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ContraVir
Summary
ContraVir’s CMX157 shows 99% drop in HBV viral load.
Nucleoside analogues, or NUCs, look to be the cure.
Risks involve if drugs work in bigger clinical trials; money raise needed soon.
ContraVir’s NUCs give hope to sufferers of HBV.
Sex, one of the most gratifying acts known to humans, can be lethal. A danger exists to thwart this - hepatitis B virus (HBV). ContraVir Pharmaceuticals (NASDAQ:CTRV) may have found a way to cure HBV, saving the world from a deadly disease while restoring the right to replicate life.
ContraVir recently stunned with evidence of its Phase II trial of HBV drug CMX157 against blockbuster Viread by Gilead Sciences (NASDAQ:GILD), originally an HIV remedy but approved for HBV; however liver and kidney damage result. CMX157 shows to be more potent at lower doses minus Viread's toxicity. Both drugs are nucleoside analogues, or NUCs, (biological antiviral agents used in HIV, HBV and herpes by interrupting DNA) but CMX157 works better without Viread's side effects.
An unprecedented 99% drop in the virus was seen using CMX157. In only two weeks, treated patients needed just a fraction of ContraVir's drug instead of an otherwise large amount of Viread to defeat viral activity (25 mg of CMX157 versus 300 mg of Viread). This figures largely into why CMX157 will prove to be a superior HBV cure.
Last June, I wrote about ContraVir and its work in HBV, highlighting how its revolutionary compounds could move fast to an HBV cure. Since then, the company has done exemplary work in a new drug to take its pioneering effort to another level - a creation of its own, CRV431, designed to block liver damage. When used with ContrVir's NUCs top-line therapy in HBV viral repression, both drugs could stop HBV and halt bodily injury.
In a study released last month, ContraVir reports work showing CMX157 and CRV431, combined, knock out HBV at its DNA source. Scientists reviewed statistics and deemed them valid. CMX157 alone stands at Phase II clinical trials with good results, and with CRV431, clinical value looks to be unrivaled. More importantly, the two drugs together have the ability to crush HBV at important stages of its life cycle (see box below).
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In my conversation with Dr. John Sullivan-Bolyai, ContraVir's Chief Medical Officer, he explained CMX157 "interferes with the first step of HBV", and studies reveal CRV431 furthers this process - preventing the virus from progressing.
Dr. Sullivan-Bolyai also said "more steps (in HBV) blocked, the bigger chance of success". Viread does indeed block one step, but CMX157 does better. It's in liver where ContraVir's drugs will have greatest efficacy since HBV conveys to this delicate organ its most damage. Next block: CRV431, under a different mechanism. This is combination therapy at its finest medical hour.
There are two HBV-associated proteins involved in progression of this deadly disease: HBeAg and HBsAg. Both appear on the surface of the virus where antibodies can't reach. Human immune response is activated to help rid the body of this affliction, but doesn't always work. Researchers remain confused about how to help.
Only ContraVir can inhibit these proteins, accomplishing a cure. Competitor Arbutus Biopharma (NASDAQ:ABUS) tried to reduce Hobart and HBsAg in blood, but could rid only one. ContraVir's potential cure is clearly better.
Research, although early, shows CRV431 given orally reduces liver damage and permits ContraVir to petition FDA for a drug application for approval of further studies - in humans, a monumental step. This will commence next year.
To CMX157's benefit, and this is crucial, the drug does not 'become' Viread inside the body, meaning CMX157 will not exhibit toxicity in liver or kidneys. A lower dose of ContraVir's drug works just as well as Viread, without bad side effects.
CMX157 is planned in 60 more patients under the same trial design as before, head-to-head against Viread. Management is confident of good safety results, and efficacy. CMX157, now combined with CRV431, are the only compounds set to cure HBV. Viread is a defeated drug; despite continued high sales, poisonous effects will eventually bring its downfall.
