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NEW THERAPIES FOR TREATMENT FOR HEPATITIS C
KAPIL BRIJMOHAN CHOPRA
1
Welcome everybody. Today we’re going to discuss the new therapies for the treatment of Hepatitis
C. My name is Kapil Chopra and I’m the Director of Hepatology at the UPMC Center for Liver
Disease. Now Hepatitis C is a very common infection worldwide. It’s been estimated there are
approximately 170 million people with Hepatitis C infection worldwide. Now if you look at the
United States the prevalence of Hepatitis C in the US is somewhere in the 2% to 3% range. And
Hepatitis C is a common cause of chronic liver disease and actually represents a major threat to the
health of many people around the world. Now it’s fair to say that across the United States there is a
reasonable variability with respect to genotypes. However, the most common strain of Hepatitis C is
genotype 1 and this is also true for countries like Western Europe and Asia.
This slide basically represents the epidemic of Hepatitis C in the United States. As you can tell the
epidemic in the U.S. began somewhere in the 1960s, 1970s and then 1980s. At that time Hepatitis C
was spread through the blood supply through injection drug use and other behaviors that involved
the sharing of contaminated blood. As shown in this slide the peak incidence of Hepatitis C
occurred around 1990 and after the time the blood supply was screened and the number of new cases
per year has dropped to a great extent. I think today in the U.S. what we face is a large pool of
patients who’ve been infected in the 1970’s and 1980’s. These people have progressed over time
and many of these patients have now developed cirrhosis. Indeed the complications of cirrhosis such
as liver failure, liver cancer are now being observed in many tertiary centers such as ours. And
without liver transplantation death is inevitable for these patients. In fact it’s been estimated that
every year about 15,000 people die from Hepatitis C related disease in the U.S.
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KAPIL BRIJMOHAN CHOPRA
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Now moving on to the treatment of Hepatitis C. I’m going to introduce certain terms that you may
be familiar with and are very common in the literature. This is something called the sustained
virologic response which means that the Hepatitis C virus is undetectable in the serum of the patient
6 months after stopping therapy. Now why is SVR so important? SVR clearly represents
eradication of the virus and it’s fair to say that people who achieve an SVR are cured from the
infection. There are now data showing that SVR is a durable response. Indeed, after 5 and up to 20
years after patients receive an SVR the individuals saw no recurrence of the Hepatitis C infection.
Another way of saying patients are cured.
It’s also important to realize that patients who will have improved in the liver histology as well as at
the clinical benefits which means a decreased decompensation of liver disease, prevention of varices,
clearly with less liver failure, liver cancer and a decreased risk of mortality in these individuals.
Now moving on to the therapy for Hepatitis C, where are we today in 2012? And I’d like to walk
you through the following areas which I’d like to highlight. The evolution of Hepatitis C therapy,
the direct acting antiviral therapy also referred to as the DAA therapy. We’ll touch upon the
approval of these two new medications called the protease inhibitors boceprevir and telaprevir. I’ll
try and highlight some of the key clinical studies. We’ll touch upon the pharmacogenomics and
then I’m going to end on something very exciting which are the new investigation therapies for
Hepatitis C, it truly is a new era.
NEW THERAPIES FOR TREATMENT FOR HEPATITIS C
KAPIL BRIJMOHAN CHOPRA
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If we consider the evolution of Hepatitis C therapy, we can go back to 2001 at which point the
standard of care was a combination of peginterferon and ribavirin. This was introduced in 2001,
more than a decade ago, and this combination led to an increased SVR to approximately 60%.
However, 60% represents the overall number, if you go down to the genotype 1 population, the SVR
rates were only in the range of 40 to 50%.
Where are we now in 2011? Clearly we’ve now entered the era of triple therapy. This includes the
standard of care, peginterferon, ribavirin which is the backbone of the therapy but now you add to it
a protease inhibitor either boceprevir or telaprevir. And I’ll share with you some of the exciting
data later in this presentation.
