Aa
Arrowhead Research ARC520
Bad day for Arrowhead Research. Its stock lost some 50% in value. Bad days for chronic HEP B sufferers hoping for good news.
http://www.thestreet.com/story/12906965/1/arrowhead-sinks-on-disappointing-hepatitis-b-drug-data.html?puc=yahoo&cm_ven=YAHOO
http://www.thestreet.com/story/12906965/1/arrowhead-sinks-on-disappointing-hepatitis-b-drug-data.html?puc=yahoo&cm_ven=YAHOO
Best Answer
Regarding HCC risk please read my comments in the other post covering the various forms of hbvbdna integrations in the genome of infected hepatocytes.
Yes a reduced hbsag means normally a reduced cccDNA burden and consequently a reduction in HCC risk.
An svr after replicor will mean a dramatically reduced cccDNA, with a huge reduction in hbsag and virion synthesis due to a small amount of template.
Using tenofovir to reduce circulating virions does not substantially reduce the cccDNA burden and all the consequences that come with it, the low or und dna has quite a different meaning. Furthermore you have to live with the side effect of gamma poylymerase inhibition and the mild but insidious consequences of a more slowly renewing mitochondrial pool with reduced mass and performance.
An svr after replicor will mean a dramatically reduced cccDNA, with a huge reduction in hbsag and virion synthesis due to a small amount of template.
Using tenofovir to reduce circulating virions does not substantially reduce the cccDNA burden and all the consequences that come with it, the low or und dna has quite a different meaning. Furthermore you have to live with the side effect of gamma poylymerase inhibition and the mild but insidious consequences of a more slowly renewing mitochondrial pool with reduced mass and performance.
While hbsag itself does not have a role in hcc development isn't it used as surrogate marker for the integration events you mentioned before so less surface antigen means less chance for hcc compared to be hbv DNA undetectable with tenofovir. Otherwise what is the difference between replicor and tenofovir if ones residual hcc chance remains same? Does being hbsag and DNA neg give benefits over being just DNA negative in terms of hcc?
If the kd of irna can be upped to 3 logs, then patients with a lower starting hbsag might obtain clinical benefit from it in a combo with immuneenhancers.
Replicors hbsag reduction is 5 logs and still needs powerful immune therapy to lead to a stable treatment free hbsag loss.
From that you can estimate what iRNA will be able to achieve in that setting.
The current results do not point to such a dramatic improvement, even with clearly higher doses. I wish it were different.
From several trials it appears that keeping the antiviral on board leads unexpectedly to a lowering of hbsag seroconversion rates.
HCC is mainly caused by a combination of integration events that disturb the genome and endless replication in the genotoxic pro oxidative milieu of chronic inflammation. While the x gene is frequently implicated in carcinogenicity and the pres2 segment, the hbsag itself seems to play a lesser role in that context.
Replicors hbsag reduction is 5 logs and still needs powerful immune therapy to lead to a stable treatment free hbsag loss.
From that you can estimate what iRNA will be able to achieve in that setting.
The current results do not point to such a dramatic improvement, even with clearly higher doses. I wish it were different.
From several trials it appears that keeping the antiviral on board leads unexpectedly to a lowering of hbsag seroconversion rates.
HCC is mainly caused by a combination of integration events that disturb the genome and endless replication in the genotoxic pro oxidative milieu of chronic inflammation. While the x gene is frequently implicated in carcinogenicity and the pres2 segment, the hbsag itself seems to play a lesser role in that context.
While current in development RNAi therapies may not cure mono, do you believe it has a role in combo therapy (at 1+log knockdown)? Could it along with Tenofovir set the table for easier/ higher rate PEG clearance or longer term clearance w/o Peg?
Also isn't their also a hope that significant KD of Hbsag may limit the development if HCC further than just HBV DNA undetected?
Also isn't their also a hope that significant KD of Hbsag may limit the development if HCC further than just HBV DNA undetected?
