Interview With Vertex/Telaprevir

http://www.pharmalive.com/extra/2009/march09_vertex.cfm
Q&A: Hepatitis C March 2009

Robert Kauffman, M.D., senior VP of clinical development and medical affairs at Vertex Pharmaceuticals Inc., spoke with R&D Directions’ managing editor Michael Christel about the progress of telaprevir, the company’s promising late-stage hepatitis C agent, and the complex challenges facing the industry in improving treatments for the virus. Vertex has completed enrollment in three Phase III trials for telaprevir, two in treatment-naive patients and the other in treatment-failure subjects. Combined, the trials have enrolled about 2,200 patients at more than 100 sites around the world, including locations in the United States, Canada, Europe, South America, Australia, and Israel.
Q: How and when did the vision of telaprevir originate?
A: I’ve been at Vertex for about 10 years. It actually started before I got here. I think the basic idea was Vertex had always had a interest in antiviral therapy really from its very beginnings. Even early on, hepatitis C was identified as a disease entity with a substantial unmet medical need. The therapy has evolved some over the years, but has [basically been] interferon and then interferon and ribavirin really since the very beginning.

It’s been very clear that there’s a highly suboptimal treatment [opportunity] for the most common form of hepatitis C in the U.S., genotype 1, which is about 70% of the patients. Even with the current sort of best therapy, if you look at all the studies overall, the ‘curator’ of sustained viral response rate ranges around the 40% level. It’s may be a little bit higher in Europe, maybe 45%. That means more than half the patients who get more than one year of therapy, which is really quite morbid, do not respond, and are left with very uncertain prospects. At the same time, the progression of the liver disease and the severity of the liver disease increases with both increasing time of infection and with increasing age. Since most patients in the U.S. were infected by blood transfusions prior to the time blood was being screened, those patients are all getting older now and are entering the period of highest risk of development of cirrhosis of the liver and then end-stage liver disease.

Even back in the beginning, Vertex recognized this as a high unmet need. There were no direct-acting antiviral agents at that time as there were, for example, for HIV. Given Vertex’s other experience with protease inhibitors – we had programs in HIV protease inhibitors since the very beginning of the company – that was a logical target for us. It’s an extremely difficult target for drug discovery based on just the structure of the enzyme you’re trying to inhibit. It took Vertex quite a bit of time to develop potent and selective inhibitors of which telaprevir was declared a development candidate. It went into clinical development in 2004.
It was really the structure-based design that Vertex was well known for that led to what we think has been a very successful program in identifying telaprevir. We published the first crystal structure in the HCV protease in the journal Cell in 1996. It’s been in our blood for a long time.  
Q: As an HCV protease inhibitor, how is telaprevir’s mechanism of action unique compared to other investigational agents that target the virus?
A: There are several targets in HCV that people are using for drug development. Protease has been the first of the viral polymers which make the viral RNA, which is the genome of the virus. There’s another more recently looked at target called NS5A, which is part of the replication complex of the virus that’s also become a target.
At the present time, I would say overall that protease inhibitors have produced the most profound, antiviral effect in patients as compared to polymerase inhibitors. Although, the recent data from Bristol-Myers Squibb on one of their NS5A inhibitors shows potency which is getting into the range of the protease inhibitors. We measure this in the amount of reduction in the viral RNA in the blood. With telaprevir and other protease inhibitors, one can get between four and five logs reduction in the first couple of days of treatment, whereas for polymerase inhibitors, they tend to run more in the two to three log reduction range.
Protease inhibitors as a class have been the most potent inhibitors. Compared to other mechanisms of action, they’ve really moved to the forefront of the development cascade, although there are many reasons why others would be valuable.

[StormRider]

Interview With Vertex/Telaprevir - Part 2

Q: Still, it looks as if several companies, like Vertex, see the potential therapy benefits in going the protease inhibitor route. Do you agree?
  
