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gilead trl7 agonist and others already marketed


i was checking for trl7 agonists and i found there are already 2 and one marketed already and even generic, they are used on viral infections to activate immune response on HPV, herpes viruses, other viruses and even soem types of skin cancers, they are in form of creams

Imiquimod ( Aldara )
http://dreampharm.com/drugs-online/aldara/aldara.5.html

The genetic control of airway responsiveness and the effect of resiquimod treatment on allergic asthma
http://gradworks.umi.com/NR/68/NR68509.html

resiquimod
http://imgenex.com/get_details.php?catalog_no=IMG-2208

Imiquimod and resiquimod as novel immunomodulators
http://jac.oxfordjournals.org/content/48/6/751.full
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Avatar universal
Here is the original publication in elife.

eLife. 2012; 1: e00049.
Published online 2012 November 13. doi:  10.7554/eLife.00049
PMCID: PMC3485615
Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus

Huan Yan,1,2,† Guocai Zhong,2,† Guangwei Xu,2 Wenhui He,2,3 Zhiyi Jing,2 Zhenchao Gao,1,2 Yi Huang,2,3 Yonghe Qi,2 Bo Peng,2 Haimin Wang,2 Liran Fu,2,3 Mei Song,2,3 Pan Chen,2,3 Wenqing Gao,2 Bijie Ren,2 Yinyan Sun,2 Tao Cai,2 Xiaofeng Feng,2 Jianhua Sui,2 and Wenhui Li2,*
Author information ► Article notes ► Copyright and License information ►
See commentary "Getting to grips with hepatitis" , e00301.
This article has been cited by other articles in PMC.
Go to:
Abstract
Human hepatitis B virus (HBV) infection and HBV-related diseases remain a major public health problem. Individuals coinfected with its satellite hepatitis D virus (HDV) have more severe disease. Cellular entry of both viruses is mediated by HBV envelope proteins. The pre-S1 domain of the large envelope protein is a key determinant for receptor(s) binding. However, the identity of the receptor(s) is unknown. Here, by using near zero distance photo-cross-linking and tandem affinity purification, we revealed that the receptor-binding region of pre-S1 specifically interacts with sodium taurocholate cotransporting polypeptide (NTCP), a multiple transmembrane transporter predominantly expressed in the liver. Silencing NTCP inhibited HBV and HDV infection, while exogenous NTCP expression rendered nonsusceptible hepatocarcinoma cells susceptible to these viral infections. Moreover, replacing amino acids 157–165 of nonfunctional monkey NTCP with the human counterpart conferred its ability in supporting both viral infections. Our results demonstrate that NTCP is a functional receptor for HBV and HDV.
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Avatar universal
There is marketing interest where there is a market and companies are notnshyndoncome forward with suggestions for ideas that at least pump up the share price for a while. But most of these approaches go nowhere in the end, since they simply do not really work. Therapeutic vaccines of many sophisticated designs were tried in HBV and have all failed for several important reasons that cannot be overcome no matter how smart you package the antigens for presentation. Eg any surface antigen tnerapeutic vaccine fails due to the paralyzing effect of the massively circulating antigen on elicited Tcell responses. And core based therapeutic vaccines fail due to the mutated single class1 epitope, the crippled multiple class2 epitopes and the lack of epitope presentation on the hepatocyte surface due to turning off the cytosolic e antigen production. There is almost nothing left to react to, thats why efficient elimination is so rare.

Therapeutic vaccines generate an immune response against the vaccine, representing a virus that does not exist in the patients body anymore due to multiple immunoadaptive mutations over time in the endless war of immunity against the virus.

Thus no wonder they have all miserably failed, in HBV AND HCV.

The only place for such a vaccine would be in the setting of the Teplicor patient after his artificial surface antigen suppression ends, to stabilize and reenergize the vaning immune response against the surface antigen once the VL is very low and tne natural immune stimulation against this antigen becomes also low, leading to a slow recovery of the virus after month or a few years. If you look carefully at the replicor poster inset from the aasld2012 you will notice that only 25% of the patients of the first trial were able to hold their svr, hence no cure for most, back to square one. Now in the second trial they added immunostimulation with ifn or thymosin alpha towards the end. It remains to be seen if this will long term stabilize the svrs once all therapy has stopped for a longer  This is one of the most fascinating questions right now in HBV therapy, but we will have to wait for the answer for quite a while.
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Avatar universal
    a Inserm, U748/1110, Institut de Virologie, Université de Strasbourg, Strasbourg, France
    b School of Immunity and Infection, NIHR Liver Biomedical Research Unit, University of Birmingham
    c Pôle Hépato-digestif, Nouvel Hôpital Civil, Strasbourg, France
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Avatar universal
It is interesting that Mycrludex binds to this receptor. I guess you have read the following draft paper:
A bile acid transporter as a candidate receptor for hepatitis B and D virus entry
Fei Xiaoa,
Jane A. McKeatingb,
Thomas Baumerta
http://www.sciencedirect.com/science/article/pii/S0168827813000834#
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Avatar universal
The preclinical studies for Myrcludex were done in mice, rats and most importantly beagle dogs. I dont think they have tested for bile acid accumulation in thse studies since the receptor was not known at this time.

