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475555 tn?1469304339

Why is research on stand-alone PIs being squelched?

I just saw the following on the CCO website. I just can't understand why, instead of follow-up trials of ITMN-191 (R7227) as monotherapy, the developer has switched to a ITMN-191 + SOC trial? Was there some biomedical reason for this, or is it political pressure, bribery, or what?

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Rapid HCV RNA Decline in Treatment-Naive Genotype 1 Patients With ITMN-191 Combined With Peginterferon alfa-2a Plus Ribavirin

Posting Date: April 25, 2009

    * Randomized, double-blind, placebo-controlled phase Ib trial[1]

Summary of Key Conclusions

    * Rapid and sustained HCV RNA decline with ITMN-191 combined with peginterferon alfa-2a and ribavirin in treatment-naive genotype 1 HCV–infected patients over 14 days of treatment
          o No viral rebound observed in any treatment arm
    * ITMN-191 well tolerated with no serious adverse events

Background

    * ITMN-191 (R7227) a selective inhibitor of HCV NS3/4A serine protease
          o Previous phase I study showed high potency when administered as monotherapy in patients with genotype 1 HCV[2]
    * Current study evaluated efficacy and safety of ITMN-191 in combination with peginterferon alfa-2a plus ribavirin in treatment-naive chronic genotype 1 HCV–infected patients

**********************************
35 Responses
179856 tn?1333547362
I'm doubtful that it's a cover up or bribery more like it didn't work so they had to start over. Everyone knows the person who can develop this stand alone drug is going to be in the loot for good. Since it would make money for big pharma I can't see why they or the gvt would cover it up.

Plus I thought the folks were working towards that with things right now - since they haven't even proven to FDA Tele and Boce I imagine they are steps away from the next big step in medicine that people will 'wait' for that might never happen.
Avatar universal
they tried tele and boce as stand alone drugs and they did not work. right now, if you use a stand alone drug and it does not work, PI treatment is a no go forever,  that might be the reason or like nygirl says they are working on it.  so they must have found something in that trial that gave them concerns.  
Avatar universal
here you go:

ITMN-191/R7227 + Pegasys/ribavirin

ITMN-191/R7227 is also being studied in combination with the current standard-of-care regimen. Stefan Zeuzem presented findings from a double-blind, placebo-controlled, multiple ascending dose study in which 191 treatment-naive genotype 1 chronic hepatitis C patients were randomly assigned (8:2) to receive ITMN-191/R7227 (100 to 900 mg every 8 or 12 hours) or placebo in combination with standard doses of pegylated interferon alfa-2a and weight-adjusted ribavirin for 14 days.

Viral load levels declined rapidly, with HCV RNA decreasing by about 5.5 log10, compared with 2 log10 in the standard-of-care arm. At the end of dosing, 57% to 88% of participants had HCV RNA < 25 IU/mL (compared with 8% in the standard therapy arm) and 13% to 57% had undetectable HCV RNA < 9.3 IU/mL (vs none in the standard therapy arm). Viral rebound did not occur in any of the treatment arms. Overall, ITMN-191/R7227 was generally safe and well tolerated. There were no serious adverse events (AEs) or laboratory abnormalities, and no AEs leading to treatment discontinuation.

InterMune is planning a Phase 2b trial of triple therapy using ITMN-191/R7227 at doses that appeared promising in this study (600 mg and 900 mg every 12 hours and 300 mg every 8 hours).

"We believe that the viral kinetic and safety results reported today provide evidence that ITMN-191 has the potential to deliver superior sustained virologic response (SVR) rates in patients chronically infected with the hepatitis C virus," said InterMune Chief Medical Officer Steven Porter in a press release issued by the company.


http://www.hivandhepatitis.com/2009icr/easl/docs/051209_a.html
87972 tn?1322661239
I believe the ns3-ns4a drugs like TVR and BOC require interferon for clean up; they tend to leave escape variants behind, and IFN is required to mop up behind them.

Bill
Avatar universal
Well, I don't think it is due to a lack of profit motivation. A single drug that worked would make a whole lot of money. And don't we always say that it's always about the money?
Mike
Avatar universal
i think you are correct.  the single dose stuff does well, but is not yet complete.  looking this up reflected that thought over and over again.
971268 tn?1253200799
Oh, Mike, I understand your skepticism, believe me, but in this case it's misplaced.  The reason why they don't test the PI's alone any more is that they discovered that monotherapy causes the creation of resistant variants, just like you were discussing in one of your earlier threads. Unfortunately, they need SOC drugs as well to make sure that, after the PI's knock out the wild-type virus, the peg & riba can mop up any variants.

Of course they would be THRILLED to find a single drug that would work to cure HCV genotype 1. There's no conspiracy.

By the way, thought you might like to know my husband is SVR -- after doing that Phase IIb trial of TMC435.
Avatar universal
I am all about new treatments now that SOC did not work.  I truly believe Telarevir will rule for only 2-3 years.  The next group will be an improvement and Vertex is in phase 2 trials.  I struggle with waiting for the next better thing, but unless this new Mayo doc I see in Oct has some great information, I plan to treat as soon as Telaprevir hits the market.

