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ContraVir Reports New CRV431 Data Highlighting Synergistic Activity with CMX157
ContraVir Reports New CRV431 Data Highlighting Synergistic Activity with CMX157 Against Hepatitis B
EDISON, N.J., Sept. 12, 2016 /PRNewswire/ -- ContraVir Pharmaceuticals, Inc. (NASDAQ: CTRV), a biopharmaceutical company focused on the development and commercialization of targeted antiviral therapies, today announced that it has taken a major step forward in its pursuit of a potentially curative combination therapy for chronic hepatitis B (HBV). The Company presented new preclinical data profiling the robust anti-HBV activity of its potentially best-in-class cyclophilin inhibitor CRV431, including evidence of synergy with CMX157, ContraVir's highly potent prodrug of tenofovir, when the two drugs are used together. CMX157 is currently in Phase 2 clinical trials in Thailand.
The peer-reviewed findings were presented at a joint meeting sponsored by the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) called HBV Treatment Endpoints Workshop: From Discovery to Regulatory Approval, in a poster titled, "CRV431: An Optimized Cyclophilin Inhibitor with Multiple Anti-HBV Activities, High Selectivity Index, and Synergy with CMX157."
Human liver cells (AD38) treated in vitro with multiple combinations of CRV431 and CMX157 showed synergistic inhibition of HBV replication, as measured by a reduction in HBV DNA. These data are the first to demonstrate synergistic activity of these drugs against HBV, confirming ContraVir's belief that a combination of CRV431 and CMX157 may be more effective at killing the virus by potently targeting multiple stages of the viral life cycle.
"This study validates our approach and the significant opportunity we have to leverage our two HBV assets to create a uniquely powerful combination therapy and potential functional cure for hepatitis B," said James Sapirstein, CEO of ContraVir. "On its own, CRV431 demonstrates the potential to address multiple key endpoints thought to be essential for curing HBV. As we have seen with other successfully cured viral diseases, combination with a proven backbone therapy like tenofovir/CMX157 may unlock the full potential of these drugs and bring us closer to an HBV cure."
Data from the study also describe the in vitro anti-HBV activity of CRV431, as well as other clinically relevant findings. Importantly, CRV431 was shown to have the widest selective index of any known cyclophilin inhibitor, calculated by CC50/IC50 ratio. This optimized selective index may correlate with a best-in-class therapeutic index, and therefore, enhanced clinical utility against HBV. Other key findings for CRV431 monotherapy in vitro include:
Cyclophilin-independent inhibition of viral uptake by liver cells through its common route, the sodium taurocholate co-transporting polypeptide (NTCP) receptor;
Significantly greater potency compared to a related cyclophilin inhibitor, alisporovir, as measured by inhibition of intracellular HBV DNA in AD38 cells; and
Inhibition of production and/or secretion of HBV antigens HBeAg and HBsAg by infected or transfected Huh7 cells. Reduction or elimination of these antigens is considered to be a key requirement for a curative HBV regimen.
In vivo studies in rats and mice highlighted additional characteristics of CRV431 that enhance its profile. Dosing studies showed that CRV431 is suitable for oral dosing, demonstrating a significantly improved oral pharmacokinetic profile compared to cyclosporine A, the parent molecule from which CRV431 is derived. Additionally, in a mouse model of liver fibrosis, orally-administered CRV431 was shown to reduce the area of fibrosis in a dose dependent manner. This activity is independent of viral inhibition and instead may be a result of CRV431's interaction with host cyclophilins, which are implicated in multiple pro-fibrotic mechanisms.