The hepatera study in humans that has just begun is not likely to show any problems, since the dosing is so low that a 24 hour receptor blockage cannot be expected, hence there will be no problem with bile acid retention in the blood, even if myrcludex would be an effective functional inhibitor of the transporter receptor. The only problem with this is that the blocking effect on HBV entry will be also insufficient, therefore I sadly predict that the trial will end up as a failure due to suboptimal dosing.
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Avatar universal
I also wanted to share this news with you.

A company called Transgene is looking into HBV treatment. It looks like the market interest for HBV Drugs is opening up since HCV therapy is getting saturated.

http://www.bloomberg.com/news/2013-02-07/transgene-won-t-sign-tg4040-partnership-soon-ceo-says-1-.html
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Avatar universal
Thank you for responding. I have followed every single one of your posts to learn as much as I can.

I am wondering if Hepatera studied this possible problem in pre-clinicals with other Mammals that produce Bile Acid such as Mice or Chimps. Even if this is a problem, they may have some rescue options.
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Avatar universal
This is exactly the same receptor that Myrcludex binds to.There is no shadow of a doubt.
The university of Heidelberg and the Hamburg group have identified the same receptor as the chinese, but it seems that the chinese published it first.

For the impact of this on the potential side effects of Myrcludex please read my above post.
If the transport function of this transmembrane bile acid transporter is blocked by the Myrcludex binding it could mean that bile acids accumulate in the blood.
But it is possible that the myrcludex binding DOES NOT interfere with the function of this symporter, then we would be in luck.
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Avatar universal
What will be really interesting is to see if this is the same Receptor that Myrcludex-B is binding too.

I thought the HBV Receptor was disocvered by the Dept. Internal Medicine, University Medical Center Hamburg-Eppendorf;Hamburg, Germany.

But I could be wrong.
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Avatar universal
I missed the hbv receptor paper, it is already published.
Basically they identified the sodium taurocholate peptide cotransporter as the binding membrane protein to which the pres1 region of the incoming virion will attach.
This membrane protein normally serves the function to pump back intestinally reabsorbed bile acids into the liver cell for reuse.
Myrcludex will bind to this receptor and block attachment of the virions.
The big question now is whether that binding will incapacitate the transporter to perform its regular job of recycling bile acids. If the transpoters function will be blocked, then an accumulation of bile acids in the general circulation can be expected, as well as a lower output of bile for fat digestion and emulsification. All this is important, since it concerns potential side effects of long term Myrcludex therapy.
But it might well be that this binding does not incapacitate the transporters true function. We will know that very soon.
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Avatar universal
I heard from a German researcher that he had also discovered it and that there is another group that did. He was hesitant to disclose its exact nature, because it was not published yet. I assume that we will hear about it at the EASL in Amsterdam soon.
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Avatar universal
Wow, I went back and re-read the Chimp study a few more times. The dosing was really high in comparison to the max for humans which was one single dose of 12mg.

That's like giving doses of 240mg for someone who weighs 60kg, where people were having flu like symptoms at 12mg!!!

"METHODS:: GS-9620 was administered to chimpanzees every other day (3 times each week) for 4 weeks at 1 mg/kg and, after a 1 week rest, for 4 weeks at 2 mg/kg"
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Avatar universal
Many thanks for that explanation and observation.

Off topic: Chinese scientists claimed they have discovered the receptor for hbv and that they are now in a position to build better cell models with these receptors to study hbv.

Amy comments?
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Avatar universal
Antigen staining for core and surface antigen is routinely done on HBV liver sections using labelled antibodies. The staining for the surface antigen is more sensitive than core. Any positively stained cell is considered infected.