It's the cocktail of all 3 drugs to sweep up the mutants that is currently needed.  It will be more simple in  the future, but look has long it's taken for these new PIs.  I have seen threads back in 2007 that it was coming soon.  So it will be at least 3 years for the next phase of tx.  It will come because money is to be made.
Judy
Avatar universal
Looks like we will be crossing that line in the sand together.:0)

DJ
Avatar universal
I think you misunderstood me - I was simply saying that it sure isn't a lack of a profit incentive that's slowing things down. Yes, I know about wild type etc and I agree with you about that.
Mike
971268 tn?1253200799
Sorry, mikesimon, I was directing my comment at the OP, Mike716.

I agree with you -- I am myself a skeptic -- it IS always about the money, but I was just saying Mike716's skepticism is misplaced here, because they are 100% correct not to be testing ITMN-191 as a monotherapy. In fact it would be almost criminal to do so, with what they know now about resistant variants.
Avatar universal
I think there may be a monotherapy someday.  It is the holy grail of HCV treatment, but that is likely 10 years away.  I've been reading a lot about future tx.  
568322 tn?1370165440
Because after the 14 days the virus came back.  I know somebody who was in one of the studies.

Co
971268 tn?1253200799
There may well be, but not with the PIs they've tested so far.
179856 tn?1333547362
I know somebody who was in one of the studies. "

A good friend and member of this community was one of the folks who did not get riba with the PI and interferon in her arm of the trial and the whole shebang did not work. Why they had to test this crazy idea on her (who has treated ten times) I will never know but it proved that it does not work without the SOC behind it sufficiently to me.

When you know someone who is trying to achieve SVR and then something like that happenes, it makes it all the more personal and you understand why the two other drugs are necessary much more than just reading about it on line.
Avatar universal
From everything I have read. I don't believe scientists expect to control or destroy the virus with mono-therapy. Everything points to some sort of cocktail. With HIV they may take one pill, but that pill usually contains three different drugs that act on different parts of the virus and are effective against different mutations.

If the real question is whether they will have a pill that does not include INF and RIB, that seems to be the goal in the next five years or more. I believe it will definitely happen and that the people that have been infected in the past few years will most likely be able to cure with little or no side effects, In a short period of time, before they have sustained any liver damage.
475555 tn?1469304339
Way to go!!! Is the trial over? Is his SVR an EOT? How many weeks did he do?

Mike
475555 tn?1469304339
When I read this:

" Previous phase I study showed high potency when administered as monotherapy in patients with genotype 1 HCV[2]"

I figured, what the heck, why aren't they continuing to test it as monotherapy? But I guess that question's been answered. And if what nygirl7 says above is true (I have no reason to doubt her, although it's a pretty incredible and kinda awful story), maybe they shouldn't have been testing it as monotherapy in the first place. It sounds like one of those "greed trumps greed" things.

Personally, I'm rooting for the therapeutic vaccine, although if the company developing it doesn't get more funding to run better trials, they'll never prove it to work.

BTW, there was also some stuff in CCO about the 2010 EASL that said that the escape variants of at least one of the PIs aren't reverting to wild-type virus even after two years, so it looks like the issue of what happens to those who do triple therapy and aren't cured is getting more important. If the gov approves any of these PIs without waiting long enough to time and quantify virus reversion, they may be sorry.

Mike
971268 tn?1253200799
Thanks, we're pretty darn happy!

The trial as a whole is not over yet; but my husband finished his treatment at the beginning of this year, and we recently got the news that he is SVR (six months after end of treatment still UND).  He got lucky and only had to treat for 24 weeks. We don't know yet which are he was in, just that he got the trial drug, and was RVR.
971268 tn?1253200799
are = arm
Avatar universal
Therapeutic vaccine.  That's the holy grail of HCV treatment.  Someday, but not soon enough for me I'm afraid, or for the bulk of those with HCV.
Judy
Avatar universal
I thought that it was the FDA that required SOC in all trials.
475555 tn?1469304339
That's great!. 24 weeks, and SVR after six months! Sure makes me wish I'd made a bigger effort to get into that TMC435 trial. Maybe my turn will come this year, if these darn Argentine hospitals can get it together to join the trials.

BTW, how did your husband do with the side effects? Also, did he have to decrease any dosages or go onto save drugs at any point? (Maybe you already told me this stuff, but I can't remember. Sorry.)

The thing that's really been keeping me from making a big effort to get into a trial is, of course, the fear of the side effects. I don't like to think I'm any more cowardly than anyone else, but I have a terrible fear of losing my good physical condition, which I have spent so long and so much effort to maintain (at the age of 66). The thought that a year on Tx could wreck it has put me off completely.

So hearing about othert people's experiences, like your hubby's, is very important to me. Thanks for sharing it with me.

Mike
475555 tn?1469304339
Maybe I'm just dreaming. I never was too good with reality.

M.
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