VX-950 Clinical trial non-responders

A good  friends  mother has unsuccessfully been treated in the past for hep c and I told her around this time there would be a VX-950 trial for non-responders/relapsers that I would look into for her. Whatever happened to this schelduled trial?  Did they  cancel it?  I've been to clinicaltrials.gov and I still can't come up with an answer for her.

[macna]

Hi,
You are late. The trails started in spring of 2007. I don't think you can get in it now. There shown be more. There is one for people who have never been treated starting up soon.

[andiamo]

There will be a phase 3 trial for non-responders starting in the next few months.  Vertex is meeting with the FDA this month to get approval.

If you want to participate, you need to become a patient at a center that will participate in the trial.

[Willy50]

There are several Vertex trials in the works now.  There's a link to the current ones which are considered phase 2.  Several are for genotype 2, 3 and 4 being conducted in Europe by a Vertex partner Tibotech.  There is also a Phase 2 "rollover" trial for Vertex trial participants who failed in various ways in the phase 2 trials.  Generally that trial is ONLY for people who failed the SOC control arm or the "no-ribiviren arms" of Prove 1, 2 or 3.  Don't confuse these treatment failure arms for anything open to the public.

There may be Phase 3 trials for non-responders.  I've heard that there will not be but as Eric said the news will likely be out very soon.  The scope of the Phase 3 trials are yet to be officially announced.  That means there may or may not be a trial for past treatment failures.  You won't have long to wait I believe; likely less than a month for the announcement.  As Eric said, the trials may fill up quickly; best to be in place and ready to go.

Even if Vertex VX-950 is closed to further trials for treatment failures they have a follow-up drug, VX-500, that is in or about to be in phase 1 trials.  That's a possibility.  I think it quite likely that Scherring-Plough may have another trial in which Boceprevir is given in triple therapy to past treatment failures.   Other drugs to are on the way and show promise.

best,
Willy

[St. George]

I have no way of finding these participating centers because like I said they are not listed on clinicaltrials.gov.  If you know of any of these places in New England I would be most appreciative if you could let me know of the locations.

                Thank You

[Susie2007]

You might try Dr. Ray Chung at UMass. If this woman did not have a 2 log drop at any time during her past treatment she should probably not go into a Vertex Trial. It looks as though those people will not respond to this triple combination either and she could ruin her chances when they add something else. I'm told there will need to be another drug added to SOC and VX950 to have complete nonresponders to Peg + riba possibly respond.

[jmjm530]

Susie: If this woman did not have a 2 log drop at any time during her past treatment she should probably not go into a Vertex Trial.
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Hi Susie,

I know we had this discussion right after AASLD 2007, but now that some time has passed one would think some papers, editorials or articles on what you state.

Also, if evidence does exist, then why is Vertex enrolling prior non-responders in the new trials? Certainly it is not to their advantage to sign up those know will end up not responding to triple therapy.

Is the source of this information still your conversation with Dr. S, or do you have something more for us that someone could pursue.

Hope this finds you well,

-- Jim

[Andiamo1]

The phase 3 trial does have an arm for non-responders.  I am in the phase 2 trial and the center in NY is going to participate in the phase 3 trial.  They don't have all the details yet, but did say that there is going to be a non-responder arm.

The best way to find a center is to call all the major centers near you and ask for the research coordinator in the GI department.  I am sure there are a couple in Boston, New Haven and most major cities.

Good luck.
Eric

[dointime]

"There is also a Phase 2 "rollover" trial for Vertex trial participants who failed in various ways in the phase 2 trials.  Generally that trial is ONLY for people who failed the SOC control arm or the "no-ribiviren arms" of Prove 1, 2 or 3."

I never heard that people who failed the no-riba arms were eligible for rollover.  Do you have a reference for that?  Not that I fancy it, but I really thought the rollover was exclusively for those who failed the control arms.  

dointime.

[Susie2007]

I've been on a couple of conference calls where this is being discussed. The reason Vertex is still enrolling non-responders is that many of them will respond. It's the ones without the 2 log drop who probably will not respond. You won't see papers on this for at least a year or two would be my guess. They won't publish anything until and unless they do a trial with people they know who never got that drop.

[Willy50]

You are correct; sorry.  If I could modify it I would.  I hope that this correction will suffice.  I WISH that they had offered it for the no-ribiviren arm.  Here's the info from Prove 3;

PROVE 3 STUDY ARMS BELOW:
Group A: Patients will receive placebo (a sugar pill made to look like the study drug but does not contain medication), Pegasys® and Copegus® for 24 weeks. Then, 24 weeks of Pegasys® and Copegus® only. Patients in Group A will have the option to receive telaprevir through a roll-over study.

Group B: Patients will receive the study drug telaprevir, Pegasys® and Copegus® for 24 weeks. Then, 24 weeks of Pegasys® and Copegus® only.

Group C: Patients will receive the study drug telaprevir and Pegasys® for 24 weeks.

Group D: Patients will receive telaprevir, Pegasys® and Copegus® for 12 weeks. Then, 12 weeks of placebo (sugar pill), Pegasys® and Copegus®.  

(note only Group A had the rollover)
--------------------------------------------------------------------------------------------
The only reason that I brought it us was the origional post.  St George was asking about a Vertex trial in which treatment failures could treat with triple therapy.

Although this is a Vertex trial....and it IS for past treatment failures......it is a closed trial open only to failures from Prove 1, 2 and 3.  It appears that it is also ONLY for the control (SOC ONLY) groups and NOT the no-ribiviren arms of Prove 2 and 3.  

Thank you for catching the error.  

Best,
Willy

[Andiamo1]

My understanding on probability is the same as Susie's regarding the 2 log drop.

The NY center does not have the protocol details yet, so I don't know the acceptance criteria.  I think the use the term non-responders to include all treatment failures.  People like me that did have a two log drop by week 12 and relapsed after EOT have a very good chance of SVR with triple therapy.