And looking beyond 2011 there’s going to be whole new ___ therapies in the future. We will have
a large variety of different options which includes combinations of peginterferon, ribavirin
backbone, with any of the different DAAs. There are also different drug classes and one can
combine the DAAs alone, possibly omitting the use of ribavirin and/or the peginterferon. I think it’s
fair to say that the ultimate aim would be to achieve an all oral treatment that eradicates the virus in
almost every patient without side effects and this truly is the goal for the future.
There are a lot of compounds out there in clinical development and I’ll show you some of the
exciting data. This is just a list of some of the newly developed antiviral agents, it is not complete.
NEW THERAPIES FOR TREATMENT FOR HEPATITIS C
KAPIL BRIJMOHAN CHOPRA
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But it does list many of the compounds with reported data so far in a major national and
international meetings. I’ve listed here, they are listed by their clinical phase of development, some
of them in Phase I right up to Phase III. The majority of these compounds can be categorized into
different classes of protease inhibitors. The nucleoside or the nonnucleoside polymerase inhibitors
and then of course the NS5A inhibitors.
What happened in May of 2011? Clearly this will be an historic landmark in the treatment of
Hepatitis C. The U.S. FDA approved two new Hepatitis C drugs and within two weeks of each other,
these two drugs were approved boceprevir and telaprevir. Now it’s important to stress that these
therapies have been approved for adult patients with chronic hepatitis C genotype1 and have to be
used in combination with peginterferon and ribavirin.
Now let us try and see, compare these two therapies. This slide represents a summary of the clinical
development of the protease inhibitors. Both boceprevir and telaprevir. Both these drugs are potent
inhibitors of the NS3/4A serine protease and both have been tested in combination with the standard
of care which is peginterferon ribavirin in large Phase III clinical trials.
The Phase III trials for boceprevir which is on your right of the slide are basically SPRINT-2 and
RESPOND. In SPRINT-2 only naïve patients were enrolled. The nonresponder trial for boceprevir
also called the RESPOND-2 trial basically had patients who had a partial response to previous
therapy or a relapse. Partial responders were defined as patients who had more than a two log
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KAPIL BRIJMOHAN CHOPRA
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decline in the ATV/RNA at week 12 after previous therapy. If you look at the pivotal Stage III trials
for telaprevir these are the ADVANCE, the ILLUMINATE and the REALIZE trials. Pretty fancy
words right? The ADVANCE trial investigated the treatment for patients who are naïve meaning
patients never treated before. And basically there was either 8 or 12 weeks of telaprevir depending
on the response and this was added to standard of care. The ILLUMINATE trial investigated the
question whether treatment could be shortened in rapid responders. And the REALIZE study is a
nonresponder study for telaprevir but this trial had not only partial responders and relapses but also
those who experienced a null response to previous therapy, those patients who had less than a two
log decline in HCV/RNA with the previous standard of treatment. And actually it’s the null
responders which is the most difficult patient population and I’ll share with you what the data for
response was.
To understand the data that is emerging among the DAAs, one has to now use a little new language.
And there are new definitions that have been now incorporated and this slide basically summarizes
all the new definitions. The definitions for rapid virologic response RVR, early virologic response,
end of treatment response and of course the ultimate end, SVR are all the old definitions and you’re
all familiar with this. However, in the trials of the DAAs a new term has been implemented and this
is called the extended RVR also known as eRVR and this is defined as undetectable, Hepatitis C
RNA at week four of therapy using a very sensitive molecular test. Now the definitions are
different and some define the ERVR over a period of 12 weeks, some 24 weeks and we’ll come to
that later in this presentation.
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It’s important to stress that the ERVR indicates that the patient does not relapse after having
achieved an undetectable RNA level.
This slide basically is a summary of the data. It clearly is not a head to head comparison but does
illustrate to you the patients who were treated with either boceprevir or telaprevir clearly had a
much better response as compared to standard of care. If you compare the red box to the left as
compared to the red box on the right, one can see that in patients who were treatment naïve
approximately 30% more patients could be cured with the addition of either boceprevir or telaprevir
to standard of therapy which is peginterferon ribavirin. This treatment is even more striking in
previous non respondents. Here one can see a success rate of anywhere from 17 to 21% with repeat
peginterferon ribavirin therapy and the SVR that is reached is about 59 to 66% in these previous non
respondents when a protease inhibitor is added. Thus you can see clearly how important it is for
patients who have been previously unsuccessfully treated, the addition of a protease inhibitor clearly
leads to a much higher success rate.
