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ytdthjznyj

Feb 02, 2012

To: studyforhope

Thank you for your comments.

chrissto

Feb 06, 2012

To: studyforhope

is Myrcludex based on the liver cell receptor? I recall hbv's receptor has not been discovered. So does it mean Myrcludex is based on try/error approach?

How is Myrcludex trial going now? When can we see the result?

Rep9ac may soon release a new set of data on a taiwan conference in Feb. Looking forward to their latest result.

studyforhope

Feb 07, 2012

To: christo

The entry blocking mechanism of Myrcludex is based on its attachment to the HBV receptor on the surface of the liver cells. While this receptor has not been characterized yet, the blocking mechanism has been clearly proven.There is no urgent need to know the exact structure of this receptor.

It can be expected that the phase II Mycludex trial will start in summer of 2012.

It blocks the entry of HBV and HDV equally well. It represents a great hope in particular , for patients with Hepatitis D for which no other therapy works , even long term pegylated Interferon fails in the majority of cases. A very small amount of remnant HBV is able to support the ongoing spread of the HDV virions leading to high HDV viremia even with HBV undetectable. The infected cells will produce the small and large HDV antigen, which leads to immunological attack with no decoy ( like the HbSAg in HBV) present, hence the more agressive hepatitis and faster development of cirrhosis.

chrissto

Feb 18, 2012

To: studyforhope

Many thanks studyforhope,
It's great to hear Myrcludex is based on proven blocking mechanism. It boost my faith in it.

Now is the 1st quarter of 2012, summer 2012 is surely the most anticipated summer of all.

It's really great that myrcludex blocks both hbv and hdv via a proven blocking mechanism (even though the receptor left uncharacterized yet, but the most important is still the proven blocking mechanism), because hbv treatment is not a permanent solution, and hdv does not even have a temporary one.

StephenCastlecrag

Feb 22, 2012

Here is the abstract about REP 9AC from APASLD 2012 Conference in Taiwan:

REP 9AC / REP 9AC’: Potent HBsAg release inhibitors that can rapidly elicit durable immunological control of infection in patients with chronic hepatitis B
Mamun-Al-Mahtab1, Michel Bazinet2 and Andrew Vaillant2
1Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
2REPLICor Inc., Montreal, Canada
BACKGROUND: HBsAg suppresses host immunity and permits chronicity of HBV infection. REP9AC / REP9AC’ are nucleic acid-based polymers (NAPs) that block HBsAg release from infected hepatocytes. The current clinical results with REP9AC and a 4th generation NAP (REP9AC’) are disclosed.
METHODS: Patients with pre-treatment HBV DNA titers between 106 and 1012 copies/ml were treated by IV infusion. Virologic response was assessed using the Cobas and Architect testing platforms.
RESULTS (REP9AC): > 99.5% reduction of HBsAg occurred in seven of eight patients within 7 days to 32 weeks of treatment. All responders achieved 3 - 7 log reductions in HBV DNA. Four responders achieved complete control of their infection with 20-44 weeks of treatment (HBV DNA < 500cpm). Off treatment, three patients had sustained immunological control of their infection (HBV DNA < 500cpm, and HBsAg 90% reductions in HBsAg and 2-7 log reductions in HBV DNA). Mild pro-inflammatory side-effects accompanied drug administration.
RESULTS (REP9AC’): REP9AC’ is more stable with reduced pro-inflammatory activity compared to REP9AC. Interim data show robust HBsAg reductions in all seven patients in the first 10 weeks of treatment. Three patients have already experienced a 3-4 log decline in HBV DNA. Pro-inflammatory side-effects during administration were substantially reduced.
CONCLUSIONS: NAPs can affect rapid clearance of HBsAg, allowing restoration of host immunity. These results suggest that NAPs may become an important new tool in the treatment of chronic hepatitis B.

BeachTiePurist

Feb 22, 2012

To: StephenCastlecrag

>99.5% reduction of HBsAg? wow

4est

Feb 23, 2012

To: StephenCastlecrag

they made some comments regarding the 8'th patient (the one that was not reduce the HBsAg) ?

StephenCastlecrag

Feb 23, 2012

As you can see, only limited information in the abstract. It was an oral presentation, so someone who was at the presentation may have more information. I was told the presentation was well received and that not all patients started the clinical trial at the same time.

OrientS

Feb 23, 2012

To: StephenCastlecrag, studyforhope

when it will be in market? either rep9ac' or mycruludex ..

indmd

Mar 17, 2012

This is so far the best discussion forum I have ever seen on Hep B. So much to learn about innovative drugs in trials, and trial results etc. Thank you all for sharing this information. God bless.