0,3log but even 2log is cure of nothing, just to clear most hbv cases you need 4logs decline then you have to see if peginterferon add on make stable immune control since hbsag clearance is not enough when cccdna is inside cells
i dont know which is the most ridiculous results between arc520 and myrcludex, for sure treatments and cures are not here
i dont know which is the most ridiculous results between arc520 and myrcludex, for sure treatments and cures are not here
I've seen multiple notices of class-action shareholder lawsuits. This misstep will prove to be costly for Arrowhead. But I still hope for good news.
They didn't stop, they only had data for 1 and 2 mg/ kg so that is what they are presenting. They are currently in middle of 3 mg and will likely move to 4mg by year end. They are also setting up for sequential phase 2b trials next year with the 2 and 3 mg (hopefully 4mg as well)
The stock loss was higher expectations and a perception of management deception, which I agree occurred to some degree.
The stock loss was higher expectations and a perception of management deception, which I agree occurred to some degree.
then the question comes, how comes they allowed to lose 30% in shares and not duplicate the results in chimps, and only stopped at 0.3 log reduction ?
These results are not as bad as some would believe, in fact they are the same as the chimp. The problem is the study design was not sequential like the chimp study. This human study was only a single dose of 1 or 2 mg/kg, while the chimp was given 2mg and then 3mg 15 days later which achieved the .8 log knockdown. At 15 days after the 2mg/kg the chip was at .3 log the same as the human study. No sure what they didn't replicate the chimp study with humans.
In addition phase 1 in healthy shows 4mg/kg with no sides, I would think a sequential 3mg 4mg treatment like the chimp with produce the desired 1+log knockdown. Conclusion is ARC-520 is not dead by any means and the drug does show knockdown, just need to get the dosing correct
In addition phase 1 in healthy shows 4mg/kg with no sides, I would think a sequential 3mg 4mg treatment like the chimp with produce the desired 1+log knockdown. Conclusion is ARC-520 is not dead by any means and the drug does show knockdown, just need to get the dosing correct
stef,
what is meant by "sequential nucs peg"
you mentioned that genotype is not relevant in this case?
what is meant by "sequential nucs peg"
you mentioned that genotype is not relevant in this case?
We dont even know if it works in real humans....
wrong words, i meant if it is capable of clearaning hbsag definitively and stable by peg add on
wrong words, i meant if it is capable of clearaning hbsag definitively and stable by peg add on
They must get same results as replicor with hbsag und and hbsab detectable to stabilize svr with pegintf add on.they are too far 0.3log is nothing
We dont even know if this will work on real humans.....to me it is all money wasted for investors
the only things working to cure hbv are in order of svr
sequential nucs peg aorund 90-91%
replicor plus peg/zadaxin but not even reaching same svr percentage as sequential
and keeping in mind hbsag undetectable is no svr, i think they are going nowhere
the only things working to cure hbv are in order of svr
sequential nucs peg aorund 90-91%
replicor plus peg/zadaxin but not even reaching same svr percentage as sequential
and keeping in mind hbsag undetectable is no svr, i think they are going nowhere
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.
i tried to blog with Mr Dirk Hausecker the iRNA analyst about that topic, but got arrogant and naive responses only. .
the replicor trial should have opened the eyes of the world towards seeing, how powerful or limited the hbsag reduction is and how complete it has to be to have an effect.
It seems that the iRNA mechanisms, with the limitation to get enough drug into the nucleus of the hepatocytes, are not powerful enough to shut down the messenger RNA production complete enough.
What would people say if someone came along with a drug that affords a stunning 90% reduction of HBV DNA, obviously "paralyzing? the virions production.
Oh yes, that will probably lead to a functional cure...??
FACT:
5 logs or more of replication inhibition are not enough to wipe out the presence of HBV In the liver.
the HBV system is extremely powerful and has gigantic reserves. It overproduces its virions and antigens more than 100000 to million-fold over what it needs to stay permanently in the liver.