Mr. Sapirstein concluded, "We are highly encouraged by these findings, which clearly support further development of CRV431 into IND-enabling studies and ultimately into clinical development in human combination studies with CMX157. We expect to continue preclinical development of CRV431, with a potential IND filing in the last quarter of 2017."
http://www.prnewswire.com/news-releases/contravir-reports-new-crv431-data-highlighting-synergistic-activity-with-cmx157-against-hepatitis-b-300325961.html
EDISON, N.J., Sept. 12, 2016 /PRNewswire/ -- ContraVir Pharmaceuticals, Inc. (NASDAQ: CTRV), a biopharmaceutical company focused on the development and commercialization of targeted antiviral therapies, today announced that it has taken a major step forward in its pursuit of a potentially curative combination therapy for chronic hepatitis B (HBV). The Company presented new preclinical data profiling the robust anti-HBV activity of its potentially best-in-class cyclophilin inhibitor CRV431, including evidence of synergy with CMX157, ContraVir's highly potent prodrug of tenofovir, when the two drugs are used together. CMX157 is currently in Phase 2 clinical trials in Thailand.
The peer-reviewed findings were presented at a joint meeting sponsored by the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) called HBV Treatment Endpoints Workshop: From Discovery to Regulatory Approval, in a poster titled, "CRV431: An Optimized Cyclophilin Inhibitor with Multiple Anti-HBV Activities, High Selectivity Index, and Synergy with CMX157."
Human liver cells (AD38) treated in vitro with multiple combinations of CRV431 and CMX157 showed synergistic inhibition of HBV replication, as measured by a reduction in HBV DNA. These data are the first to demonstrate synergistic activity of these drugs against HBV, confirming ContraVir's belief that a combination of CRV431 and CMX157 may be more effective at killing the virus by potently targeting multiple stages of the viral life cycle.
"This study validates our approach and the significant opportunity we have to leverage our two HBV assets to create a uniquely powerful combination therapy and potential functional cure for hepatitis B," said James Sapirstein, CEO of ContraVir. "On its own, CRV431 demonstrates the potential to address multiple key endpoints thought to be essential for curing HBV. As we have seen with other successfully cured viral diseases, combination with a proven backbone therapy like tenofovir/CMX157 may unlock the full potential of these drugs and bring us closer to an HBV cure."
Data from the study also describe the in vitro anti-HBV activity of CRV431, as well as other clinically relevant findings. Importantly, CRV431 was shown to have the widest selective index of any known cyclophilin inhibitor, calculated by CC50/IC50 ratio. This optimized selective index may correlate with a best-in-class therapeutic index, and therefore, enhanced clinical utility against HBV. Other key findings for CRV431 monotherapy in vitro include:
Cyclophilin-independent inhibition of viral uptake by liver cells through its common route, the sodium taurocholate co-transporting polypeptide (NTCP) receptor;
Significantly greater potency compared to a related cyclophilin inhibitor, alisporovir, as measured by inhibition of intracellular HBV DNA in AD38 cells; and
Inhibition of production and/or secretion of HBV antigens HBeAg and HBsAg by infected or transfected Huh7 cells. Reduction or elimination of these antigens is considered to be a key requirement for a curative HBV regimen.
In vivo studies in rats and mice highlighted additional characteristics of CRV431 that enhance its profile. Dosing studies showed that CRV431 is suitable for oral dosing, demonstrating a significantly improved oral pharmacokinetic profile compared to cyclosporine A, the parent molecule from which CRV431 is derived. Additionally, in a mouse model of liver fibrosis, orally-administered CRV431 was shown to reduce the area of fibrosis in a dose dependent manner. This activity is independent of viral inhibition and instead may be a result of CRV431's interaction with host cyclophilins, which are implicated in multiple pro-fibrotic mechanisms.
Mr. Sapirstein concluded, "We are highly encouraged by these findings, which clearly support further development of CRV431 into IND-enabling studies and ultimately into clinical development in human combination studies with CMX157. We expect to continue preclinical development of CRV431, with a potential IND filing in the last quarter of 2017."
http://www.prnewswire.com/news-releases/contravir-reports-new-crv431-data-highlighting-synergistic-activity-with-cmx157-against-hepatitis-b-300325961.html
Best Answer
First sentence should read "in e ag NEGATIVE patients the quantity is drastically reduced."
