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87972 tn?1322661239

Direct-acting Drugs Danoprevir plus RG7128 Suppress HCV without Interferon

While this still hasn’t been ‘SVR proven’, the preliminary 5 log-10 reduction at 14 days looks very interesting; more in the article from the hivandhepatitis site:

“SUMMARY: Results from the INFORM-1 trial, which evaluated 2 experimental agents that target different steps of the hepatitis C virus (HCV) lifecycle, showed that a combination of direct-acting drugs can suppress viral replication without interferon or ribavirin. As described in the October 14, 2010 advance online edition of The Lancet, the HCV protease inhibitor danoprevir (RG7227 or ITMN-191) plus the polymerase inhibitor RG7128 reduced HCV RNA by about 5 logs in both treatment-naive and previously treated patients, and caused no serious side effects in this 14-day study.”

http://www.hivandhepatitis.com/hep_c/news/2010/1022_2010_a.html

--Bill
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1113735 tn?1273174430
Thank you all for this information, but we all know how long it takes for medication to become available.Good thing is that people have something to think about, but let,s wait untill Telaprevir appear first!
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233616 tn?1312787196
Bali,
well that is the 64 dollar question, yes.
You may recall the NGI-labcorp had such a test, (>2 or >1 depending on who was talking)
then HR said they were discontinuing it, but I'm not going to give up on the idea. Someone somewhere will have that test,
and if I have to draw my own blood and ship it off I will!!

The point here is I beat the horse dead dead with 2 years of drugs and anemia, and if I'm not UND by a certain point then there is no point. I'll cut my losses and live to fight another day...not pound myself with stuff that cannot kill the mutant strains.

Willing,

thanks for the references, I missed that thread and will view the slides.
I just kinda concluded as I did based on the smattering of research papers I had read, but will gladly look at more. Nice to know that the medical community agress with me!!
I did not know that.

As far as the lead in goes, well it's going to be an uphill battle again I fear...the Boca crowd is more in favor the Tels crowd less so...it depends on which company a doc goes with...and in this case...I'll have a struggle just getting the lead-in unless he's kept up...
Maybe, maybe not, remember it took me 6 months to convince him to add Alinia...so if Vertex is saying no lead in is needed...well...

I take it you are convinced that the lead in is crucial???
Can you recall what convinced you?
I know the boce trial with Lead impress me, but has there been more info on that, or did vertex ever get off their behinds  and try???

Gee, I didn't realize you were treating again already. I'll have to go read your updates.
Helpful - 0
895634 tn?1283989210
One day the HCV community will learn from our HIV brothers how to fight an RNA virus.  Hope it gets out quickly,  Makes the most sense to attack the virus at 2 points of replication.

R
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Avatar universal
Well this is certainly interesting if unwelcome knowledge from my point of view.  In the Prove2 trial I had a breakthrough at day 15 but I was not informed about it until I had done my 12 weeks of tela.  So I suppose I must have developed a crop of lean and mean mutations by that time.  Oh cr@p.

Oh well, it's done now.  This info is very useful as it puts to rest any idea I might have had about taking a chance with a new drug unless I absolutely know that it is effective against tela mutations.

I'd appreciate your posting any more info about this that you come across, like the Pockros slides that you mention.  Thanks for this and all the research work that you bring to the board.

dointime

  
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Avatar universal
dointime: Sorry, I may not have written clearly, but believe that the main point is valid - PI-resistant mutations will become more fit over time. That is why some early low-riba and monotherapy trials were criticized as unethical and why essentially all trials will boot you off as soon as VL starts to increase in the presence of PI (breakthrough).  To simplify, let's assume the mutation  in that note on my journal, A156T,  is the only one that confers PI resistance (though in fact there are  lots). So only virus that has a threonine (T) at position 156 rather than an alanine (A) can replicate in a cell in which tela or boce molecules are floating about. For all other virus the drug will bind to the protease and interfere with its job. There is some disadvantage to being A156T which is why those mutants are a minority population (otherwise the drug wouldn't work). Maybe the protease doesn't work as well with a threonine at that position, maybe something else can now bind to the protease and interfere with it etc. In the crowded  competitive world of viral replication, the A156T mutants never get a chance to find out whether it's possible to be both A156T and efficient (maybe pick up a few other mutations that can make the protease work as well as in wild type). However if you give enough tela/boce over enough time (and assuming the SOC drugs don't  eliminate the virus first) the mutants have a perfect opportunity to explore how to improve their fitness. I'm sure Pockros's slides will say this more clearly once they're available but discouraging further evolution of PI-resistant mutants (essentially quitting early) will be a key part of triple-tx.