Thus indeed the meaning is that apoptosis is increased and simultaneously the infected cell number has decreased. So the assumption is that infected cell underwent apoptosis triggered by the medication, although some apoptosis might also occur in uninfected cells.

In perfect apoptosis, the ALT need not to increase, since it is a removal process started from the inside. CccDNA can  decrease without substantial ALT flares, but mostly some collateral damage wiill occur, in particular if rather unspecific inflammation is induced. CTLs work clean, helper T cells are messy and coactivate eg monocytes and can cause death of noninfected cells by necrosis with ALT increases. In real life all shades of grey can be present.

GS9620 is likely more effective than pegIFN if the dosis is high enough. But the VL reduction data are still somewhat disappointing in this chimp study. By comparison the woodchuck data were dramatically impressive. Maybe woodchucks complain less at higher doses....
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Avatar universal
Thank you for sharing these results.

Well the good thing is that it has an effect on HBVDNA and that it is tolerated in Humans. Right now it seems as Interferon isn't effective on certain Genotypes and this drug may help those groups.

Also I am wondering if Gilead will come up with some type of combo of this drug, TDF and hopefully GI-13020.  Maybe this could lead to curing Hepatitis B over a period of months of treatment similar to the triple therapy that the Hep C folks are benefiting from.

Thanks again!
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Avatar universal
Many thanks for the reports. I wonder whether you can expand on the following statement in the anstract:
"numbers of HBV antigen-positive hepatocytes, were reduced as hepatocyte apoptosis increased."

Does HBV antigen-positive mean HBV infected?
What causes the hepatocyte apoptosis?
Is apoptosis an orderly process such that serum ALT level is not significantly raised as the dead cells are disposed by other cells (sorry for the poor terminology)?
Finally, does the data suggest GS9620 is more effective than the existing PegIFN weekly injection?

Many thanks in advance.
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Avatar universal
Here is a single ascending dose human phase I study.


Antivir Ther. 2013 Feb 12. doi: 10.3851/IMP2548. [Epub ahead of print]
Safety, pharmacokinetics and pharmacodynamics of GS-9620, an oral Toll-like receptor 7 agonist.
Lopatin U, Wolfgang G, Tumas D, Frey CR, Ohmstede C, Hesselgesser J, Kearney B, Moorehead L, Subramanian GM, McHutchison JG.
Source
Gilead Sciences, Foster City, CA, USA.
Abstract
BACKGROUND:
GS-9620 is a novel oral agonist of toll-like receptor 7 (TLR7) in development for the treatment of chronic viral hepatitis. TLR7 is a highly conserved innate immune receptor expressed primarily on plasmacytoid dendritic cells and B lymphocytes. The aim of this double-blind placebo-controlled, single ascending dose study was to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of GS-9620 in healthy volunteers.
METHODS:
Seventy five healthy volunteers (8 subjects in each of 10 cohorts, 5 subjects participated in 2 cohorts) were randomized (6:2) to receive a single dose of GS-9620 (0.3, 1, 2, 4, 6, 8, or 12 mg) or placebo.
RESULTS:
GS-9620 was well absorbed and well tolerated in oral doses up to 12 mg. Minimal treatment related adverse events were seen at doses up to 8 mg. Serum interferon-alpha was only detected in subjects who received 8 or 12 mg doses, and the adverse event profile at 8 and 12 mg doses was generally consistent with that associated with interferon-alpha exposure (flu-like symptoms), consistent with the mechanism of TLR7 agonism. All adverse events resolved within 72 hours. Induction of chemokines/cytokines and interferon-stimulated genes (ISGs) were seen at GS-9620 doses ≥2mg, well below doses that induced serum IFN-α or led to clinical adverse events.
CONCLUSIONS:
GS-9620 demonstrates safety and pharmacodynamic activity at doses up to 12 mg. Pharmacodynamic activity is seen before adverse events, suggesting the potential for induction of an antiviral response without systemic adverse events in patients with chronic viral hepatitis.
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Avatar universal
A chimp trial on gs9620 was just published. The results are mediocre.