This slide summarizes the similarities and the differences in the Phase III trials using either the two
drugs. The first difference is that the studies that used boceprevir incorporated what was called a
lead-in phase of peginterferon and ribavirin before boceprevir was added. During this lead-in phase
patients received peginterferon ribavirin for the first 4 weeks without the proteases inhibitor. In the
telaprevir trials all patients were started immediately with all three compounds i.e. the peginterferon,
ribavirin and telaprevir all together.
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The next difference noted that the peginterferon alpha formulation is different between the trials. All
the telaprevir Phase III trials used peginterferon alpha 2a whereas the boceprevir trials use
peginterferon alpha 2b. The dosing intervals of both drugs are similar, that is three times a day, daily
dosing is required for both the protease inhibitors. The duration of the protease inhibitors is also
slightly different, the telaprevir, the addition of the protease inhibitor is generally for 12 weeks
followed by another 12 to 40 weeks of peginterferon ribavirin. The addition of boceprevir however
is typically longer, for 24 weeks at least. Another difference is the qualification for shortened
therapy as defined by ERVR for both the compounds. In the telaprevir trials ERVR was defined
from week 4 to week 12 and for boceprevir it was defined from week 8 which means four weeks
after the addition of boceprevir until week 24, optimal therapy.
The proportion of patients who qualified for these shortened therapies was slightly larger for
telaprevir as compared to boceprevir. However, the SVR rates which is what matters in the end were
quite similar as indicated in this slide. There were clearly differences in the adverse events profiled
and we’ll show this a little later. Some of the side effects for telaprevir are typically rash, anemia,
pruritus and nausea. Whereas the typical side effects for boceprevir were anemia and dysgeusia also
referred to as bad taste.
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Moving on to a little more information on each of these therapies, boceprevir as previously
indicated is indicated for the treatment of Hepatitis C infection, genotype 1, adult patients with
compensated liver disease including cirrhosis. The key word here is compensated cirrhosis.
Now this is a busy slide but this basically summarizes the treatment duration, it is also called the
response-guided therapy guidelines. Now if you look to the left, patients who were previously
untreated and undetectable at week 8 and then week 24, these were completed 3 drug regime at 28
weeks. However, if you’re detectable at week 8 but undetectable at week 24 you will now continue
these medicines through week 36 and then you get peginterferon riba alone through week 48. On the
other hand, the patients who were previous partial responders or relapsers the duration of therapy,
the triple therapy is 36 if you’re undetectable at week 8 and week 24. On the other hand, if you’re
detectable at week 8 but undetectable at week 24 these therapies have to be continued for a total of
48 weeks.
I would actually urge you to look at the FDA approved literature because this is sometimes very
confusing and one must be very familiar with these guidelines. What is also very important is what
is called the treatment utility guidelines. And basically this is determined by the HCV-RNA level at
week 12 which if this is greater than or equal to 100 units, therapy should be discontinued. Because
this would then lead to futility which I will show you a little later.
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It’s important to highlight that response-guided therapy was not studied in patients who had less than
a two log drop by week 12 during prior therapy with interferon and ribavirin. If considered for
treatment, if you’re going to pick this patient population for treatment, these patients should receive
at least 4 weeks of interferon ribavirin followed by 44 weeks of interferon ribavirin and boceprevir.
Consideration should be given to treating previously untreated patients who had poorly interferon
responsiveness for at least 4 weeks of lead-in peg-riba followed by 44 weeks of the triple therapy
and this would actually maximize your rate of an SVR. And lastly patients who have compensated
cirrhosis should again receive a total of 48 weeks of therapy.
I touched upon this earlier and this is very important when you do triple therapy you have to be
familiar with the futility rules. And this is just to repeat what I said earlier, treatment must be
discontinued if the HCV-RNA level is greater than or equal to 100 units at week 12 or if there’s any
undetectable HCV-RNA level at week 24.
