Telaprevir - Is this True?

[JennyPenny]

Did this surprise anyone besides me? Have I been asleep lately? This is the first I've heard that Geno 3's do not do well on Telaprevir. Tell me it's not true!!!!

Telaprevir Effective for Genotype 2 But Not For Genotype 3


  
  EASL April 23-26 2009
Copenhagen, Denmark
Reported by Jules Levin

In phase IIb studies in treatment-naives, mostly caucasians, telaprevir in combination with peg/RBV improved SVR rates in half the time of treatment compared with standard of care:

--PROVE1: 61% vs 41% (p=0.02)
--PROVE2: 69% vs 46% (p=.004)

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.

ACTIVITY OF TELAPREVIR ALONE OR IN COMBINATION WITH PEGINTERFERON ALFA-2A AND RIBAVIRIN IN TREATMENT-NAIVE GENOTYPE 2 AND 3 HEPATITIS-C PATIENTS: INTERIM RESULTS OF STUDY C209

G.R. Foster1, C. Hezode2, J.-P. Bronowicki3, G. Carosi4, O. Weiland5, L. Verlinden6, R. van Heeswijk6, T. Vangeneugden6, G. Picchio7, M. Beumont-Mauviel6 1Barts and The London School of Medicine, Institute of Cellular and Molecular Science, London, UK, 2Hôpital Henri-Mondor, AP-HP, Université Paris XII, Créteil, 3Centre Hospitalier Universitaire de Nancy, Vandoeuvre-lès-Nancy, France, 4Clinic of Infectious and Tropical Diseases, University of Brescia, Brescia, Italy, 5Karolinska University Hospital Huddinge, Stockholm, Sweden, 6Tibotec BVBA, Mechelen, Belgium, 7Tibotec Inc., Yardley, PA, USA

Background: Telaprevir (TVR) produces rapid and consistent reductions of HCV-RNA plasma levels in G1 patients. Study C209 is an ongoing, partially blinded, randomized, Phase-2a study of TVR, administered alone or with peginterferon-alfa-2a (Peg-IFN) and ribavirin (RBV), investigating early viral kinetics of HCV-RNA decay in treatment-naIve subjects with genotype 2/3 (G2/3) infection. We report the results of the primary analysis conducted after 15 days of treatment.

Methods: 49 subjects were randomized to receive 15 days of either TVR 750mg q8h alone (armA;G2/3;n=10/8), TVR 750mg q8h with Peg-IFN 180µg/week and RBV 800mg/day (armB;G2/3;n=5/9), or Peg-IFN 180µg/week and RBV 800mg/day plus placebo (armC;G2/3;n=8/9) . Viral load was measured using Taqman assay (LOD1-log increase in HCV-RNA above nadir or >100 IU/mL HCV-RNA after previously undetectable HCV-RNA. An ITT analysis was performed when all treated subjects had completed 15 days of dosing or discontinued earlier.

Results: Mean baseline log10 HCV-RNA was 6.45 and 6.44 IU/mL among G2- and G3-infected subjects, respectively. The mean (SE) log10 changes in HCV-RNA at days 3/15 in G2-infected subjects were -3.0(0.37)/-3.1(0.64), -3.9(0.23)/-5.3(0.27), and -2.2(0.56)/-4.0(0.70) and in G3-infected subjects -0.8(0.33)/-0.5(0.11), -2.9(0.24)/-4.7(0.32), and -2.6(0.40)/-4.5(0.36) for arms A, B, and C, respectively. The mean (SE) log10 maximum HCV RNA change in G2/G3-infected subjects was -4.0(0.49)/-0.8(0.33), -5.5(0.24)/-4.7(0.32) and -4.0(0.70)/-4.5(0.36) for arms A, B and C, respectively. In G3-infected subjects, responses varied across subtypes. The proportion of G2/G3-infected subjects with undetectable HCV-RNA at day15 was 0%/0%, 40%/22% and 25%/11% for arms A, B and C, respectively. Among G2/G3 subjects receiving TVR monotherapy, 6 and 5 patients, respectively, developed a vBT by day15; no vBTs were observed in arms B or C. Overall incidence of AEs was similar across arms and the most common AEs in TVR arms were rash-related events, nausea, and influenza-like illness, in line with previous reports. One patient in arm B discontinued therapy due to rash. No SAEs were reported in this trial.

Conclusions: TVR demonstrated substantial antiviral activity against HCV G2, while its activity against G3 was limited. These findings support additional investigation of TVR for the treatment of G2 HCV infection.  
  