mekea: yeah, sounds nice doesn't it! I think bms-824393 is BMS' next-gen NS5A follow on. Good news about many of the new drugs is that they are *much* less sensitive to escape mutations than tela/boce. I'm sure this will be part of what the FDA will be weighing over the next few months - is it worth approving what are at this point more primitive drugs (let's hope the answer is YES). It's also why developing resistance to tela/boce is not such a catastrophe. Even if you can never use them again - there will be other options.
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Avatar universal
In February of this year, a woman on the Daily Strength Hep C forum posted that she had just finished an 8 day study which she called "bms-824393".  Here's here post:  

"8 Days in lockdown, no side effects, and I left Baltimore with no detectable viral load. 14 million to untraceable in 8 days!! It may not stay gone forever but I did respond and know that if it does come back I can be treated with the same class of drugs longer term. If anyone wants the study info please message me and I will be happy to share it with you."

Unfortunately, she never came back to tell us if she reached SVR or not.  

Wouldn't it be lovely!!
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Avatar universal
"The great thing about PI-resistant mutations is that they're less fit than wild type. They never get a chance to improve their game because the available replicative space is always taken up by the gung-ho wild-type virus. In the presence of the PI all of a sudden they're the only ones left and viral evolution being what it is, they will learn  quickly how to optimize for survival. Not good for the patient. Breeding bugs that are both fit and resistant to NS3/4A Pis pretty much excludes using any PI of that type in a future tx. On the other hand if you quit early enough, wild-type should bounce back and you can count on the PI to at least eliminate the wild-type again in another attempt."

This is not exactly my understanding of resistant mutations.  I think that resistant mutations are already optimized for survival in the presence of a PI.  The mutation is how the virus escapes being latched on to by the PI.  I don't think that mutations become more fit given more time.  To become more fit they would have to revert back to wild type which is the optimum state for the virus, and they do that slowly when the PI is removed, no matter how long or short a time the PI was used.  

I do agree that if the PI does not get you to UND within a short time - I would say 4 - 8 weeks - then it is probably useless after that and pointless to carry on poisoning yourself with it.

dointime  
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Avatar universal
>Also, I'm thinking if I do the PI/Soc when it's available that I'll quit in > 2 months unless I'm UND with a >1 PCR. What do you think of this >approach. I'm only considering it because I think the 25% that won't >succeed are those that have a new mutant strain, and if the PI
> and Riba at peak levels aren't wiping it out completely by then,
>they never will.
>What are your thoughts on this??

First, good luck with your surgery today. The approach above makes good sense to me. If you have a minute check out the arithmetic in the comment on Trin's thread:
http://www.medhelp.org/posts/Hepatitis-C/A-couple-of-good-links-regarding-Telaprevir-and-Boceprevir/show/1382103
(you'll need the table at the bottom of abstract 216 from the boce "respond-2" aasld presentation and additional data from the second of the two links Trin gave).

The tx is messing with my head in a big way, so it's quite possible, there's a mistake, but if not the conclusion is that if 4w lead in and 8w of soc+boce don't get you to UND it may be time to think about plan B.

The great thing about PI-resistant mutations is that they're less fit than wild type. They never get a chance to improve their game because the available replicative space is always taken up by the gung-ho wild-type virus. In the presence of the PI all of a sudden they're the only ones left and viral evolution being what it is, they will learn  quickly how to optimize for survival. Not good for the patient. Breeding bugs that are both fit and resistant to NS3/4A Pis pretty much excludes using any PI of that type in a future tx. On the other hand if you quit early enough, wild-type should bounce back and you can count on the PI to at least eliminate the wild-type again in another attempt.

BTW, relying on your Dr. to make  these sort of decisions for you may not be so wise. From the advert for Pockros's Debrief talk  (to be included in the '10  "best of the liver talks " summary)

"To aid medical professionals in learning this new information, an enduring document will be made available for reference a few short months following the meeting, both online and in print. “We cannot make true AASLD guidelines,” Dr. Pockros elaborates, “until the drugs are labeled by the FDA. However, we can provide a set of rules to follow for anyone treating patients with hepatitis C.” The slides of the Hepatitis Debrief will be available as part of the Best of The Liver Meeting®.