Another important highlight is various drug-drug interactions and this is a large kind of laundry list,
I would definitely urge you all to become familiar with different drugs that interact with both these
protease inhibitors. And I think the reason this is because co-administration of drugs that are highly
dependent on the CYP3A4/5 for clearance lead to elevated plasma concentrations and are associated
with serious or life-threatening events. Also co-administration with potent CYP3A4/5 inducers
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where significantly levels of the drug may be seen and this may really lead to reduced efficacy of the
boceprevir.
One thing that I talked about earlier is anemia. Clearly, when you add boceprevir to peginterferon
and ribavirin there’s an additional decrease in the hemoglobin. And the proportion of patients who
experience hemoglobin values of less than 10 and less than 8 were clearly higher in patients who
received combination therapy.
And this kind of just summarizes what I said earlier, dose modifications due to anemia occurred
twice as often in patients who had combination therapy up to 26%. The proportion of patients who
discontinued the study drug however was only 1% and the proportion of patients that required
erythropoietin was as high as 43% in the boceprevir arms as compared to 2% in the control arms.
I must admit a very small percentage of patients did require blood transfusions, 3% versus 1% in the
control arms.
One of the side effects that peculiar to this class, this drug is dysgeusia or alteration of taste.
Hopefully this is not limiting in continuing the therapy. And another important factor is the
development of resistance. And this is where the futility rules are very important. Among patients
who did not achieve an SVR more than half the patients had one or more specific point mutations
determined by sequencing assays. And I think the clinical importance of these mutations still needs
to be understood in future studies.
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KAPIL BRIJMOHAN CHOPRA
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Moving on to telapravir, we’ve talked about the mechanism of action, it’s similar to boceprevir.
The treatment duration is slightly different. And once again I would urge you to look at the FDA
approved literature. Again for patients who are naïve or prior relapses, if the patient is undetectable
at week 4 and week 12 you have triple therapy for the first 12 weeks and an additional 12 weeks of
peg-riba dual therapy. On the other hand if you have detectable virus at week 4 or undetectable at
week 12 then you go for 12 weeks plus 36 weeks.
Again for prior, partial and null responders all patients would get 12 weeks of triple therapy followed
by 36 weeks of dual therapy. Now the futility rules are slightly different for telapravir as compared
to boceprevir and what’s different here is that the HCV/RN levels for cutoff is 1000 IU both at week
4 and at week 12.
The list of drugs that are contraindicated are similar to both drugs so this list is pretty similar to
what I showed you earlier. One serious skin reaction that occurs with telaprevir is something called
DRESS which basically stands for drug rash with eosinophilia and systemic symptoms. It’s pretty
rare luckily, less than one percent of the overall patient population and can present with rash, fever,
facial edema and evidence of some internal organ environment. Clearly, if a serious skin reaction
occurs all components of treatment must be discontinued immediately, the patient must be referred
for urgent medical care.
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KAPIL BRIJMOHAN CHOPRA
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If you look at the studies, some type of rash did develop in up to about 56% of patients but luckily a
severe rash only occurred in 4% of patients. The rash may have manifestations of eczema, patients
with mild to moderate rashes should be just followed for progression development of systemic
symptoms. If the rash progresses and becomes severe telaprevir should be discontinued. Ribavirin
and peginterferon may be continued. However if you don’t see any improvement within 7 days I
think it’s fair that all three drugs must be discontinued. Clearly, patients should be monitored very
closely until the rash has resolved. One important thing to highlight is telaprevir cannot be dose
reduced or restarted if discontinued due to the rash. And one can treat the rash with oral
antihistamines, topical corticosteroids, whatever it takes for symptom relief. Definitely systemic
steroids should not be used.
Anemia again is a problem. When you add this therapy to existing interferon ribavirin clearly
hemoglobin values of less than 10% was seen in up to 36% of subjects, values of less than 8.5 in
about 14% of subjects. However, if you look at the patients who actually discontinued therapy it
was only as low as 4%. Clearly about 1/3 of patients did require some modification in the ribavirin
dose because of the anemia. And then one other side effect that’s peculiar to telapravir is anorectal
sign and symptoms must be looked out for.
