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29837 tn?1414534648

The rules at Cedars-Sinai for VX-950 treatment

Got a call from Dr. Porodad's office at Cedars-Sinai Medical Center in Los Angeles, one of the sites holding VX-950 clinical trials.

Here's the interesting point. Non-responders (like myself) are soon to be entered. However, there is a perquisite. If you want to go near the front of the line, you MUST get a liver biopsy before they will enter you there. If not, you will be at the back of the line... Hmmm....

The costly part for myself and any Las Vegan Heppie, is that you must drive there approximately 14 times in the one year period. That's a 600 mile round trip, or approximately 9000 miles...

They are very helpful, but the bottom line is that they must follow the guidelines of Vertex Pharmaceuticals.
This is a tough decision, but the bottom line is that my life could be at stake.

The 2005 biopsy showed Bridging Fibrosis, borderline Cirrhosis. I've had Hep C for at least 14 years. I think I'm going to go for the biopsy and the (5th) treatment, albeit there is a 33% chance I may get a Placebo instead of Telepravir. I will find out next week or so regarding... If I get the placebo and don't clear (for the fifth time), will I then get the VX-950? Rules, rules, rules... I will keep you posted as to what will happen...

Magnum
18 Responses
Avatar universal
It sounds as if this would be a great opportunity for you.  Go for it; the odds look good for you.

I hope that you are correct about them accepting some past treatment failures as there aew a few people that I know who might be interested.

The sad news that I have is that I have heard that there may not be a roll over trial.  I don't know if that is "set in stone" yet.  IF there was a roll over one would get the triple therapy sooner or later.  They would also get the additional data about how past treatment failures can still respond following a recent course of triple therapy.  I think it would also encourage people to stay put on the SOC arm.  I will be interested to read about when they unblind results.

By the way, there will also be another phase 3 trial which is set to be a "12 & 12" and a SOC control arm later in this year.  (or at least that's what they have mentioned in news releases)

Good luck!!!

Willy
Avatar universal
I just want to wish you the best of luck whatever you decide. That's a lot of miles to drive to get to SVR but I think you're going to get there. Be well, Mike
220090 tn?1379167187
Those are essentially the same rules they used in Prove 3, the trial I am in.  I ended up renting an apartment in Manhattan so that I could get into the trial.  I ended up in the 24 + 24 arm and stayed in NY until I was done with the PI.  I went back to Florida once the blood tests became one per month and flew back to once a month.

It looks like it was all worth it even with the inconvenience and cost of participation.  I am 8 weeks post treatment and starting to feel better and I was undetectable at post 4 weeks.  I anxiously await the post 12 test on June 9.

Eric
Avatar universal
The Vertex trial in Minnesota (that I had been hoping would be for treatment naive) will only be a non-responders trial.

Grand Oak if you are still out there, phone home. BUT I don't know if they will be taking cirrhotics. Maybe very well compensated will be allowed. Magnum did they tell you what the exclusions are?

Also when I talked to the trial contact at Cedars he said that they would have a dermatologist on board, but didn't think they would allow rescue drugs. Toughluck in Boston, who will be a part of a trial there thought they would be allowed. I suppose that they could be totally different for treatment naive and non responders though.

Thanks for any and all info!
Avatar universal
look a bit like the choice between a rock and a hard place - I'm thinking similar thoughts. Though I'm still trying to sort out my inconsistent bx/fs  results, I  have a hunch I might need to (re)start within the year.

IMHO, trial participation doesn't look like the best option for those with a history of unsuccesful txs and  some urgency: no rescue, no combos (eg adding alinia), easy exclusions and the placebo risk. Also, notwithstanding the current vx lead there seems to be no shortage of contenders hot on its trail  and no indication that vx has any advantage other than time. On those considerations, I've also been thinking about low dose ifn as a way of buying some additional time.
Avatar universal
Given your latest biopsy date/stage, I think a biopsy now is an excellent decision whether or not you decide to continue treatment. If your fibrosis has advanced, treating seems the most reasonable decision and personally the Vertex trial sounds like the best offering at present time.

The only caveat being that if you never had a two-log drop during the first twelve weeks of previous treatments, you might do some additional research and/or discuss with your medical team. Some speculation/discussion about Telaprevir not being effective for prior null-responders, however that issue may have already been resolved to some degree with the more recent data which I haven't fully assimilated. Maybe others will chime in on that.

