Good News/Bad News from AASLD

[Susie2007]

I've just returned from AASLD and was able to learn some good things and bad things. The good news is that both the Schering protease and Telaprevir are doing rather well with treatment naive and relapsers. The bad news is that patients who have treated before and are null responders (didn't have a 2 log drop by 12 weeks) will not respond to the protease inhibitors. A number of the hepatologists talked about this, among them Drs. Sulkowski, Shiffman, Terrault and Zezeum....all very well respected. If a patient had enough viral load checks, complied with treatment and didn't miss injections or ribavirin, had no dose reductions, and didn't have at least a 2 log drop by week 12, they are now considered interferon resistant. The combination of SOC and protease will not be enough to overcome that resistance. They feel that these patients will need combinations of protease and polymerase and that these are about 10 years out. I, for one, as a non-responder, is really bummed about this.

The other lousy news is from the HALT C trial regarding maintenance therapy. Unless a person can keep their viral load undetected (in other words, they relapse without interferon) it does not work. If  the doctor can get them to undetected again and play with the dose of Peg to keep them at that level, it probably will work. HALT C showed no improvement in fibrosis scores, HCC, ascites, from maintenance in virus detected people. The only benefit was a reduction in the incidence of varices.

This was not a happy year for me at AASLD.

[miked]

Susie,

From your comments I assume that you didn't get a 2log drop on SOC tx (I've heard so many criteria for non-responder).  I'm really sorry for how you must feel.  

Hopefully your grade and inflammation are low.  What's your stats?

Were these presentations made by these docs that you attended at AASLD?

Thanks for attending and reporting back to us.

Mike

[miked]

I reread you post.

Null responder is defined as not attaining a 2log drop.

[Susie2007]

I've come close to a 2 log drop, but never actually achieved that. I was diagnosed in 1992 and had cirrhosis at that time. I was really counting on the telaprevir. But I'll get over this, I always do. Thanks for your interest in my situation.

[susan400]

Susie,

I, too, am disappointed to hear this news.  I'm in the same boat....   I was hoping that the maintenance study (HALT-C) was going to show better results.  I don't really like the idea of having to go through 4 drugs w/Interferon, Riba, Polymerase and Protease inhibitors as I feel like the sides would be unbearable for most of us to have to deal with.  My body has already endured 9 treatments and I am just tired...    I was really hoping for some sort of low dose maintenance type of thing because I figured I could just manage this disease like diabetics do with insulin.  I wish there had been better news..., I'm with you though, we'll get over it together, okay?   Susan (another Sus)

[fightit]

Sorry to hear the news. I received my 8 week labs today and had a 1/2 log drop from the beginning of treatment. Then I came home and read this. Not one of the best days. I guess it's good to know your not alone but it would sure be nice to hear something a little more encouraging from them.
I was going to wait for Telaprivir to treat but my doctor convinced me to treat now. I wonder now if I had waited would it have been different. I'll never know for sure. We can pray for a miracle. You never know something may come along sooner than we think.

[copyman]

thanks for the update. really sorry for the bad news for you. if you are the susie that has the other HCV forum you will be fine as i have been going to that site for over a year now and you are a very strong and good person. if i was you i would still try one of the PI's when approved and if not unde at 4 weeks stop. what do you have to lose by giving it a try? right now alot of what docs say are still guesswork. no one really knows. if you are the susie i'm thinking of you will be cured someday, you have helped to many people not to be paid back with something good. good luck and god bless

[merryBe]

so sorry to hear this new for you.
not to spread false hope, but it was encouraging to read of the discovery of the role of the genome proj. regarding activin suppression.
there was another new sulfa drug that England's been working on, dr.David Ward maybe, sheesh mind is a sieve... have to go find it again now. both these approaches deal with reversal of fibrosis, which would be the other approach, to find something that, in spite of viral load or not will repress or reverse the process of fibrosis.
I would think one day, they'll do both simultaneously, and that the race will be one as to how to turn the gene off (there are four of them).
the one in england is available now though and may be a stop gap you could press for, even if on a transplant list I'd still check it out.
will try to find that link for you. hope it helps!

[merryBe]

http://64.233.167.104/search?q=cache:Klfsamq6jiIJ:www.ncl.ac.uk/icm/people/profile/derek.mann+newcastle+university+liver+fibrosis&hl=en&ct=clnk&cd=2&gl=us

getting there

[MKAndrew]

Hey Susie - fancy meeting a nice girl like you in a hepC forum.  Okay, so you know how we're given all these contradictory stats and anecdotal stuff - I just came across an article from Japan about a study on HCC recurrence.  Apparently, patients who are cured of HCC have a significantly lower recurrence rate, and significantly increased survival when treated with 24 months SOC dose monotherapy IFN-a post-HCC cure.  The hits just keep comin in.

[merryBe]

well finally, this is what I get for not earmarking everything of importance, someone just posted this a couple days ago, but since I can't take sulfa drugs I hadn't flagged it.

it may help you, especially if you don't drink, even though they were trying it on drinkers, make sense that it would help non-drinkers even more.

http://news.bbc.co.uk/2/hi/health/5382172.stm

[TravelMom]

Hey Susie,  must have missed you there...took Amanda to the meetings as well... I actually did not hear the news about the 2 log drop and the PI's....As a matter of fact, I really think that if Amanda had triple therapy in Prove3 she would be SVR right now...and she is a perfect example of a previos non-responder...so she never even had a 1 log drop, was in Prove 3/no riba group...cleared  between week 1 and 2 and had breakthrough at week 20...so there is hope and if you can try the triple therapy, I say go for it!!!!  

Sorry I missed you there..

Jodi

[Willy50]

Hi.......I've been out of town and I am not well read on the results of the trial but I want to throw out a few concepts and see how they resonate.  You see.....I think there was good news offered.