[jmjm530]

Susie: he reason Vertex is still enrolling non-responders is that many of them will respond. It's the ones without the 2 log drop who probably will not respond.
-----------------
But the definition of "non-responder" is someone who doesn't drop 2 logs in 12 weeks. So what I still don't understand is why is Vertex currently enrolling non-responders (no two log drop in 12 weeks) if they know these people will fail treatment? It's not only not in the patient's interest, but it's not in Vertex's interest. Certainly the trial coordinators will have access to a patient's previous treatment history. So unless Vertex is specifically excluding those who didn't have a previous two-log drop by week 12 -- then I still don't understand it.

-- Jim

[Susie2007]

I learned from the post above that I need to be much more careful about the actual words I use. Vertex is not admitting to a thing and I'm sure they won't. Who would? It's the docs who were involved in the trials with patients they have been caring for who are raising these concerns and making these statements to each other. It is definitely anecdotal. I just feel that people should have the benefit of knowing what the hep docs are saying and thinking and they can make up their own minds. At least they won't go into treatment with unrealistic expectations and be horrifically disappointed in the end. I know exactly how that feels. In the early 90's I was told by Amgen that Concensus interferon would definitely clear me. It was made for the geno 1's who did not clear. Well guess what. After a horrific 12 weeks on 15 mcg a day my viral load went up. It gave me the feeling that something was definitely wrong with me. The bottom line is, that Telaprevir looks like a very exciting drug for treatment naive patients as well as relapsers and even patients who got a previous 2 log drop. For those of us who didn't, the doctors do not feel it is our time yet. We will need something to get us past interferon resistance.

And did you guys really think I meant non-responders in the technical way? Sorry about that.

[jmjm530]

Susie: Vertex is not admitting to a thing and I'm sure they won't. Who would?
---------------------------

First, I want to thank you for sharing your insider anecdotes, the more information we have the better.

My main point, to the above, is that Vertex no doubt has all this information. And if they know in advance that previous non-responders will fail if they re-treat with triple, then why would Vertex set up a trial they know in advance will fail? Wouldn't that be their undoing in the long run? Wouldn't then Vertex be better off limiting the enrollment into the new trials to those that responded to treatment the first time (but relapsed) as opposed to non-responders?

Hopefully, we will hear more about all this -- perhaps from either Vertex or these doctors you have spoken with. If they have the stats, hopefully one of them will write something in a journal.

-- Jim

[jmjm530]

As to the word "non responder", thanks for clarification,  I just wanted to be sure what you meant in regards to what the doctors were discussing, and looking back at my previous post, I see that some confusion may still exist.

To be clear for myself, I was using "non-responder" to mean less than a two-log drop by week 12. And if I understand you correctly, it is this group that the doctors think will fail on re-treatment with triple.  I’ll use that definition from now on.

I guess where I’m unclear is what is the basis of the doctor’s concern. Is it from previous Telaprevir trial data where previous SOC non-responders were enrolled? Because if so, then it should be black and white for all to see, including Vertex. Or is that data for some reason not yet available and therefore differences of opinions may exist? In any event, I would think that the answers lie in those trials -- and if not, hopefully someone will publish at least an article on this issue to help raise awareness.

-- Jim

-- Jim

[Andiamo1]

The information I am getting is identical to what Susie is saying and my own personal experience with triple therapy is that relapsers do have an excellent chance of SVR.

I think the reason Vertex is not saying anything is that they do not have enough trial data to prove it even though all indications are pointing to non-responders having low probability of SVR with triple therapy.  I think the prove 3 trial should give them the data.

I am in the leading group of Prove 3 patients in the 48 week arm.  I will complete treatment March 17, so 12 weeks beyond that, that data will first start to be accumulated.  Up to now, only anecdotal information is available.

[jmjm530]

If I'm understanding you correctly, you're then saying that you heard that
SOC non-responders (less than two-log drop by week 12) will not respond to Telaprevir Triple Therapy. Therefore Telaprevir triple therapy only makes sense for SOC responders who relapsed? If so -- and that is what Susie has been saying -- this is important news.

When you say "(Vertex) do not have enough trial data to prove it" -- I thought that trial data was in already for non-treatment naives treating with Telaprevir. Wasn't some of that presented at AASLD 2007?

I guess where I'm still confused ( you say "even though all indications are pointing to non-responders having low probability of SVR with triple therapy") is that if Vertex pretty much has a good idea that non-responders will fail -- then why are they setting themself up for a trial failure? Wouldn't the smarter move be to exclude non-responders from the newer trials. I guess I'm missing something here.

-- Jim

[jmjm530]

Elaine: So...Vertex is excluding non-responders
--------------
I do not believe that is what Susie and Andriamo are saying.

What they appear to be saying is that Vertex is including non-responders to SOC but they will fail. . Personally, I'm not accepting any of this as "good" or "bad" news -- just trying to figure things out and at this point, just a bit confused. One would think that all this would be sorted out before the new round of trials.

-- Jim

[Andiamo1]

I think Vertex would be foolish to jump to any conclusions based on anecdotal evidence and that is all we have at this point.

I think one of the main purposes of the trial I am in is to see if triple therapy for 12 or 14 weeks plus 24 additional weeks of SOC changes that.  I do not think it is a 100% guarantee that non-responders will fail.  So far, the only people that report here as failing on triple therapy are non-responders.

I don't think Vertex or the FDA wants to see a trial set up to boost success rates.  I think they want to definitively define the probability of success for all the various flavors of previous failures.  That works to all our benefits except for those that fail on triple therapy; they might increase their resistance to treatment with PIs.

Eric

[jmjm530]

I mentioned before the AASLD data, but it appears that was only for treatment naives and btw a very good summary here: http://www.hivandhepatitis.com/2007icr/aasld/docs/110607_a.html

I'm not really current on the Telaprevir trials, so do either of you know what trials have enrolled those who treated before (treatment experienced) and at what stage they are at. I imagine this is where the data is coming from that is making the doctors you spoke to so pessimistic.

-- Jim

[FullOfHope77]

Relapsers and nonresponders to SOC is the context that you should be discussing. 2 log drop has only to do with those enrolled in the study and is anecdotal as mentioned.