“All hepatologists don’t know about these antivirals yet,” Dr. Pockros expounds. “These rules are new and our knowledge in special populations such as HIV-coinfected patients and decompensated cirrhosis patients is lacking. This program will benefit anyone who is seeing patients in the next year, hepatologists and non-hepatologists alike.” Attendees will walk away from this half-hour presentation with up-to-date information they may use in treating hepatitis C patients in 2011."

So that half hour of training will likely be a large part of  the background that goes into Dr. recommendations about how to use DAAs in '11. No one has a clue yet. And if there's one thing that's sure, it's that we'll be thinking about all this  more than they will.
Helpful - 0
691935 tn?1421027090
I posted part of an article on the other side about how it seems that HCV is becoming the virus of choice for the big pharma firms as well as some small ones.  They are competing, in a race!! There have been a lot of articles in Bloomberg, Marketwatch, etc.  The big pharmas see it as a profitable endeavor with a market that is forecasted to more than double by 2015.  Whatever the reason, it will help the victims.

"10/29/2010-A number of pharma firms including Merck (NYSE:MRK), Johnson & Johnson (NYSE:JNJ) and Bristol-Myers Squibb (NYSE:BMY) are in a heated race to come up with newer more affective treatments for hepatitis C.  The global market is forecasted to more than double by 2015 to $9 billion.  Large pharma firms are hitting it hard to find other avenues of growth".
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979080 tn?1323433639
where do you get <1 PCR ?
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233616 tn?1312787196
thank you for the great explaination. It's making more sense now.  You are probably right, the Pharms may not lock arms, but then again there have been some aquisitions lately that may have benefit to us, of late.

I'm thinking they can't be too far from at least having maintainance drugs as well, it's just doesn't seem right that they'd continue to resist that approach.
After all, the average HIV person has a VL under 100....and we have 1 million on average. If we were maintained at 50 or 100, then then need for transplants might all but disappear.
Do you think there will be any efforts in this direction?
I'm just kind of blown away that they did this for aids, and yet have no intention of doing it for HCV because of fear of "super strains"....shouldn't they worry with HIV as well?

I mean, obviously the VL that sticks around with HIV is composed of the drug resistant virons, and they could go airborne anytime, in which case the whole planet will be affected, and yet they now medicate all 30 million HIV people and think nothing of it.

So why is there no movement towards this with HCV??? Not that I'd want that to cross to mucosa either, but it seems unjust that the medical community decides one group should be spared while another should just die the death.

Also, I'm thinking if I do the PI/Soc when it's available that I'll quit in 2 months unless I'm UND with a >1 PCR.
What do you think of this approach. I'm only considering it because I think the 25% that won't succeed are those that have a new mutant strain, and if the PI and Riba at peak levels aren't wiping it out completely by then, they never will.
What are your thoughts on this??
Helpful - 0
Avatar universal
"  So even among ifn-challenged null responders two DAAs aren't enough, which is consistent with the prediction from Rong et al. A three DAA combo (NS5B, NS5A and NS3) may reach the threshold  - and of course this is not being tested. On a practical level it may not matter. If even the weak ifn-response typical of null-responders is enough - that's all that matters!"

But will it be enough?  That is my new million dollar question.

dointime
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Avatar universal
Well.  Good on Scotland.  I'm guessing they're not predominantly Geno 1 in Scotland.

http://www.hepcscotland.co.uk/home.aspx

A new campaign has been launched by the Scottish Government to raise awareness of Hepatitis C amongst the public in Scotland. The campaign seeks to make people aware of Hepatitis C as a cause of liver disease,  the type of activities that put people at risk of catching the virus, and that treatment is available in Scotland which can cure up to 80% of those infected.

A separate campaign has also been launched to raise awareness of Hepatitis C amongst doctors, nurses and other health professionals who may come into contact with people living with the virus but unaware they are infected. The aim of this campaign is to ensure that as many people as possible at risk from Hepatitis C are offered a test and, if positive, treated for the virus.