A: Sure, Schering-Plough is probably closest to us in the development timeline. They’re developing a drug called boceprevir. The first company in patients with a protease inhibitor was Boehringer Ingelheim with a drug called BILN-2061. They have certainly continued very active in the field (BI201335 is in Phase II/II).
InterMune in California is also very prominent in the field (ITMN-191 is in Phase I). Merck has a protease inhibitor program that actually looks pretty good. It’s a very active area of investigation [overall]. There’s 50 or more companies developing anti-hepatitis C therapies in various stages.
Q: What are the biggest challenges associated with developing effective treatments for hepatitis C?
A: The initial challenge is the protease is a very hard target. I would say the polymerase has also been a hard target just in terms of getting the kind of potency that people would like to see. Then there is the issue of viral resistance. Vertex has been in the forefront of investigating resistance of hepatitis C to direct-acting antivirals as a result of our early work on telaprevir. It’s fair to say that resistance is an issue for all antivirals. That’s well known form the HIV arena.
It seems very clear at this point that combination therapy is going to be required for all agents in order to prevent resistance from developing. For now, the combinations are the current pegylated interferon and ribavirin, plus the direct-acting antiviral. The ultimate goal is to develop treatment regiments that do not include interferon and ribavirin. Those drugs have lots of side effects. However, most people in the field believe that is still a number of years away and that the combinations that are most likely to be out there first are going to be interferon, ribavirin, and the direct-acting antiviral.
Resistance has been and will be an issue. It’s a little different than HIV in that there is not a structural basis for the resistant virus to hang around for a long time. But no one knows quite yet what’s going to happen in terms of HCV. We do know that in some cases, in our own studies, the resistant variants go away and wild-type virus, the normal virus returns again. However, in some cases also it seems to hang on for a while. That’s going to be an area of continuing investigation. It’s clear it’s an issue for all agents and everyone’s going to have the problem. Different companies have been more or less visible with this information, but I can assure you it’s an issue for everyone.
  
Other challenges are identifying the patients. The current treatment is fairly morbid. There’s a lot of patients who aren’t good candidates for interferon and ribavirin for various reasons. The treatment is long and difficult. There’s an issue of the number of physicians who are capable of treating hepatitis C well, who can really take care of the patients and get them through the process.
It’s always been our view that the two things that would really drive the field would be to shorten the duration of treatment, which is currently one year, and to increaser the response rate. [With] the response rate being in the 40% range, we obviously would like to get that much higher. We have some early evidence that that’s going to be the case. We’d like to be able to shorten the treatment from a year down to six months for most patients. Again, we have evidence from our Phase II program that looks like that’s going to be OK and work. That’s what our Phase III program is really all about, to confirm that shorter duration treatment will work for most patients and that the response rates can be increased fairly substantially. We’ve seen more than a 20% increase in response rates in the telaprevir Phase II programs.
Q: What is the market potential for telaprevir?
A: In general, if the kinds of data that we’ve seen in the Phase II program are confirmed in Phase III, then physicians will see this as a valuable treatment for both treatment-naive and treatment-failure patients. We reported some interim data in a Phase II study in non-responder patients at last year that suggests that there is a potential for a really substantial increase in response rates in non-responders, in particular. They do represent a very larger group of patients. There is a substantial market in both populations, both of which are large and both of which we believe can become bigger, in a sense, by bringing more people into treatment as a result of better treatment outcomes.  

Q: Executives have indicated that Vertex is on target to file an NDA for telaprevir in the second half of 2010. Is there a chance discussions with FDA might lead to an earlier filing date?
A: We’ve basically said second half of 2010 for filing and that’s still what are expectations are. There are other potential filing strategies, but a lot of them are data driven, so it’s very hard to do anything more than say what our most likely scenario is.  

[StormRider]

Q: Executives have indicated that Vertex is on target to file an NDA for telaprevir in the second half of 2010. Is there a chance discussions with FDA might lead to an earlier filing date?
A: We’ve basically said second half of 2010 for filing and that’s still what are expectations are. There are other potential filing strategies, but a lot of them are data driven, so it’s very hard to do anything more than say what our most likely scenario is.  
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Looks like 2011 for approval.

