Irbesartan, might be 60 times more powerful to supress HBV entry than ezetimibe

[studyforhope]

A recent paper studied the effect of most FDA approved drugs on the inhibition of NTCP, the now known entry receptor for HBV. Ezetimibe was found to have a 50%inhibition conc of  25micromolar, while irbesartan, a commonly used angiotensin inhibitor to reduce blood pressure, was found to inhibit at 11.9 micromolar. Both compounds have similar MW, but irbesartan is given at up to 300mg per day, while exetimibe is dosed at 10mg. Thus the combination of 30fold higher approved dose and the double micromolar inhibition potency makes, in theory, irbesartan 60 fold more potent to inhibit Hbv entry. Of course, binding of these drugs to plasma proteins could cause substsntial differences in the available concentration on the hepatocyte membrane receptor, and the pharmacokinetics could further influence the in vivo efficscy. Tests in chimeric mice are urgently needed to determine the in vivo efficacy of this common, mostly beneficial medication on HBV reinfection inhibition.

[stef2011]

we need some members to test it for 1 year at least but that is not easy and test it while on pegintf.same thing ezetimibe and simvastatin

i am worried about another study that finds irbesartan inactivating cd-8 lymphos, so it is very complex

[dreft]

Makes sense irbesartan helps against HBV. It is an ARB, and angiotensin 2 was found increased in hbv patients: http://www.ncbi.nlm.nih.gov/pubmed/1748416 ...too bad that members who already tried did not saw it working, maybe the concentration was not enough for the liver, who knows

But, maybe more important, irbesartan is a VDR agonist, meaning in the right concentration is able to activate the VDR by displacing all that stuff that blocks VDR (25d, bacteria, viruses, etc)...once the VDR is active, the cells can cure themselves

[stef2011]

i tried it with etv plus tdf plus ezetimibe plus ibersatan, it simply did not work, there has been no blocking on hepatocytes hbv receptors at least not enough to rise bile acids (which are a clear sign of potent hinibition of hbv receptors)

[newtr]

can this  irbesartan be taken with nucs, can we expect hbsag reduction with high base level, its possibility with interferon, its optimized doseing and possible side effects if any idea? may anybody summarise  this whole disscussion.

[Ashi2010]

I receive this information from hepatara site that they have clear the 1a study and myrcludex b is in Phase II clinical trials. so is any one has idea about outcome of phase I clinical study results


Product: Myrcludex B, a peptide inhibiting the penetration of virus into the liver cells.

Therapeutic focus: Chronic viral hepatitis B (HBV); chronic hepatitis D (HDV). In the future, indications for use can be expanded: viral encephalitis and other forms of hepatitis, HIV.

Status: Phase II clinical trials.

Partner: MYR, GmbH (Germany)

Description: Myrcludex B is a novel drug candidate, being a linear 47-amino acid chemically synthesized peptide. So far it is the single representative of a novel class of anti-HBV molecules, called entry inhibitors. The postulated mechanism of antiviral action is the highly specific and highly stable binding to HBV receptors on the surface of hepatocytes, which misdirects HBV to an unproductive pathway and thereby prevents an infection of the cell. This unique mechanism of action offers the possibility to address the two most important medical needs, namely long-term HBV eradication as well as antiviral activity against hepatitis D virus (HDV).

Despite the availability of appropriate drugs, there is still a number of unresolved medical problems concerning the treatment of hepatitis B, namely, how to achieve long-term eradication of the virus and how to prevent drug resistance. In view of the above it is essential to develop new therapies aimed at the still untouched stages of viral replication, such as the stage of the virus into hepatocytes.
In addition a similar mechanism of action provides the opportunity to prevent the development of delta hepatitis (hepatitis D).

In a series of preclinical studies Myrcludex B showed good safety and the ability to completely block the development of infection HBV. Phase Ia clinical trial showed the safety and good toleration of Myrcludex B in humans.