OrientS

Mar 19, 2012

New news about myrcludex b .. today news ..

(Hepatera is going to use the funding to co-develop its first drug candidate, Myrcludex B)

Hepatra is a russian company ..

http://www.laserfocusworld.com/news/2012/03/19/maxwell-biotech-venture-fund-founded-with-participation-of-russian-venture-company-invests-in-hepati.html

StephenCastlecrag

Mar 19, 2012

To: OrientS

Good news, thanks.

joc2011

Mar 20, 2012

Great news. Any idea the time frame before it becomes available?

4est

Mar 20, 2012

To: OrientS

thanks for info!

it seams to me that Myracludex B will go on some deeper trials.

4est

Mar 20, 2012

Myracludex B looks to me that move faster than REP 9AC or maybe is just a media exposure.

stef2011

Mar 20, 2012

wow very good this is competitionand this will move the others faster too especially gilead

europe and russia are so indipendent from fda, especially russia, i think we will see this drug available extremely fast

4est

Mar 21, 2012

Dr. Alexander Alexandrov, MYR CSO, commented: "We have brought this landscape-changing approach through Phase 1 clinical testing and are excited about the collaboration with Hepatera, enabling the initiation of a proof of concept trial within a few months".

vootoodoo

Mar 21, 2012

Good news!

enolia

Mar 24, 2012

To: all

Looking forward to more advancement!

chrissto

Mar 25, 2012

Great news! Thanks.

Any idea what does it mean by "Proof of concept trial"?

calmama

Mar 25, 2012

To: chrissto

Means phase 2 clinical trial--to see if the drug shows the expected efficacy on people with hbv.

chrissto

Mar 26, 2012

To: calmama

If they follow Germany rule, does it mean the drug has to follow phase 1,2,3, which will be ten years long expected, as in US?
How long does it take a drug to be available on market normally?

calmama

Mar 26, 2012

To: chrissto

In Europe, the European Medicines Agency (also known as EMA or EMEA) approves drugs in a similar fashion to the FDA. Maybe a little more efficient than FDA??

Perhaps other people living in EU can comment on this.

ytdthjznyj

Apr 04, 2012

Oksana Markova, the director of Hepatera Company ( "Markova Oksana" ), reported that second phase of Myrcludex B clinical trials will begin in august - september of this year in several Russian cities.

stef2011

Apr 04, 2012

To: ytdthjznyj

very very good viread will be forced to move tr7 agonists fast...hope myracludex+peginterferon will be able to clear hbv on most

ytdthjznyj

Apr 04, 2012

At the moment they select the group with Hbe-, but don't tell the name of drug (we think that drug is Myrcludex). The treatment will last 3 month as a subcutaneous injection. The control group will be entecavir - three month.

ytdthjznyj

Apr 04, 2012

3 month as a subcutaneous injection every day

stef2011

Apr 04, 2012

To: ytdthjznyj

wow so they have little data it may lower hbvdna in just 3 months, i thought it was slow activity

very very good, it looks like russians dont waste time like US trials, if they also publish results fast on internet and get it on market in russia in a very short time this may change hbv treatment for next years

ytdthjznyj

Apr 04, 2012

From autumn will be several groups, perhaps, with different methods of treatment. I will inform when there will be any news.

4est

Apr 04, 2012

To: ytdthjznyj

do you have some link's to this discussion / announcement / clinical trials ?

ytdthjznyj

Apr 04, 2012

No, I didn't look for. My info is from the e-mail answer of Oksana Markova and from Moscow clinic, which is now recruiting for clinical trial

stef2011

Apr 04, 2012

To: ytdthjznyj

please ask when they will have drug available on people already on longterm nucs or nucs+peginterferon, this will be the final therapy i guess

chrissto

Apr 07, 2012

To: ytdthjznyj

This is great news. From now on, 3 months to prepare the trials, and 3 months to proceed the trials and get the result. It's total 6 months only to see the myrcludex b result.

Is there any knowledgeable one who can comment on what mycludex b can really achieve in 3 months treatment? Is there scientific reason that 3 month treatment should be enough?

Comparing to slow process of FDA, shorter period of trials is great, but i do want the treatment to be long enough for the medicine to take effect.

However, comparing to rep9ac's weeks of treatment period, 3 months seem adequate.

Anyone please comment, thanks.

chrissto

Apr 07, 2012

revise: aug-sep is 5-6 months from now. So total is 8-9 months, not 6 months. Sorry for the miscalculation.