[viaduk]

Thanks for posting the link.  and the $50,000 question is...

Q: Executives have indicated that Vertex is on target to file an NDA for telaprevir in the second half of 2010. Is there a chance discussions with FDA might lead to an earlier filing date?

A: We’ve basically said second half of 2010 for filing and that’s still what are expectations are. There are other potential filing strategies, but a lot of them are data driven, so it’s very hard to do anything more than say what our most likely scenario is.  

[viaduk]

our posts crossed. thanks again

[Isobella]

Thanks for posting this.  So many of us are waiting for this to come available.

[Willy50]

"However, most people in the field believe that is still a number of years away and that the combinations that are most likely to be out there first are going to be interferon, ribavirin, and the direct-acting antiviral."
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For me that means that we should not expect a silver bullet anytime soon.  We will be dealing with IFN for a while, but the exposure times should drop.  Josh Boger recently said that he thought there could be FDA approval of a Polymerase/Protease inhibitor combo used in TX by mid next decade (2014-15).  Unclear at this point if that would have IFN or RBV but it would probably have greatly diminished total dosing.
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"Resistance has been and will be an issue............. But no one knows quite yet what’s going to happen in terms of HCV. We do know that in some cases, in our own studies, the resistant variants go away and wild-type virus, the normal virus returns again. However, in some cases also it seems to hang on for a while. ........."
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I have wondered if the resistance to PI's could over time "reset to default".  This seems to suggest that this could be true or partially true.  Current SOC is needed following triple therapy since it tend to mop up the resistant virii.  It may also be true that a faster acting and more potent form of TX could trump the resistance even if it continues following lets say a first failed exposure to a PI.  There are a few members of this board that were exposed to Telaprevir (but without ribaviren) and therefore may face the issue of resistance.

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"........... The current treatment is fairly morbid. There’s a lot of patients who aren’t good candidates for interferon and ribavirin for various reasons. The treatment is long and difficult. There’s an issue of the number of physicians who are capable of treating hepatitis C well, who can really take care of the patients and get them through the process."
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I think that is a reason that bulletin boards have the effect of bridging the gap in patient care.  We *think* that we see this shortage or gap in our treatments, but look like whiners if we bring it up.  Apparently other people in the medical field can see this deficit as well.  The answer for now?  Keep reading and staying involved with your treatment.  I sometimes wonder if staying ahead of the curve through participation on boards could raise one's chances of clearing by 10% or better.  I'd love to see a study on THAT.

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"Again, we have evidence from our Phase II program that looks like that’s going to be OK and work. That’s what our Phase III program is really all about, to confirm that shorter duration treatment will work for most patients and that the response rates can be increased fairly substantially. We’ve seen more than a 20% increase in response rates in the telaprevir Phase II programs."
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This was unclear to me but I am interpreting that he is saying that the Phase 3 trials are doing about 20% increase in response over Phase 2?  I wish it had been stated a little differently but I believe that is what they meant.  IF the 2 Phase 2 naives trials had a SVR rate (keep in mind he said response, not cure) of 65 and 68 percent then a 20% increase over that would bring us closer to an 80% cure rate.  I believe that the European SVR rate in Phase 2 trials hit over that mark.  It leads one to believe that we may see that 80% cure in 24 weeks of TX +/-

One wonders if this could further be impacted with predosing or lead in, attention to IR issues if they exist, a dosing "surge" in the first 2-4 weeks of TX and other adjuncts such as Alinia.
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Thanks for the article; good reading.

