Any new news on VX-950?

[ChrisDDD]

Hey, troops.  I haven't been around for a while.  I've read some of the posts, and they seem to verify that VX-950 is not going to be the cure we all hoped it would be.  Am I right?  I'm 53, Grade 2, Stage 3 by biopsy July '04.  Stage 3 is the one before cirrhosis, right, or is it Grade 3?  Anyway, based on the rashes being reported here and then seeing the rate of resistance due to mutations, etc., I have decided not to treat until they come up with something that doesn't include interferon (I developed retinal hemorrhaging on Infergen Feb. '05) and that will actually cure me.  I see my hepatologist next month and we had originally discussed trying to put me in Prove 3 in January, but I'll bet he's changed his mind.  All the good news Vertex has to offer is for treatment-naive patients, right?  Um, that would not be me, three-time non-responder.  Best to all.

[denzelbrown]

any news about vx-950 phase III yet?
thanks

[geterdone]

Question here,
If I am reading this right the new telaprevir study will be treating the first 12 weeks with just telaprevir at different does and times and then the remaining 24 weeks with the two pegylated interferons alfa 2a and 2b with Ribavirin. Isn’t this what everyone has been discussing prior to the abstracts being released?
Would this not show what the telaprevir could do to the viral load and the baseline side effects of the drug before introducing the INF and Riba.
jasper
  
Telaprevir, Phase II
The purpose of the study is to explore the safety and effectiveness of each treatment combination and to study the amount of telaprevir in the blood. Two different doses of telaprevir (750 mg every 8 hours, and 1125 mg every 12 hours) will be studied in combination with the two standard therapies commercially available for chronic Hepatitis C Virus infection. Telaprevir will be administered for 12 weeks in combination with 24 weeks of standard therapy. In case of sub-optimal response, standard therapy will be extended to 48 weeks.

There will be 4 treatment groups: 12 weeks of telaprevir 750 mg every 8 hours + 24 weeks of Pegylated interferon alfa 2a + ribavirin;
12 weeks of telaprevir 750 mg every 8 hours + 24 weeks of Pegylated interferon alfa 2b + ribavirin;
12 weeks of telaprevir 1125 mg every 12 hours + 24 weeks of Pegylated interferon alfa 2a + ribavirin;
12 weeks of telaprevir 1125 mg every 12 hours + 24 weeks Pegylated interferon alfa 2b + ribavirin.

[frijole]

Lots of good stuff in here.  None that I can really coment on intelligently but lots of food for thought.  I have to admit the thought of becoming interferon resistent is down right spooky.  I think I would be tempted to not treat with telaprivar now -- and I had really been hoping for a trial.

snow wave - so nice to see your name.  I haven't seen you around these parts for a long time.  So, you have decided to wait huh? Climbed any mountains lately )I remember you did remarkably well on tx climbing)
frjole

[SnoWav]

No liver damage ,sounds like you could wait out the new drugs. My wife and I both had hep C for 30 yrs and during that time had 5 amazing kids,Im glad I diden't know I had C until 6 yrs ago I might not have met 5 of the best friends and people in my life. ( none of our kids were hep C positive) my wife and I  both TX ed and she cleared I diden't,waiting for the new stuff myself.
later
jeff

[denzelbrown]

i am genotype 1b, 2.3mill, 35 ALT, 25 AST, no liver damage, whats the point of treatment now? can i wait for vxd950? also my wife is negative but how can we get pregnant now?
any advice folks?

[jmjm530]

You didn't mention your're genotype. But if you're genotype 1a or 1b, my general opinion is that you have time to wait for better drugs. There is however, another school of thought, that says treat early as possible. I just personally don't subscribe to that school at this point in time, except if you're in the acute stage which very few of us are when we treat. Have you discussed this all with a liver specialist (hepatologist)? If not, you might wan to.

-- Jim

[denzelbrown]

hi my stats are liver enzymes normal, viral load 2.3mill, no liver damage yet

[jmjm530]

This not a simple question. Depends on a lot of variables with emphasis on genotype and amount of liver damage. However, age, sex, race, weight and other health issues also play into the decision and what kind of assessment your qualified (hopefully) doctor makes. Not to mention your personal philosophy of treating early verus waiting for something better.

My thinking is that geno 1's with little or no liver damage are probably best served at this point in time by watch n' waiting until better treatments are available. This is just a general recommendation without knowing any of your stats. YMMV.

-- Jim

[jmjm530]

This not a simple question. Depends on a lot of variables with emphasis on genotype and amount of liver damage. However, age, sex, race, weight and other health issues also play into the decision and what kind of assessment your qualified (hopefully) doctor makes. Not to mention your personal philosophy of treating early verus waiting for something better.