ContraVir is a pre-revenue firm. As of fiscal year-end 2016 (ended June 30), operating expenses stood at $20.8 million versus $13.9 million in the prior period, due, not surprising, to investment in research and development. Liquid assets were $7.4 million. There is no long-term debt.
As a new entrant into HBV and a micro-cap company, risks can be high. ContraVir's approach with two pipeline drugs must prove to work either alone or synergistically. CVR431 looks to be a strong contender in helping CMX157 to eradicate HBV although the former is preclinical. Whether both can be effective remains uncertain, although safety data is in place and early efficacy sound. ContraVir will soon need cash, causing potential dilution to existing shareholders.
Nearly 400 million people worldwide suffer from HBV. Something must be done. ContraVir forefronts this effort with drugs that can effect a cure, giving those suffering this disease hope for a better way of life. NUCs, a new way to rid HBV, represent ContraVir's devoted stand in drug development and will, I believe, triumph.
ContraVir’s CMX157 shows 99% drop in HBV viral load.
Nucleoside analogues, or NUCs, look to be the cure.
Risks involve if drugs work in bigger clinical trials; money raise needed soon.
ContraVir’s NUCs give hope to sufferers of HBV.
Sex, one of the most gratifying acts known to humans, can be lethal. A danger exists to thwart this - hepatitis B virus (HBV). ContraVir Pharmaceuticals (NASDAQ:CTRV) may have found a way to cure HBV, saving the world from a deadly disease while restoring the right to replicate life.
ContraVir recently stunned with evidence of its Phase II trial of HBV drug CMX157 against blockbuster Viread by Gilead Sciences (NASDAQ:GILD), originally an HIV remedy but approved for HBV; however liver and kidney damage result. CMX157 shows to be more potent at lower doses minus Viread's toxicity. Both drugs are nucleoside analogues, or NUCs, (biological antiviral agents used in HIV, HBV and herpes by interrupting DNA) but CMX157 works better without Viread's side effects.
An unprecedented 99% drop in the virus was seen using CMX157. In only two weeks, treated patients needed just a fraction of ContraVir's drug instead of an otherwise large amount of Viread to defeat viral activity (25 mg of CMX157 versus 300 mg of Viread). This figures largely into why CMX157 will prove to be a superior HBV cure.
Last June, I wrote about ContraVir and its work in HBV, highlighting how its revolutionary compounds could move fast to an HBV cure. Since then, the company has done exemplary work in a new drug to take its pioneering effort to another level - a creation of its own, CRV431, designed to block liver damage. When used with ContrVir's NUCs top-line therapy in HBV viral repression, both drugs could stop HBV and halt bodily injury.
In a study released last month, ContraVir reports work showing CMX157 and CRV431, combined, knock out HBV at its DNA source. Scientists reviewed statistics and deemed them valid. CMX157 alone stands at Phase II clinical trials with good results, and with CRV431, clinical value looks to be unrivaled. More importantly, the two drugs together have the ability to crush HBV at important stages of its life cycle (see box below).
Advertisement
In my conversation with Dr. John Sullivan-Bolyai, ContraVir's Chief Medical Officer, he explained CMX157 "interferes with the first step of HBV", and studies reveal CRV431 furthers this process - preventing the virus from progressing.
Dr. Sullivan-Bolyai also said "more steps (in HBV) blocked, the bigger chance of success". Viread does indeed block one step, but CMX157 does better. It's in liver where ContraVir's drugs will have greatest efficacy since HBV conveys to this delicate organ its most damage. Next block: CRV431, under a different mechanism. This is combination therapy at its finest medical hour.
There are two HBV-associated proteins involved in progression of this deadly disease: HBeAg and HBsAg. Both appear on the surface of the virus where antibodies can't reach. Human immune response is activated to help rid the body of this affliction, but doesn't always work. Researchers remain confused about how to help.
Only ContraVir can inhibit these proteins, accomplishing a cure. Competitor Arbutus Biopharma (NASDAQ:ABUS) tried to reduce Hobart and HBsAg in blood, but could rid only one. ContraVir's potential cure is clearly better.
