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

[willing]

Upbeat: yep, VRTX, Roche and BMS are all pursuing multi-DAA cocktails in which they own all the ingredients. NOBODY is testing best-of-class, multi-vendor, multi-DAA cocktails. The best strategy for the stockholder is deadly, or at least hazardous, for the patient.

MB; have no access to detailed content at the moment but in summary I believe the resistant mutation issue can be summarized as simply selecting the fittest for survival. The high HCV reproduction rate coupled with the high error rate of its polymerase results in a broad distribution of sequences. The results from modeling by Perelson et al indicate that of all possible 9600^4 HCV genomic sequences representative examples of all viable sequences are present at any point time. For example,  some of your infected liver cells, already contain virus with A156T and other mutations resistant to tela and boce. If you start taking  a PI, those virions  will be the only one still doing business and those cells the only ones cranking out new infective virus. Again from mathematical modeling (may seem abstract, but it's the only effective tool for studying this ) Rong et al found that the threshold required to overcome this Houdini act  is a cocktail from which the virus cannot escape without 4 or more evasive mutations:
http://www.ncbi.nlm.nih.gov/pubmed/20445200

Hence, like a chessboard, cutting off paths of escape is the key - not time. Once you approach checkmate, victory is quick:
"if drug resistance could be avoided by using combinations of direct acting antivirals, 95% of patients might achieve SVR within 42 days and 99% within 56 days. "
(Guedji and Perelson, abstract 962, AASLD'10)

[Upbeat]

Same approach Vertex is taking with the vx-950 and vx-222 compounds.   Sure am dissapointed I never was allowed into this trial.  All for 7000 platelets.  They expect RVR in 2 weeks and treatment stop in 12.  Almost makes you wonder if the new PI's with SOC is old news even before it comes out.

[merryBe]

I have to laugh....but do you think glacial really covers it....it reminds me of when the pope first looked through a telescope...and continued to proclaim the planets as flat for another 50 years.   Imagine how Pasteur must have felt trying to get clueless icicles to accept germs.

So now you know how I felt when I read that Inovios vaccine will knock out 98-99% of the virus NOW in only a day or 2, with NO side effects.  And yet here we go glacial again. Why the most promising things go ignored is beyond me.

I think though the question will remain for sometime as to whether we can expect any PI, or vaccine for that matter to do a total mop up without the INF. That remains the crucial question to which NO seems to still be the present answer.

However, don't you think that given the 48-72 hour window in which many now say is all the time it takes to get a wild strain that the vaccine approach, knocking things out in 2 days vs 2 weeks, would seem the more reasonable way to go?
I mean in light of the mutations I really don't understand why the focus is even still on the things that can't achieve this within the 72 hr limit... when there are vaccines, and evn some new drugs able to achieve it.
If you can explain to me why they are focusing on things likely to still lead to mutations I'd love to know what that reasoning could possibly be as it truly, truly escapes me.
mb

[willing]

thanks for posting Bill, but this just makes my blood boil (must mean the rbv is reaching optimal level). This is not news, it's reason to be p.o'd.  It's been obvious for at least 5 years that combinations of DAAs targeting distinct viral proteins is the the way to quickly knock the virus on its a**. There are two NS3 targeted proteases about to pass FDA approval. Roche has been sitting on a very good NS5B inhibitor (r7128) moving it forward at a glacial pace (there is not a single R7128 abstract in the upcoming AASLD10)  Do you think there has been a single trial anywhere in the world testing the tela/boce+r7128+soc combination? Nada. This combo  could quite likely quickly NOW cure a large segment of the hcv   population for whom soc-only based regimes have failed. But test it ? Nada. Meanwhile Roche continues to dicker around with its very own NS3 protease. But hey, it's all good. After more of us slide towards cirrhosis and hcc Roche will be able to sell us plenty of palliative care support.

