Direct-acting Drugs Danoprevir plus RG7128 Suppress HCV without Interferon

[Bill1954]

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

[Trish77]

"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.

[willing]

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.

[spectda]

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.

[dointime]

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          

[eureka254]

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.

[Bill1954]

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