1)  The results of Telaprevir may be lower than expected or desired but they still represent a vast improvement over current TX/SOC;
     a)  Treatment times cut in half
     b)  Lower relapse rates
     c)  dramatically higher RVR rates
     d)  The ability to at least try a treatment and if you don't RVR one can quit treatment.  EVEN in FAILURE of treatment we see an improvement.
     e)  There has not been any evidence so far of long term toxicity issues.  Rather, so far those (the handfull we've seen at this board) who treated....even with severe sides during treatment have had a good even great recovery.
     f)  There still looms the possibility that we may see proof that this compound may have higher cure rates on the prior treatment failures (in the Prove 3 trial) than Boceprevir; still way too early to make a call on that but several Prove 3's here seem to have achieved RVR's quite early and were able to maintain them.  This bodes well as a predictor of SVR.  It's true that this has little to do with the results of AASLD but keep the results in perspective
     g)  In a month or two we may see the commencement of PROVE 4 (Phase 3 trial) and we may also see the shape and scope of the trials.  I think the HCV and investment community would love to see what the compound can provide if full dosage and full term treatment as allowed (via the use of rescue drugs).  
     f)  Also keep in mind.....if any improvements can be made in countering the sides of Telaprevir we won't see them in the Prove 1 results.  Improvements may be seen in Prove 3 results.  Further refinements may also be seen in the criteria seen in the upcoming Phase 3 trials.  (another assumption here too; I'm assuming they will get the greenlight to move to Phase 3)
    g)  Straying from the concept of the AASLD..... but we've seen no evidence provided in the conference which suggests that the compound won't proceed to Phase 3 trials.  If that happens we will see the culmination of what this compound may do.  This could entail shorter treatment times (might some be able to treat in less than the "12 and 12 treatment"), a potentially lower dropout rate (due to rescue drugs and greater confidence in the treatment)

Regarding Boceprevir;  Many of the same issues will pertain to this compound as well.  The trial id still early Phase 2....... there will be improvements during the duration of Phase 2.  Once again the real proof of what the drug may do won't be till Phase 3.  I continue to feel that both drug companies may shelter the real data so as to keep their competitors in the dark.  That will also keep us in the dark along the way but I'll assert that scant information does not equal proof of poor performance.  Now we have at least another (and in fact there are several more) possible alternatives to Telaprevir.

Alinia offers a possibility of a drug which is already approved, low in price and while it may be too early to have solid SVR rates we can be hopeful that we may soon have a third drug which can be combined with current SOC.  This drug may increase RVR & SVR rates.  It seems to be cheap and largely free of troublesome side effects.  It may also loom as a drug which could also raise the efficacy rates of the Telaprevir or Boceprevir treatments should they be approved.  Even people who have failed in the past can possibly soon treat and with a greater expectation of a better chance of clearing.  Thsi may be very important for people with advanced liver disease.

This is a long enough post...... but there are other new compounds which look promising.  We may have more assurance that one will make it through approval.  In this, I think that the future looks far brighter than it did a year ago.

If there have been failures...... or disappointments I would still suggest that even in failure the drug companies end up with a better understanding of the virus.  We already have a 40-50% SVR rate.  The treatment time is about to decrease, the SVR rate is soon to increase and lots of new treatments are in the pipeline.

I understand that it's an expected result; things may not be as great as we had hoped for but keep things in perspective.  The half empty glass just filled up another 25%.

best,
Willy

[Cheesegrater]

I am interested if the info you mentioned about non-responders (to SOC) not having a chance with protease inhibitors has been released to the public yet?

I have heard no mention of prove 3 data from Vertex yet. Prove 3 started dosing non-responders a little over 24 weeks ago and the study is not over yet.
Is interim data available somewhere?  Or is all this talk just talk?

Cheese

[willows]

Wow, I guess it's time for me to rethink my paradigm and sit down in again with my big brain doc.  My last biopsy took me from stage 2 to stage 3, but Doc Scott convinced me to wait until telaprevir was approved to tx again.  Now I'm not sure I'm a classic null responder, I had a 2 log drop at week 12, but virus spiked back 10 fold at 24 weeks.   When I think real hard, I remember Doc saying I was inteferon resistant...not a memory I'm glad to have..in light of your news.

Mutha freakin apricots, this changes everything.  I'm gonna go cry for a bit and then figure out a new plan.  Things will have to get better tomorrow.

Willow

[jmjm530]

Sounds like by the definition given previously, you're a responder who had a viral breakthrough -- as opposed to a non-responder or relapser. That sub group was not addressed in Susie's post, so no reason to be discouraged. In fact, I'm sure the whole story is more complex than stated, and hopefully more positive -- at least for the non-responders. Keep in mind that previous non-responders have responded with variations of SOC, and maybe some variation of triple tx -- still not trialed -- will be the winning combination.

All the best,

-- Jim

[willows]

Will you marry me?  Well, accept my thanks anyway for the comfort.  I'm just rattled because I distinctly remember the doc tellin me that I was interferon resistant.  But you are right, it will take time for the data to be sorted out.  Come to think of it, aren't we all interferon resistant?  I mean, who in their right mind would not resist it?  I say let's mount a campaign and eradicate interferon from the planet, right after we find the FDA fool who approved it as  tx for the virus and force that fool to watch "Judge Judy" daily until common sense returns.

My reticence about being dang sure a person needs to treat and is really ready to tx was a prophetic notion, I think.  I know you share a version of the caution too.  If only I knew then what I know now....but how to make sure about something like interferon?  I keep remembering the absolutely gawdawful movie the gyno made me watch before my first child was born....simply because I had stated I wished to try natural childbirth.  At the time, the movie was a major annoyance, well, except for my husband blanching white and excusing himself for a smoke...and I popped out the most beautiful baby au natural.  Too bad I did not have such luck with the ole interferon and riba...and perhaps with this news from AASLD, someone will create protocols a bit more stringent now, at least until a combo of PI's is approved and tested.  

To be a null responder, or interferon resistant now has a bigger price tag...dang...just when I was getting used to the usual run of the mill long term effects.  