[studyforhope]

if you have a regular meal with some fat or oil or egg in it, then the bile will flow. This will secrete between 5 to 10 grams of bile acids into your jejunum, which will be reabsorbed almost completely in your ileum in one to two hours.
Blood and extracellular space will hold only about 0.5grams at 50micromolar of bile acids. All that means, that if NTCP is blocked efficiently, the bile acids will rise strongly after 2 hours post cenam. If you take the drugs at the same time as the food,  a clear increase in bile acids should occur if the test is done 2 or 3 hours later. It should increase to 20 or even 50 micromolar, if an effective blockage of NTCP is present.

If you stop the drugs now, it might be advisable to take them also one day before the test.

I would like to mention, that there is a second paper on finding substances that can block NTCP, where a database of a million compounds was screened and a few were found that were more efficient than irbesartan. But the efficiency was only moderately higher and those were esoteric chemicals far from any clinical or medical use. Thus the hope, that small moleule drugs can be found that will effectively block HBV entry and that could replace myrcludex seem to have little chance at this time.

[stef2011]

can i stop both drugs and take them again only the day for the test of bile acids 2 hrs after?

[studyforhope]

yes, this is bad news, if the bile acids are not up, then the ntcp is not blocked. It might well be that the blood concentration of irbesartan falls to rapidly, then the blockage will disappear. Unfortunately, unless the blockage is consistent all 24 hours, it will allow reinfection. You could measure the bile acids 2 hours after drug intake, but even if it will increase it does not matter unless the effect lasts. The blockage of ntcp by myrcludex works so efficiently, that the bile acids are between 50 and 100 micromolar all the time, sometimes even higher after meals.

A combo with ifn is not going to increase the entry blocking effect, except of course that the further drop in produced virions will reduce the amount of visions seeking entry, but those will still be plenty enough. IFN will have another effect, however also limited, it will lead to destruction of a good percentage of virions whose core has entered the cytoplasm and prevent establishment of cccDNA in these cells, reducing the overall infection rate. But again, it will not be enough.

[stef2011]

bad news from bile acids test:
25 mar 2013 zetia 50mg bile acids 1.2 micromol/l
11 apr 2013 zetia 50m plus irbersatan 300mg bile acids 1.0 micromol/l

normal range less than 6 micromol/l.drugs taken about 20hrs before test

i havent tested bile acids 2hrs after taking the pills, do you think it worths testing since it seems no ntcp block has happened?does it worth to try these drugs with peginterferon from other members to see if any boosting effect happens under that combo?

irbersatan is starting to be too heavy, extreme tireness especially at wake up has become not tollerable now, i can t get up before 10-11am

[veteranB]

people, we should be more focused where do they apply all this to real life cases.

For those of you that are doing research all this is very interesting sit and discuss things.. But we actually live with this nightmare. I am more interested in access to clinics where they apply all this. I will be the mice if it has to be.

The way I see things if things are known to work and not kill right away lets try it. That is what they should be doing.

[studyforhope]

As long as you have your own liver cells regenerating themselves  there is no need or use for stem cells. Once the majority of these will have died and somehow their capacity to regenerate is exhausted , this type of treatment will make more sense, like in ESLD.
But the problem remains, that in the severely fibrotic and cirrhotic liver, there is also so much collagen, that the establishment of a meaningful liver micro-architecture is exceedingly difficult.

[ronny12]

Can you please share your opinion regarding stem cell treatment for chronic liver diseases? I have read a lot regarding this type of treatment and a lot emphasize that it will become the mainstream in the near future for liver disease mainly for ESLD which is curable only by liver transplant. Thank you in advance.