The treatment period part still applies, hope anyone can comment. Thank you

studyforhope

Apr 07, 2012

To: chrisso

Infected cells die in the liver every day and are replenished with de novo infected cells from reinfection or division of infected cells.  This is normally in equilibirum, hence no change in cccDNA and surface antigen levels. Myrcludex can block the reinfection, thus under the assumption of a high rate of infected cell elimination the infected pool will start to shrink.
The daily rate of  hepatocyte destruction ( or noncytolytic clearance, as an alternative mechanism) will vary strongly from patient to patient. So will the effectiveness of Myrcludex on the speed of pool reduction, for that reason.
The relative poolsize during treatment can be estimated by VL measurements and quant HbSAg determinations. In 3 month they might see a development towards clear reduction in some patients that have a more rapid intrahepatic turnover of infected cells and a total percentage of infected cells that is rather low, since only then Myrcludex can work, since it cannot prevent viral spreading by infected cell division.
Treatment should be monitored and continued until negativity if the initial 3 month show a signal of reduction  in a patient. The majority of chronic HBV patients are unlikely to clear within 3 month. Nevertheless the results of such a trial might give enough information to design the next trial towards a more lasting endpoint.

chrissto

Apr 08, 2012

To: studyforhope

thank you for the helpful analysis, and please allow me to ask further questions.

1. Is your above cell replenishment scenarios apply to hdv as well? If so, does it mean myrcludex can be expected to be equally effective on hbv and hdv in 3 months time?

2. From the natural history perspective, how the ratio of infected cells changes over time? Is it always 100% meaning all cells are infected all the time? Or at first 100%, then drop to 50%, drop to 30%, then bounce back to 70%? and so on.

3. What is the percentage of two replenishment mechanism take place? E.g., 50% is from re-infection of non-infected cells, the rest 50% from infected cell division? Given the fact that drugs like entecavir can effectively keep the virus load low, it implies the re-infection of non-infected cells is very important to hbv's life, so same fact should result the myrcludex to be at least same effective as entecavir or more likely to be more effective than it. Is this reason ok?

4. question 2 is under the context of no treatment. If under the treatment of drugs like entecavir, what will ratio of infected cell comparing to non-infected cell change over time?

thank you very very much

from ytdthjznyj's posts, it seems this round of trials only recruit hbv carriers. Just feel strange why not arrange the hdv trial in the same time. Maybe ytdthjznyj have some more information about this?

stef2011

Apr 08, 2012

To: chrissto

i ll try to answer some of your questions:

1 hdv uses hbsag so both hbv and hdv are tied together, when there is no more hbsag also hdv is cleared, infact only hbv carriers can be infected by hdv

even those with some hbsag mutants cna t be infected by hdv

i guess they use 3 months time just to see the general trends, there is too much difference from person to person due to different balance virus/ immune system so there would be just a general trend.probably combos of antivirals, interferon and myr will make the most difference is resuts

2 the ratio of infected cells is different person to person according to balance immune system/virus.those with lowest hbsag have lowest number of infected cells

3 4 no antiviral can block reinfection this is why they all fail to cure hbv, if you look at the most useful tests by biopsies you will see little difference in intrahepatic hbvdna, pgrna, cccdna, hbsag stained cells on antivirals
ratios are different from person to person i guess

studyforhope

Apr 08, 2012

To: chrissto

HDV uses the L protein of HBV for entry and therefore HDV entry should be approximately equally inhibited as HBV.
The "replenishment" of HDV infected cells occurs in two different ways:
1. Reinfection of a cell already infected by HBV, this cell will become a starting point for efficient new HDV virion production.

2. Infection of a cell NOT  infected by HDV.
This happens  very frequently and a large amount of heppatocytes are infected in this way. These cells CANNOT further spread HDV, but they present the delta antigens epitopes and also activate cd4 helper Tcell responses in the liver upon necrosis, leading to a more severe hepatitis..

Myrcludex will block the spread of hdv and a reduction of HDV viral load can be expected after some time. Hard to say if 3 month are enough to show a clear effect.

The percentage of infected cells does change during the natural history of hbv and during antiviral treatment, it is best reflected by the quant surface antigen, but it is not a fixed factor, since the efficiency of expression figures in this relation.
Antivirals DO NOT reduce the infected percentage or the total cccDNA content in the liver to the extent one would expect or hope, since the relative efficiency of reinfection goes way up upon a low viral load. Most of the high VL in untreated patients is not used for reinfection,but is a waste and surplus of the viral system. Once only a few virions are produced under antiviral partial blockage, they all start to count and stick to the liver instead of circulating in the  body. Blocking this reinfection becomes critical in this phase to break through this endless simmering and low level propagation/destruction equilibrium.