My thinking is that geno 1's with little or no liver damage are probably best served at this point in time by watch n' waiting until better treatments are available. This is just a general recommendation without knowing any of your stats. YMMV.

-- Jim

[denzelbrown]

i need to make a tretment decision, and i am thinking of holding of treatment till this new drug gets into market, what do u guys think?

[Willy50]

Orleans. you can take what Vertex says with a grain of salt but there could be a few things in favor of the Phase 3 trials.
Vertex says that they expect a better trial in all ways.
   1)  They've maintained again that some folks could treat for shorter times.
   2)  The naive trials SVR rates seem to be trending upwards since people may be less likely to drop out knowing the product essentially works and is safe
   3)  There is a possibility that rescue drugs COULD be allowed in Phase 3; wouldn't that possibly mean a higher SVR rate?
--------------------------------------------------------------------

I am not really up on the theory about the resistance issues but I believe that they are still a theory which is being defined.  All theories are that; theories.  I believe that some of this is still being proven and understandings refined.  For instance one might say there there are null responders and that all null responders won't respond to interferon.  This doesn't mean that all past interferon treaters will be null responders due to interferon resistance.  Even if this were true...... when one adds a new compound (such as TVR or Boceprevir) that increases efficacy I believe it's a whole new ballgame.  (and believe me...... if I am wrong I'd like to hear it.  puh-lease correct me where I'm wrong)

Look at it this way....... it's reducing it to the absurd but if you get too caught up in worrying about resistant virii one could rationalize that nobody should have treated with interferon since they will need to preserve their "naivity" for the upcoming better treatments.  I'm making a little joke here but one can become frozen and unable to move.  

The flip side of this theory about resistance if that indeed....there is some basis and that for some individuals they may be burning a bridge.  Predicting exactly which individuals are affected may not soon be known.  Here's another treatment anology......  Just as there are so many decent new treatments coming that will increase the SVR rate or shorten treatment time......if we can wait at all there may be some big payoffs for us; not only in positives but in having fewer negative aspects of treating NOW.  The big change that's a-coming is akin to shifts in past treatment.
How would you feel treating with monotherapy (10% SVR rate) right before they added Ribiviren which bumped the SVR rate to 30-35%.  Even if you treated then.....there would be a time which it might be prudent to wait again.....because when they pegalated interferon the SVR rate went up another 10% or so.  In about 2 years we may see the SVR rates for geno 1's go from about 40% to 70.....75% or even higher in half the treatment time.  Further, we are finding out that in treating some of us will develop or acquire a resistance to interferon..... or other compounds one treats with.

One will have to weigh the risks versus the rewards.  IF for instance with the addition of rescue drugs to Telaprevir we may quite easily see an SVR rate around 75 or 80%.  That means that the resistance issue becomes mute for 75-80% of those geno 1's who treat and SVR unless they re-aquire the virus.  Of the 20-25% who are left not all (once again correct me if I'm wrong) will have the resistant variants.  Further....(once again correct me if I'm wrong) a new treatment paradigm may be able to overcome that resistance.  In this scenario the group of infected people keeps shrinking and shrinking because they get cured.  IF we wait toooo long for new treatments the group of infected people also may shrink......but because of people dying of liver disease.

The premises are sound which surround the theories of resistance.  I haven't seen it mentioned but perhaps a good example might be being in a study where one was underdosed or where was given a treatment which might be too short (or both).  You are creating a perfect situation where you create the resitant virii with little hope of destroying them.  Most failed treatments will produce a group of people who have an acquired resistance to the treatment chemicals.  The size of that group is being determined as we speak

I'm hoping that I've dummied things down sufficently so as to be understandable without misrepresenting the theories.  Forgive me if I'm wrong and better yet correct me.  It seems clear to me that this is new theory and we are trying to grasp it and that we've seen little which explains it.......and so we are stumbling as we try to describe it.  Even if I'm wrong this may provide some basis to tell me where I'm incorrect.

One last thing.....is that one other theory which is progressing is that there is a strong connection between RVR and SVR.  The "null responders" may breakthru in the first 4 weeks in the TVR trial.  There really don't seem to be others after that.  IF you RVR (in the TVR triple therapy arm) you tend to stay clear through treatment's end (this has been true for Prove 1's and 2's but may or may not be true for Prove 3's).  In about 12 weeks we will see how the Prove 3's made out.  The SVR12 data should be available around January or Feb 2008.  We may see then if a FAST RVR rate may trump some of the interferon resistance issues being discussed.