I'm a bit bitter right now...late in the evening like this is probably a good time for it.  Tomorrow is another day...great day for a new plan.  As soon as I figure out what it is.  Thanks, jmjm

[Willy50]

Susy wrote;  "If a patient had enough viral load checks, complied with treatment and didn't miss injections or ribavirin, had no dose reductions, and didn't have at least a 2 log drop by week 12, they are now considered interferon resistant"
------------------------------------------------------------

I'm not challenging this.  I think that it may very well be true.  The question however is; what will be the ultimate RVR rate (and SVR rate) for prior nonresponders in protease inhibitor trials?  I don't think we know the answer yet for Vertex although if one based the results on Andiamo or Miked one would not be pessimistic; rather the opposite.  They are in Prove 3 (and therefore past treatment failures) who cleared in one and two weeks respectively (or pretty close to thereabouts).  Another trial participant, dmhrdh was able to clear, but not as quickly partially possibly due to a reduction in ribiviren.  This is an example of a case where rescue drugs may have been of some assistance.  Until we are able to see the results of a complete optimal treatment we cannot expect optimal results.  I'm not positve that the Boceprevir trials were the optimal results that one can expect in treating treatment failures.  They also may not reflect what we can expect from the Telaprevir trials.  In these trials so far it appears that there have been several members of this board who attained (and maintained) RVR, at least 3 who have cleared by week 12.  As time goes on we will have more results.  The real question is the issue of SVR.  So far it looks a long ways from discouraging, at least to me.

I don't recall......but don't about 80-90% of those who stay on treatment (SOC and TVR)  end up with a RVR?  With standard SOC during the trials I believe that about 11% (the control arm) on SOC hit an RVR.  Yes.....that still leaves out some people but it is a much smaller group, no?  The quote above may pertain to that group but even so....... I don't believe that any of them were issued rescue drugs.  Would the results have been the same if they had been allowed the use of some of these drugs (for instance Procrit or Neupogen)?

I just happen to believe that it is better to dwell on the positives....and there are more than a few.

Willy

[Proactive]

I posted this on another thread, very preliminary stuff, but it does seem to be a different direction
"Conatus Pharmaceuticals Reports Positive Results of CTS-1027 in Multiple Preclinical Studies of Liver Disease

SAN DIEGO, November 05, 2007 /PRNewswire/ -- Conatus Pharmaceuticals Inc. today reported positive preclinical results on its lead compound, CTS-1027 in multiple models of hepatitis, an inflammatory liver disease. The results were presented in a poster session today at the American Association for the Study of Liver Diseases (AASLD) in Boston, MA.

CTS-1027 significantly reduced liver damage following oral administration in four different preclinical models of liver injury. CTS-1027 markedly reduced aminotransferase (ALT) activity and improved survival and liver histology in the TNFalpha/Gln model. CTS-1027 was equally effective dosed at the same time as the insult or post-insult in the LPS/Gln model. CTS-1027 significantly reduced ALT activity in the Fas and Con A models. Dosing was well below or equivalent to exposure levels previously tolerated in human clinical studies.

"CTS-1027 represents a potential new and exciting approach to treat patients infected with Hepatitis C Virus (HCV), and in the treatment of other liver diseases. Our initial goal for the development of CTS-1027 is to establish safety and efficacy in patients infected with HCV who have failed or can not tolerate standard of care," stated Alfred Spada, Ph.D., SVP Research and Development. "We plan to initiate a Phase 2 clinical trial within the next few months."

CTS-1027 is an oral, small molecule, matrix metalloproteinase (MMP) inhibitor under development for chronic use to protect the liver from damage due to a variety of insults including virus infection, obesity, alcohol use, and autoimmune diseases. Preclinical studies demonstrate strong efficacy in multiple models of liver disease. In previous clinical trials in other therapeutic areas, CTS-1027 was chronically administered to over 500 people, some for over 18 months.

Matrix metalloproteinases (MMPs) are a well studied family of proteolytic enzymes. In the liver, as in other solid organs, MMPs play a key role in maintaining the integrity of the extracellular matrix. Excessive MMP activity has been demonstrated to occur in the liver in response to a variety of acute and chronic insults. This results in the loss of scaffolding that maintains the normal architecture of the liver and the recruitment and activation of inflammatory cells that perpetuate liver damage. In addition, important cytokines in the progression of liver damage, such as TGF-beta, stimulate the expression of MMPs from hepatic stellate cells, the main cell type involved in the pathology of fibrosis. MMPs are also well recognized to play an important and direct role in regulating inflammation. These dual activities of tissue remodeling and modulating inflammatory networks make MMPs an attractive target in the setting of acute and chronic liver disease.

Conatus Pharmaceuticals Inc. is a privately-held specialty pharmaceutical company engaged in the development of innovative human therapeutics to treat liver disease. Chronic liver disease affects millions of people worldwide and can be caused by many different conditions or "insults" to the liver including Hepatitis C and other viral infections, obesity, chronic alcohol abuse or autoimmune diseases. Conatus was founded by the executive management team of Idun Pharmaceuticals in July 2005 following the successful sale of Idun to Pfizer.

http://www.conatuspharma.com

CONTACT: Steven J. Mento, Ph.D., President and CEO, [phone],, or Alfred P. Spada, Ph.D., Sr. VP R & D,[phone], , both of Conatus PharmaceuticalsInc. ***@**** ***@**** "

[charm27]

i was told if i treat with SOC then I cannot treat with the new protease inhibitor unless I relapse.
I can see from above post this is true

Charm

[charm27]

this was not the information that we had all expected. I find it a total mind blower.
I have an appt with My Doc who attended the meeting and I will se him Friday.


Trying to look on the positive side but not sure what that is anymore.

I was told I would be resistant because of SOC.....bummer bummer bummer

I need to vent I will get over it.
Im starting tx next week and need to go thru this with a positive mindset.

[susan400]

Where have you been???   Haven't seen you around in awhile and good to hear that you're still alive!