The study Prove 3 Phase is only for those who have tried treatment and failed.

Hope that helps...

Scotty

[FullOfHope77]

Prove 3 Phase II (sorry)

[Bill200]

My doctor is/was heading one of the Prove studies and he told me that all the Prove studies up until that point (prove 1 and 2) were only open to treatment naive patients.  How is Vertex have any data on SOC non-responders (no 2 log drop) if they haven't done any trials with them?
regards, David

[Andiamo1]

As Full of Hope said, Prove 3 is for previous treatment failures of all types.  It began enrolling patients in late March.  It had two 24 week ARMs: one with no Riba and one with triple therapy for 12 weeks and soc for an additional 12 weeks.

The only data available so far is from The 24 week ARM.  I will be one of the first Prove 3 patients in triple therapy and in the 48 week arm to complete the study March.

All previous studies were for naive patients.

Eric

[jmjm530]

Andiamo: The only data available so far is from The 24 week ARM.
-------------------------------------------
Do you have a link to that data? Does it suggest that prior SOC non-responders will not clear with Vertex triple therapy? Is that why your doctor told you such? Just trying to understand things.

Ful of Hope: Relapsers and nonresponders to SOC is the context that you should be discussing. 2 log drop has only to do with those enrolled in the study and is anecdotal as mentioned.
--------------------

Here's where it's important to define things so there is less confusion. The definition of "non-responders" is less than a two-log drop by week 12 in the context of SOC. It is that sub group that I believe Susie and Andiamo are saying will fail on SOC based on anecdotal information from their doctors. Hope we're on the same page here

[jmjm530]

A few of our posts crossed, so that may explain some of the back and forth. I wasn't at all suggesting Vertex should skew results by not enrolling non-responders.

What I was saying is that if they knew for certain that previous SOC non-responders would fail, then what would be the point of including them in the trial.

Really, just trying to figure out how much weight to put with what Susie originally posted and what you said you also heard. And part of my process is to try and figure out what was the basis of what both of you were told.

Be well,

-- Jim

[Andiamo1]

Jim,

We are on the same page regarding the definition.  The only data available so far is anecdotal from the 24 week arm and from breakthrough reports from all arms.  Most of the breakthrough reports I have seen in this forum are from people in the no Riba arm.  I did see one from  a non-responder though.  I have not heard of any failures of relapsers on triple therapy.

The problem with anecdotal information is that it does not prove anything.  It just give some indication of what might be proved when the study completes.

Eric

[FullOfHope77]

Not sure why I feel the need to say this again but I'll go with it:

Vertex Prove 3 Phase II study was ONLY for relapsers and nonresponders to SOC tx. IOW, if you experienced 48 weeks of Peg/Riba and relapsed or didn't respond then you were a candidate for the Prove 3 Phase II study. Otherwise you were NOT a candidate.

In 2008 the study will focus on tx naive folks and narrow the tx protocol but that's not for this topic.

[jmjm530]

I guess the question then is when will complete data from the 24-week arm be analyzed? Because if the data does end up showing that SOC non-responders will fail on Telaprevir Triple, then wouldn't it be reasonable to stop enrolling new SOC non-responders in their future trials?

[jmjm530]

I don't think anyone has disagreed with that statement.  I was referring to something else but be glad to drop it. The reason I've asked for some clarifications is because it's not uncommon that people are not on the same page in these kinds of discussions. FWIW I have only been talking about non-responder trials and only been talking about non-response in terms of previous SOC as defined by the two-log/12 week rule.

[Andiamo1]

My bet is that the data will not be presented until the entire prove 3 trial is ended and enough participants have passed the 12 week post treatment.  My guess to the answer of your question is that 24 week data will not be released separately.  The earliest we could see 48 week data would be 12 weeks from mid April.  I base that on when most people started in Prove 3 and I am probably too optimistic.

Eric

[dointime]

Here's previous posts where Susie kindly informed us about this:

http://www.medhelp.org/posts/show/341876
http://www.medhelp.org/posts/show/344627

[dointime]

"Because if the data does end up showing that SOC non-responders will fail on Telaprevir Triple, then wouldn't it be reasonable to stop enrolling new SOC non-responders in their future trials?"

Dead right Jim!  This is the next group that could go to the trials like lambs to the slaughter, same as the people who got no-riba arms when we already knew that it didn't work.  Thankfully, at least the people on this forum have been informed.

dointime.      

[jmjm530]

Assuming these results aren't available but strong anecdotal accounts exist, it then makes sense for a previous SOC non-responders to think about waiting till the end of the year when apparently the full data will be released. I was assuming that Telaprevir was privy to the data now, and would therefore not want to lead those lambs (for among other things their own interest) but perhaps other forces are at work such as compliance to FDA trial guidelines that were already set up. It it were me, and I had to make that decision, I'd be writing and talking to a whole lot of Telaprevir trial honchos to get their personal take before proceeding.

-- Jim

[APKhaos]

Does anyone here have a copy of the Telapravir Phase 3 trial design?
If not, then all this talk about 'lambs to the slaughter' and 'Vertex is excluding non-responders' is bogus at best and probably closer to rumor mongering. I'm not nearly as close to the trail design details as I was back before and during participating in Prove 1, but AFAIK the only Phase 3 trial that Vertex is close to recruiting for in the US is for Geno 1 treatment naive subjects.

Prove 3, which is the last of the Phase 2 trials, is limited to subjects who failed previous treatment. Did the Prove 3 trial design make a distinction between relapsers and non-responders? I don't recall that being the case, but could be wrong.

So, it looks like the only other case is the roll-overs from previous Phase 2 trials. The roll-over candidate are those subjects from previous Phase 2 trials who were in control arms or non-Riba arms - period!  Once again, no sub-selection is being made between relapsers and non-responders.

Don't get me wrong here. Taken as distinct classes, relapsers and non-responders may well have different outcomes from a given treatment. Its certainly possible. All I'm saying is that there is no case that I'm aware of where any clinical trial has established that as a fact, and none where Vertex have made that distinction in the selection criteria of their trial design. Once again, I have no connection with Vertex beyond being a very happy Prove 1 24 week tx = SVR statistic.