Research, although early, shows CRV431 given orally reduces liver damage and permits ContraVir to petition FDA for a drug application for approval of further studies - in humans, a monumental step. This will commence next year.
To CMX157's benefit, and this is crucial, the drug does not 'become' Viread inside the body, meaning CMX157 will not exhibit toxicity in liver or kidneys. A lower dose of ContraVir's drug works just as well as Viread, without bad side effects.
CMX157 is planned in 60 more patients under the same trial design as before, head-to-head against Viread. Management is confident of good safety results, and efficacy. CMX157, now combined with CRV431, are the only compounds set to cure HBV. Viread is a defeated drug; despite continued high sales, poisonous effects will eventually bring its downfall.
ContraVir is a pre-revenue firm. As of fiscal year-end 2016 (ended June 30), operating expenses stood at $20.8 million versus $13.9 million in the prior period, due, not surprising, to investment in research and development. Liquid assets were $7.4 million. There is no long-term debt.
As a new entrant into HBV and a micro-cap company, risks can be high. ContraVir's approach with two pipeline drugs must prove to work either alone or synergistically. CVR431 looks to be a strong contender in helping CMX157 to eradicate HBV although the former is preclinical. Whether both can be effective remains uncertain, although safety data is in place and early efficacy sound. ContraVir will soon need cash, causing potential dilution to existing shareholders.
Nearly 400 million people worldwide suffer from HBV. Something must be done. ContraVir forefronts this effort with drugs that can effect a cure, giving those suffering this disease hope for a better way of life. NUCs, a new way to rid HBV, represent ContraVir's devoted stand in drug development and will, I believe, triumph.
While this article has been written with some silly technical remarks, the prospect of cmx157 is actually quite fascinating.
As Stephen mentioned correctly, it has to be compared with TAF not TDF.
But if one undergoes the difficult task to compare it with TAF based on the available info from meetings and publications some critical differences appear.
The fact that cmx157 has a palmitate lipid tail seems to cause a substantially higher first pass liver extraction and accumulation. 87% are extracted compared with about 60% in the case of TAF.
the intracellular conversion to TFV diphosphate, the actual final working molecule to inhibit the hbv polymerase, seems equal or better in the liver cells.
The general advantages of a low systemic and in particular renal exposure to TFV are present in both drugs, the dose required is very similar.
But a key advantage of cmx157 might be that the overall body burden of extrahepatic drug and the uptake in tissues other than the liver, partially due to the lipid nature, partially due to the superior first pass liver extraction could be substantially less with cmx157 compared toTAF.
Thus the pesky problem of TAF entering organs other than the liver exposing them to unnecessary intracellular TFV might be a much lesser issue with cmx157.
As Stephen mentioned correctly, it has to be compared with TAF not TDF.
But if one undergoes the difficult task to compare it with TAF based on the available info from meetings and publications some critical differences appear.
The fact that cmx157 has a palmitate lipid tail seems to cause a substantially higher first pass liver extraction and accumulation. 87% are extracted compared with about 60% in the case of TAF.
the intracellular conversion to TFV diphosphate, the actual final working molecule to inhibit the hbv polymerase, seems equal or better in the liver cells.
The general advantages of a low systemic and in particular renal exposure to TFV are present in both drugs, the dose required is very similar.
But a key advantage of cmx157 might be that the overall body burden of extrahepatic drug and the uptake in tissues other than the liver, partially due to the lipid nature, partially due to the superior first pass liver extraction could be substantially less with cmx157 compared toTAF.
Thus the pesky problem of TAF entering organs other than the liver exposing them to unnecessary intracellular TFV might be a much lesser issue with cmx157.
Good news, 99% knockdown of viral load in just two weeks treatment at a dose of only 25mg daily is really amazing. We could almost say only a single tdf drug would give this much drop in hbv dna. Imagine how the results would be with increased dose as in their upcoming clinical trial? I really hope this drug also targets the hbv dna reserve lurking inside the liver itself, that would do the miracle of eventual cure.