All the best moving forward,

-- Jim
Avatar universal
Jim wrote;
Some speculation/discussion about Telaprevir not being effective for prior null-responders, however that issue may have already been resolved to some degree with the more recent data which I haven't fully assimilated. Maybe others will chime in on that.
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According to Vertex in a recent conference they questioned whether the term "null responder" is really an apt term given some of the recent data on TVR.  The deal is that even so called "null responders" actually do respond with substantial viral load drops.  Vertex seems to wonder if these groups of people may indeed suffer from stalled response to SOC and yet respond sufficiently to TVR to no longer be considered null responders.  They seem to feel Vertex triple therapy has indeed created response in populations which had been prior considered non or null responders.  They are hoping that if the viral load is brought down in these groups sufficiently low and quickly whether standard SOC might be able to bring the group (or at least some of them) all the way home to SVR.  Only longer trials and larger groups will answer that question.

The ultimate question is whether or not these groups can be brought to an undetectable status and as to whether that can be maintained.  Clearance of the virus is in part produced by ones immune system and the issue of null response might well hinge on the immune system and not only on the treatment.  We may end up seeing increased numbers of "null responders" actually responding and clearing with more potent treatments.  They may not be able to clear all of them or even most of them but it is quite possible that the numbers who qualify for the term "null responder" may get smaller.

This is just theory and I don't know if I'm expressing it well or correctly but that's more or less what I think I understand.  I think that they may have to retool the definition of what a null responder is.

Willy

best,
Willy
Avatar universal
Thanks for the clarification/update/"theory" or however you might want to phrase it. In that spirit, I'll add some of my own thoughts.

The idea of "stalled" response is an interesting one and something I believe touched upon by one of our members in relating what she heard from a doctor involved in many of these trials. If I have those thoughts correct -- and I'm sure she'll chime in if I don't -- the idea was that the many so-called "null responders" actually are responders but are missed because in most cases viral load is only tested infrequently. Often just at week 12, and more recently at weeks 4 and 12.

The idea being that there are many who probably did respond somewhere between the tests (>2 log drop) but then "stalled" and regressed by the week 12 test. This doctor would still consider this hypothetical group "responders", or let's say "missed responders" (my words). This doctor, and what you seem to be saying, support the notion that at least the sub-group of missed responders should respond to Telaprevir and possibly even other sub-groups of previously marked "non-responders" for perhaps even other reasons not fully understood.

I'll offer my case as an example.  My doc tests viral load weekly which is not the norm but probably should be both for tx management and informational purposes re possible future treatments such as we are discussing.

I had a two-log drop at week 1 (or very close) and was under 600 IU/ml at week 2. I was expected to go UND by three but the virus hung around (actually rose a little between weeks 3-5 (stalled). I  became UND at week six.

Had I been unlucky, the possiblity existed that my viral load may have continued to rise between weeks 5 and 12. In that scenario, had I only tested viral load at week 12 -- and had my viral load risen to a certain point -- I would conceivably have been incorrectly categorized a null-responder (by the doctor in question), but in fact I was a responder (perhaps even a rapid responder in a sense) since I had a two-log drop at week 1.

In this scenario I therefore probably would have been an excellent candidate for Telaprevir which perhaps could have kept the virus down in conjunction with my SOC fulled immune system.

All said, trials are a gamble, and certainly that hold true for those categorized as prior null responders entering a Telaprevir trial. For that reason and others, waiting out the trials is a very reasonable option for those that choose to wait either because of non-significant liver damage or other reasons. But for those who decide to treat again, I still see current Telaprevir trial for non-responders as the best choice being offered right now.

-- Jim
Avatar universal
this question seems to very much  a part of the "new order" of tx and, from the patient perspective, it would seem unwise to assume anyone has reliable answers yet. We do know, from what's already quite a large pile of studies on ns3 resistance, that mutations conferring existence to ns3 proteases surface readily , eg
http://www.ncbi.nlm.nih.gov/pubmed/17938182

Replicative fitness of virus with the necessary mutations is a bit of an open question, but though there seems to consensus it's not as spry as wild type, it doesn't seem to be that badly handicapped, eg
http://www.ncbi.nlm.nih.gov/pubmed/18215275

So taking tv or boce will clearly select for these mutants and something has to kill them off. From earlier data on SOC we know patients who never got a 2-log drop  were very unlikely to reach SVR, hence the term "null-response" was introduced. However whether a 2-log drop does or does not correlate with whether the ifn effect is strong enough to kill off ns3 resistant mutants remains to be seen. This would seem to argue for just jumping in and trying - lack of the 2-log drop may mean one would never get to SVR with SOC but may still be good enough to get to SVR with triple tx.

