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.

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.