The spreading by cell division of HBV infected is more important at a high percentage of infected cells than in the setting of a low remnant amount, asssuming equal opportunity to participate in hepatocyte regeneration between uninfected and infected cells. This is quite obvious.
Thus the effect of an entry blocker becomes more pronounced in a low remnant infection level.
You cannot compare the effectiveness of entecavir with that of Myrcludex, since the mchanisms are entirely different They will cooperate however, since the total daily reinfection rate will be the number of virions available to enter times the blocking factor exerted by Myrcludex,  eg 001. We do not know this factor yet and it will obviously depend on the dosing.

StephenCastlecrag

Apr 08, 2012

To: studyforhope

Thanks for a very informative explanation.
I am a little puzzled by your comment that "the percentage of infected cells does change during the natural history of hbv".I recalled reading that the levels of qHBsAg vary during the various phases of the natural history, the level being lowest during the inactive phase. Obviously the level chnages during the transition from one phase to another. As you have stated the percentage of infected cells "is best reflected by the quant surface antigen", so can we assume the percentages of infected cells also vary during the natural history but relatively stable during the various phases?

It is exciting to see how Mycrludex B will pan out in the trials. Fingers crossed.

studyforhope

Apr 08, 2012

To: StephenCastlecrag

I was responding to Chrisstos question that I understood to question if the infected percentage of hepatocytes changes as a patient goes through the phases of the natural history. In that sense the infected percentage changes to lower once the inactive phase is reached. The term "natural history' was understood as the progression thorugh the various phases in many patients.
Within each "phase" there will of course also be some variations. What matters in this context is that Myrcludex will exhibit its full benefits in a phase with a low infected cell percentage. Finally the ongoing elimination of infected cells will have a net effect and is not endlessly compensated by the reinfection and spreading that goes on merciless every day.

StephenCastlecrag

Apr 09, 2012

To: studyforhope

Please accept my sincere apology for wasting your time. I completely agree with your comment that "the percentage of infected cells does change during the natural history of hbv".
For some stupid reasons (my real puzzle :-( ) I thought you said "the percentage DOES NOT change" Mea maxima culpa!

Very best regards.

chrissto

Apr 10, 2012

To: studyforhope

Thanks again for the information.

1. I'm a little confused by this paragraph:
"Antivirals DO NOT reduce the infected percentage or the total cccDNA content in the liver to the extent one would expect or hope, since the relative efficiency of reinfection goes way up upon a low viral load".

Not sure if correct, I assume the severity of the disease is related positively to the percentage of the cells infected. More cell infected, more severe and more damage the liver could get. Because non-infected cell would not get damage by itself or by immune system indirectly.

But if the percentage of infected cells do not vary much with antiviral treatment, I find it hard to understand why the antivirals are effective to prevent the further progress of the disease.

Essentially, i try to understand the relationship of percentage of infected cell vs the progress of the disease.

chrissto

Apr 10, 2012

2. I've formulated a very simple dynamics about the percentage of infected cells under myrcludex treatment, not sure it's correct or not or useful for the folks, I just throw it out here for the review:

x(t) is the number of infected cell; y(t) is the number of non-infected cells. t is time variable.
I formulated the two equations:
(1) dx(t) = k1 x(t) + k2
(2) dy(t) = k3 y(t) - k2
(1) says two scenario for the "replenishment" of infected cell. The division is proportional to existing number of cells infected; second part is the re-infection, assuming it's constant.
(2) says the non-infected cell only have 1 scenario for replenishment, which is division from non-infected cell, and a negative scenario, when a cell got reinfected.
Solved the equation:
(3) x(t) = (1/2) k1 x(t)^2 + k2 x(t)
(4) y(t) = (1/2) k3 y(t)^2 - k2 y(t)
This seems to be a non-controllable setup, so not much sense to calculate the absolute number.
I calculate the ratio.
(5) x(t) / (x(t) + y(t)) = ( x(t) / y(t) ) * ( (k1 x(t) + 2 k2) / (k3 y(t) - 2 k2) )
So it shows two forces are in place:
1. The existing ratio: the higher infected ratio, the higher infected ratio will be, vice versa.
2. The second part is where treatment comes in, I call it r(t) for short. Without myrcludex, k2 is very high, r(t) is also very high.
with myrcludex, if it makes k2 very low, then r(t) is approximately (k1 x(t)) / (k3 y(t)), equation (5) becomes approximately (k1/k3) * ( x(t) / y(t) )^2.