Susan400

[returntosender]

The study you refer to - or at least the one I found - also seems to indicate that using the Riba/Peg combo for SVR patients without HCC is useful to reduce the chances of contracting HCC.   Am I reading this right -- are they saying we should continue to treat with Interferon and Riba even AFTER we are SVR??  They throw in some things about the condition of the liver, age, length of time with disease and such but they seem to say that continued tx with Interferon and perhaps Riba reduces the chances of liver cancer fivefold.  I dont know what to think about this whole article but thanks for the post.  I was running out of things to worry about.  LOL

Are you still blogging?   Still writing?  Havent seen you in a while.  What is your status these days?  You had some significant reduction of fibrosis last I heard.  Any new discoveries?  

[miked]

Willows; are you certain that your doc said that you are Interferon restant?  I too had a viral breakthrough on SOC tx at Week 32.  At Week 12 I got a 3log+ drop and then began a slow VL decline until it rose at Week 32.  If you got a 2log drop at Week 12 you responded to INF and ARE NOT a null responder which is what Susie is talking about.  I'd talk to your doc very specifically about this.

Susie; I'm curious, was this data given in a formal presentation at AASDL or was it sidebar comments or perhaps meeting discussions by these docs.  What I'm picking at is this may just be initial observations or speculation.  There's no data anywhere on the topic.

Two AASDL presentations that I am anxiously awaiting the details are:

1.) November 5th @ 8:15 AM -     PROVE2: Phase II Study of VX950 (TELAPREVIR) in Combination with Peginterferon ALFA2A With or Without Ribavirin in Subjects With Chronic Hepatitis C, First Interim Analysis C. Hezode; P. Ferenci; G. M. Dusheiko; S. Pol; T. Goeser; J. Bronowicki; S. Gharakhanian; D. Devonish; R. Kauffman; J. Alam; J. Pawlotsky; S. Zeuzem

This presentation gives interum data about the Arm C which is 12week VX950+INF+RBV followed by 12 weeks of SOC.  This protocol is the same as Prove 3 Group D that I finished treatment for.

2.) November 6th @ 800 AM -     Evaluation of Viral Variants During a Phase 2 Study (PROVE2) of Telaprevir with Peginterferon alfa-2A and Ribavirin in Treatment-naïve HCV Genotype 1-Infected Patients.  T. Kieffer; Y. Zhou; E. Zhang; M. Marcial; R. Byrn; T. Pfeiffer; J. Miller; A. Tigges; D. Bartels; A. Kwong; P. Ferenci; G. Dusheiko; S. Zeuzem; J. Pawlotsky

I was excited to hear the Prove 1 and Prove 2 correlation between RVR and SVR.  For VX950 tx RVR is defined as UND by Week 4.  I started May 4th and became UND somewhere before May 18th.  As Willy references, most Prove EVRs maintain their UND status throughout tx.  After tx 91% of EVRs go on to be UND at post-tx Week 12.  Of post-tx Week 12 UND, 100% are UND at 24 weeks after stopping tx, which is considered cured.  For Prove 1&2, if a relapse occurs, it would within 4 weeks after successfully completing tx.

The numbers between Prove 1 and Prove 2 vary greatly.  These may not be totally accurate but in Prove 1 like 2% of patients relapsed while in Prove 2 like 14% relapsed.  Why the differnece between studies?  Is it the cars that Europeans drive or the small portions of food they eat?  :-)

Today I'm on pins and needles because soon (like yesterday) I'm to receive the results of my Week 26 (two weeks post tx) labs.  It's in God's hands now and I hope he has good news.

One closing thought to Susie2007....any thoughts about future treatments with Albuferon, VX-950 and Ribivirin?  It's not going on (yet) but that combo always seemed ike a powerful punch.  I believe that many INF resitant people respond to Albuferon.

Mike

[charm27]

So for alll the people who have relapsed after tx they will be able to tx with a P.I.?
Does that also apply for people that have had breakthru's during tx? will they too be able to tx with a P.I.?

To my understanding if you dont have a 2 log drop within 12 weeks you should stop tx and P.I.'s will not be offered

Just trying to absorb this.
t y

[wyntre9]

Thanks for posting this.

Excellent info for all tx'ers.  I'm learning a lot.

wyntre

[miked]

I had a viral breakthrough on my first treatment of PegIntron + Ribivirin.  Just finished 24 weeks on Prove 3.

[charm27]

thanks for your comment. Good luck to you in finishing up 24 weeks!
Ive been in a liitle state of confusion re the resistant issue.
just trying to understand it all.

best of luck to you!!

[Susie2007]

I'm going to try and answer some of your questions. But please bear with me because I am not a medical professional and I have tons of articles, abstracts, notes, etc and I will do the best I can answering the questions I feel confident about.

First, Travelmom, I can't believe you and Amanda were there and I didn't know about it. Big bummer. Miles, you stinker, I love ya! Copyman, it is me, from Voices, and thank you so much for your kind words. I needed that today. Susan, I know who you are and I do believe that you have even beat Miles and me with the number of treatments you have tried. Charm, a relapser can certainly retreat with higher doses, longer duration and with PI's successfully. It's the null responders who have a problem. I'm guessing that what you were told is that you can only join the next Telaprevir trials if you are a relapser or non-responder. So if you do SOC and can't treat in the next Telaprevir trial it means you would have been successful with SOC.

What I said about maintanence treatment comes from two places. I had a face-to-face talk with Dr. Shiffman in his hospital while he was performing a biopsy on my friend in May. The rest I got from the HALT C trial paper that was published as a late breaking abstract at AASLD and attending an evening session with Emmett Keeffe, Stephen Harrison, David Nelson, Mitchell Shiffman and Norah Terrault, all hepatologists who did a 90 minute discussion on Treatment Challenges in an Era of Advances.