[jmjm530]

How are you doing. Long time no see.

I don't think anyone was suggesting that Vertex is excluding non-responders from the upcoming trials. More to the point was whether they should be excluding non-responders based on what some are calling anecdotal conversations with trial doctors and what you are referring to as "rumor mongering". Based on what I've read so far, I have more questions than answers, but I do see this discussion as positive as long as folks don't start making decisions without checking things out more for themselves. How is life post SVR for you these days?

-- Jim

[APKhaos]

Hey Jim.
Life post-tx is pretty good. Once the tx funk lifted, I seemed to pick up a step or two all around, both physically and mentally. Getting a lot more done and enjoying it too! Its hard to say just how much of this is due to the lifting of that the terrible uncertainly and supressed fear that we all carry once dignosed, but I suspect that is a very major factor post-tx. I see you are still doing great work here, and helping many more newbies navigate the darkness of the HCV cave. You deserve a medal.

[foofighter]

Was at the doc this week for some tests and during my appointment PA said they will be participating in an upcoming Vertex trial (even though they were not part of any other Prove trial).

Trial nurse chatted me up while I was having blood drawn and said "that's right" and to contact her. They both know I wanted to wait for something better than SOC before I would treat. I have been trying to get my ducks lined up so I can get out to California for a Fibroscan, but have had one health issue after another.

If whatever they have coming up includes SOC for all arms, maybe I should go for it, especially since they rolled over the placebo arm for nonresponders (whatever that is!). I guess a no riba arm is a concern as well.

Anyway, I looked at clinical trials and don't see anything that makes sense.. So, this must be the Phase 3 per your post of the 15th? Hopefully I will get a call from her Monday with more info.

I am a 1A, treatment naive with a liver biopsy that says I am 2/1. It will be two years old at the end of July so hopefully whatever they have going on will happen before then. And that window between  qualifying and before you actually sign on the dotted line may still give me enough time to do the Fibroscan.

[Aquila]

http://biz.yahoo.com/bw/080107/20080107005882.html?.v=1

Telaprevir Regulatory Update for Treatment-Naïve Genotype 1 Patients
-----------------------------------------------------------------------------------------------------

*     In collaboration with Vertex, Tibotec is developing and commercializing telaprevir in Europe, South America, Australia, the Middle East and other countries. Tibotec has obtained formal scientific advice from European regulatory authorities on the telaprevir development program. Following receipt of this formal scientific advice, Vertex has submitted a Phase 3 protocol to the U.S. Food and Drug Administration (FDA) for review. The submitted Phase 3 trial design includes a 48-week control arm and both 8 and 12 weeks of telaprevir treatment as part of 24-week combination treatment regimens. The Company plans to use rapid viral response (RVR) criteria to determine which patients stop all treatment at 24 weeks.

*     Vertex plans to review this Phase 3 clinical trial design, as well as recently submitted clinical data, at a scheduled meeting with the FDA in January 2008. Tibotec is also in the process of finalizing Phase 3 development plans in Europe. Vertex expects to provide an update on its discussions with the FDA no later than February 11, 2008, the planned date of its year-end financial results conference call.


Telaprevir Clinical Development Plans for Treatment-Failure Genotype 1 Patients
-------------------------------------------------------------------------------------------------------------------


*    Vertex is conducting PROVE 3, a Phase 2b clinical trial of telaprevir-based combination therapy in patients with genotype 1 HCV who have not achieved a sustained viral response (SVR) with a previous pegylated interferon-based treatment. Vertex plans to discuss with regulatory authorities in mid-2008 the next steps in the telaprevir development program for treatment-failure HCV patients after the first interim clinical data are available from the PROVE 3 clinical trial.


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

As that last sentence reads, Vertex is waiting for interim clinical data from PROVE 3 before talking to the FDA in mid-2008 about the next steps.  That fits with Eric's progress:  March 17 plus 12 weeks = June 7th.  

I don't think they can get approval for further studies based solely on the 12+12 arm/s of PROVE 3.  They will need some 48 week plus at least 12 weeks of follow up data.

For treatment naives waiting for Phase 3 protocols, Feb 11 is the date to watch.

[APKhaos]

foo: Thats consistent with what my clinic is saying. They are advertising for candidates in the Washington Post to be ready for the Phase 3 screening. The Phase 3 sohort is much larger than the previous Phase 2 trials, so many new clinics not previously involved in Phase 2 trials will be participating. Sounds like you have already found one of those. The clinics are waiting for the final FDA approval of the trial design. When that comes, the flag is dropped. That's when you will see it on the clinical trials site list.

aquila:
Exactly! Feb 8 for Phase 3, which will be for treatment naive Genotype 1 subjects. Their next step for reatment failure HVC patients will not come until the Prove 3 data is in hand, analysed, and reported in the literature.

[Susie2007]

"The definition of "non-responders" is less than a two-log drop by week 12 in the context of SOC. It is that sub group that I believe Susie and Andiamo are saying will fail on SOC based on anecdotal information from their doctors."
................................................................................................................................
Yes, Jim. That is exactly what I meant. Although it didn't sound that way. I apologize for starting the confusion. I will really try to be more careful in how I say things and get the jargon correct.

Adiamo, I think I'm in love. You have explained just what I meant and you seem to be getting the very same information.

My first contact hearing about this was in a CME at AASLD where Dr.David Nelson & Mitch Shiffman gave their impressions about what exactly happened to their patients in the Telaprevir trials. Now, I could be wrong, but it was my impression that Vertex did not look at the complete records of the participants. Dr. Shiffman went so far as to say that it is almost impossible to know for sure who is a true non-responder, who has had a breakthrough, etc., etc. His reason for saying this is that doctors out in the community do not do nearly enough PCR's to know what is going on. For example, most still do a beginning of treatment PCR then 12 week, 24 week, etc. A person without a 2 log drop at 12 weeks, could have had that drop at 10 weeks and be coming up again. The reason that is important is that he claims for a person to have had a 2 log drop at any point in treatment, should actually be considered a responder.