The awareness campaigns are part of the Scottish Government's Hepatitis C Action Plan for Scotland.
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Avatar universal
Also the fact that it takes us so damn long to die from hcv makes it "appear" less urgent, although from the transplant numbers, liver cancer numbers, and deaths from liver disease we know it anything but. It's also not less urgent to those who are at or close to the end of the line, and more of us have had it longer and are getting sicker.
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Avatar universal
The perception by some uninformed people that HIV was a gay disease is also what politicized it and in a strange way eventually created the cohesiveness that caused the HIV community to act and push the government to respond, a lot in the name of discrimination.

The conservative right forced people to take a position, and the government was forced to deal with the accusations of discrimination, and the world suddenly had the horrible reality reality of HIV in their faces.

The HCV community lacks any cohesive force except the fact that we are all infected, you would think that would be enough, but apparently not.

Helpful - 0
Avatar universal
Well, I dd not expect the word w-h-o-r-e-s to get censored, but there it is.
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Avatar universal
"Boy do I disagree with that. HIV is an every man's disease? Right, sure it is. "

I did not say it IS an everyman's disease.  What I said was:

"HIV/AIDS was also able to make it an everyman's disease. "

And what I meant were the organizations working with HIV/AIDS.  There is a book called "The Wisdom of ******" by Elisabeth Pisano and it's an interesting read.  It explains how they had to manipulate the system to get funding and how they had to sell HIV/AIDS to be able to do it because nobody, including the U.S., wanted to donate money for what was perceived to be a gay person's disease only.    And it isn't in Africa and other parts of the world where sexual practices make it much more a hetersexual disease.

What they did was package HIV/AIDS in such a way that they could get funding.  I do believe Hep C will have the same challenge.  The few times that the topic has come up on Hep C in either of the national newspapers here in Canada, the subsequent discussion on the associated news forums generally has a tone of unwillingness to help people who brought this on themselves, which is what HIV/AIDS faced in the early days, I believe.  I think that will be one of the challenges of Hep C as well.

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Avatar universal
"....we'd have to come out of the closet.  HIV/AIDS was also able to make it an everyman's(sic) disease....."

Boy do I disagree with that. HIV is an every man's disease? Right, sure it is.
Helpful - 0
Avatar universal
"I DO blame us, the HCV community  (me included) for being spastically incompetent in our ability to organize a united front. The FDA is the only organization capable of guiding/enforcing co-operative effort in the sandbox. ACT-UP made this happen in '88. We're not even trying. "

Hm.....I've thought about this also and it's the same here in Canada, although depends on which part of the country you're from.  Out in BC, they seem to be plenty organized and doing well.  Not so much anywhere else except for pockets here and there and alot of the support groups are organized by the treating doctor or health unit, when what I prefer to see is a patient-driven support group that advocates for it's own.

Why do you suppose the HCV community is so unorganized?  My own theory is that if we got organized, we'd have to come out of the closet.  HIV/AIDS was also able to make it an everyman's disease.  I don't see how we're going to be able to do that.  Many of the folks getting diagnosed now could still be due to blood transfusions and unsterile practices etc - however new diagnoses are far less likely to have that as a source of transmission and much higher likelihood to be IVDU.  That's not so much an everyman's disease when it comes to new diagnoses and far less sympathy from the general public.  HCV needs to be able to sell itself and the selling point is that the people being diagnosed now caught it years before and are the ones who will be requiring the liver transplants over the next years at great cost if something isn't done NOW.    It takes some real organization to mobilize and make the case.  How to do that, I'm not sure although I have some ideas.  

I know we're having a hard enough time just getting along locally amongst all the various groups serving the HCV population each within their own agenda and finding a way to be cohesive is an ongoing issue.
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Avatar universal
There are actually quite a few  NS5-related abstracts at AASLD10. BMS seems to be pursuing this very aggressively. One related to  this topic is LB8 "Combination therapy with BMS-790052 and BMS-650032 alone or with pegIFN/RBV results in undetectable HCV RNA through 12 weeks of therapy in HCV genotype 1 null responders ". This is their NS5 inhibitor along with a BMS-brand NS3A. They only have results to w12 but these are consistent with spectda's suspicions:

"Treatment with BMS-790052 and BMS-650032 with or without PegIFN/RBV demonstrated similar RVR rates in HCV infected GT 1 null responders. 6/11 subjects receiving 2 direct antiviral agents alone experienced viral breakthrough by Week 12 while a four-drug combination maintained viral suppression in all subjects. Should this activity predict SVR, these results will have significant implications for future combination HCV antiviral therapy. "  So even among ifn-challenged null responders two DAAs aren't enough, which is consistent with the prediction from Rong et al. A three DAA combo (NS5B, NS5A and NS3) may reach the threshold  - and of course this is not being tested. On a practical level it may not matter. If even the weak ifn-response typical of null-responders is enough - that's all that matters!