E antigen is synthesized in e ag pos and e ag neg patients. In e ag paints the Quantity is just drastically reduced.
at the same time an anti e antibody is present in both groups. What you can actually measure in the blood depends on which is in excess.
the immuncomplexes cannot be measured with commercial assays, they are invisible to doctor and patient.
The quantity of e immuncomplexes in e ag pos patients depends on the ..also invisible..quantity of anti e antibody present, which will be fully absorbed into the circulating immuncomplexes and therefore free antibodies cannot be found.
in research work it was determined that some e ag pos patients actually have a very high level of such invisible anti e antibodies, all bonded by an even higher level of e antigen. In these cases the level of the small e immuncomplexes is very high and they tend to accumulate in the kidney glomerula podocytes layer, causing immune mediated damage there.
at the same time an anti e antibody is present in both groups. What you can actually measure in the blood depends on which is in excess.
the immuncomplexes cannot be measured with commercial assays, they are invisible to doctor and patient.
The quantity of e immuncomplexes in e ag pos patients depends on the ..also invisible..quantity of anti e antibody present, which will be fully absorbed into the circulating immuncomplexes and therefore free antibodies cannot be found.
in research work it was determined that some e ag pos patients actually have a very high level of such invisible anti e antibodies, all bonded by an even higher level of e antigen. In these cases the level of the small e immuncomplexes is very high and they tend to accumulate in the kidney glomerula podocytes layer, causing immune mediated damage there.
thanks guys for that explanation, it clarifies a lot.
E antigen complexes you mean complexes made in hbe+ people ? I guess it's not dangerous short term when adult person recovers from acute hbv but more dangerous in chronic hbe+ ?
E antigen complexes you mean complexes made in hbe+ people ? I guess it's not dangerous short term when adult person recovers from acute hbv but more dangerous in chronic hbe+ ?
In this case immuncomplexes are simply virions or surface antigen spherical particles that have been covered or bonded to hbsag antibodies. This process makes virions noninfectious, but the pcr method will still detect the hbv dna inside.
Liverpatient is correct, these immuncomplexes can accumulate in the kidney glomerula and do harm there, since they can activate macrophages and complement. Normally, small amounts are no problem.
The complexes between the e antigen and it's antibody are more dangerous compared to the hbsag complexes. Due to their small size they can pass through the glomerular basement membrane and reach the sensitive podocytes layer where they can cause hbv related membrane nephropathy, a dangerous disease.
Liverpatient is correct, these immuncomplexes can accumulate in the kidney glomerula and do harm there, since they can activate macrophages and complement. Normally, small amounts are no problem.
The complexes between the e antigen and it's antibody are more dangerous compared to the hbsag complexes. Due to their small size they can pass through the glomerular basement membrane and reach the sensitive podocytes layer where they can cause hbv related membrane nephropathy, a dangerous disease.
I am sure free hbsag is not infectionous, but I guess it will trigger antibodies production in vaccinated/immuned person, correct ?
What are immunocomplexes ? Virions catched by antibodies, so not harmful ?
What are immunocomplexes ? Virions catched by antibodies, so not harmful ?
1 Comments
Yes, of course, it will trigger antibodies, that being the idea behind vaccination. Regarding immunocomplexes i can only write what i read on the internet; they are basically antigen-antibody complexes. They are formed when the immune system reacts to antigen invasion by binding with the antibodies. I think they are intermediary in the process of our immune system dealing with pathogen invasion. But these complexes can themselves cause illness when they are deposited in certain organs like the kidney.
This is a very complex subject for me, it is immunology, and i've only basic knowledge.
This is a very complex subject for me, it is immunology, and i've only basic knowledge.
If hbv dna can be detected in case of a neg hbsag and pos surface antibody, then this will reflect the fact that the virions are present in the blood as immuncomplexes.