When I was in a intron A riba trial for previous intron A failures, in the mid 90's, for Schering, they took a lot of blood and they also looked at the last treatment the person had as far as VL at start and finish. Do we know for sure that the later trials such as the VX 950 trials,  are actually going to differentiate between true non-responders and those who responded but never reached SVR? Because according to what I'm hearing, the true non-responder, like myself, should wait for that elusive 4th drug to be added. I'm not so sure that the pharma complanies have as much info on the patients as the patients believe they have......an interesting aside....I sat in on a meeting where Vertex discussed whether or not to biopsy patients before they entered the trial. This was a discussion about an upcoming Telaprevi trial for Stage 3 & 4 patients. They wanted to know what the advocates thought. So we sat there with them and talked about the benefits and risks of doing biopsies where there was just one person reading the results in order to make sure that everyone was on the same page as to who was Stage 3 or 4. Some of us felt that the risk of biopsy was too great for Stage 4 people. Vertex listened and did agree not to ask for new biopsies.

APKhaos, lambs to the slaughter and rumor mongering as well as "bogus"?  I truly hope you are just having a bad day. I think Dointime was very expressive as to what he meant. And I try very hard to share information to the best of my ability as I am so lucky to be invited to so many of these types of meetings. The last thing I would do is spread rumors or bogus information. I have not stated what Vertex has done regarding their Prove I and Prove II trial designs. I thought it was fairly clear where I got the information. If attending CME's at AASLD is where you hear rumor mongering, well that's your opinion.

[jmjm530]

From release, and per "APK's" comments to "Aquila",  above: http://biz.yahoo.com/bw/080107/20080107005882.html?.v=1

"...Vertex plans to discuss with regulatory authorities in mid-2008 the next steps in the telaprevir development program for treatment-failure HCV patients after the first interim clinical data are available from the PROVE 3 clinical trial.."
-----------------------------
So if I'm understanding this correctly, it appears that my questions -- and Dointime's concerns -- about enrolling previous SOC non-responders in future trials has been answered. As "APK:" stated, no decisions will be made for treatment experienced subjects until "the Prove 3 data is in hand, analyzed...", i.e. no lambs will be led to slaughter. Sounds like we will know most of the story by mid year.

-- Jim

[foofighter]

Awesome! At least I think it is awesome. An HR thread a while back had me re-thinking participation in any clinical trial and trying to hang on for approval of 950 (or whatever).

I would imagine my Trial Coordinator won't have much info for me until the February date, but if I learn anything at all, I will post the info.

jmjm, get prepared to give your opinion on trial participation (from one "wait-to-treater" to another). Who knows it may look good enough whether you are a stage 2 or a 4 : )

[jmjm530]

Our last posts crossed, but thank you for the detailed response.

A lot of my questions were answered by Andiamo's, Aquila's and APK's, explanation of the Vertex time line. Assuming the anecdotal info you present is correct, there then will be no "lambs led to slaughter" because nothing will proceed until at least the Prove 3 interim data is analyzed.

I do remember you spoke before of Shiffman's comments regarding the definition of non-responder. Without going back into too much detail, I can understand why in some cases that might be difficult, but hopefully more frequent viral load testing will solve this in the future. Hope "Willing" is following this because for some time one of the reasons I've given for more frequent viral load testing is future use when new data or theories arrise such as stated by Shiffman, although not sure I share his concerns 100% but then again he makes the big bucks and I don't :) Anyway, I think there's a good reason that some doctors do weekly viral load tests until UND, and then test monthly.

As to the "rumor mongering", and "APK" -- I respect you both. I don't think you were rumor mongering, but rather sharing with us some very important information that we otherwise would not be privy to. Thanks once more. APK, on the other hand, was just trying to point out that this is not a fore-gone conclusion yet. Over all, I think the diaglogue has been good, and by MH's standards, quite tame :)

As to you and Andiamo -- not sure how your prospective spouses will react, but I do wish you the very best :)

-- Jim

[geterdone]

Man, I thought that is what FOH had said way up there. I seen the yahoo release a couple of days ago and was not confused?

jasper

[jmjm530]

Foo,

Hard to comment fully on the upcoming Phase III trials, but depending on exactly what/how is being offered -- it does potentially present an excellent opportunity for many who are waiting for something beyond SOC, yet don't want to wait until the projected FDA approval date. I'll be happy to offer an opinion, but try and get as much info on the trial as possible, including: how many ARMS, protocol for each ARM, placebo arms, etc. I assume all that is still not in stone, but really not following the Vertex trials that closely lately. It would be nice if there was a simple chart, article or something, that did all that. Between the PROVES and the PHASES it can get pretty confusing. My guess is the same people who come up with these names also do the names for the viral load tests. Trust me, they could never get a job in my business -- marketing :)

-- Jim

All the best,

-- Jim

[willows]

Okay, so I've been reading this thread for three days now and I think I finally understand.  My doc (in 2003) only ordered vl testing at 12 and 24 weeks..and I did have a 2 log drop at 12, but rebounded at 24.  So I did have a response, it was just one that didn't want to last and I have to take some responsibility...it became almost impossible to keep my ribavarin inside me..I had lots of puking problems..so the virus rebounded.  At the time tho, my doc was worried about my weight loss, and his knowledge, like everyone in general...was short...so he took me off tx.  

Today, he probably would have done different, but that is irrelevant.  What's relevant is that I DID respond..so perhaps telaprevir is indicated for me...when it is approved.

And it makes total sense that PHASE III, as in the phase three the FDA needs, not Prove III as named by Vertex....will begin after the meeting with the FDA on February 11th.  At least..the February 11th date is what I find as the most current info online.  There is some speculation that the FDA will request a longer timeline for PHASE III, as in 48 weeks, but I do not understand the logic behind that and am writing it off as pure speculation.  But it will be interesting to see what sort of conditions the FDA puts on PHASE III.....the last step before approval.  And me getting a go at SVR with the triple combo.  And then a go at a very big party!!