This is if reinfection is extremely highly blocked. Under this idealistic scenario, the existing ratio still matters a lot, if existing infection ratio is close to 100%, then myrcludex cannot help much. The relative ability to divide between infected cells and non-infected cells is also a factor, this factor should be independent to myrcludex.

Under this setting, I have two more questions:
1. existing ratio for infected cell and non-infected cells, what would they normally look like dynamically? Will they ever dropped under 1 (half cells infected) in any phase or under any treatment?

2. what is the relative ability to divide between infected cell and non-infected cell? Are they equally capable or one kind is more capable? If so, any treatment can target on the capability cell division? Possibly means, control the percentage of the infected cells to die.

Finally, the above result may illustrate studyforhope's this paragraph "What matters in this context is that Myrcludex will exhibit its full benefits in a phase with a low infected cell percentage."

stef2011

Apr 10, 2012

To: chrissto

my doctor made a study on infection dynamics and complex formulas, dr colombatto, i think you can find it by googling doctor colombatto or doctor brunetto pisa

but i dont think it is possible to cover this by formulas, everything can change in the balance immune system/host plus there are immune escape mutations created during the phases of inefction, i think this is mostly wasted time

studyforhope

Apr 10, 2012

To: chrissto

"But if the percentage of infected cells do not vary much with antiviral treatment, I find it hard to understand why the antivirals are effective to prevent the further progress of the disease.

Essentially, i try to understand the relationship of percentage of infected cell vs the progress of the disease. ."

The percentage of infected cells does reduce during antiviral reatment but only by about 50 to 90% as numerous cccDNA studies on biopsies have shown.

The key question, in light of the above, is therefore why do antivirals prevent, in most cases, a further progression of liver disease, reduce ALT, inflammation and fibrosis?

While this is now an undisputed fact, most hepatologist will not be able give you an answer to this question because their training in immunology is limited and the detailed mechanisms are only partially clarified.

However, the most likely reason for this very critical and beneficial phenomenon is, that it is the amount/number of virions, secreted and often captured in the liver by macrophages and dendritic cells,

MOSTLY BY THE PRESENCE OF INTACT CORES WITHIN THOSE VIRIONS,

that ACTIVATE immune responses, often of a type with low effectiveness, but a higher grade inflammation cytokine profile, that cause the intensity of inflammation in the liver,
Remember that a virus has to be seen by its products, by immune cells. The core protein, mostly intact or partly assembled cores as well that are displayed to the macrophages upon hepatocyte death is highly immunogenic and has several classII T cell epitopes that will stimulate CD4 helper T cells upon contact with macrophages or dendritic cells . These stimulated cd4 Tcells then produce inflammatory cytokine cocktails and also stimulate Bcells, cd8Tcells and NKcells by direct contact (cd40 ligand mediated).
All this increases the severity of ongoing hepatitis B, is only moderately effective in inhibiting cccDNA expression and HBV replication and leads therefore to the battle with no end that we call chronic hepatitis B.

Antivirals strongly reduce the primary stimulus (the secreted virions) to this vicious cycle, thats how they exert their fundamental benefit.

studyforhope

Apr 10, 2012

An additional important reason that makes virions so much more immunostimulatory than surface antigen particles ( they actually suppress macrophage activation and dendritic cell activation) is the presence of the single stranded region in the HBV DNA inwside the virons. Single stranded DNA is a very strong immunostimulant, it combines with the presence of the core to activate a whole cascade of immune reactions as described above.
It needs to be emphasized that not all cytokines are equally effective to induce antiviral mechanisms inside the infected hepatocytes. Interferon gamma, Interleukin18 and Il-12 are the most effective without having an excessive collateral unspecific proinflammatory effect. Their preferential secretion by cytotoxic cd8 posiitive Tcells specific for virus specific epitopes is most likely the basis for the sometimes surprising reduction of virimia and cccDNA seen in some patients with very little ALT elevations.

This is the "good" antiviral immunity that is desirable, but we have not yet found the magic switch to turn this on, possibly because it depends both on the presence of high affinity HBV classI epitopes combined with CTLs that are not tolerized and impaired in their response.

We can speculate, that the powerful results that we see currrently emerging from the TLR7agonist trials are due to a selective direction of the cytokine response profile in the direction of this "effective, good" immunity, with less collateral damage.

studyforhope

Apr 10, 2012

To: chrissto

chrissto:
"Under this setting, I have two more questions:
1. existing ratio for infected cell and non-infected cells, what would they normally look like dynamically? Will they ever dropped under 1 (half cells infected) in any phase or under any treatment?