On the other hand....one of the lessons from HIV noted in that Perelson editorial I posted a while back is that one does not want to attempt multiple, weak, sequential anti-viral therapies. There is no surer way of breeding a viral super-strain than carefully selecting those resistant to tx A, then carefully selecting from that subset those resistant to txB etc.

Hopefully the prove 3 data will shed enough light on how to make that decision. Quite possibly the old "null-response" label with its 2-log criterion may not be applicable and the new cutoff for triple therapy may be as little as  1-log drop on SOC. I suspect most early patients will just have to make a guess  -  assuming anyone knows the answer until data becomes available seems unwise.

jim: some flattening of the VL curve seems common in many who eventually get to SVR, but, aside from measurement variability, if VL ever consistently increases that tx would clearly seem a failure.
Avatar universal
Willing: jim: some flattening of the VL curve seems common in many who eventually get to SVR, but, aside from measurement variability, if VL ever consistently increases that tx would clearly seem a failure.
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My hypothetical assumed a viral increase between weeks 5 and 12, not a "flattening" which does seem to happen frequently.  And while of course, if viral load "consistently increases" we would by definition have a tx failure, but the point I made was different.

What Dr. S (as related by one of our members) appeared to be saying was that there may be a very large sub-group who were labled non-responders who actually did respond to treatment (>two log drop) but weren't caught because they only had a week 12 test. (In other words the two-log drop was achieved prior to the 12 week mark and then the viral load increased).

Dr. S. contends that this sub group are in fact responders but responders who failed to hold their response. The implication is that this sub group would be good candidates for Telaprevir. So while this population might be deemed "failure" in the initial treatment, re-treatment with an agent like Telaprevir appears hopeful. No way of knowing, of course, if one fit into that particular group unless viral load had been tested on a weekly basis -- or in theory on a constant basis which is real-world infeasible.
220090 tn?1379167187
If you read other threads on the topic of the new drugs, it will become apparent that most people that comment on this topic have a bias: some say take it others say don't.  The important thing to remember is that none of us are scientists or doctors.

Vertex has a website, and on it they have a bunch of presentations on the efficacy of Telaprevir.  Unfortunately, they spin the data as much as they can, which is not too much, so there is enough there to help you decide.

As far as anecdotal information is concerned, all the participants on this forum that have participated in the Telaprevir trial and did receive the triple therapy, have responded save one.  This is not a large enough sample to provide a conclusive opinion, but Vertex has data on 1000 people.  Some of it is from the prove 3 trial for relapsers, but that data is from week 4 and is RVR data only.

There are other studies that tie RVR to SVR with very strong results, but none of this is what you would like to see: a phase three trial of non responders with enough participants to provide a good statistical sample.

In the end, we are at a point in time where there is no conclusive data that will provide any degree of certainty for you.  I failed treatment 7 prior times; now I am undetectable at 4 weeks post treatment - a very good sign.

I am seeing one of the top hepatologists in the world.  His advice was to participate in the trial.  I did, and so far, it is looking like a very good decision.

What all this means, is that this very important decision will have to be made by you and your doctor.  Hopefully, the information here will help you come up with questions to discuss with your doctor.

Good luck,
Eric
Avatar universal
A few more points to clarify what I think I have understood from listening to the webcasts and from reading;

I don't think there is an argument that some resistance to PI's or to interferon could develop.  I personally question whether it will be as large as an issue as one could extrapolate it to be.  Quite often this virus is self limiting.  Many of us were exposed decades ago and are not at risk to infect others whether we in effect create a more resistant form through multiple treatments.  It might be a greater worry for IV users or if the virus could be spread through coughing, for instance.  It is rather early to state things as "fact" but there is evidence that nearly all "respond" to triple therapy with large drops in viral load.  As Eric mentioned RVR and response rate has been shown to be an excellent means of predicting success.  Of course, to merely experience a large viral load reduction is not enough.  One has to clear and stay clear for many weeks to have a shot at an SVR.  Triple therapy will likely reduce the numbers of people who may have fit the old standard definition of null responders.  Quite possibly new and additional forms of treatment could further increase the response rate and make the group of "null responders" smaller still.  As the non responder group diminishes I would think that the threat of resistance could also become less of an issue since the virus is durable but not particularly virulent.

Jim, just as you mentioned that your treatment "stalled", I think that we have also witnessed that same phenomena also with some folks on the Vertex triple therapy and also on some other trials.