At least I think I finally understand.  Jeez, I hope so.  You are all putting so much good info out here, I love it.  Thank you very much.

Willow

[APKhaos]

Somebody needs to explain to me why the FDA insists on a 48 week control arm for the Vertex Phase 3 trial design. It seems entirely wrong-headed.

Does anyone anticipate any statistically important new data to arise from yet ANOTHER 48 week SOC arm comprising treatment naive subjects? There were a raft of these subjects in the Phase 2 trials, so it seems to add no significant benefit to the Phase 3 trial design.

Assuming the Telapravir Arms are 8 and 12 weeks of Telaprivir + SOC followed by 12 weeks of SOC, the truly valuable data will be available once these arms  are 12 or 24 weeks post tx. Am I missing something obvious here?

[APKhaos]

Somebody needs to explain to me why the FDA insists on a 48 week control arm for the Vertex Phase 3 trial design. It seems entirely wrong-headed.

Does anyone anticipate any statistically important new data to arise from yet ANOTHER 48 week SOC arm comprising treatment naive subjects? There were a raft of these subjects in the Phase 2 trials, so it seems to add no significant benefit to the Phase 3 trial design.

Assuming the Telapravir Arms are 8 and 12 weeks of Telaprivir + SOC followed by 12 weeks of SOC, the truly valuable data will be available once these arms  are 12 or 24 weeks post tx. Am I missing something obvious here?

[APKhaos]

Somebody needs to explain to me why the FDA insists on a 48 week control arm for the Vertex Phase 3 trial design. It seems entirely wrong-headed.

Does anyone anticipate any statistically important new data to arise from yet ANOTHER 48 week SOC arm comprising treatment naive subjects? There were a raft of these subjects in the Phase 2 trials, so it seems to add no significant benefit to the trial design.

Assuming the Telapravir Arms are 8 and 12 weeks of Telaprivir + SOC followed by 12 weeks of SOC, the truly valuable data will be available once these arms  are 12 or 24 weeks post tx. Am I missing something obvious here?

[Willy50]

This has been an interesting read.  For now all that I can say is to avoid reaching conclusions.  You haven't heard them voiced yet as fact since the data doesn't support making statements of fact; merely hypothesis.  I think this thread helps in making some of the issues more clear but there are some fuzzy recollections (of which I'm guilty) holes in data, imprecise wording in which makes drawing conclusions even less desirable.  

To the best of my knowlege the Prove 3 allowed all types of treatment failures in (some of which presumably were null or non-responders).  Yes; the overwhelmin majority of failures tended to be in the early term of treatment.  It looks as if the response is durable during treatment that the response will remain durable after EOT.

All Prove (1, 2, and 3) trials so far have had a "control arm" (SOC only).  I believe that those who failed in the SOC arms were allowed to enroll in the "rollover trial".  IN such as case Vertex will possess very solid data on those who failed the SOC arm (once again presumably some of which will be the null-responders with the theoretical interferon resistance).  ONLY when this group is tested with triple therapy will there be decent data and their response to triple therapy with TVR.  IF rescue drugs are allowed we may see a sampling of what response rates could look like after (and IF) the drug gets approved.

I'm not sure if we know what percentage of treatment failures are null-responders.  Would it make a difference to know if we are talking about 1%, 10% or 50%?  My feeling is that IF the interferon resistant people were 100% ....then one might conclude that sheep were being led to the slaughter.  On the other hand.....and perhaps reducing this to the absurd..... but IF resistance to interferon only accounted for 1% then to make such a statement would be ill advised.  IF it were 1% then 99% might see benefit in the trial (and if 10% then 90% might see benefit in the trial etc).

So far as the "failure" of the no-ribiviren arms .......there were some SVR's from that trial but even in failure they were able to learn that ribiviren was needed to substantially raise the response rate and SVR rate.  They may have learned that the magic number for triple therapy may indeed be less than 12 weeks.  For this reason there has been talk that the Phase 3 trials may also include a shorter triple therapy arm; perhaps an "8 & 12" in addition to the "12 &12".  The viral kinetics and results of the trials may support trying a shorter treatment for some groups.

I think that I agree with Dointime that after the "no ribiviren arm" produced less than stellar results in Prove 2 that it may have been redundant even perhaps harmful to enlist another group to prove the results again, especially presumably if they might be even harder to treat successfully.  That group would have stood more of a fighting chance with triple therapy for 6 or 8 weeks followed by SOC.  That would have provided a better new set of data than replaying the Prove 2 no-ribiviren results.  That's the deal with these trials though....... they are doing the trials cause they don't know the answers and have to PROVE them.  Woulda coulda shoulda; it comes with the territory.  Even in failure there is information gained that increases the likelihood of success in the future.  Indeed; Vertex may have some sort of proof that a rollover of the no ribiviren arm into triple therapy may have proven fruitless.  It seems in some ways that it may have been reasonable thing to try.  YET, when you notice that Vertex didn't it leads one to suppose that there could be a reason they didn't; perhaps the results would have been poor.  I don't know.  It just never was proven in trial.

I think we will see some of the fruits of the studies when the Prove trial stats are revealed.  I think we'll see even more when the Phase 3 trials are started.  I think we'll have plenty to celebrate when EASL finally rolls around this year.  I'm also looking forward to seeing/hearing about the Boceprevir results.  Before too long we may be reading and posting about the follow-up drug VX-500 which will soon be providing data in phase 1 trials.

Getting back to the concept of interferon resistance..... wait for the data.  EVEN if there is resistance some may respond when countered with a superior force like triple therapy.  Even IF the theory is sound try to keep in mind that the percentages of those affected may end up being smaller than is feared and that ultimately even those can be overturned with newer and more potent treatments on the way.

Hang in there and keep the faith.

willy
(I have a question; how would one discern the difference between one with interferon resistant virii and mere insufficient immune response?)

[Andiamo1]

According to my doc, there are no interferon resistant virions, since interferon does not directly attack the virus.  It works through our own bodies anti viral capability and that is where the problem lies.

