TITLE: Safety, Tolerability and Immunogenicity of GS-4774, an HBV-specific Therapeutic Vaccine, in Healthy Volunteers
AUTHORS (FIRST NAME, LAST NAME): Anuj Gaggar1, Claire Coeshott2, Mani Subramanian1, John G. McHutchison1, David Apelian2
INSTITUTIONS (ALL): 1. Gilead Sciences, Foster City CA, CA, United States.
2. Globeimmune, Louisville, CO, United States.
ABSTRACT BODY: Background: Chronic HBV (CHB) infection is in part characterized by diminished T cell responses to viral antigens. A therapeutic vaccine enhancing the adaptive immune response to HBV may provide a strategy to improve the rate of HBsAg loss and seroconversion in CHB patients compared to nucleos(t)ide HBV polymerase inhibitors alone. GS-4774 is a yeast-based vaccine (Tarmogen) expressing a chimeric protein comprising of 60 amino acids of HBV X protein, the full 399 amino acids of HBV surface protein, and 182 amino acids of the HBV core protein.. The aim of this study was to evaluate the safety and immunogenicity of GS-4774 in healthy volunteers.
Methods: A Phase 1 study was conducted in healthy volunteers (n=60) to determine the safety and immunogenicity of GS-4774 using different doses and schedules. Doses of 10 yeast units (YU), 40 YU or 80 YU/dose were evaluated as either a) weekly dosing for 5 doses then a single monthly dose, or b) monthly doses for 3 consecutive months. The immune response to GS-4774 was assessed on Days 15, 29, 36, 57 and 85 by lymphocyte proliferation assays (LPA), IFN-γ ELISpot assays, and antibody response to specific HBV antigens.
Results: GS-4774 was well tolerated with no serious adverse events, no grade 3 or 4 adverse events, and no laboratory abnormalities observed in the study. Adverse events were more frequent with weekly dosing compared with monthly dosing and at the 80YU dose compared to the 10YU and 40YU group. There was one treatment discontinuation due to adverse event (skin reaction) in the 80 YU cohort. Available immunogenicity data until day 36 are summarized in the table. The majority of subjects demonstrated evidence of an HBV-specific immune response as assessed by LPA. No dose response in HBV-specific immunogenicity of GS-4774 was observed by LPA, and monthly dosing was similar to weekly dosing. An early HBV-specific T-cell response by IFN-γ ELISpot was observed in a greater number of subjects receiving the 10YU dose. As expected given the cellular immune targeting characteristics of the platform, no antibody response to core and surface antigens was observed at the early time points. Complete immunological and safety results of the study will be presented.
Conclusions: GS-4774 was well tolerated, and elicits HBV specific immune activation at the lowest monthly dose of 10 YU. Further evaluation of GS-4774 in patients with chronic hepatitis B is warranted.
it is good thing that more and more companies coming to fight against HBV
Tuesday, October 8, 2013
ISIS/GSK and Tekmira Come Out with HBV Knockdown Plans
If you did not appreciate the value the pharmaceutical industry has come to place on the HBsAg knockdown concept for achieving a functional cure for chronic Hepatitis B (HBV) infection, the last two days will have woken you up.
Yesterday, ISIS Pharmaceuticals reported that it had received a $7M milestone payment related to the development of an antiviral RNaseH development candidate (ISIS-GSK3Rx, aka ISIS-HBVRx) which, although undisclosed for competitive reasons, has got to be for HBV. And today, Tekmira publicly announced that they will file an IND for an HBV-RNAi candidate in 2014 while hinting at the partnering potential of such a treatment candidate.
Arrowhead Research is thus not alone in their efforts any more. Coincidentally, Arrowhead reported today the completion of their enrollment of the phase I single-dose, healthy volunteer study with ARC520, their DPC-delivered candidate for chronic HBV. Accordingly, the dose escalation was able to run through all the pre-planned 6 dose cohorts up to the top dose of 2.0mg/kg.
Apparently, there were no signs of significant dose-related toxicities. The only finding of concern among the 36 volunteers, 24 of which received drug, was 2 cases of lightheadedness of uncertain clinical relevance. As these occurred at the highest dose, it seems that the company suspects that it could have been drug-related although the study remains blinded for follow-up.