Willing, I agree that resistance is an issue and that some of the importance may lay in not underdosing people.  For the time being it seems pretty clear that the "no-ribivren" arm in the Vertex trial might be an example of a treatment which through underdosing could lead to resistance.  I think what remains to be seen is whether future treatment results will trump the issue of resistance.  Nobody truely knows yet.  I lean towards optimism.

best,
willy
29837 tn?1414534648
I will be seeing the Hepatologist Dr. Gish (chief of liver transplants for the West Coast) on the 28th. His opinion will be valuable also. The cost of travel and lodging is one thing, the 5th time suffering through yet another treatment is another. I just pray my body can handle it again. The last four treatments have taken their toll on me. But, being that I'm a fighter, I will go for it, placebo or not. At the very least, we can slow down the progression...

Magnum
220090 tn?1379167187
Best of luck to you.

Eric
Avatar universal
>all the participants on this forum that have participated in  >the Telaprevir trial and did receive the triple therapy, have responded save one.

andiamo: that's a pretty impressive record. Outcomes for tx-naive won't give much insight into outcomes for non-responders/relapsers but it'll definitely be interesting  to see how the prove 3 results come out - in particular relative to the log drop people had seen on unsuccessful SOC. Since your own experience included so many txs,  do you recall what sort of drop you saw in the past on SOC?

willy/magnum: optimism is definitely a good thing, but since you live in Las Vegas I'd bet you'll agree that neither optimism nor having an MD are any guarantee of success at the **** tables.  Knowing the odds on the other hand might be helpful.  There doesn't seem to be any reason why the old 2-log cutoff should apply to how much ifn response one needs to mop up ns3 PI escape mutations - but there will be some new cutoff - and if one is near it, for example if previous tx never showed more than  a 1-log, it might better to go for a bet with better odds (and all the best of luck if you decide to go with the trial!).
Avatar universal
I agree that resistance is an issue.  The earliest TVR trials showed that the subjects all responded with monotherapy and then very quickly the response stalled and reversed.  The question is.....how big of an issue will it be?  I don't claim to know.  I think what we are seeing is that the so called interferon resistant virii are being overpowered by a stronger triple therapy.  We may also see a similar dynamic in retreating people who have failed in past Vertex trials.  A stronger treatment or different treatment could provide success for those who have experienced a treatment failure with Vertex.

The [email protected] table is a good metaphor for treatment or treatment with PI's.  There will be odds of success and odds for losing.  I simply don't think those "odds" have yet been established.  There are many new compounds that will soon be added to SOC.  It seems to me that Vertex triple therapy could drop our population by close to 70 percent.  If it is determined that other therapies can up the SVR rate it would seem that the HCV infected population will dramatically drop, and fairly soon.  Who knows what the SVR rates will be when they add polymerase inhibitors to the mix, alinia, etc?  I only see treatment getting shorter, safer, and more effective.  The next 5 years will bring a lot of changes, IMHO.

best,
Willy
220090 tn?1379167187
In the past, I had a two log drop by week 12 and undetectable by week 24.  With prove 3, I had a one log drop within 5 hours and undetectable by week 2.  On the first day, blood is drawn before you take the drugs and every hour for five hours after that.  I don't have the numbers in from of me, but I recall that I started with 8.8 million IU and within an hour I was down to 5 million IU!  My memory isn't great these days (since treatment) so I better verify the numbers when I get home next week.
Avatar universal
andiamo: thanks! It sounds as you clearly were on the EVR side of soc response and this was enough to obliterate any residual resistance. As more prove 3 data comes in it'll be clearer whether even those with less than a 2-log can get by.

willy: hopefully dointime will succeed in her request for the sequence information collected as part of her unsuccessful vx tx. Whether her post-tx viral distribution is or is-not enriched in resistance-conferring mutations will affect whether reusing vx or other ns3s with a similar resistance mutation profile is  remains viable option. All we seem to know at this point is that

(a) resistance mutation are fairly easy to come by:
"V36A/M or T54A substitutions conferred less than eightfold resistance to telaprevir. Variants with double substitutions at Val36 plus Thr54 had ~20-fold resistance to telaprevir, and variants with double substitutions at Val36 plus Arg155 or Ala156 had  gt 40-fold resistance to telaprevir"
from http://www.ncbi.nlm.nih.gov/pubmed/17938182

and (b) the mutations are handicapped with respect to soc
"those sequences that are more distant from an optimal sequence being less able to resist the pressures of interferon-based therapy."
from http://www.ncbi.nlm.nih.gov/pubmed/18463735

The quantitative part of "so exactly how unfit are they?" and "how much soc response does it take to obliterate them" still seems to out of reach.
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