Willy

[odalaigh1]

Thank you for sharing this information.
I would love to see if I could be a canidate for the trials
Great info thank odalaigh1

[odalaigh1]

Do you know if any clinical trails for this drug in penna.
                                                           odalaigh1

[StormRider]

http://clinicaltrials.gov/ct2/results?term=hcv+pennsylvania&recr=Open

Above is a link to Clinical Trials.gov for hcv studies (open) in Pennsylvania. This site changes constantly so you might want to monitor it often. Also, you may want to call around to teaching hospitals in your area, they might know of something coming up. You can also try to find a Hepatologist in your area that specializes in treating HCV, they also participate in clinical trials. Hope this helps and best of luck to you.

[StormRider]

Below is a cut and paste of stats for the Boceprevir Sprint 1 (phase II) study. I don't have anything handy for Teleprevir, but I think they are similar. The stats are pretty impressive.
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Published: December 9th, 2008

https://www.espicom.com/prodcat.nsf/Product_ID_Lookup/00002357?OpenDocument

In this issue...

Schering-Plough highlights HCV pipeline

Schering-Plough has provided an update for investors on its research pipeline, highlighting a rich and innovative portfolio that includes 46 new entities in clinical trials or under regulatory review and 29 in preclinical studies. The company has nine new molecular entities in Phase III trials, plus three in pre-registration. In reviewing the company's portfolio, presenters highlighted a number of projects in the company's anti-infective pipeline, including:

a clinical update on boceprevir (also known as SCH 503034), its lead investigational oral hepatitis C (HCV) protease inhibitor (PI), which is currently in Phase III development; and
SCH 900518, a next-generation oral NS3 PI for the treatment of HCV, which has begun Phase II trials (this compound has been designated fast track status by the FDA).

The company believes boceprevir has the potential to be a first-in-class and best-in-class PI for treating chronic HCV. Schering-Plough reported final results from the SPRINT-1 (HCV Serine Protease Inhibitor Therapy-1) study, a Phase II trial in 595 treatment-naïve patients with chronic HCV genotype 1, in which a 48-week boceprevir regimen achieved a 75 per cent sustained virologic response (SVR) rate at 24 weeks after the end of treatment (SVR 24) in patients who received four weeks of PegIntron (peginterferon alpha-2b) and Rebetol (ribavirin [pegINF alpha-2b/r]) prior to the addition of boceprevir 800mg twice daily (pegINF alpha-2b/r lead-in).

This represents a near doubling of the 38 per cent SVR 24 rate for patients in the control group receiving 48 weeks of pegINF alpha-2b/r alone (intent-to-treat). In a 28-week boceprevir pegINF alpha-2b/r lead-in regimen, the SVR 24 rate was 56 per cent. Importantly, for patients who received the boceprevir pegINF alpha-2b/r lead-in regimen and had rapid virologic response (RVR), defined as undetectable virus in plasma after four weeks of boceprevir treatment, SVR was 94 per cent in the 48-week regimen and 82 per cent in the 28-week regimen. RVR has been shown to be a reliable predictor for achieving SVR.

Additionally, the company has now completed patient enrolment in the HCV RESPOND-2 (Retreatment with HCV Serine Protease Inhibitor Boceprevir and PegIntron/Rebetol-2) study, a pivotal Phase III trial in subjects who have failed prior treatment and has screened more than 1,200 patients in the HCV SPRINT-2 study, a pivotal Phase III study in treatment-naïve patients.

As part of its long-term commitment to HCV therapy, Schering-Plough is also developing SCH 900518. A Phase IIa study with the drug (NEXT-1) is currently ongoing. The company reported that SCH 900518 has been shown to be ten-times more potent in vitro than other PIs currently in Phase III development and has the potential for once-daily dosing. The compound has also shown decreased emergence of resistance in vitro. Given its pharmacokinetic profile, the company anticipates that SCH 900518 may be active against some HCV strains that are resistant to other PIs. Phase I proof-of-concept studies with SCH 900518 in treatment-naïve patients and those who failed prior treatment, both as monotherapy and in combination with pegIFN alpha-2b/r (without ribavirin), demonstrated enhanced antiviral activity, with up to 4 and 5 log10 decreases in circulating HCV, respectively.