TVR and geno 3

[desrt]

http://www.natap.org/2009/EASL/EASL_13.htm

In this study genotype 2 treatment naive patients achieved a mean 4 log reduction in viral load after 6 days on monotherapy with telaprevir. The triple combination of telaprevir + peg/RBV achieved a mean 5.3 log reduction in viral load at day 16. But genootype 3 patients only achieved a -.80 reduction in viral load so therapy for genotype 3 won't be pursued.

[RCM829]

oops, meant to say 38%, not 58%. I'm not going to post for a while....

[RCM829]

Yes, the takeaway that I got from my appointment (on this subject at least) was that it was ironic that geno 3's would be one of the last to receive significant cure rates but that these new drugs in the pipeline should be available shortly after Teleprevir and Boceprevir.
BTW please excuse my typos and mis-spellings. Can you tell I'm currently treating?
Thanks for all the good info....

[Willy50]

I agree that even though THIS trial was not good news for genotype 3's there may prove to be other drugs in the pipeline which will work.

Strictly speaking...... the genotype 3's had about a .8 log reduction..... I think in 14 days.  Now......that is nearly a 1 log drop.  It isn't like it is utter failure .......but it is when you compare it to other new therapies.  IF there was nothing else coming this could still have a minor potential.  Since there are other far better compounds this will simply not be worth treating genotype 3's it appears.  Others will step up to the plate fortunately.

I haven't had the time to check everything out yet but YES it looks as though R7128 is going to be good.  It is also in a double trial;

R7128 the polymerase and ITMN191 and I think arms with IFN and RBV.  That will be 4 drugs but it could be a great response and I believe that as monotherapy R7128 was well tolerated.  I think there was a presentation on this trial today and it may be the hot thing that we are conversing about tomorrow.

=========
One other *little* thing that I think that I noticed....... is that in the Boceprevir presentation the effect of the "lead in" with 4 weeks of SOC ends up bringing the SVR (I think it was SVR; and not response) rate about 10%.  (one can see this in both of their 24 and 48 week arms; about a 10% difference between the 4 week lead ins versus the *no lead in* arms)

This could mean that Telaprevir could potentially bump up any of it's response rates 10% by adding a 4 week SOC lead in.  I've wondered (and written) about this.  It may be incorrect but anyone please feel free to correct me if I'm wrong. This also could explain why TVR has performed better on past TX failures.  When we've compared the two compounds we have never had a trial which compares them evenly.(ie; a TVR lead in study)
=================

There is going to be a tremendous amount of material to digest after this conference.  In addition to polymerase inhibitors there are also "stat c" trials coming which combine Polymerase and Protease inhibitors.  Geno 3's don't give up hope.  ; )

best,
Willy

[RCM829]

According to the doctor I just saw who heads the liver disease and transplant center at Cedars Sinia in L.A., teleprevir will NOT work well for geno 3's non-responders.
It is the NEXT round of polymerese inhibitors currently in clinical trials (such as R7128) that will target geno 3's. So we will have to wait a little longer but the preliminary response rates -again, according to him- are quite significant.

[RCM829]

Wow, thank you both for that valuable information.
As a g3 previous non responder with a very low viral load, minimal fibrosis and no other health issues (insulin resistance, fatty liver, etc) I was beginning to wonder: what's wrong with me? Now, if I dont clear with current SOC, I will at least know the answer.
I may simply be in that unfortunate 58%.
And lets hope that the polymerese inhibitors currently in clinical trials  that target other genotypes (such as R7128) are given fast track status as well.

[Willy50]

Well, first let me say that I am mighty surprised and disappointed.  I had expected that the same response dynamic would simply continue evenly across all genotypes.  That does not appear to be so; certainly not for genotype 3's anyway.  One other bit of news is that if I recall they also did a genotype 4 study separate of this one.  Maybe that's coming tomorrow; I've been busy and haven't looked yet but I'm pretty sure there is one coming at EASL.  It could be better news or more bad news.