Thanks for the good wishes - much appreciated. The strategy is ntz + high-dose rbv +soc with a 6-month PI chaser. I'm winding up the ntz/rbv priming and 1st shot will be in a week. Getting back on cussing terms with some old friends (rash, itching and insomnia) I hadn't seen in a while  - and the best is yet to come!

Re the flaming above I should clarify that I don't for one minute blame pharma. They are a machine for making money and there's no sense getting mad at a machine. And I don't blame the FDA - like all government bureaucracies they will naturally gravitate towards the path of least action in the absence of external force. I DO blame us, the HCV community  (me included) for being spastically incompetent in our ability to organize a united front. The FDA is the only organization capable of guiding/enforcing co-operative effort in the sandbox. ACT-UP made this happen in '88. We're not even trying.
Helpful - 0
Avatar universal
I have wondered often if the cocktails of antivirals will only be able to maintain viral suppression as with hiv and hep b, or whether we will always need something else like inf and ribavirin to svr.

I really have my doubts about the direct anti viral svr. I think people are being enticed into these trials of direct antivirals combos thinking a quick und means svr. I wouldn't personally want to be that guinea pig.

It seems of course more likely that interferon will be able to be removed from the mix then riba. perhaps the anti virals in combo with something like Taribavirin will do the trick and reduce side effects.

This study of bms 790052 for prior relapsers and nonresponders to soc includes the initial 24 weeks of either soc or triple therapy, and the remaining 24 weeks with only ribavirin. This makes a lot of sense to me and seems like a logical step towards removing inf from the mix

http://clinicaltrials.gov/ct2/show/NCT01170962?term=bms+790052&rank=2

These pharmaceuticals companies have no incentive to share their information. I think years ago a lot more of the research was done at universities rather then or in conjunction with the pharma companies.  

I wonder if vertex will market vx-222 as co-tela and only sell the two together. what a concept.







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Avatar universal
Very interesting info on the modelling by Perelson & Rong.  Brings the possibility of success with the right combo so close you can almost taste it.  Oh the frustration!  

if, for example, Roche were to market R7128 on it's own with SOC then I for one would ask my doc use it in a combo with a protease inhibitor, whether the mix was tested or not.  Maybe that is why R7128 and possibly a lot of other drugs are being held back - to let somebody else prove the concept and then produce their own killer combo for marketing.

That somebody else seems to be Vertex who have stepped up to the plate again, first with tela and now first with a large scale 2PI trial.  This will no doubt further the cause, and praise to them for it.  

Meanwhile I gather it is looking good for tela to be approved in time to help you at the end of your tx to slaughter any stragglers.  I am very much going to enjoy hearing about that so spare no details when it happens!

dointime          
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419309 tn?1326503291
Thanks, interesting stuff.

It's the yet unbreakable link between research and funding that's landed us in the current game.  Since neither academia nor government has the capital to spearhead research or clinical trials, it's been the case that each pharmaceutical company promotes its own interest in testing their own products .  Until a lucrative collaboration can be devised or enforced, multi-combo cocktails won't get much research time or data until the new drugs become FDA approved. Once the PIs get approval the landscape will change, but we're still a long way from the players in the sandbox not throwing sand in each others eyes...

willing: adding my good wishes along with Bill's.
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87972 tn?1322661239
Thanks for your perspective, Willing. I guess Pharma would be hesitant to share data or proprietary formula with other companies without being somehow forced, correct? I guess we should ask how could market forces be changed to make this attractive; so that Roche, Merck and the others can play in the same sandbox?

What is the reasoning for not including any NS-5 data in the 2010 conference? Marketing again?

I agree; the HCV community lacks the cohesive nature that drove research and funding during the HIV crisis. Interestingly enough, the bulk of HIV/HCV coinfected patients that share their stories in here lately tend to be more frightened about the HCV aspects; many of them consider HIV the lesser problem, and have their HIV well controlled.

At what point will you initiate IFN into your diet; and will you also include NTZ eventually as well?

Good luck, old friend—

Bill
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