GS-9620, an Oral Agonist of Toll-Like Receptor-7, Induces Prolonged Suppression of Hepatitis B Virus in Chronically Infected Chimpanzees.
Lanford RE, Guerra B, Chavez D, Giavedoni L, Hodara VL, Brasky KM, Fosdick A, Frey CR, Zheng J, Wolfgang G, Halcomb RL, Tumas DB.
Source
Department of Virology and Immunology, Texas Biomedical Research Institute, San Antonio, TX 78227, USA; Southwest National Primate Research Center, San Antonio, TX 78227, USA. Electronic address: ***@****.
Abstract
BACKGROUND & AIMS:: Direct-acting anti-viral agents suppress hepatitis B virus (HBV) load but must be given lifelong. Stimulation of the innate immune system could increase its ability to control the virus and have long lasting effects, after a finite regimen. We investigated the effects of immune activation with GS-9620-a potent and selective orally active small molecule agonist of Toll-Like Receptor (TLR)7-in chimpanzees with chronic HBV infection. METHODS:: GS-9620 was administered to chimpanzees every other day (3 times each week) for 4 weeks at 1 mg/kg and, after a 1 week rest, for 4 weeks at 2 mg/kg. We measured viral load in plasma and liver samples, the pharmacokinetics of GS-9620, and the following pharmacodynamics parameters: interferon (IFN)-stimulated gene expression, cytokine and chemokine levels, lymphocyte and natural killer cell activation, and viral antigen expression. Clinical pathology parameters were monitored to determine the safety and tolerability of GS-9620. RESULTS:: Short-term oral administration of GS-9620 provided long-term suppression of serum and liver HBV DNA. The mean maximum reduction of viral DNA was 2.2 logs, which occurred within 1 week of the end of GS-9620 administration; reductions of greater than 1 log persisted for months. Serum levels of HB surface antigen and HB e antigen, and numbers of HBV antigen-positive hepatocytes, were reduced as hepatocyte apoptosis increased. GS-9620 administration induced production of IFN-ą and other cytokines and chemokines, and activated ISGs, natural killer cells, and lymphocyte subsets. CONCLUSIONS:: The small molecule GS-9620 activates TLR-7 signaling in immune cells of chimpanzees to induce clearance of HBV-infected cells. This reagent might be developed for treatment of patients with chronic HBV infection.
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Avatar universal
The russian trial using myrcludex has started realistically on dec 12.2012.

The dosing was unfortunately chosen however in a range that cannot be expected to work effectively, if one takes into account the realistic analysis of human blood levels and dynamics curves from the phase I poster at the aasld 2012.  Thus even if the hepatera trial comes back with disappointing results, it does not mean that Myrcludex is not capable of working. It will have to be dosed higher to block with sufficient efficacy IMO..

It is also important to understand that in combo with Myrcludex the antivirals will have a clear direct synergistic effect on the efficacy of prevention of spreading of HBV into uninfected liver cells. This will become even more important when truly small levels of infected cells remain.
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Avatar universal

thank you very much for your help, i ll give ezetimibe a try, i saw human studies with safety until a 50mg dose, i ll try 20mg

expetections from this are very very low but as you said it wont hurt or at beast help in the hcc/fatty liver prevention

do you know if any data is available about myrcludex human trials?any early hbsag drop in the combo arm?
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Avatar universal
I am sorry that the Imiqimod did not work.But this was foreseeable now for quite a while from the dynamics of your results.

Also the strophantin/ quauabin proposal from the hepatitis B foundation research group ..Timothy Block....to selectively kill infected cells has way to weak an effect to lend itself to in vivo human use.
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Avatar universal
I studied the ezetimibe paper from the Munich research group.
The pills for human use are 3mg. Considering the molecular weight of the compound, even the one micro molar concentration seems hardly achievable in vivo with this dose, unless it accumulates somehow in the liver after oral uptake. It is a fairly harmless compound, so testing it in the typical dosing does not seem to involve any major risk, but expectations that it will shift the total cccDNA content by influencing the speed of daily infection spread should be kept very low.
It's mode of action, according to the paper, is to block the processing of the incoming virions at a step later than the primary uptake.
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Avatar universal

i just got hbsag result after another 3 months of suppository use of imiquimod and this lead to no results, hbsg remained stable at 4200iu/ml (previous result about 4400iu/ml, baseline about 7300iu/ml)

it is exactly like the alinia try, hbsag deosnt get to less than 4000iu/ml, at least for me

next try will be peg-intf alpha add on to my regimen of antivirals tenofovir plus entecavir and also started use of ezetimibe
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Avatar universal

i just want to double check if 25mg suppository all at once have an effect on hbsag quant since from previous trial oral doses had no effect at all while the suppository ones who were very few like 25mg per month in april/may had a decrease of about 2000iu/ml in 3 weeks

since sides are none now and cost is extremely cheap i think it worths a try
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