2. what is the relative ability to divide between infected cell and non-infected cell? Are they equally capable or one kind is more capable? If so, any treatment can target on the capability cell division? Possibly means, control the percentage of the infected cells to die. "

Measurements of cccDNA in liver biopsies in particular in eAg neg patients have shown ratios of infected vs noninfected of well below 50% anywhere from less than 1% to 30% all approximately.

It does not seem that the infection by HBV reduces the capacity of a cell to divide. But overall this is a difficult question, siince there also liver stem cells involved in this regeneation process that are speculated to be not infectable by HBV, which would favor the replenishment of cells from uninfected sources and thus limit the capacity of the virus to spread by cell division.

To complicate matters even further it is now known, in particular by work of Bill Mason, that in a long standing HBV infection a sustantial number of hepatocyte clones develop in the chronically infected liver that are resistant to HBV infection - up to 30% or so.

This is a logical consequence of selection of hepatocytes that are non infectable due to mutations in the hepatocyte genome, so they are spared from direct epitope mediated immune targeting.

Nevertheless, while this seems to be a good thing, those clones are also often precursors of HCC and represent a dangerous development.
And the remaining infectable hepatocytes are still in such high numbers that the inflammatory damage continues.

chrissto

Apr 11, 2012

sorry folks, the above equations solution is wrong. And assuming reinfection is proportional to non-infected cell is more correct than constant.

correction:
(1): dx(t) = k1 x(t) + k2 y(t)
(2): dy(t) = k3 y(t) - k2 y(t)
with initial condition:
(1a): x(0) / y(0) = r0 - initial percentage of infected and non-infected cells

solution:
http://www.wolframalpha.com/input/?i=DSolve%5B%7Bx%27%5Bt%5D+%3D%3Dk1*x%5Bt%5D+%2B+k2*y%5Bt%5D%2C+y%27%5Bt%5D+%3D%3Dk3*y%5Bt%5D+-+k2*y%5Bt%5D%7D%2C+%7Bx%5Bt%5D%2C+y%5Bt%5D%7D%2C+t%5D
(3), (4) : x(t), y(t) refer to above link, too long to type here and not main concern.

(5): x(t) / y(t) = (k2 / (k1+k2-k3) + r0) e^((k1+k2-k3) t) - k2 / (k1+k2-k3)
1. if reinfection is high, then the percentage is highly correlated to the balance of two force: replenishment of infected cell and non-infected cell. Assuming k1+k2 is overwhelmingly higher than k3, infected cell replenishment is higher than non-infected cell, then the percentage will always go up, until hit by the ceiling, which is not captured in this model

2. if reinfection is highly efficiently blocked by myrcludex, then k2 -> 0. Then equation (5) becomes
(6): r0 e^((k1 - k3) t)
the initial percentage of infected and non-infected cell becomes less relevant, more important is the net increment between infected cell thru division, and non-infected cell thru division. Whichever is stronger, the percentage will go to that direction.

Therefore, the conclusion might be:
1. blocking reinfection is necessary for clearance.
2. it is not sufficient. In order to clear, number of non-infected cell division needs to be larger than number of infected cells.
According to studyforhope:
"It does not seem that the infection by HBV reduces the capacity of a cell to divide."
, assuming infected cells and non-infected cells are equally capable to divide, then it's important that the infected cell percentage drops below 50%.

according to studyforhope:
"Measurements of cccDNA in liver biopsies in particular in eAg neg patients have shown ratios of infected vs noninfected of well below 50% anywhere from less than 1% to 30% all approximately",
the number of infected cell division should be less than number of non-infected cell division, in eAg neg patients. Blocking reinfection will therefore able to make the final clearance of the virus in this simple dynamics.

I guess, this is probably why they targets eAg neg patient in myrcludex trial.

chrissto

Apr 11, 2012

To: stef2011

thanks for the info,
i searched for colombatto and found one of his article in 2008:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2653343/