We also attended an hour long discussion with Dr. Zezeum and Dr. Mark Sulkowski and the name of that discussion was Current and New Therapies for HCV. At that discussion and again, at the evening discussion with the doctors mentioned above who did the Treatment Challenges Discussion,  they discussed why the PI's will not work for null responders. Whoever mentioned that there have been no trials with Telaprevir in previous non-responders/relapsers, I believe you are correct. If we understand this correctly, the doctors are making these statements based on the fact that hep C is made up of wild type virus and mutant virus. The wild type is the main and much larger number of virons and the mutant type is the type that if, as Dr Shiffman mentioned, your interferon switch is broken, will not be gotten rid of by interferon. Protease does not affect the mutant type at all. So if you are a non-responder, and it is due to being interferon resistant, or having a "broken switch" any other drug that MUST be paired with interferon will not work.

That is the best I can remember and I double checked with the person who attended with me, and this is what she remembers also.

Miked, I agree that this has to be considered speculative at this point in time. However, my experience with these doctors, who I have been listening to lecture for many years, and in fact one or two of them make themselves available to me as advisors to my organization, has been that they have hit it on the head just about every time. It would be wonderful if they are wrong this time, but what's the chance?

Plus, we all know people who have been previous non-responders, and the ones I know who somehow  got in the trial and got in the arm that got all 3 meds, have  broken through after being originally undetected.That is not to say that some few previous non-responders won't respond because their lack of response to SOC may have been for other reasons than interferon resistance. I certainly hope that is the case with you guys here who are waiting for results.

I don't want to be the bearer of bad news. And, I would give almost anything to be wrong, but I promised on this board, and my own, that I would come back with the best information I could. I just wish it could have been different.

Miked, Miles and I are trying to get some decent information on Alinia.

Oh, something else really exciting to me. Last spring I found out about a study that was going on at Mayo for late stage people to reduce fibrosis...which is just as important as getting rid of the virus. They are using a simple ace inhibitor called Diovan (80mg) and it looks like it is working. I saw an abstract out of UMass (Dr. Ray Chung) who published results from a study they did with an ace inhibitor (didn't say which one) and with paired biopsies and insulin resistant people vs regular hep people, they got good reduction in fibrosis scores with no side effects in both sets of people. So it looks like there will be help for future non-responders to cut down on the amount of fibrosis.

[Susie2007]

Hang in there. It sounds to me like you might be one of the ones who can benefit from re-treatment with telaprevir. Dr Shiffman repeated numerous times during his part of the discussion that multiple PCRs need to be done because they are needed for the doctor to know if someone is truly a null responder. I do not think you are by his definition which said it is someone who has never achieved a 2 log drop.

[copyman]

do you know anything or hear anything about a new drug from pharmasett & roche. not sure of the name. it is in the very early development stage with phase 1 trial starting in the next month or so.  was suppose to have some abstracts about it at the boston meeting? if i remember the name i will post. thanks for the great info.

[TravelMom]

Heard it is very promising...

Roche's Oral Polymerase Inhibitor Shows Robust Antiviral Efficacy in Treatment of Chronic Hepatitis C


  
  BASEL, Switzerland, November 2 /PRNewswire/ --
- Roche Progresses R1626 Into Phase IIb Study Called POLI 1
R1626, one of Roche's new investigational drugs for hepatitis C (HCV), has shown promising antiviral efficacy when given in combination with PEGASYS(R) (peginterferon alfa-2a (40KD)) and COPEGUS(R) (ribavirin), according to results being presented at the American Association for the Study of the Liver (AASLD) meeting in Boston(1). After 4 weeks of treatment with the triple combination, the hepatitis C virus could no longer be detected in up to 81% of the HCV-infected patients. Patients receiving the triple combination had a mean decrease in viral load of 5.2 log10 from baseline, indicating a robust and rapid virological response.

R1626 belongs to a class of antivirals called polymerase inhibitors, which are being investigated in combination with the current standard of care, pegylated interferon and ribavirin. The hope is that this potent combination will increase the number of patients who manage to clear the hepatitis C virus from their system and become cured of this disease.

Lack of Resistance Demonstrated
R1626 has also demonstrated a high barrier to the development of resistance, according to a second abstract being presented at the conference(2). Resistance to R1626 was not identified following intensive testing for either 2 weeks of treatment with R1626 as monotherapy or for 4 weeks in patients treated with R1626 in combination with the standard of care.

"The results from this phase IIa study show that R1626 has a profound effect when used in combination with PEGASYS plus COPEGUS," said Dr Paul Pockros (Scripps Clinic, San Diego, California), the lead investigator of the study. "The synergistic antiviral effect of R1626 along with the lack of resistance means that R1626 could be an exciting antiviral treatment option for patients with hepatitis C if a safe and acceptable dosage regimen can be determined in future studies."

The study found(1):
- Up to 81% of patients treated with R1626 1500 mg BID + PEGASYS + ribavirin had an undetectable HCV viral load by week 4 (mean reduction of 5.2 log10 IU/ml)
- ALT, a liver enzyme, normalised in approximately 50% of patients in R1626 treatment groups
- Most reported adverse events were mild to moderate. A higher incidence of grade 4 neutropaenia was reported in R1626 treatment arms (ie, 39% of patients receiving the R1626 1500 mg dose in combination with PEGASYS and ribavirin), and it was the main reason for dose reductions and discontinuations

Further phase II studies are underway to investigate R1626 in combination with PEGASYS plus COPEGUS.

Start of the Phase IIb Trial
As a result of the robust antiviral effect seen in the phase IIa study, R1626 is being progressed into a phase IIb study to further investigate new treatment regimens, in combination with a standard or lower dose of PEGASYS(R) plus a standard dose of COPEGUS(R). This phase IIb trial, called POLI 1, is now open and about to enroll patients in eight countries - Austria, Australia, Canada, France, Germany, Italy, Spain and the US. More information about R1626 and these clinical studies can be found on http://www.roche-trials.com.

