VX-950 Clinical trial non-responders

[St. George]

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.

[wguimb]

Thanks so much for the info.

[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

[Bill1028]

This may help:

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

[HCA]

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

[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.

[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

[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..

[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

[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

[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 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

[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    

[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.

[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.

[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]

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]

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

[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.

[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

[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?)

[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?

[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?

[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