"On October 11, 1988 ACT UP closed down the U.S. Food and Drug Administration (FDA) outside Washington, DC, to protest the slow process of drug approval. They argued that because there were few treatments for AIDS, new drugs should be reviewed as quickly as possible. The FDA streamlined the review process for key AIDS medications including AZT, and within a few years introduced rules to fast-track approval for drugs that could save lives. "
http://apps.nlm.nih.gov/againsttheodds/exhibit/action_on_aids/fighting_discrimination.cfm

the HIV community fought hard to get HAART. The HCV community does nothing and gets watchful waiting. It's the 2004 tsunami vs global warming.

[blondie717]

A simular study is going to or is recruting. It uses Danoprevir and other with dano, but has Soc included with this trial. 4 arms. I did not read it all because it is not in my area. But everywhere else....It is # NCT01220947....I am noticing that on www.clinicaltrials.gov   That just because they say not recruiting yet, does not mean it is so. The clinical trial I have been accepted in does not say it is closed yet, but it is...so just because it says not recruiting yet, does not nessarly mean it is so. This NCT does not have many exclusions. I would cherck into it if I had not just got a job. It is enrolling 405 peoples. sounds better than my 39. I hope this is usefull

[nygirl7]

New Hepatitis C Drugs in the Works
Study Show 2 Experimental Drugs Are Able to Reduce Virus Levels in Blood
By Salynn Boyles
WebMD Health NewsReviewed by Laura J. Martin, MD Oct. 14, 2010 -- The long wait for new drugs that cure hepatitis C virus (HCV) may soon be over.

In early research, a combination of two experimental, oral, direct-acting antiviral drugs dramatically reduced levels of the virus in the blood of infected patients over two weeks of treatment.

And studies of other experimental drugs that also directly target HCV are under way.

For decades, injected interferon and oral ribavirin have been the only treatment options available, but only a small fraction of patients have access to the drugs. And many patients who start them soon stop due to side effects.

Today’s standard HCV treatment -- combination pegylated interferon and ribavirin -- cures about half of patients with genotype 1 HCV. Genotype 1 is the most common HCV type in the U.S. and the hardest one to treat.

“We are on the eve of a new era in hepatitis C virus (HCV) treatment,” HCV expert David L. Thomas, MD, of Johns Hopkins School of Medicine writes in an editorial appearing in the Oct. 15 issue of TheLancet.

He adds that in the foreseeable future, “nearly all those who are treated might be cured.”

Avoiding Drug Resistance
Researchers say the newly published study represents a “proof of concept” that the combined oral direct-acting antiviral therapy similar to that now used to manage HIV can dramatically lower virus levels. But longer studies are needed to determine if the approach can cure patients by completely eradicating the virus.

Direct-acting antiviral drugs work by blocking viral replication. When the drugs are given as single agents, patients typically become resistant to them, often within as little as two to four weeks, study researcher Edward J. Gane, MD, tells WebMD.

“The point of this approach was to use a combination of direct-acting agents that have different mechanisms of action to avoid resistance,” he says.

The study included 88 patients with chronic HCV infection living in New Zealand and Australia, treated for up to 13 days with various doses of a combination of the experimental antiviral drugs RG7128 and danoprevir or placebo.

All the patients had genotype 1 infections. Some had been treated unsuccessfully with interferon and others had never been treated before.

Over the course of treatment, HCV levels in the blood of some patients who took the experimental drugs dropped so low that they were undetectable.

Few treatment-related side effects were reported, even at higher doses. And none of the patients developed drug resistance.

New Treatments Coming
Perhaps most significantly, patients who had been treated unsuccessfully with interferon responded almost as well as those who had never been treated.

“Right now we really have nothing to offer patients who have failed interferon,” Gane says. “This would be a big step forward.”

The researchers estimate that the total treatment time to eradicate HCV infection would be about 8 to 12 weeks -- about one-fourth the length of a standard course of interferon treatment.

They hope to confirm this in future studies and to determine if adding ribavirin to the treatment regimen improves outcomes.

Thomas says it remains to be seen whether this combination or another combination of direct antiviral drugs will prove most effective.

“But there will be interferon-free treatment of hepatitis C. It is just a matter of time,” he tells WebMD. “This is the first study to be published that moves us in that direction, but it won’t be the last.”