the uptake of the virions from internalizrd vesicles into the cytosol. It was a lucky streak, that one of the three NAPs failed in mechanism two due to inactivation of the compounds amphipatic structure in the increasingly acidic environment in these uptake vesicles.
Furthermore the results pointed to the need of frequent application and a minimum dosage to obtain the effect. This is of critical importance since the weekly dosing with intravenous infusions is unlikely to maintain the minimal extracellular concentration of the NAPs required for the entry blocking effects.
The high solubility of the NAPs in water will lead to rapid renal clearance. The uptake into liver cells is efficient and they are stored somehow in a cytosolic or nuclear compartment, allowing the blocking effect on surface antigen particle formation and release to persist.
But the entry blocking effects are likely to be lost in this mode of administration, which could lead to a critical loss in overall efficiency in cccDNA clearance. All this points to the formidable difficulties in designing trials with these NAPs that harvest the astounding mechanistic capabilities of these compounds to their fullest extent.
There are of course good reasons why the current application mode has been chosen. the intravenous application of many NAPs is not well tolerated, requiring long hours of infusion and patient compliance has to be ensured, which gets uncertain once you send them home for self administration.
On summary, there are powerful additional capabilities in these NAPs against HBV that have not yet been brought to full use. The Australien duck research has, as strange as this might sound, proofed beyond doubt that there exists an entry and reinfection blocking effect. It might be just what is needed to bring this therapy to its maximal efficiency.
two independent mechanisms of blocking entry were also revealed. The first involved binding to the cell surface and the second the uptake of the virions from internalizrd vesicles into the cytosol. It was a lucky streak, that one of the three NAPs failed in mechanism two due to inactivation of the compounds amphipatic structure in the increasingly acidic environment in these uptake vesicles.
Furthermore the results pointed to the need of frequent application and a minimum dosage to obtain the effect. This is of critical importance since the weekly dosing with intravenous infusions is unlikely to maintain the minimal extracellular concentration of the NAPs required for the entry blocking effects.
The high solubility of the NAPs in water will lead to rapid renal clearance. The uptake into liver cells is efficient and they are stored somehow in a cytosolic or nuclear compartment, allowing the blocking effect on surface antigen particle formation and release to persist.
But the entry blocking effects are likely to be lost in this mode of administration, which could lead to a critical loss in overall efficiency in cccDNA clearance. All this points to the formidable difficulties in designing trials with these NAPs that harvest the astounding mechanistic capabilities of these compounds to their fullest extent.
There are of course good reasons why the current application mode has been chosen. the intravenous application of many NAPs is not well tolerated, requiring long hours of infusion and patient compliance has to be ensured, which gets uncertain once you send them home for self administration.
On summary, there are powerful additional capabilities in these NAPs against HBV that have not yet been brought to full use. The Australien duck research has, as strange as this might sound, proofed beyond doubt that there exists an entry and reinfection blocking effect. It might be just what is needed to bring this therapy to its maximal efficiency.
Sounds like a pretty expensive treatment. Hopefully its efficacy will be at high levels to convince countries to go for it.
For those that are treatment naive or haven't done anything for a few years I'd keep an eye out for these trials.
For those that are treatment naive or haven't done anything for a few years I'd keep an eye out for these trials.
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