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First human HBV birinapant data in melbourne
On Wednesday March 11 at 1pm at the Eliza Hall Institute a one hour presentation of birinapant in HBV is scheduled. It can be assumed that the first results of the human trial that started in Nov 2014, only 4 weeks of treatment per patient planned, will be presented. Maybe Stephen Castlecrag could attend to report the details. the key data will be the quant hbsag reductions after 4 infusions of birinapant, since the patients are und on antivirals, no DNA data can be expected. This trial is one of the most exiting new developments with a high degree of likelihood of effectiveness. It has the potential to turn a weak T cell response in one that is nevertheless effective in eliminating infected cells. If hbsag reduction will be achieved, it is because infected cells die, NOT because of some blockage of its production or release.
I do not have access to the full paper from my current location.
It seems this was a pilot trial in which the effect of one or two doses of the GS 9620 was tested. It remains unclear if multiple doses, longer treatment, or higher doses will be leading to a meaningful effect on the surface antigen or the viral load. I do not have realistic hopes that this toll like receptor agonist will lead to improved treatment options.
It seems this was a pilot trial in which the effect of one or two doses of the GS 9620 was tested. It remains unclear if multiple doses, longer treatment, or higher doses will be leading to a meaningful effect on the surface antigen or the viral load. I do not have realistic hopes that this toll like receptor agonist will lead to improved treatment options.
Well, heard nothing regarding the seminar at Walter Eliza Hall Institute. However, a full paper about the two Phase 1B clinical trials of GS9620 has now be published:
Can you get a copy of this paper?
J Hepatol. 2015 Feb 27. pii: S0168-8278(15)00147-6. doi: 10.1016/j.jhep.2015.02.037. [Epub ahead of print]
The Oral Toll-Like Receptor-7 Agonist GS-9620 in Patients with Chronic Hepatitis B Virus Infection.
Gane EJ1, Lim YS2, Gordon SC3, Visvanathan K4, Sicard E5, Fedorak RN6, Roberts S7, Massetto B8, Ye Z8, Pflanz S8, Garrison KL8, Gaggar A8, Mani Subramanian G8, McHutchison JG8, Kottilil S9, Freilich B10, Coffin CS11, Cheng W12, Kim YJ13.
The abstract is much the same as that published at AASLD(?), but being a full paper, it has more details. So studyforhope may have a look at it and give us his expert comments. As we knew, the results were not as impressive as those reported for the chimps by Lanford. However, I noticed that the human doses were up to 4 mg, but for the chimps, they were up to 2mg/kg. So I would think the dosages used on humans were very conservative.
Can you get a copy of this paper?
J Hepatol. 2015 Feb 27. pii: S0168-8278(15)00147-6. doi: 10.1016/j.jhep.2015.02.037. [Epub ahead of print]
The Oral Toll-Like Receptor-7 Agonist GS-9620 in Patients with Chronic Hepatitis B Virus Infection.
Gane EJ1, Lim YS2, Gordon SC3, Visvanathan K4, Sicard E5, Fedorak RN6, Roberts S7, Massetto B8, Ye Z8, Pflanz S8, Garrison KL8, Gaggar A8, Mani Subramanian G8, McHutchison JG8, Kottilil S9, Freilich B10, Coffin CS11, Cheng W12, Kim YJ13.
The abstract is much the same as that published at AASLD(?), but being a full paper, it has more details. So studyforhope may have a look at it and give us his expert comments. As we knew, the results were not as impressive as those reported for the chimps by Lanford. However, I noticed that the human doses were up to 4 mg, but for the chimps, they were up to 2mg/kg. So I would think the dosages used on humans were very conservative.
http://tetralogicpharma.com/wp-content/wbuploads/wb_publications/TLOG%20Corporate%20Presentation%20-%202015.pdf
this is a presentation of the product probably 2014 data
this is a presentation of the product probably 2014 data
potential....we have to see on humans but anyway i think this is very interesting for all of us because targeting the host is the smartest way and especially targeting apoptosis for both hbv infection and cancer
Does anyone have a link to this article? My doctor is very intrigued by this type of information and asked I send it his way...
You are right, since these results are market sensitive they will likely keep them under lock until maybe the EASL or even later. I was too optimistic in the sense assuming that they will openly share the preliminary data, which they must have at this point. The mouse data were already presented at the molecular biology meeting in Los angeles, but they might have some additional preclinical information.
I have asked, but I am not hopeful of a reply as these information is market sensitive. Natap recently reported from CROI that:
Treatment with a TLR7 Agonist Induces Transient
Viremia in SIV-Infected ART-Suppressed Monkeys
So this may be used as part of the Kick and Kill strategy for HIV. I don't know whether the study shed any further light on GS9620 as treatment for HBV, the clinical trial is still ongoing.
Treatment with a TLR7 Agonist Induces Transient
Viremia in SIV-Infected ART-Suppressed Monkeys
So this may be used as part of the Kick and Kill strategy for HIV. I don't know whether the study shed any further light on GS9620 as treatment for HBV, the clinical trial is still ongoing.
The Abivax trial is basically a repeat of the Cuban trial with the hbsag/core particle combo vaccine in Bangladesh on a larger scale, so we can roughly expect a similar outcome. It worked comparably to interferon, with lesser side effects and the end of treatment stability was higher.