6 Comments
The integrated hbv dna cannot be targeted by this drug, since it inhibits the hbv polymerase blocking replication of hbv. The chromosomally integrated hbv fragments are transcribed like any human gene and produce mainly hbsag.
Thanks for the reply; just curious: does this drug and other similar drugs enter the hepatocyte nuclei where the cccDNA hides? And how about designing a drug that would somehow identify only infected hepatocytes and kill them or make them kill themselves; something similar to birinapant; how challenging is it to design such a drug?
TFV DIPHOSPHATE the intracellular active compound, will go to the nuclear space but has no meaningful function there. It attaches to the hbv polymerase while it synthesizes hbv dna, incorporates itself and breaks off the chain at this point, since it does not supply the hydroxyl group to bond the next nucleotide, aborting synthesis.
At this point birinapant is the only drug known to selectively target infected and likely also just integrated liver cells inducing apoptosis.
At this point birinapant is the only drug known to selectively target infected and likely also just integrated liver cells inducing apoptosis.
Hi studyforhope, when i think about cure for chronic hepatitis b i always wonder why the pharmaceutical companies did not target the cccDNA earlier. It seems to me the knowledge of the role of cccDNA in maintaining and reactivating chronic hbv have been here for at least a decade. Despite this the companies were mainly focussing on the dna polymerase, which has not a durable suppression or "cure" after end of treatment; a treatment that almost always goes life long.
I also think the companies are only now beginning to try and find a cure for chronic hbv, a desease that mostly affects the poorer third world. In comparison hepatitis c is more common in the developed world, as it is mainly transmitted through drug abuse; hence there was big effort to find a cure for this disease which finally bare fruit in 2014.
I also think the companies are only now beginning to try and find a cure for chronic hbv, a desease that mostly affects the poorer third world. In comparison hepatitis c is more common in the developed world, as it is mainly transmitted through drug abuse; hence there was big effort to find a cure for this disease which finally bare fruit in 2014.
CccDNA exists embedded in a mini chromosome in the nucleus and there is no easy way to target it. Under high interferon gamma and TNFalpha stimulation liver cells can activate intracellular enzyme systems capable of lysing cccDNA, but the details are not well understood.
HCV was much easide to eliminate since several independent macromolecular targets exists against which inhibitory drugs can be found which will work in full synergism.
also HCV is a dynamic Flux system with no static genetic storage system.
If you interrupt the dynamic flow long enough and complete enough, it will disappear.
In hbv treatment has focused on the hbv polymerase because it is the only clearly defined molecular machine that can be directly inhibited and the serendipity of the vulnerability of the viral polymerase to faulty nucleotides that the human polymerases reject due to their high stringency.
Furthermore the fact that the hiv enzyme is almost exactly the same as the hbv polymerase made the hiv anti polymerase drugs directly usable for hbv.
HCV was much easide to eliminate since several independent macromolecular targets exists against which inhibitory drugs can be found which will work in full synergism.
also HCV is a dynamic Flux system with no static genetic storage system.
If you interrupt the dynamic flow long enough and complete enough, it will disappear.
In hbv treatment has focused on the hbv polymerase because it is the only clearly defined molecular machine that can be directly inhibited and the serendipity of the vulnerability of the viral polymerase to faulty nucleotides that the human polymerases reject due to their high stringency.
Furthermore the fact that the hiv enzyme is almost exactly the same as the hbv polymerase made the hiv anti polymerase drugs directly usable for hbv.
Thanks a lot for the useful info
CMX157 is a prodrug of Tenofovir, and it should be compared with TAF, rather than TDF.
CRX431 is a cyclophilin inhibitor. a class of drugs that has been around, yet to be proven successful, on its own.
CRX431 is a cyclophilin inhibitor. a class of drugs that has been around, yet to be proven successful, on its own.
2 Comments
I'm a bit perplexed as to why they're plowing ahead with CMX157, when TAF has already been approved and TDF was largely good enough to begin with. Where is the money in this?
Because TAF will be expensive.
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