chrissto

Apr 12, 2012

Addition for the importance of blocking reinfection:
From further analysis from eq(5) above:
Firstly, the percentage of infected cell over non-infected cell is an exponential function of time. If infected cell is stronger (+ve: division, reinfection, etc), it will go up to infinity (towards 100% infected cell); if non-infected cell is stronger (+ve: division, etc, -ve: reinfection), it will slope down towards the long-term limit determined by the ability of reinfection over the net effect of force combination (division + reinfection + etc).
There’re four places to look at this percentage: k2/(k3-k1-k2) + (r0 + k2/(k1+k2-k3)) e^((k1+k2-k3)t):
1. The direction of the exp function (up or down). This is determined by the relative strength of infected cell and non-infected cell: k1+k2-k3.
If k1+k2-k3 > 0, meaning generating relatively more infected cell, then percentage will go up; if k1+k2-k3+infinity): K2 / (k3-k1-k2). Important when the percentage is going down (k1+k2-k3+infinity. The minimal is 0 when reinfection is totally blocked (k2=0); when reinfection is not blocked, the life-long treatment will be higher than 0 ,i.e, dynamic equilibrium between virus and immune system.
3. Initial percentage (when t=0): r0 + k2/(k1+k2-k3). This is not a determining factor. No matter how high it is, it could be mitigated by exp fall.
4. Speed of the percentage change: k1+k2-k3 (same as the direction factor). If k1+k2-k3<<0, meaning infected cell growth plus reinfection is much smaller than non-infected cell growth, the percentage should drop pretty quickly.
The above model and its cryptic parameter relates to the treatment option:
k1: reduced by Interferon treatment (or other immunity boost treatment);
k2: reduced by Myrcludex (block the reinfection);
k3: not controllable (non-infected cell division and other mechanisms and complexities studyforhope mentioned).
As we see, reinfection is a very important factor in the virus dynamic equilibrium with immune system, which makes myrcludex an irreplaceable treatment option. Luckily we have this option on the horizon.
This truly tally with studyforhope's statement:
"What matters in this context is that Myrcludex will exhibit its full benefits in a phase with a low infected cell percentage. Finally the ongoing elimination of infected cells will have a net effect and is not endlessly compensated by the reinfection and spreading that goes on merciless every day."

Sorry for the long post, and thanks for all the patience in you to see me rambling.

chrissto

Apr 12, 2012

Repost for readability, really sorry to spam the post.

Addition for the importance of blocking reinfection:
From further analysis from eq(5) above:

Firstly, the percentage of infected cell over non-infected cell is an exponential function of time. If infected cell is stronger (+ve: division, reinfection, etc), it will go up to infinity (towards 100% infected cell); if non-infected cell is stronger (+ve: division, etc, -ve: reinfection), it will slope down towards the long-term limit determined by the ability of reinfection over the net effect of force combination (division + reinfection + etc).

There’re four places to look at this percentage: k2/(k3-k1-k2) + (r0 + k2/(k1+k2-k3)) e^((k1+k2-k3)t):

1. The direction of the exp function (up or down). This is determined by the relative strength of infected cell and non-infected cell: k1+k2-k3.

If k1+k2-k3 > 0, meaning generating relatively more infected cell, then percentage will go up; if k1+k2-k3+infinity): K2 / (k3-k1-k2).

Important when the percentage is going down (k1+k2-k3+infinity.

The minimal is 0 when reinfection is totally blocked (k2=0); when reinfection is not blocked, the life-long treatment will be higher than 0 ,i.e, dynamic equilibrium between virus and immune system.

3. Initial percentage (when t=0): r0 + k2/(k1+k2-k3). This is not a determining factor. No matter how high it is, it could be mitigated by exp fall (hopefully).

4. Speed of the percentage change: k1+k2-k3 (same as the direction factor).

If k1+k2-k3 << 0, meaning infected cell growth plus reinfection is much smaller than non-infected cell growth, the percentage should drop pretty quickly.

The above model and its cryptic parameter relates to the treatment option:

k1: reduced by Interferon treatment (or other immunity boost treatment);
k2: reduced by Myrcludex (block the reinfection);
k3: not controllable (non-infected cell division and other mechanisms and complexities studyforhope mentioned).

As we see, reinfection is a very important factor in the virus dynamic equilibrium with immune system, which makes myrcludex an irreplaceable treatment option. Luckily we have this option on the horizon.

This truly tally with studyforhope's statement:
"What matters in this context is that Myrcludex will exhibit its full benefits in a phase with a low infected cell percentage. Finally the ongoing elimination of infected cells will have a net effect and is not endlessly compensated by the reinfection and spreading that goes on merciless every day."

Sorry for the long post, and thanks for all the patience in you to hear me rambling.

chrissto

Apr 12, 2012

To: ytdthjznyj

May I ask one question about myrcludex trial?

According to ytdthjznyj,
"From autumn will be several groups, perhaps, with different methods of treatment. I will inform when there will be any news."

So is it confirmed that they will try other combinations (such as myrcludex + interferon), not just myrcludex alone?

chrissto

Apr 12, 2012

Sorry again, my arrogant point 1 to 4 was gone for some sentence. This is due to the symbol i use for "t approaches infinity", the website thought it was HTML tag and hid it after posted. Hopefully this time is ok.
-----------
1. The direction of the exp function (up or down). This is determined by the relative strength of infected cell and non-infected cell: k1+k2-k3.