I have the vague sense that this is over my head and that I shouldn't be attempting to write about it.  IF I'm way off base tell me.  Worse yet I'm pretty tired and so this may be incoherent on top of being incorrect.  I'd love it If we could edit our posts to correct out errors.  However IF incorrect this is....it is what I think I currently understand.. Hindsight will be 20-20.  That may come in a few months or tommorro morning when I am brought up to speed.  It's a start.

Best,
Willy

[orleans]

Let's say one started the 3 combo trial, had to quit early for some AE, that would not make them a non, nulI, partial or any other kind of responder would it? I wonder how my insurance co would view that. My understanding is that they do not cover re-treatments.  I would hate to give up my virginity only to come down with the dreaded rash! jerry

[jmjm530]

You certainly have the right viral load and your doctor could be on the money with the 65% figure. On the other hand, Telaprevir offers similar odds with half the treatment time. Of course, you could treat SOC, and do the short course (24 weeks) if UND at week 4 But would you? Dunno, I say as a stage 3 to go with all the guns --- peg, riba and Telaprevir. On the other hand, the SOC drugs under the right doctor, can be very indvidualized. But you're right,  the math is important and maybe someone with a calculator will drop in soon :)

-- Jim

[orleans]

I have a good chance to get into phase 3, am naive and stage 3. My hepatologist is well known, published and claims to have treated over 800. He gave me a 65% chance of clearing with SOC (low VL, body weight, genaral good health) When we were talking later I said 60% was not too bad he stopped me and said I SAID 65%. Soooo, here's my question/concern. With 75% of those finishing 24 weeks SRVing, 18% dropping out, the math may be better for me with SOC. Any math whizzes out there? Another thing, if memory serves (yeah, right!) it was 18% drop out, 13% because of AEs, what about the other 5%. Seems like alot of non-consent and lost to follow ups. jm

[jmjm530]

I think we will know more when we have some actual Prove 3 (treatment experienced) trial data from Vertex. Assuming of course that someone takes the time to analyze triple therapy response against previous SOC response.

As far as the risks of mutation versus not treating with PI's -- at least for the tx naive, triple therapy seems like the best road now for those who have to treat. A better response rate than SOC with half the exposure to the treatment drugs. How can anyone argue with that? Again, for those that have to treat. If one doesn't have to -- minimal liver damage -- than a good argument can be made to watch and wait.

But assuming someone does treat with triple, and fails, and develops Telaprevir mutants. My question is -- and only that because this is an area I don't pretend to understand -- so what? All it seems to mean is that they will be resistant to Telaprevir, which by all accounts appears to be a transitional drug anyway -- with more advanced and multiple PI's, as well as polymearase inhibitor's on the way.

So while there might be that "hidden danger" HR alludes to, in the end it's weighing that and otherrisks against the rewards of treating right NOW for those that need to treat now. Certainly for treatment naive's, the 'now' drug appears to be triple with Telaprevir. As to the treatment experienced, either we have to wait for SVR data to be analyzed -- and perhaps correlated with viral response on SOC -- or maybe we can already make assumptions based on where the trial data stands now. Not sure, because I haven't been following Prove 3 all that closely.

Sorry I couldn't answer your question more directly, but I"m admittedly still somewhat in the fog re the null/partial responder issues, especially with more than one definition floating around.

So where the heck are the papers from the experts who should be writing about this now?

All the best,

-- Jim

[ChrisDDD]

My, this turned out to be some good dialogue.  I'll still never understand non-, partial and null responder.  I cleared on my first treatment (interferon only) in '98 by week 4, detected by week 24 and booted from the trial.  Same for the Peg/Riba treatment in 2000, though never cleared but had 2-log drop, I think.  Infergen/Riba in '05, PCR 2,000,000 plus at start, week 4 PCR 50,000.  That's a 2-log drop, right?  Each doctor who took me off treatment said it was because I was a non-responder, not partial.  In my dictionary, non- would mean non-, no response.  Anyway, I am concerned about the mutation issue at this point and feel that if my doc tells me at my appointment in three weeks that he wants to put me in Prove 3 (?), which he probably won't anyway, I should still decline.  It's lousy to feel so awful if I can't even get well, which brings me to my next question.  Would retinal hemorrhaging on Infergen equal interferon resistance?  If not, then what is interferon resistance?

It looks like I'm just screwed no matter what.  Post-treatment side effects?  Yes!  Short-term memory loss, brain fog, and I lose my balance easily and just start tipping over.  Sleep 10 to 14 hours a day, but OTHERWISE, I feel pretty good most of the time.  Sometimes I feel great.  The good news to some may be that I won my Social Security Disability case on the basis of the HepC.  That seems to not happen too often, and I think for those who need it, like "moi", it's a turning of the tide and an acknowledgement of the havoc this disease wreaks with our entire body.  Thanks for all the input.