"The strong synergistic antiviral effect seen among R1626, PEGASYS and COPEGUS in the Phase IIa study together with the design of the phase IIb study makes me confident that we will find the right balance between the safety and efficacy," said Dr. Stefan Zeuzem, Professor of Medicine at J.W. Goethe University Hospital, Frankfurt, Germany, and a lead investigator in this Phase IIb study.

About Hepatitis C
Hepatitis C, the most common chronic blood-borne infection, is transmitted primarily through blood or blood products. Hepatitis C chronically infects 180 million people worldwide, with an additional three to four million people newly infected each year(3). It is a leading cause of cirrhosis, liver cancer and liver failure, despite being potentially curable. The future of hepatitis C therapy is likely to involve combinations of new small-molecule antiviral drugs and pegylated interferon-based treatment, like PEGASYS.

About Roche
Headquartered in Basel, Switzerland, Roche is one of the world's leading research-focused healthcare groups in the fields of pharmaceuticals and diagnostics. As the world's largest biotech company and an innovator of products and services for the early detection, prevention, diagnosis and treatment of diseases, the Group contributes on a broad range of fronts to improving people's health and quality of life. Roche is the world leader in in-vitro diagnostics and drugs for cancer and transplantation, is a market leader in virology and is active in other major therapeutic areas such as autoimmune diseases, inflammation, metabolic disorders and diseases of the central nervous system. In 2006, sales by the Pharmaceuticals Division totalled 33.3 billion Swiss francs, and the Diagnostics Division posted sales of 8.7 billion Swiss francs. Roche has R&D agreements and strategic alliances with numerous partners, including majority ownership interests in Genentech and Chugai, and invests approximately 7 billion Swiss francs a year in R&D. Worldwide, the Group employs about 75,000 people. Additional information is available on the Internet at http://www.roche.com.

All trademarks used or mentioned in this release are protected by law.

References:
1. Pockros P. Robust synergistic antiviral effect of R1626 in combination with Peginterferon alfa-2a (40KD), with or without ribavirin - interim analysis results of phase 2a sudy. In: 58th Annual Meeting of the American Association for the Study of Liver Diseases; 2007 November 2-6; Boston, USA; 2007.
2. Le Pogam S. A high barrier to resistance may contribute to the robust antiviral effect demonstrated by R1626 in HCV genotype 1-infected treatment-naive patients. In: 58th Annual Meeting of the American Association for the Study of Liver Diseases; 2007 November 2-6, 2007; Boston, USA; 2007.
3. World Health Organization. Initiative for Vaccine Research, Viral Cancers, Hepatitis C. 2006. (Accessed July 24, 2006, at http://www.who.int/vaccine_research/diseases/viral_cancers/en/index2.html) Contact: Janet Kettels, Roche, [phone]; Natalie Henson, Axon Communications, [phone]  
  
  



  

[TravelMom]

Pharmasset Presents R7128 14-Day Monotherapy Study Results for the Treatment of Chronic Hepatitis C


  
  -Nucleoside polymerase inhibitor demonstrates >99% mean decrease in HCV RNA with no serious adverse events-

PRINCETON, N.J., Nov 02, 2007 /PRNewswire-FirstCall via COMTEX News Network/ -- Pharmasset, Inc. (Nasdaq: VRUS) announces the results of a 14-day Phase 1 multiple ascending dose monotherapy study of R7128 for the treatment of chronic hepatitis C infection. In this study, being presented as a "late-breaker" abstract at the 58th Annual Meeting of the American Association for the Study of Liver Diseases, R7128 demonstrated potent antiviral activity and was generally safe and well-tolerated. R7128 is an orally administered prodrug of PSI-6130, a cytidine nucleoside analogue polymerase inhibitor of hepatitis C virus (HCV) that is being developed through Pharmasset's collaboration with Roche.

"R7128 has provided positive proof-of-concept that a single, direct-acting antiviral can deliver sufficient potency to suppress HCV in an interferon non- responder population," stated Dr. Michelle Berrey, Pharmasset's Vice President, Clinical Development & Chief Medical Officer. "Since robust synergy has been observed with other potent inhibitors when combined with the standard of care for HCV, we hope that these monotherapy results will translate well when R7128 is used with standard of care for longer duration in a treatment-naive population."

Dr. Rajender Reddy, Professor of Medicine and Surgery in the Division of Gastroenterology at the University of Pennsylvania and a clinical investigator in the study, noted "R7128's safety profile is encouraging, with no serious or treatment-limiting adverse events reported even at the highest dose tested. In addition, there were actually a higher number of adverse events reported in the placebo group than in the treated arms of this study. Safety is an important aspect of new HCV therapies, because the current standard of care is not always as well tolerated as desired."

The R7128 scientific presentation will be available for download in PDF format following the conference in the "R7128 Presentations & Publications" section of Pharmasset's website at http://www.pharmasset.com/pipeline/R7128-publications.asp.

R7128 Phase 1 Multiple Ascending Dose Study Overview

The Phase 1 clinical trial is a multiple center, observer-blinded, randomized and placebo-controlled study was conducted in 40 patients chronically-infected with HCV genotype 1 who previously failed interferon therapy. The primary objective was to assess the safety, tolerability and pharmacokinetics of R7128 after once-daily (QD) or twice-daily (BID) dosing for 14 days. The secondary objective was to assess antiviral activity by measuring the change in HCV RNA.

R7128 Safety Summary

R7128 was generally safe and well tolerated, and all patients completed the study. There were no serious adverse events, no adverse events requiring dose modification, no dose-related gastrointestinal adverse events and no clinically significant changes in hematologic or other laboratory parameters. The preliminary data on adverse events (AEs) reported shows the highest incidence of AEs was in the placebo group with 34 events in 7 of 8 patients receiving placebo. During treatment in patients receiving R7128, most of the AEs reported were of mild intensity. Eighteen AEs were reported in 7 of 8 subjects that received 750mg QD, 6 AEs in 3 of 8 subjects receiving 1500mg QD, 13 AEs in 4 of 8 subjects receiving 750mg BID and 14 AEs in 4 of 8 subjects receiving 1500mg BID. The most frequently reported AEs for patients receiving R7128 were headache (13), dry mouth (3), nausea (2), fatigue (2), tiredness (2) and upper respiratory infection (2). In subjects on placebo, the most commonly reported AEs were headache (4) and diarrhea (4).