Eric

[Aquila]

I think the FDA plays a role in determining trial protocols, especially in Phase 3 trials.  Or at least they must approve them.  As a drug approaches regulation, the FDA decides what makes it to market and what dose is deemed safe and efficient.  It appears to me that the no-riba arm doesn't work so I feel that it would be the FDA as well as Vertex that would nuke having a no-riba arm in Phase 3.  It's in nobody's interest to have patients fail treatment.

As for the control arm, it would be nice to think there is enough data about 48 weeks of SOC results to make a control arm redundant.  However I think a trial needs a control arm to make it "controlled".  No way around that.  And since SOC is 48 weeks, there will surely be such an arm in the Phase 3 trial.  Maybe they will make it a smaller group of patients though than in the earlier phases.

More speculation.

[Aquila]

By the way, in the Phase 2 trials of Roche's polymerase inhibitor R1626, the protocols have recently been announced and patient recruitment is underway.  

There are 7 arms, including a 48 week SOC arm, but the VERY INTERESTING thing is there are 4 arms with 90mg of Peg.  I have never seen any trials of new drugs in which they combine with Peg and Riba but use a half dose of Peg.  When I Googled 90 mg Peg the only thing that came up was data from HALT-C and maintenance dose of Peg.  That trial showed that maintenance dosing is ineffective.

So I find it very strange to have not just one but 4 of 7 arms of a Phase 2 trial where they use the new drug with only 90 mg of Peg, and full dose (1000-1200) of Riba.

Any input on that, anyone?  Sorry to get off topic.

Aquila

[willows]

Sounds like an extremely large study and I agree with you...kind of strange.  But the idea of a reduced dose of IFN sounds just dandy to me if it works.  Now if they could just get the riba dose reduced, perhaps I would not be so full of dread when I consider re-treating again.  

With all the new drugs being worked on, there will a be "nearly" perfect combination by about 2010, I just know it.  I have to believe this....and I can wait until then...but not alot longer.  I ain't as young as I used to be!  Lowered doses of SOC, with additional help from PI's sounds like almost perfect to me.  Four drugs to attack all the different aspects of the virus, plus boost my own immune response to virus....it sounds like a LOT better chance that standard SOC.  

I can hardly wait!

[Aquila]

I'm with you, willows.  I can wait til 2010.  I think.  At this stage I'm feeling pretty well even though I'm stage 2-3 grade 0 but as we know, with this virus things can change quickly.

And the half dose of peg sounds dandy to me too - if it works.  I think we've learned from the no-riba arm of the PROVE studies that in phase 2 trials they're still experimenting and don't necessarily know what works.  The fact that it's Roche trialing their own Polymerase Inhibitor with their own SOC tends to give some feeling that they know what they're doing.  But in the phase 1 trial of the same drug they used the full 180 mg dose of Peg.  Very strange indeed.

I found the podcast from Vertex at JPMorgan very interesting in their approach to future treatments.  This may be posted elsewhere but I'll put it up again anyway.

http://tinyurl.com/3aghx5

It is accompanied by a slideset which you have to click to advance yourself but it's worth it to try to keep up.  The charts help with understanding what is being said.

Overall this presentation does not address the items he himself states are what people are most interested in, ie Phase 3 protocols, treatment centres and start dates.  But it does give a very interesting profile of hepC itself and where the company is heading.

Of note is that there are 170 million people worldwide with hepC and most of them were infected in the mid seventies to late eighties.  It is expected that those people, if not treated and cured, will lose 8 - 12 years in lifespan.  That's us, kids.  Treatment rates are decreasing, with treatment duration the greatest deterrent.

Vertex is expecting that they will become the first new drug to market and will initially capture the "low hanging fruit" which is the treatment experienced population who are waiting anxiously for new drugs.  

They are looking at treatment duration of 8-12 weeks of Telaprevir with RVR critical, ie without RVR then treatment would be extended.  

Vertex is also already developing VX500 to follow VX950 (Telaprevir) and they expect to initiate Phase 2 trials of it in 2008.  Things are moving along.  The goal is to create treatment that consists of 2nd Generation Protease Inhibitors + Polymerase Inhibitors + Novel Interferons -  getting rid of Ribavirin which is the real killer in current treatment.

One of the slides shows their expectation of huge sales of Telaprevir in 2012 which indicates to me, without them saying so, that they expect it to take 5 years before it is approved and widely marketed.  That is what the US share market analysts were predicting when they downgraded the share price.  I hope to not wait 5 years for it but with other drugs hot on their heels perhaps the market will be driven forward faster.

[willows]

My very special specialist in Washington state believed...as of last year...that I might get lucky and it would be the end of 2009 or early 2010 when telaprevir was approved.  Now a few years might not make a lot of difference in people years, but in virus/liver years, it is huge and if I have my druthers...well, I'll take the druthers and the telaprevir in 2009, thank you very much!

I realize that the older I get, my chances get slimmer that I can take the tough regimen of tx to a successful SVR.  So I get a bit antsy doing all this waiting.  I was a stage 2, but last year my bx showed two areas of stage three.  So it's getting more important to me by the year.  How do we balance...feeling like we need to do something sooner than later...with the knowledge that there are good alternatives we have to wait for...on the way?   Slowly yes, but on the way?  I struggle with it every day.  

I know if I walked into another doc's office that I could try to tx again and they would agree.  My current doc says 20% chance, now that isn't very much, but it is 20% more than sitting here on my thumbs.  What a pickle.  Usually, I love pickles.  Not this one tho.

Great info, thanks.  As for the market, Vertex gets tossed around like a bottle in an ocean storm, has now for two years.  I just hang on and try to keep track of it, both for the excitement and because I have such a very big stake in the success of Vertex.  Keeps me thinkin all the time...and that's a good thing.  I will never get rich from Vertex, but man, if I get well?  Hooha, how can I put a price on that?  In the meantime....what a freaking rocky ride!  I'd like to go to sleep and wake up when I feel better...about 2010.

Take care.