If k1+k2-k3 > 0, meaning generating relatively more infected cell, then percentage will go up; if k1+k2-k3< 0, meaning generating relatively more non-infected cell, then percentage will go down.

2. The life-long treatment percentage goal (the limit, when t approaches +infinity): K2 / (k3-k1-k2). Important when the percentage is going down (k1+k2-k3<0), not important when percentage goes up, because we care only t approaches +infinity.

The minimal is 0 when reinfection is totally blocked (k2=0); when reinfection is not blocked, the life-long treatment will be higher than 0 ,i.e, dynamic equilibrium between virus and immune system.

3. Initial percentage (when t=0): r0 + k2/(k1+k2-k3). This is not a determining factor. No matter how high it is, it could be mitigated by exp fall.

4. Speed of the percentage change: k1+k2-k3 (same as the direction factor). If k1+k2-k3<<0, meaning infected cell growth plus reinfection is much smaller than non-infected cell growth, the percentage should drop pretty quickly.
-------------

ytdthjznyj

Apr 13, 2012

To: chrissto

"So is it confirmed that they will try other combinations (such as myrcludex + interferon), not just myrcludex alone?"

Unfortunately, there is no exact information for now. I asked this question to director of Hepatera company by mail. She recommended to ask her this info in August. So, we will wait for August ..

usagirl781

Apr 25, 2012

To: ytdthjznyj

Is Myrcludex effective for high viral load individuals,antigen positive or Immunotolerant pt? Earlier you mentioned that they are now testing the antigenn negative pt? Is this drug intended for both groups?

thank you for your response

MHMD

Jul 29, 2012

Hi,,

What is the latest happy news of Myrcludex trial?

Thanks a lot...

ggtm

Sep 03, 2012

To: stef2011

My dr said that myracludex B is still in phase 1 study: meaning still many more years before actual approval. Phase 1 study generally means trying out and see if people can tolerate the drug. Many drugs starts and actually ends with phase 1 study. Phase 2 study usually is dose-finding; meaning trying out different doses and see what is appropriate in terms of benefit and risk. Phase 3 is the proper clinical trial in real patient. each phase can take months to years.

Anyone has latest news abt myracludex B?

stef2011

Sep 04, 2012

To: ggtm

they are using russia instead of germany because they dont have all the stupid laws that drug makers use to benefit and wait for patents to expire in western countries,

moving to russia it will probably be available next year possibly still on trial so free of charge, as to safety it is safer and less toxic than approved drugs we use now

ggtm

Sep 04, 2012

To: stef2011

If I start on tenofovir now, and in future would like to switch to myracludex B, is it safe? I don't want to cause unecessary flares due to switching of meds.

stef2011

Sep 04, 2012

To: ggtm

myrcludex is used added to standard care antivirals or peginterferon, also trials that started now in sept use combo

i dont think myrcludex alone can clear hbv

LilHope2010

Sep 05, 2012

Any update on rep 9ac?

Mrt79

Sep 05, 2012

To: stef2011

Hi Stef,
"myrcludex is used added to standard care antivirals or peginterferon, also trials that started now in sept use combo"
Where's the source of this info pls?
Cheers mate.

stef2011

Sep 05, 2012

To: Mrt79

the doctors making the trials, you just email them if you are interested in that trial
they require to stay in russia for 6 months and be available for tests weekly if not more often.75% will get myrcludex+stadard of care and 25% will have standard of care+placebo

i d go in russia for 6 months but only if i know i am getting myrcludex 100%, at this time better wait for trials with 100% myrcludex

chrissto

Sep 17, 2012

really good to hear myrcludex is on schedule.

veteranB

Sep 18, 2012

phase 2 where everybody will start getting myrcludex B will be in spring of 2013.

Phase 2 is planned all over Eastern Europe. O hope Gilead people that follow us on this forum very closely are aware of it and act accordingly with doing better clinical trials of their Imiquimod pills.

R_2012

Oct 16, 2012

To: chrissto

Here is update for Arc-520. It looks like proceeding on schedule, for clinical trials next year.

http://www.dailyfinance.com/2012/10/16/arrowhead-research-receives-notice-of-patent-allow/

chrissto

Nov 03, 2012

To: R_2012

What is Arc-520?

R_2012

Nov 10, 2012

To: chrissto

It is drug candidate from Arrowhead Research. It works by RNA interference. They are planning on filing IND by 2nd quarter next year. Below is an excellent discussion on how it works and it's possible shortcomings.

http://www.medhelp.org/posts/Hepatitis-B/Arrowhead-Presents-Data-Showing-99-Target-Knockdown-in-/show/1834213#post_8472641

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