The abstract of the cuban trial was posted here a while ago.
The abstract of the cuban trial was posted here a while ago.
Yes, they might just cover the preclinical research, in their hydrodynamic mouse model. But the announcement was written in a way that it claims that it works in the human system. Since by now they will have at least a few patients beyond the four weekly doses and the effect on hbsag should be quite immediate, they certainly must have human data by now. He might just present these in a last slide - or not.
Would it be able that you ask them more specifically if some preliminary data on the ongoing trial will be part of the discussion?
At any rate, thank you for the effort you already made.
The fundamental difference between all the inhibitory drugs to block the HBV system, which do not destroy the source but just limit the virion or accessory protein output while they are dosed and this approach is that it aims to eliminate the source of the infection itself cccDNA or integrated.
The mechanism operative is hoped to be that a not so effective immune signal tries to initiate apoptoses in infected cells. This is a scenario that we expect in chronic HBV, particularly in e negative, because the key cd8 epitopes are adapted and mutated, so the attack CTLs are too weak to push the cell into apoptosis with the signals provided.
However a key mechanism by which the cell avoids apoptosis under stress is the production of anti apoptotic proteins, that block milder apoptotic signaling. By introducing the SMAC/DIABLO mimetic birinapant, these antiapoptotic protectors are themselves inactivated, so now apoptosis happens.
The drug has been used in several human cancer trials, side effects seem to be very mild, the worst being Bells Palsy, reversible.
The mouse data are stunning, hbsag was lost in 4 weeks. But of course the model has its limits and the human situation can be quite different.
the biggest fear was or is that the effect is too strong and if a large percentage of liver cells are infected, acute fulminant hepatitis could result.
The plan apparently is to start with patients on antivirals which are UND and also to use a very small starting dose.
Would it be able that you ask them more specifically if some preliminary data on the ongoing trial will be part of the discussion?
At any rate, thank you for the effort you already made.
The fundamental difference between all the inhibitory drugs to block the HBV system, which do not destroy the source but just limit the virion or accessory protein output while they are dosed and this approach is that it aims to eliminate the source of the infection itself cccDNA or integrated.
The mechanism operative is hoped to be that a not so effective immune signal tries to initiate apoptoses in infected cells. This is a scenario that we expect in chronic HBV, particularly in e negative, because the key cd8 epitopes are adapted and mutated, so the attack CTLs are too weak to push the cell into apoptosis with the signals provided.
However a key mechanism by which the cell avoids apoptosis under stress is the production of anti apoptotic proteins, that block milder apoptotic signaling. By introducing the SMAC/DIABLO mimetic birinapant, these antiapoptotic protectors are themselves inactivated, so now apoptosis happens.
The drug has been used in several human cancer trials, side effects seem to be very mild, the worst being Bells Palsy, reversible.
The mouse data are stunning, hbsag was lost in 4 weeks. But of course the model has its limits and the human situation can be quite different.
the biggest fear was or is that the effect is too strong and if a large percentage of liver cells are infected, acute fulminant hepatitis could result.
The plan apparently is to start with patients on antivirals which are UND and also to use a very small starting dose.
Just got this reply from WEH, it is a routine seminar, so I don't think it is related to the clinical trial. Just have to wait.
"Thank you for your interest in medical research at the Walter and Eliza Hall Institute.
Dr Greg Ebert is presenting a seminar here at the institute in Melbourne next Wednesday from 1-2pm on preclinical studies into using birinapant to treat chronic HBV infections. The seminar is open for public to attend, however it will not be webcast and no transcript will be published. The presentation is part of our 'Wednesday Seminar' series and is generally aimed at a scientific audience.
If you or any of your members are interested in attending, our address is 1G Royal Parade, Parkville VIC 3052. Our reception staff will be able to direct visitors to our auditorium for the seminar at 1pm."
"Thank you for your interest in medical research at the Walter and Eliza Hall Institute.
Dr Greg Ebert is presenting a seminar here at the institute in Melbourne next Wednesday from 1-2pm on preclinical studies into using birinapant to treat chronic HBV infections. The seminar is open for public to attend, however it will not be webcast and no transcript will be published. The presentation is part of our 'Wednesday Seminar' series and is generally aimed at a scientific audience.
If you or any of your members are interested in attending, our address is 1G Royal Parade, Parkville VIC 3052. Our reception staff will be able to direct visitors to our auditorium for the seminar at 1pm."
Thank you for that information. I am based in Sydney, so to attend I would need to fly to Melbourne. I have written to Walter Eliza Hall for further information. It would certainly be exciting if they have good news to announce on the results of their clinical trial.
Not much is known about Brininapant, and because it targets the host rather than the virus, side effects are always a concern. I believe it blocks IAP (Inhibition against Apoptosis Protein) which is over-expressed in virally infected cells. I also believe apoptosis is driven by TNF? Because WEH has such a good reputation, it certainly raises a lot of hope.
Not much is known about Brininapant, and because it targets the host rather than the virus, side effects are always a concern. I believe it blocks IAP (Inhibition against Apoptosis Protein) which is over-expressed in virally infected cells. I also believe apoptosis is driven by TNF? Because WEH has such a good reputation, it certainly raises a lot of hope.
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