Before I go further lets look at the trial design;


http://clinicaltrials.gov/ct2/show/NCT00561015?term=telaprevir%2C+genotype+2&rank=1

Estimated Enrollment: 48

Study Start Date: December 2007

Detailed Description:
The purpose of this Phase IIa multicenter, partially blinded, randomized (study drug assigned by chance), stratified for genotype, multiple dose study is to assess the effect of telaprevir on HCV early viral kinetics in treatment-naïve patients who are chronically infected with genotype 2 or 3 hepatitis C virus (HCV). The trial will consist of a screening period of approximately 4 weeks, a treatment period of 26 weeks, and a follow-up period of at least 24 weeks. The treatment period will be made up of a 2-week investigational treatment phase and a 24-week standard treatment phase. A total of 48 patients who have never been treated for HCV (24 patients infected with HCV genotype 2 and 24 patients infected with HCV genotype 3) will be enrolled in the trial. All patients will receive the investigational treatment regimen to which they have been randomized for 2 weeks. Subsequently, they will receive 24 weeks of standard treatment consisting of pegylated interferon (Peg-IFN) alfa2a 180 µg once-weekly and ribavirin (RBV) 400 mg twice per day. Patients will be followed for at least 24 weeks after the end of treatment (EOT; Week 26 or early discontinuation) in order to assess sustained virologic response (SVR24) or to collect samples for viral sequencing. HCV viral load quantification and safety/tolerability assessments will be performed frequently throughout the trial. Extensive virologic and pharmacokinetic assessments for pharmacokinetic/pharmacodynamic analysis will be performed during the investigational treatment phase.

There are 3 treatment groups in this study, each group will consist of 16 patients, 8 patients genotype 2 and 8 patients genotype 3. Group A. telaprevir 750 mg 3 times/day; B. telaprevir 750 mg 3 times/day + pegylated interferon alfa2a 180 µg once-weekly + ribavirin 400 mg twice per day; C. telaprevir placebo 3 times/day + pegylated interferon alfa2a 180 µg once-weekly + ribavirin 400 mg twice per day. This will be followed by 24 weeks of standard treatment with Peg-IFN and ribavirine.
========================================================

That final paragraph tells you that the genotype 3's were supposed to be evenly randomized into 3 arms although it looks as though it didn't play out that way;
Group A   TVR monotherapy TID
Group B   TVR TID and SOC (IFN and RBV)
Group C   tvr  PLACEBO and SOC (IFN and RBV)  ie; the control arm

This post may be getting too long so I'll post it but the genotype 3's were in all three arms IMHO.

best,
Willy   (copied and pasted to the other thread as well)

There will likely be more commentary on this soon with graphs and better explanation.
By the way; looks like the final results of the study may all be in around June or July and probably released at fall AASLD.

[Marcia2202]

Oh, I forgot, it makes me think that the German study you referred me to, when I was researching extending treatment for g3, of.... (can't remember his name) suggesting that SOC for g3's could be 36 weeks, does make sense.

[Marcia2202]

Thank you so much for posting that... I had quite a strong feeling that the previous 'myths' around g3 being an easy one to treat were just a myth. I'm glad I extended treatment, but lets wait for the outcome first.

I remember the big liver head at RH in Cph telling me that my gt was easy to treat, 'easy to treat my A§§', I was thinking to myself. Thank God my doctors didn't seem to be under the impression that it was easy to treat.

[epiphiny]

Thanks for posting that, such statistics have been a long time coming. I was going to hazard a guess at around 60% but I see that was optimistic.

I can still hear them telling me, 5 years ago, that Geno 3 was the easiest to treat!

[zazza]

http://www.kenes.com/easl2009/Posters/Abstract528.htm

"ROLE OF RVR AND VIRAL LOAD ON SVR IN TREATMENT OF GT3 HEPATITIS C PATIENTS WITH PEGINTERFERON ALFA-2A (PEG) AND RIBAVIRIN (RBV) IN REAL LIFE"

"Conclusion: Comparing SVR results from this cohort with results from ACCELERATE revealed that GT3 patients overall and especially those with RVR achieve lower SVR rates in daily routine as under study conditions. Since most of new antivirals are predominantly active in GT1, treatment optimization studies with PEG/RBV are urgently needed."

For once a study with SVR rates for geno 3 alone, not lumped together with geno 2. Look at the SVR rates:

G-3, LVL: Total: 62.1%; RVR: 68.6%; non-RVR: 47.5%
G-3, HVL: Total: 52.6%; RVR: 56.4%; non-RVR: 43.0%
G-3, total: Total: 57.2%; RVR: 62.5%; non-RVR: 44.7%

[epiphiny]

Wow, that's out of left field...  Geno 3 is quite hit and miss when it comes to successful treatment, statistics need to reflect the reality of treatment success for this Geno.  I would hazard that 80% clearance rate is too high.  Perhaps there is a specific sub type of 3 that deserves it's own treatment protocols.

That info makes me feel very positive about the R7128 trial for Geno 2 & 3 non-responders, of whom 90% achieved RVR at 4 weeks.

http://www.pharmasset.com/download/Phase_I_Analysis_Cohort_4.pdf

The quest for a universally succesful treatment for all HCV Genos goes on...