[Whrose]

i read again HR's comment above regarding the sliding scale of null response and non response. it appears SOC will not get them to undetected although they may have decline in viral load (less than 2 logs week12). i take his comment to say these ones will not benefit from the protease inhibs and would possibly do more damage taking them by development of drug resistant mutations.
but...is this true for the partail responders as well?
i know we are using alot of boxes here but it helps to define the box to discuss treatment options for each as opposed to lumping them in the broad non response area. seems like the partial responders may be charting ? an increase risk of developing drug resistant mutations also. because if they are still DET at week 24, interferon will probably be of little value. of course infergen has some results and perhaps albumin based IFN.  am i understanding this right? that poor response to IFN no matter where you are in the box ( null, partial, breakthrough) will not do well with protease inhibs. whats your take?

[Whrose]

ahhh. yes i see now what you mean. it does make one consider that 4 wk pcr with more weight if the 2 log drop was documented before the 12 week detected result which in theory was more than a 2log drop from baseline.  i think that by definition this would be labeled a partial responder according to Shiffmans definition (with the weeks changed).

the unknown land comment is the partial responder. it seemed the right word at the time because treatment that placed them there will no longer be effective for them and they chart the edge of SOC with innovative and risky doses/med changes with no real stats to back them. often the treating docs made no tx changes at week 24 so they continued till week 48 and remained detected.

now heres a scenario. 2 log drop at week 12, continued decline at week 24 (but not UND), then at week 48 pcr comes back with higher log from 24 week test.( same tx continued) are these ones by definition a partial responder. they don't exactly fit the breakthrough definition. hmmm?

i do understand the disturbing things. people get comfortable in their own shoes and function quite well there, but give them a different size and they can't walk. lol "not my problem mon"

hugs    Whrose

[jmjm530]

Although fast changing, these evolving tx protocols are not rocket science. You would think a motivated GI could get up to speed in a weekend seminar (or less) if so motivated.

The disturbing thing is that a lot of these doctors -- and I'm not just talking about liver doctors -- don't seem motivated to keep up to date. My ENT for example, told me several times during my year plus of visits with him, that he didn't know anything about Hep C and how tx could affect some of my ENT symptons. My g*d, then why didn't he take an hour or so and do some research! If I didn't research out my client's issues, I'd be fired in a minute!

Oops back on the soap box :)

[jmjm530]

I don't disagree but was trying to surmise what Shiffman had in mind in terms of definitions per Susie's posts.

I thought what was suggested is that if somone has a two-log drop (or greater) before week 12 and then has less than a two-log drop at week 12, then that person would be labled a partial responder as opposed to a non-responder. And that the purpose of the week 4 test was to catch this sub group, who if missed would otherwise be labled as non-responders?

I don't see it that way, just using it for discussional purposes, because even "if so", I still see it as a very small group.

My understanding, like yours is that a "breakthrough" is a positive test following an UND, all while on the treatment drugs. And from what I've learned, breakthroughs are uncommon.

You said, "i have many friends who fall in this unknown land. many partial responders have not been well identified because of the 12 wk detected result and discontinuation of treatment at the detected 24 week mark."

Could you elaborate a little on the above. If they were detectible at 12 (and I assume had at least a two-log drop) and still detectible at 24, then aren't they classical partial responders? What then is  the "unknown" land?

-- Jim

[Whrose]

i am as usual in full agreement with you ;)

yes its about time the info about running more frequent PCRs become mainsteam. the last 6 months i have noticed a shift to their value by the top hep docs in their discussions. but even better will be the research that defines the best combo of meds for the various response patterns...this is my favorite soapbox.

[Whrose]

i would think that your addenum scenario would describe a breakthrough response. a null responder never has a 2 log drop.  again the significance of this response and the protease inhibs would be welcomed as this population i would theorize have a greater tendency to drug resistant mutations? i have many friends who fall in this unknown land. many partial responders have not been well identified because of the 12 wk detected result and discontinuation of treatment at the detected 24 week mark. how do we know what med combo will be the best option for this response?
Whrose

[jmjm530]

Actually some have written on the utility for more frequent testing in general terms, but it would be nice to see these thoughts translated into clinical guidelines that the average GI would follow. Come to think of it, would be nice if A LOT of what is often called "cutting edge" treatment would be made more readily available to the average GI who seems to be treating a good part of the HCV population. OK. Enough soap box for today :)

[jmjm530]

If they really need more frequent viral load testing, then it would be nice if one of them wrote a paper to this point. I'm one of the lucky ones with a doctor who did frequent PCR testing, but many here have to pull teeth just to get a week 4 test. In other words, let's get these theories into clinical practice *today* when it's needed.