  



  

[merryBe]

Geno 3's must feel the ocstricized lepers at the leper colony right now.
I mean, they know you are hard to treat and STILL won't treat you out like they do type 1's to solve it ...in many countries...??   What kinda shiet is that.

but be of good cheer...I'm really psyched about the newest PI's mentioned above,
and IF they were combined with say, loading up the Inovio vaccine first...to reduced the VL by 99% first...and they followed with 2 PI's that DO work...it would be just a mop up job...and might require much reduced dosages to get to SVR. That should be the push right now, get these non toxics on line...to knock it out quickly, and let people be productive, not debilitated by tx.

mb

[CoWriter]

"In terms of TVR monotherapy I have to agree with you, and I assume that is what you are referring to when you say "doesn't sound at all positive to me". "
-----------------

I was responding to your comment that said....

"My guess is that the study is positive in that mono therapy seems to at least deliver RVRs to geno 2's. "

Monotherapy wasn't positive for geno 2's and it didn't "deliver RVR's" to geno 2's.  

So you must have changed your mind.  First you said it was positive and now you're agreeing with me ; )

Co

[BelB64]

I'm not surprised as another protease inhibitor also performed well on Geno's 1,2 and 4 but nothing on 3 (IDX 184)  HOWEVER all is not lost for geno 3's as the closest thing to a silver bullet may not be far away. At the 2009 easl Pharmassett reported on INFORM-1, the trial that combined two oral inhibitors R7227 and R7128(which has proven to be VERY potent against all genotypes including 3) without interferon or rib Here is the wonderful preliminary news:

After 14 days, 63% of testers reduced viral load below the quantification limit of the diagnostic assay (less than 40IU/ml) Furthermore 25% were below the limit of detection of virus in their blood(less than 15IU/ml) after 14 days.

R7128 has been tested aginst geno 2 and 3 non responders combined with SOC and there was 90% RVR after 4 weeks with the results EQUAL between geno 2's and 3's.

Also Pharmassett is now beginning a trial with a similar inhibitor that is 15-20 time MORE potent than R7128. I believe like many other drus and products, Teleprevir and Boceprevir will be first, will help MANY who couldn't clear the virus, especially geno 1's, but more potent and across genotype effective inhibitors will shortly be in the mix and will be better for the ultimate goal of interferon free treatment.

[jmjm530]

So no RVR and viral breakthrough of 60% by day 15 doesn't sound at all positive to me.
   ====================
In terms of TVR monotherapy I have to agree with you, and I assume that is what you are referring to when you say "doesn't sound at all positive to me". However, in the broader scheme of things, things apparently look good per author's conclusion for geno 2's with triple although would have be nice if study continued on to week 4 and also if they used weight-based ribavirn. Also would have been nice if they included a TVR/weight based riba Arm. Surprised you didn't mention the IR angle/possibility with the geno 3 group as maybe they were't screened for that :)

-- Jim

[CoWriter]

"I read it as geno 2's can clear in a short time with teleprevir alone."
----------------------

By day 15, none of them was undetectable and 60% of them had viral breakthrough.  Obviously, they needed the interferon.

Co

[CoWriter]

"Why disappointed? Seems geno 2's fare better with Telaprevir than geno 1's and may be able to treat with monotherapy."

"My guess is that the study is positive in that mono therapy seems to at least deliver RVRs to geno 2's."
-------------------

NONE of the Geno 2's (or 3's) on monotherapy were undetectable at day 15.  (and there's no data for week 4).

Subjects undetectable at Day 15:

Arm A (Telaprevir monotherapy)...Geno 2 (0%).....Geno 3 (0%).
Arm B (SOC+Telaprevir)..............Geno 2 (40%)....Geno 3 (22%).
Arm C (SOC+placebo)................Geno 2 (25%)....Geno 3 (11%).


In the monotherapy arm, 6 out of 10 Geno 2 patients had viral breakthrough (vBT) by day 15.  That's 60%.

So no RVR and viral breakthrough of 60% by day 15 doesn't sound at all positive to me.
  

"I'm sure it's in there in the badly written fine print but  unclear to me  if it was Telaprevir mono or triple in re to genotype 3's that was ineffective."
------------------------
Both.  

HCV-RNA log decrease by Day 3 and Day 15:

Arm A (monotherapy)...Day 3 (-0.8 log)....Day 15 (-0.5 log)
Arm B (SOC+Telaprevir)...Day 3 (-2.9 log)....Day 15 (-4.7 log)
Arm C (SOC+placebo)....Day 3 (-2.6 log).....Day 15 (-4.5 log)

On the monotherapy arm, response was low at Day 3 and dropped even more by Day 15.  And the drop in viral load at Day 3 and Day 15 was about the same for SOC+Telaprevir and SOC alone.  