[Ashi2010]

April 08, 2013 12:05 PM Eastern Daylight Time
Transgene to Present New Data on TG1050 and TG4040 to Treat Chronic Hepatitis B and C at EASL 2013

STRASBOURG, France--(BUSINESS WIRE)--Regulatory News:

“TG4040 has recently completed successful phase 2 trial in patients with CHC”
Transgene SA (Paris:TNG) (Euronext Paris: FR0005175080), a biopharmaceutical company that develops targeted immunotherapy products to treat major unmet medical needs in cancer and infectious diseases, today announced that favourable pre-clinical and clinical data on two Transgene products – TG1050 and TG4040 to treat chronic hepatitis B (CHB) and chronic hepatitis C (CHC), respectively – will be presented in oral presentations at this year’s European Association for the Study of the Liver (EASL) Conference (Amsterdam, Netherlands, April 24-28, 2013). The full abstracts are available at http://www.easl.eu.

“We are delighted to have the opportunity to present data at EASL, Europe’s largest liver conference. TG1050 is a novel immunotherapeutic to treat CHB that has shown very promising preclinical results and will soon be moving to early clinical development” stated Philippe Archinard, Chairman and CEO of Transgene. He added: “In addition to the preclinical proof-of-concept data published in September 20121, we have today released supplementary information, obtained in pre-clinical naïve and HBV murine models, on the immunogenicity of TG1050 and its capacity to induce long-term T cell response. This evidence further underlines our belief in the product’s potential to become an important new first in class immunotherapeutic to treat CHB, an area of unmet medical need.”

[studyforhope]

If a patient becomes und on ifn mono then he should stay on ifn for at least a year, even if no drop in hbsag.
The reaction to ifn in terms of side effects is quite variable, many suffer from intense fatigue,  feel like having a constant flu or become depressed, aggressive, even loose their jobs or marriages. If the sides are tolerable, then it should be given a chance to at least switch to a state of better immune control, even if hbsag loss cannot be achieved, which is currently the case in the majority of patients.
If there is any sign of autoimmune disorders, then the use of ifn can exercabate these, so there is a need to consider many variables.

[stef2011]

i also like to menthion that on lampertico study with intf use for about 2 years there was one patient with no response for the first 48weeks who experienced  the best response at 72 or 96weeks with the highest hbsab titer of the all patients in the trials....this is to say that sometimes you can t predict everything

[andrey19]

«so that unnecessary harmful ifn treatment can be early terminated»
Why is interferon treatment harmfull? How bad is it harmfull? I think many people on interferon mono experience situation when there is no strong decline in hbs but DNA becomes undetectable. Statistics say if no decline in Hbs than stop interferon and switch to Nucs. The nucs goal is to make DNA undetectable. The question is – If hbv dna is already undetectable during the treatment by interferon and If interferon high cost is not an issue, what are the reasons for switching to NUCs rather then keeping interferon for 96 weeks? Are there any advantages of staying undetectable with interferon even no hbs decline (in short term, we all hope for hbs decline in long term post treatment) comparing to staying undetectable on NUCs?

[studyforhope]

If you can measure the bile acids under irbesartan treatment, it would be useful to measure them before taking the pill and then again two hours after,
If there is no increase after, then it means that the ntcp blockage is simply too  weak in vivo even at max blood concentrations. If the bile acids are not elevated before the drug intake, then it would mean that the effect is not lasting long enough since the blood levels fall too quickly. Ideally they need to be above norm at both time points to hope for realistic HBV entry inhibition.

[studyforhope]

The practice guidelines draw somewhat arbitrary lines to allow the practitioner to follow a programmed path and reduce responsibility in case there is a later bad development. I think that at Fibroscan or in certain cases even the addition of a biopsy helps to see the true status of the liver. The quant hbsag will help to decide whom to recommend for the ifn add on therapy and even more importantly to assess the response and likelihood early , so that unnecessary harmful ifn treatment can be early terminated.

[wishful01]

"..the majority of virions released at a low production like under antivirals is locally absorbed onto hepatocytes and never reaches the circulation. Thats why the UND viral load is so misleading."

So do you agree with AASLD's practice guidelines for treatment criteria of hbe- Hep B? And the difference between chronic hbv and inactive hbv? (Or would you add/emphasize something else (tests like fibroscan, or even invasive ones like biopsy) in addition to the usual ALT, ultrasound and HBVDNA?).