[fightit]

If we don't know how many true null responders were in the vertex trials then what will the results mean to us?
I see the logic in what some are saying that triple therapy will not work for non responders. We may have to wait until it is on the market before we start seeing any worthwhile stats that will be conclusive one way or the other.
I still think it hasn't been shown that it will or will not work for non responders. The sooner it is approved and is being used by many, the sooner we will know if the non responders have a chance at SVR. I personally haven't given up hope that there might be a chance that it will work. If not vertex then some other combination of drugs.

[dointime]

" Even in failure there is information gained that increases the likelihood of success in the future.  Indeed; Vertex may have some sort of proof that a rollover of the no ribiviren arm into triple therapy may have proven fruitless.  It seems in some ways that it may have been reasonable thing to try.  YET, when you notice that Vertex didn't it leads one to suppose that there could be a reason they didn't; perhaps the results would have been poor.  I don't know.  It just never was proven in trial."

I think that's a reasonable assumption Willy.  The fact that nobody on the planet has been treated with VX950 for a 2nd time may well imply that Vertex does not believe that would be a winning strategy.  This can only be because of resistance issues.  

This is just my speculation but I wonder if their VX500 has been engineered to kill all the resistant variants that they found emerged out of treatment failures of VX950, in addition to the wild-type virus?  One thing for sure - I hope that VX500 fixes the rash problem.    

But do you notice the lack of information on VX500?  What do they mean by '2nd generation protease inhibitor'.  One would assume it means there have been significant improvements but I can't find any details of what those improvements might be?      

dointime    

[susan400]

I am wondering if this was the combination of drugs that my Hepatologist referred to, when he mentioned talking to me about a '4' drug regimen, when I come in for my appt. in April.  He did not mention anything definite, but did say that he had something in mind to discuss w/me regarding the above, on my April appt. coming up in April 2008.  I also was told back in Oct., the VX was discussing a rollover for group C (no Riba) group...but that it would be a 'change to the original protocol'.  So, I've basically just heard these whispers.  At least now I know that if I did ever treat again, that I'd know ahead of time, to prevent any sun exposure on the VX, since I had significant rash issues of VX+sun.  That's all I know about it.

Susan

[Willy50]

I do not want to believe that the resistance issue is going to be a great one.  It may be..... I'm starting to hear talk about it but I still don't want to believe it.

I didn't quite understand why they did the no-ribiviren arm with the Prove 3's again after tepid results with the treatment naives of Prove 2.

I didn't understand why instead they didn't do a short course of ribiviren in Prove 3 instead of the no-ribiviren arm for a second time.

I didn't understand why not allow a no-ribiviren arm failure to TRY triple therapy after failing that arm.  Why do SOC's get a rollover treatment but not the no-ribiviren arm? (sorry, I can't remember which arm that was and don't want to look it up)  You might draw conclusions about resistance being the cause.  But, if you were already resistant (from the exposure of TVR and IFN-no ribiviren) what would be the harm in trying a second time with triple therapy?

One could conclude that there was a reason....... but.....I'm still holding for waiting for the information and data to come out.  We'll get our answer at some point in the future.  There is SO MUCH that I don't understand about HCV, current treatments and trial treatments..... it's a lot more that I do know.  They seem to be creeping closer and closer to having a good treatment for us.  There will likely be some news presented on the Vertex Annual report in a few weeks; both on VX-950 and VX-500 (which is in mid phase 1 trials)

Susan, at one time Scherring-Plough had partnered the right to combine the use of Boceprevir (a protease inhibitor) and HCV-796 (a polymerase inhibitor).  My understanding was that HCV-796 was dropped from trials due to liver toxicity.  I don't know if it is truely dead in the water or whether it could be used or partnered in a smaller dose or for a shorter period of time with a PI (like Boceprevir).

willy

[susan400]

I was in the Prove 3 Group C (no Riba) group.  I did have a response - in fact, quite a big one in the first 4 weeks, but I didn't clear it in 4 weeks, as was the requirement to stay on it past the first stage.  

I have no idea what drugs my doctor was thinking of.  For all I know it might be Alinia for the 4th drug.  I won't know anything until I see him in the spring.

Susan

[Andiamo1]

In a Webcast today, Vertex said that of the patients that achieved RVR and were undetectable at week 12, there was a 6% relapse rate.  The also said the rate did not vary with treatment duration between the 48 week and 24 week arms.

I prefer to think about it as a 94% SVR rate :).

Eric

[KDH59]

As a non-responder too. I really feel that they are going to skew the results buy not allowing Non Responders in..... FACE IT PEOPLE IT IS ALL ABOUT MONEY..

[Willy50]

It would seem from listening to the latest news from Vertex that the results of the trial (prove 3 for past treatment failures) may have been successful enough that they might try to treat it as a registration trial for past non-responders.  Their wording was pretty fuzzy and guarded.  Yes, I wish that they could skip yet another SOC "control group" and replace that arm with another treatment failure arm.  That way they will have had several treatment failure arms as well as several naive arms.

I may be right or wrong, I don't think they are trying to hide anything.  I get the feeling that they are proud of the response and that they are in the lead in regard to positioning with the strongest antiviral response, PROOF of concept with lots of DATA, and the strongest response rate so far in treatment failure populations.

I don't follow everything but they are the scientists and they are the ones that have to deal with the FDA.  They seem to have carried this compound thru trials further than anyone has yet carried a PI.  Have some faith; we'll get there.

Willy

[wguimb]

Is there a site with a table of all current HCV treatments/drugs and what there current status is?  Sorry, if this is naive question but I haven't been following the Hep C news lately.

[HCA]

Yes here;
http://clinicaltrials.gov/ct2/results?cond=%22Hepatitis+C%2C+Chronic%22

[Bill1028]

This may help:

http://www.hcvadvocate.org/hepatitis/hepC/HCVDrugs.html

[Magnum]

Just spoke to Cedars-Sinai hosp. in Los Angeles today regarding why I haven't been called after being in line for 6 months for the VX-950 clinical trial. They have no answer, but they said that a new trial will start at the end of this month. There is hope?

Magnum

[wguimb]

Thanks so much for the info.