"On face, it doesn't make sense that only a .8 log at week 4 with geno 3's unless it was mono because I would think you'd get a lot better than that drop with just SOC> "
--------------------

It was a 0.8 log decrease at Day 3.....and 0.5 at Day 15....but  week 4 data is not included, which I find strange.

Co

[Willy50]

Jim if you look at the link I provide for the geno 4 study the pattern will be similar. -W

http://www.medhelp.org/posts/Hepatitis-C/EASL-2009-Telaprevir-G-4-Results/show/934925

Whether I plugged the numbers in the correct spaces is another question.  ; )

The day that I explain something to you is noteworthy to me.  And I was so certain you knew Martian.

I was also hoping you were right.  I put a slightly nicer spin on the subject in the other TVR G2 and G3 thread but the bottom line was that even though they still got nearly a 1 log drop in 2 weeks in the G3 triple therapy arm there will be many other compounds which will do better, or so it appears.

best,
Willy

[jmjm530]

I agree the abstract was written in code. Martian code. LOL. But since you seemed to have a negative interpretation of martian speak, I thought I'd put in a positive spin. My guess is that the study is positive in that mono therapy seems to at least deliver RVRs to geno 2's. As to the rest -- translator pleaseeeee :)

-- Jim

[Willy50]

I don't know what that active link is doing in my sig.  ?????

Look at the way the article was written;

"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. ******* (my emphasis-willy)

[Willy50]

I would like to see it on a graph or graph.  The written description is really not helping me; like reading binary code.  I've yet to read a summary which showed clearly how the triple therapy arm did (and of course, this is only at 15 days; not a final results trial).  I saw elsewhere and may have misinterpreted it that there was virtually no response in the arms.  I have to either build my own graph or find one.  So...what did you see the 2 week response with triple therapy being.  Once again I'm writing and not looking clearly at the study.

I hope I was just too hasty; jumping all over.  I'm sure that a table will pop up soon and this will become more clear.

Willyhttp://www.medhelp.org/posts/Hepatitis-C/Telaprevir---Is-this-True/show/934195#

[jmjm530]

Willy: 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.
---------------------------------
Why disappointed? Seems geno 2's fare better with Telaprevir than geno 1's and may be able to treat with monotherapy. As to geno 3's, it looks like only monotherapy didnt do well but maybe Im reading this study wrong.

[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;
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.

[Marcia2202]

I see. I personally find it a bit stupid (sorry the expression) to compare monotherapy, as in practice no one will do monotherapy with TVR anyway. Maybe geno 3's don't bite on mono, but would do just s well on triple. I guess they won't be able to tell us, 'cause they did not do it. I would find it reallly realllllly stuuuupid, if they would actually give up trying TVR on g3's because of this one result.

Well that's my opinion, and I'm sure I'm not the only one.

[JennyPenny]

Hmmmmm. I think you guys are right. Geno 3's appear to be only telaprevir monotherapy. But that .8 must be compared to 4 which was the log drop for Geno 2's on the telaprevir monotherapy for the first 6 days. It looks to me, that both genotypes did the first 6 days with monotherapy. What a disappointment for geno 3's.

[Marcia2202]

I was just reading desrt's post. He explains it the same way. That they will not pursue further trials of TVR on g3's. What a freakin' bummer. In the end we will end up being the genotype the most difficult and longest to treat.

Do you guys see the irony? I was always skeptical when ppl and docs said that I had an easy to treat gt. Why did I not RVR and had to extend?

[newleaf09]

I read it as geno 2's can clear in a short time with teleprevir alone.  2's already are most responsive group and require shorter treatment, so clearing on teleprevir makes sense.  Sadly the short treatment with teleprevir alone did not work so well on 3's.  The protease inhibitors crash your neutrophils and hgb and are rough combined with peg and riba.  Wouldn't it be great to miss all the side effects of the peg and riba by treating with the PI alone?  This is a very good report for geno 2's.

[Marcia2202]

Jim, I couldn't figure it out either, after having read it several times. It jumps between mono and triple therapy and doesn't make sense to me. But there is not much to go on, as the TVR trials for geno 2/3 are way behind geno 1.

My doctor suggested I treat with TVR or BCR, if I don't make it...

[jmjm530]

I'm sure it's in there in the badly written fine print but  unclear to me  if it was Telaprevir mono or triple in re to genotype 3's that was ineffective.  Maybe someone more patient can clarify. On face, it doesn't make sense that only a .8 log at week 4 with geno 3's unless it was mono because I would think you'd get a lot better than that drop with just SOC>