R7128 Antiviral Activity Summary

R7128 demonstrated potent, dose-dependent antiviral activity across the four patient cohorts (8 active, 2 placebo per cohort) receiving 750 mg or 1500 mg administered either QD or BID for 14 days as monotherapy. Both the greatest mean and maximum decrease in HCV RNA from baseline were demonstrated in the patient cohort that received 1500 mg BID. R7128 demonstrated a mean HCV RNA decrease of -0.9 log10 IU/mL (87.4%), -1.5 log10 IU/mL (96.8%), -2.1 log10 IU/mL (99.2%) and -2.7 log10 IU/mL (99.8%) in patients receiving 750mg QD, 1500mg QD, 750mg BID and 1500 mg BID, respectively. All four dose groups reached nadir values at Day 15. A maximum -4.2 log10 IU/mL (99.9%) HCV RNA decrease was demonstrated in a patient following 14 days of monotherapy with 1500 mg BID of R7128, which was also below the level of detection (<15 IU/ml). There was no clinical evidence of viral rebound in any dose cohort during the 14 days of dosing, which provides early evidence of high genetic barrier for nucleoside inhibitors of NS5b polymerase.

Pharmasset is currently enrolling a 4-week Phase 1 clinical trial to evaluate R7128 in combination with Pegasys(R) (pegylated interferon) plus Copegus(R) (ribavirin) in up to 75 treatment-naAve patients chronically infected with hepatitis C virus (HCV) genotype 1. The primary objective is to assess the safety, tolerability and pharmacokinetics of R7128 in combination with Pegasys plus Copegus. The secondary objective is to evaluate the short- term change in HCV RNA. The study will investigate up to three oral dose levels of R7128 (500 mg to 1500 mg) administered twice-daily with Pegasys plus Copegus for 4 weeks. Please see www.clinicaltrials.gov or e-mail ***@**** for more information.

About Pharmasset

Pharmasset is a clinical-stage pharmaceutical company committed to discovering, developing and commercializing novel drugs to treat viral infections. Pharmasset's primary focus is on the development of oral therapeutics for the treatment of hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV).

Pharmasset is currently developing three product candidates. Clevudine, for the treatment of chronic HBV infection, is enrolling Phase 3 clinical trials for registration in the Americas and Europe. Clevudine is already approved for HBV in South Korea and marketed by Bukwang Pharmaceuticals in South Korea under the brand name Levovir. R7128, an orally administered treatment for chronic HCV infection, is enrolling a 4-week Phase 1 clinical trial in combination with Pegasys(R) and Copegus(R) through a strategic collaboration with Roche. Racivir, which is being developed for the treatment of HIV in combination with other approved HIV drugs, has completed a Phase 2 clinical trial.

About R7128

Also, lots of excitment about this drug as well...

R7128 is being developed for the treatment of chronic HCV infection. R7128 is a prodrug of PSI-6130, a pyrimidine nucleoside analog inhibitor of HCV RNA polymerase. A prodrug is a chemically modified form of a molecule designed to enhance the absorption, distribution and metabolic properties of that molecule. Results from an oral single ascending dose study of PSI-6130 in 24 healthy male volunteers showed that PSI-6130 was generally well tolerated with no serious adverse events in doses up to 3000 mg.

[charm27]

Thank you for answering and explaining all that you did. Im not  a relapser. actually Im starting SOC next week for the first time. Just asking lots of questions and trying to learn whatever I can.
Just trying to understand my options if the tx doesnt work.

Your posts were extremely helpful.
Thanks
I wish you the best

[spcecst2]

One thing I can suggest is wait a couple of weeks after you get your meds to start, that way you will always have a couple left when your refill is due!! Just in case!!

[charm27]

thanks alot. I need all the help I can get. :}
much appreciated.

[miked]

Thanks Susie.

[jmjm530]

I started getting nervrous if I didn't have at least 4-weeks worth of Peg shots in the fridge at all times and an xtra bottle of riba. BTW how is your treatment going? What week? What viral response so far? How are the sides? How long are you going?

Be well,

-- Jim

[Willy50]

I'm not directing this to you as a challenge; I know you are just the one trying to report what you heard.  I'm just trying to clarify the issues.  Like yourself I'm just a layman at this trying to understand.

Here is an excerpt from a news story.  Pay attention to the final sentance;
-------------------------------------------------------------------------------------------------------------
http://www.hivandhepatitis.com/2007icr/aasld/docs/110607_a.html
Boston, Nov 02, 2007 (Business Wire) -- Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) today announced results from interim analyses of PROVE 1 and PROVE 2, two large Phase 2b clinical trials evaluating the investigational hepatitis C protease inhibitor telaprevir (VX-950), dosed in combination with pegylated interferon and ribavirin. In 24-week telaprevir-based treatment regimens, genotype 1 treatment-naive HCV patients achieved sustained viral response rates of 61% and 65% in PROVE 1 (SVR 12 and SVR 24) and PROVE 2 (SVR 12), respectively. In addition, clinical researchers reported a correlation between achieving rapid viral response (RVR) and achieving SVR in a 24-week telaprevir-based regimen.
--------------------------------------------------------------------------------------------------

Am I understanding that the top researchers are saying that resistance to interferons (in prior non-responders) will in effect "trump" a very early RVR?

One of the members here, Andiamo has failed treatment 6 times and is in his 60's.  He would seem to be an example of a person not likely to clear or stay clear.  Andiamo cleared in his first week of triple dosing.  Due to the strong response and RVR it would seem that he might be on track to expect at least a greater chance of an SVR..  Am I to understand that the common thought now is that interferon resistant virii will make that unlikely in spite of the super response time?