The pcr test will detect hbv dna of free infectious virions just as well as that present in immuncomplexes.
The hbsag will not be detected in immuncomplexes.
the amount of surface antigen present in the coat of virions is tiny in comparison with the amount present in the independent surface antigen particle.
one must realize the dramatic difference in the sensitivity of dna testing and testing for the hbsag.
For example if you had a sample with 10000 virions per ml and no hbsag particle present, that sample would read as below the limit of detection for hbsag.
The pcr test will detect hbv dna of free infectious virions just as well as that present in immuncomplexes.
The hbsag will not be detected in immuncomplexes.
the amount of surface antigen present in the coat of virions is tiny in comparison with the amount present in the independent surface antigen particle.
one must realize the dramatic difference in the sensitivity of dna testing and testing for the hbsag.
For example if you had a sample with 10000 virions per ml and no hbsag particle present, that sample would read as below the limit of detection for hbsag.
From the other hand sometimes happends that someone with HBsAg negative has some very small hbv dna detected. Is that hbv dna fully functional virion or rather some dna parts catched by test ? It's impossible to have virion without HBsAg cover as I know, when there may be a lot of "free" HBsAg.
So only way to say that someone is not infectious is HBsAg negative, of course with hbv dna und ? Is HBsAg test more sensitive than hbv dna one ? I know that it's different kind of material measured so hard to answer that.
1 Comments
I've read that it is only the vrions that are infectious, the protien coat hbsag is not infectious. So if we were to inoculate someone with pure and real hbsag without any vrions that that person would not get hepatitis b.
The current antivirals allow the production and release of a small amount of virions that exit the liver cell and get absorbed and enter other liver cells.
Since the affinity of virions to hepatocyte cell membrane receptors is very high, this is a very efficient process.
The virions will enter the peripheral blood only if the capacity to produce exceeds the livers capacity to absorb them locally. This is the reason why undetectable viral load does not mean no de novo virus production.
Furthermore the sensitivity of the commercially available pcr tests is not high enough to detect the small amount of virions that nevertheless escape into the peripheral blood.
Since the affinity of virions to hepatocyte cell membrane receptors is very high, this is a very efficient process.
The virions will enter the peripheral blood only if the capacity to produce exceeds the livers capacity to absorb them locally. This is the reason why undetectable viral load does not mean no de novo virus production.
Furthermore the sensitivity of the commercially available pcr tests is not high enough to detect the small amount of virions that nevertheless escape into the peripheral blood.
No sure if I understand it well, so current antivirals are enough to do not allow new virions to enter the bloodstream and in some degree the the liver too but they are not good enough to stop reinfection of the neighbour cells ?
thanks studyforhope :)
So some of those cyclophilin inhibitors have such low that mentioned ratio that they would be toxic for the patient ?
What's your overall opinion about that combo therapy ?
So some of those cyclophilin inhibitors have such low that mentioned ratio that they would be toxic for the patient ?
What's your overall opinion about that combo therapy ?
I think it is too early to Comment on it. They are "planning" to do the IND filling with FDA late next year so no testing on humans for at least a year, if I'm reading this correctly. The good thing is there are biotech companies that are still looking for a cure.
can someone explain this: "CRV431 was shown to have the widest selective index of any known cyclophilin inhibitor, calculated by CC50/IC50 ratio"
?
?
1 Comments
It should mean the cytotoxic 50% concentration, where half the cells die, divided by the inhibitory 50% concentration, where half of the maximum inhibitory effect occurs. A high ratio means that the effective inhibitory concentration is far less than the toxic limit of the drug.
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If it is substantially powerful, then a combo with a tenofovir type drug could be very effective, since the current antivirals are simply not potent enough to limit some spreading of the infection. In combo the remaining virion production could become so low that reinfection is almost nil and the ongoing slow clearing mechanisms could then slowly reduce the infected cell burden.