Thanks

[stef2011]

sorry typing error
10 oct 2012 hbsag 4396iu/ml

used architect with automated quant kit for both tests, no sample diluition

[stef2011]

it is interesting to note that between 10 oct 2012 and 16 oct 2012 i used daily suppository of imiquimod 12.5mg and had tests among these close dates (but just had results on hbsag 16 oct now):

10 oct 2012 hbsag 43696iu/ml alt 44 creatinine 0.7, started imiquimod daily suppository for 9days
16 oct 2012 hbsag 3681iu/ml hbvdna 31iu/ml alt 42 creatinine 1.2
21 oct 2012, stopped using daily suppository and switched to weekly suppository 25mg which showed no results until i stopped definitively on early jan 2013 and started ezetimibe

if imiquimod is to be ever tried by others or me daily suppository maybe the best schedule although inflammation is high from creatinine increase, fever was not high just 37.5°

[stef2011]

i have been using about same time daily (just forgot totally ezetimibe one day)

i ll use iber every day exactly same time or if necessary even 30min in advance and recheck bile acids few hours after taking it

imiquimod did make inflammation fibroscan increased from 4.5kpa in october to 4.9kpa instead keeping constant decline as previously

i ll also keep etv+tdf, the local prescribing liver specialist prefers the combo too he wants to stay on the very safe side

thank you so much for your help

[studyforhope]

So it looks like the ezetimibe was not realistically working on entry inhibition,
or more precisely to block the NTCP in a reliable 24 hours fashion. Your biliary acids were very low, which shows that there is no blockage of the HBV receptor. You have to consider the pharmacokinetics of the ezetimibe and possibly also the irbesartan. Blockage is only effective if it is a 24 hour continuous affair. If you leave the door open for the rats just one hour a day, your house will be filled with them.

to see if the irbesartan does a better job in vivo, you can simply measure your bile acids now after you take it. Considering the intense dynamic of the bile acid re-circulation ( 15 grams are recycled about 10 times per day!) any effect of blockage will be rapidly noticeable as an increase of circulating bile acids. That level might also change dynamically in response to various level of blockage of NTCP as the drug levels in blood will vary due to the drugs pharmacodynamic behaviour.
In other words, they might increase an hour after irbesartan, only to decrease to baseline  3 hours later. This needs to be considered in order not to interpret the values naively.

Under Myrcludex full blocking dose, the bile acids go up quite dramatically but  its effect needs to be maintained 24 hours also, since obviously partial time  entry inhibition is ineffective. Virions can wait in line until the doors open again, even if only shortly within 24 hours.

[studyforhope]

Regarding blip of DNA positivity after imiquimod:
If there was a temporary increase in liver inflammation, it could reflect the temporary increased lysis of hepatocytes. The intracellular virions are by far more abundant than the ones released into the circulation and also, very importantly, the majority of virions released at a low production like under antivirals is locally absorbed onto hepatocytes and never reaches the circulation. Thats why the UND viral load is so misleading.
But you could have a temp release of intracellular virions by lysis, causing the blip.

The Pisa researchers are incorrect in saying that ENT plus TDF is less potent to suppress replication than TDF alone.
While it is fundamentally true, that the lack of synergism or even very effective additiveness among antivirals is caused by competing for access to the polymerase binding site like several cooks in a tiny kitchen, there is a slight measurable degree of additivity between TDF and ENT, when you have a clean and clear model situation to address that question.
I know of a research situation, where in a particular patient a successive exchange between TDF, then ENT, then TDF plus ENT was performed.
it was also repeated to confirm the findings. It was measured with a research only ultra high sensitive quant assay. The results were clear: TDF alone was slightly superior to ENT alone, and the combo was clearly superior over both monos, almost one log further reduction compared with the monos.

Technically the antivirals have different efficacy on the three block-able modes of the polymerase; Priming, reverse transcription and extension of the incomplete plus strand. ENT is the only one that effectively works on the priming step, but TDf is better in RT and single strand repair mechanisms inhibition.