A dose of 2mg/kg without any serious adverse events or dose-limiting toxicities is a great start for DPC delivery technology. This is especially the case when one considers that the single-molecule subQ version of DPC that I hope will form the basis for the upcoming pipeline candidates, except for the next one perhaps, will be much more potent than the two-molecule version of intravenously delivered ARC520 based on the non-human primate data presented at last year's OTS meeting.
With 2mg/kg of ARC520, I further believe that HBsAg knockdowns of over 90% are likely. The biggest challenge going forward with this program will be setting a knockdown goal and getting the dose and dose frequency right.
Well 7m is a nice figure. But if you compare to what research costs today. This is is very small number. Compare it to what DARPA gets funding wise developing mind blowing technologies and goodies for the military. And that 7million is a tear drop.
There are 360 million of us sick with Hbv. And funding for a cure is just not there.
And you have to feel for these small companies too that try to do good getting some funding.for their projects. but most often or not even if they happen to come across something like Replicor did - they wont have the funds to take the product to market. And this is where big pharma comes in. That may buy the project. Or buy it and think about what to do with it in the future.
I went for the screening phase today and await for test results. Hopefully everything is good to go so I can qualify for the study. Been on adefovir and entecavir since 2005 and wonder if I'll ever be off antiviral medication.
Thank you for posting and hope that you will qualify for the clinical trial. It is a pity that quantitative HBsAg assay is not yet commercially available in the State, together with hbvdna, it can lead to a better stopping rule for taking oral antivirals.
Please keep us posted.
I wish I can give you a good explanation, but it is a bit beyond me because immunology is so complex. I will try, but others can correct me.
The current HBV vaccine consists of the HBsAg antigen, a protein. It is very effective in inducing the production of HBsAb, antibodies to the surfact(envelope) antigen. These circulating antibodies will attach to the surface of circulating HBV viral particles and prevent the viral particle from entering a liver cell - therefore no infection.
However, in order to cure patients with liver cells infected already by the virus, we need to induce production of cytotoxic T cells, so called cd8+ T cells that specifically recognise HBV infected liver cells, thus killing or controlling these infected cells. Because HBV viral proteins are produced inside infected liver cells, the surface of these cells express epitopes of these viral proteins in MHC class I complexes. So a therapeutic vaccine has to induce the production of these HBV specific cd8+ T cells.
In order to induce the production of these T cells, special immune cells must present HBV viral antigens in MHC class 1 and 2 complexes. GlobeImmune scientists believes they can achieve this. GS4774 consists of heat killed yeast cells. These yeast cells have inserted into them, DNA that codes for the production of HBV surface, core, and x proteins. So I presume these cells, before they were heat killed, produce these HBV viral proteins inside the cell. When these cells , heat killed and then injected into a patient. The patient's APC (antigen presenting cell) such as the dendritic cells, will engulf these heated killed yeast cells, process and present various HBV viral epitopes in both MHC class 1 and 2 complexes to the immune system. So HBV specific Cd8+ T cells will be produced. Also antibodies to the yeast cells are also produced, the scientists say.
So this is the first half of the story. But a chronic HepB person already has these HBV specific cd8+ T cells, but they are not "effective" due to various factors caused by the immune braking system and HBV evasive mechanism. Whether these freshly produced T cells will meet the same fate or not is what we have to wait and see.
Yes and no. The Chinese had investigated three 3 therapeutic vaccines in the last few years, two by listed companies, one by a well-known academic. The two by listed companies, both completed Phase 2 clinical trials, but results were disappointing, no or slightly better than the control groups. Being commercial companies, they disclosed the minimum information and outsiders cannot learn from their experiences. The one investigated by Prof Wen, a novel HBsAg and HBsAb complex, completed phase 3. Again the results are no better than the control(placebo is Alum) group, even though the loss of HbeAg was as high as 30%. I am sure lessons will be learned from this study, one of them being too much and too frequent injections of the vaccine, driving, as Studyforhope described, the immune system "crazy" and exhausted.
The France has also been studying several therapeutic vaccines, but progress is very slow.
