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?

***********************
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

**********************************

[nygirl7]

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.

[banarep]

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.  

[banarep]

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

[Bill1954]

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

[mikesimon]

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

[banarep]

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.

[WriteItDown]

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.

[pcds]

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

[djbn13]

Looks like we will be crossing that line in the sand together.:0)

DJ

[mikesimon]

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

[WriteItDown]

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.

[pcds]

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.  

[CoWriter]

Because after the 14 days the virus came back.  I know somebody who was in one of the studies.

Co

[WriteItDown]

There may well be, but not with the PIs they've tested so far.

[nygirl7]

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.

[spectda]

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.

[mike716]

Way to go!!! Is the trial over? Is his SVR an EOT? How many weeks did he do?

Mike

[mike716]

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

[WriteItDown]

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.

[WriteItDown]

are = arm

[pcds]

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

[Upbeat]

I thought that it was the FDA that required SOC in all trials.

[mike716]

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

[mike716]

Maybe I'm just dreaming. I never was too good with reality.

M.

[mike716]

Don't tell anyone where you heard this, okay?, but it's the people in the FDA who own shares in the pharmaceutical companies that sell Interferon and Ribavirin.

M.

[WriteItDown]

Hi Mike,

My husband got lucky, and had what I would say were mild to moderate side effects.  His worst side effect was fatigue. He slept quite a bit more than usual, and was not able to exercise much, but he did not have to miss work. It seemed to us that he didn't have many side effects beyond what one would expect from standard of care, except perhaps minor gastric upset in the first few weeks. In fact, TMC435 is dosed at a much lower level than Telaprevir or Boceprevir; and there's some speculation that this might account for what seems thus far to be a better side effects profile.

He did not need any rescue drugs. His hemoglobin started out pretty high, about 16 1/2, and I think the lowest it got was in the high 12s. And luckily all his other blood levels stayed pretty good throughout treatment.

He did tell me that only having to do 24 weeks versus 48 made a huge difference for him, because he was starting to get overwhelmingly tired at around the time he got to stop. I think the goal for TMC435 is a 24 week treatment for those who are treatment naïve.

The Phase IIb trial is scheduled to end next April. I imagine they will be running a Phase III trial not so long thereafter, though of course this is pure speculation on my part.

I certainly understand your fear regarding the treatment.  I was extremely scared for my husband before he started.  (He was less so; fortunately for him he tends not to obsess much.) But there's no way of knowing how you'll do.  It seems to be something of a crap-shoot, like so much of life.

I'll be rooting for you!

[Diamando6]

A beast should be beated from more sides, that is my opinion!

[mike716]

I'm sure you've already told me this (problably more than once), but I have a bad memory so please tell me again: What were the factors that made it possible for him to do 24 weeks instead of 48?

Thanks.

Mike

[WriteItDown]

As with many of the new PI's, such as Telaprevir, the hope is to reduce treatment time for treatment-naïve patients to 24 weeks, and such is the case for TMC435.  

The trial was designed so that anyone receiving the trial drug would stop treatment at 24 weeks if s/he had achieved RVR, and was still undetectable throughout treatment.  

My husband was in the lucky 80% to receive the trial drug, and he also was RVR, so the trial protocol dictated that he stopped at 24 weeks.  This was one of the reasons we chose this particular trial -- to give him the chance to treat for only 24 weeks.  (Also, the Phase IIa results for the drug looked very promising.)

I believe this will be the standard protocol for Telaprevir when it comes out, i.e. that you treat for 24 weeks if you achieve RVR and are treatment-naïve.

[mike716]

Everything I´ve read about Telaprevir and Boceprevir seems to suggest that the results for 24 weeks are not as good as those for 48, even with RVR. Maybe TMC435 is better?

[WriteItDown]

Boceprevir is not trying for a 24 week tx. Telaprevir is, and my understanding is that, with treatment-naive people who respond early, their SVR rates are basically the same with 24 or 48 weeks.  Where did you read otherwise?

As to whether TMC435 will be better, much more will be known when their Phase IIb trial results are published. My hunch is that their numbers will be similar, but with a better side effects profile.  But that's anyone's guess.

[mike716]

How come Boceprevir isn't even trying for 24 weeks? Not good enough RVR rates as the other two?

I can't remember exactly where I read about the Telaprevir trials at 24 weeks not being as good, overall, as the 48 weeks arms. Probably it was on CCO, which is about all I read any more, since they send me email updates.

TMC435 is sounding like the best bet. I was a chump not to go for it. (Famous last words!)

Mike

[billm57]

24 weeks of telaprevir is good for first timers only - previous nonresponders will likely need a year - previous relapsers do well with 36 weeks - as to original question - different phases of clinical trials test for different properties - at some point monotherapy has to outperform the standard or the standard plus the study drug - if it can not then monotherapy is dropped

[billm57]

of course im referring to genotype 1 in previous post - i think i read somewhere that monotherapy may be considered for genotype 2 -not sure offhand

[spectda]

"How come Boceprevir isn't even trying for 24 weeks? Not good enough RVR rates as the other two?"

My trial doc said there is a 24 week boceprevir study coming up.