Also....since the other PI in trials that reported results on prior treatment failures (Boceprevir) did not really post much info at the AASLD I wonder if this could be too early to make predictions about outcomes?  Even if I had the info I might be hard pressed to draw a strong conclusion.  It seems that all that we've seen so far is VERY preliminary results on PI response in prior non-responders, both in the SGP and Vertex trials.  I hope that the news is better than is being reported.  It still would be safe to reiterate that this is mainly a theoretical response rather than one borne from response data from either trial?  It is also a little frustrating trying to compare the 2 compounds but I rather expect that we'll have to get used to that.

I'm envious that you were able to go to the AASLD.  Maybe that would be a future fun road trip for us heppers to make.  (it almost sounds tax-deductable)  : )

best,
Willy

[HappyDeb]

Hi, you meantioned in one of these threads, about Diovan ( 80 ml) . I have been on this for 6 yrs. for my high blood pressure. I am a slow responder. I had to go off of tx. after 12 weeks, due in part of a rash and only a 2.5 log drop. I am 1A , stated out at 6.8 million VL. biopsy 1-2-1 Minimal liver damage. My question to you is, could it be because of taking the Diovan, it at least has helped me keep my liver some what healthy ? I have an Appt. in Jan. at the university of Miami with Dr. Schiff. Hoping I can get results with him as to treating me. My previous Dr. was not up to date on things. Great, Interesting thread.


                                                        Warmest Wishes,

                                                         Debbie

[jmjm530]

Susie: The other lousy news is from the HALT C trial regarding maintenance therapy. Unless a person can keep their viral load undetected (in other words, they relapse without interferon) it does not work. If  the doctor can get them to undetected again and play with the dose of Peg to keep them at that level, it probably will work. HALT C showed no improvement in fibrosis scores, HCC, ascites, from maintenance in virus detected people. The only benefit was a reduction in the incidence of varices.
-------------------------------
I've been trying to find the study/presentation that talks about viral load being undetected. In other words, the above suggests that mainteance is a viable option if it keeps viral load UND. Couldn't find the abstract anyway, thought you might be able to help. Thanks.

-- Jim

[Susie2007]

Happy Deb, I told you all I know about Diovan. I would guess that it does not interfere with treatment but is good for slowing progression of fibrosis. It is also used in pulmonary fibrosis.As a person who had a 2.5 log drop at 12 weeks, I would think you have a decent chance of clearing in the future.

Willy, the abstracts you posted are for treatment naive patients. But to answer your question, please remember that not all null responders are interferon resistant. My info is on interferon resistant people only. I don't know if interferon resistant people who had a RVR would then relapse or fail to achieve SVR. All I know from the conference is that interferon resistant people can not achieve SVR with telaprevir, inf and riba.

Jim, I will look for that abstract for you and post it if I can find it.

[Susie2007]

JIm, All I have so far is the abstract entitled "Prolonged Antiviral Therapy With Peginterferon to Prevent Complications of Advanced Liver Disease Associated With Hepatitis C: Results of the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial ". It just says that "These findings do not support maintenance therapy with peginterferon in patients with chronic hepatitis C and advanced hepatic fibrosis who are nonresponders". The only other thing I have is a slide from Dr Shiffman's Discussion entitled: Failure to Achieve SVR: Summary: It states the following:
1. Make sure the histology warrants retreatment
2. Document the virologic response pattern. This may require retreatment with frequent HCV RNA monitoring
3. Do not interrupt Dosing
4. Partial responders need more interferon
5. Late responders need a longer duration of treatment
6. Maintenance therapy remains unproven but is logical only in those patients with cirrhosis, prior relapse and can be maintained HCV RNA undetectable.

He did tell me privately that if maintenance was easy for me, and I could keep my viral load under 100,000 to go for it.

There is no abstract at this time because this is just his opinion and the opinion of others because of the disappointing results on the HALT C trial.

[jmjm530]

Thanks. #6 from Shiffman (and what he told you) from seems to contradict the findings in his own study that state "These findings do not support maintenance therapy with peginterferon in patients with chronic hepatitis C and advanced hepatic fibrosis who are nonresponders". Am I missing something?

-- Jim

[Susie2007]

I think you are missing the fact that he believes if maintenance can keep a person undetected it is worth it. The study showwed no benefit to  relapsers because they didn't put them back on treatment to get back to undetected. They went straight from relapse onto maintenance and the 1/2 dose was not enough to take them to undetected although he believes if you can get them to undetected again by retreating, then keep them there with maintenance. Make sense?

[jmjm530]

Yes, the thought makes sense -- but considering he just published a study that concluded maintenance didn't work -- with no caveats -- I'm still a little puzzled.
Because if notion that maintenance works (if it keeps you UND)comes out of the Halt-C data, then why isn't there at least a mention of it? One would think it easy enough to extract data on the sub-group who stayed UND with maintenance. Maybe I'm just missing something. In any event, I'm assuming that maintenance is keeping you UND, which seems like a very good thing, just confused a little because of the report.

-- Jim

[jmjm530]

I just re-read your post again. So what you're saying is that his strategy is to first get to UND by SOC and then drop to maintenance before relapse? It's an interesting approach, but then how do you know you wouldn't be SVR if you stopped? Or, does he re-start treatment (on SOC) after a relapse and then drop to maintance as soon as you reach UND?

[Susie2007]

He re-starts treatment (on SOC) after a relapse and then drops to maintance as soon as you reach UND?

[Tallahassee]

I believe this strategy was implemented for a few of my past treatments.

I would reach UND on Infergen, after my dose will be reduce to maintenance levels,  but, unfortunately, my viral level also will show up at smaller, suppressed values.

Thank to both of you for all you work!

All the best!

[Susie2007]

Sorry to hear that news. But, you should be able to respond beautifully to triple therapy with a protease inhibitor since you have been able to reach undetected. So the news is not bad for you!