Cuba has of course completed a successful Phase 3 of their NASVAC vaccine. Unfortunately, we don't know whether it will be further developed.
I am sure a lot of the concepts behind these vaccines were tested on animals. Prof Wen when she began her work, spent a million US dollars to purchase a genetically modified mice from overseas.
Another great post. Gilead has also begun a Phase 2 trial of GS4774:
"This study is to evaluate the safety, tolerability, and efficacy of GS-4774 in adults with chronic hepatitis B infection (CHB) and who are currently not on treatment. Participants will be randomized to receive tenofovir disoproxil fumarate (TDF) alone or GS-4774 plus TDF for 20 weeks. After Week 20, GS-4774 will be discontinued. All participants will continue on TDF and will be followed for an additional 28 weeks. Following completion of the 48 week study period, all participants will be eligible for a 3 year registry study."
The trial will take take place in the US, Italy, Canada,Korea, New Zealand, Romania, and Taiwan.
You know looking at it based on what we know it is the immune system of individual that has to do all the work. They are using this vaccine with a nuc. That causes mitochondrial toxicity thus is immuno suppressive. So the effect that this vaccine could have with interferon or zadaxin may not be there.
Look at Repicor they use it with peg or zadaxin. GS4774 is also said to lower hbsag. So logically would be to use it with immune system booster. But no they still want it to be their own brand 1-2 punch.
So this trial may be a wash of nothing in end. But medication may actually work.
I cant say enough how frustrating it is to see ALL the business BS that is going around HBV treatment. Half the time medical students that are doing these clinical trials with their university proffesors have NO clue what so ever what these drugs do to the whole body. That immune system quality depends on the amount if toxins other infections - heath of teeth of a given person.
That it is not just give the medication and cured. We are not at this Point yet. Unless of course they make antibodies against HBV for us like they did with Ebola.
Why not give GS4774 with Imiqumod. GS9620? That will give a better effect no doubt. Because NUCs really should not be used for HBV. These are really strong and toxic drugs designed to slow down HIV. AND HIV infects every living cell in the body. And so do these drugs.
Shutting down mitochondria in the body is equivalent to power a city lights with power plant reactors turned off. In simple terms that is. But for advancedcancer and HIV that was the choice they had to make. To prolong life. But even with those diseases they admit that immune system gene therapy saves lives. Cancer can be cured better and faster with immune therapy based on the same Ebola plantibodies treatment and so can HIV.
You design anti viral anti tumor antibodies that multiply within the host body. And nature takes care of it like a common flue or cold.
And they are being silent about this. Doctors dont like hearing about this. That the so called medical standard today when it comes to treat cancer aids and hbv is not where it should be.
What is upsetting to see is that companies like Gilead dont listen. You cant even get a responce. No one even comes here and openly engages in a dialog with patients on how can all this be done better.
How to improve clinical trials. That reguar clinical trials are really a joke given so few patients and so.few possibilities in drug combos.
I hear what your saying and don't particularly disagree with you but the problem being if the immune system is swamped by viral DNA then that could be tricky. However if its suppressed followed by immune booster i like the 91% of people who did the NUC's + Peg might be a good combo.
But I also have the suspicion it will be TAF 3years + GS9620 = Immune clearance
Think it would be the most lucrative by a mile + Gilead can say we have a "cure" ramp up the price for GS9620 to astronomical levels give out the TAF fro free to so they can appear not be heartless and ease political pressure on thesmelf.
When you have a flue you have billions of its viruses in your body too. Look at viral kinetics. But our boby makes interferon and as much of antibodies to counter and win. Win HBV it is the escape mutant that establishes a chronic infection.
So viral load in itself is a greatly manipulated thing to sell medication. Or to prove its efficacy.
Where as with HBV it must be stronger or there must be a weakness in our system somewhere for it not to clear the virus.
Mate you can see some people on here have developed surface anti bodies but still have HBSAG which is rare but then what can they do?
Thats a sign there is an immune response but there's still some forrm of weakness needs addressing.
I do agree with you in terms ultimately in the end it has to be the immune system that fights the virus off and delivers our personal freedom but its just a question of how we get this to happen my brother
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