It’s important to realize that these drugs should not be used in these categories – for example in
pregnancy this would be classified as a category B drug, it’s not approved for use in nursing
mothers, children, geriatric populations, patients with severe hepatic or renal impairment. There are
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ongoing studies in patients with HIV co-infections. At the current time these therapies should not be
used with Hepatitis B co-infection and are not approved for patients who have received solid organ
transplants.
We’ve talked about the drug interactions for boceprevir, they are pretty similar to telaprevir and once
again the issue of resistance comes up. Again, the theme is similar. Patients who did not achieve
SVR or patients who had virologic failure or relapse are the ones who develop these mutations.
Clearly we need to understand the clinical significance of these resistance mutations and hopefully
we will see new studies that address this question.
Telaprevir treatment-emergent resistance occurred in a majority of the patients who did not achieve
SVR and almost all patients who failed the 12 week therapy. And in most patients who failed the
peg-riba after week 12 or who relapsed.
One additional factor that was studied in the telaprevir is the significance of the interleukin 28B
polymorphism. And I will touch upon this in pharmacogenomics a little later. It’s now well-known
that SVR rates tend to be lower in subjects with a CT and TT genotype as compared to the CC
genotype. Particularly among patients who are treatment naïve. And among those treatment naïve
and previous treatment failures, subject of all types of IL28B genotypes appear to have a higher SVR
when you add a telaprevir regime.
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So to summarize, what are the take home points. Boceprevir and telaprevir must not be used as
monotherapy and should be used only in combination with peginterferon and ribavirin. The efficacy
of these drugs has not been studied in patients who failed previous therapy with the treatment regime
that includes either boceprevir or telaprevir or any other HCV/NS3/4A protease inhibitor. These
therapies are not recommended for patients who have moderate to severe liver disease i.e. ChildPugh B or C greater than 7 or patients with decompensated liver disease.
Boceprevir in combination with peg-alpha and ribavirin has not been studied in patients documented
to be historical null responders i.e. less than a 2 log HCV/RN decline by week 12 of previous
therapy with peginterferon riba combination. Clinica studies included subjects who were poorly
interferon responsive and these subjects were less than 0.5 log RNA decline in viral load at treatment
week 4 with peginterferon ribavirin and these are predicted to have a null response at week 12 to
therapy.
Poorly interferon responsive patients who were treated with boceprevir in combination with peg
alpha and ribavirin have a lower likelihood of achieving and SVR and a higher rate of resistance or
treatment failure. Hence a word of caution with this patient population.
Moving on to some of the key clinical studies involving these two therapies. This is the SPRINT-2
study and the study design is well illustrated over there. I’m not going to spend too much on the
details on this – this slide basically summarizes the results of SPRING-2. The overall SVR rates
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were 63%, that’s the blue bar to your left in the response-guided arm and 66% with standard
duration therapy, these were not statistically significant. However both these SVR rates were
statistically higher as compared to 38% SVR in the control arm. Now if you break down the success
based on race i.e. non-black versus black patients. Again, the data from non-black patients is shown
to your left, the SVR rates were high, 67% and 68% in the response-guided and standard duration
therapy arms versus 40% in the control arm. The relapse was relatively low in the boceprevir arm,
9% and 8% respectively versus 23% in the peg-riba arm. In black patients the response rates were
substantially lower, 42% in the response-guided therapy, 53% in standard duration therapy versus
23% in the control arm.
In addition, the three groups of patients had substantially higher relapse rates as compared to the
non-black patients, 12% and 17% in the boceprevir arm and 14% in the control arm. However, SVR
rates continue to remain significantly higher for black patients receiving boceprevir plus
peginterferon riba as compared to the control population.
This slide shows the SVR rate in patients who qualified for 28 weeks of therapy. As mentioned
previously a total of 44% of patients qualified for these 28 weeks of therapy because they achieved
an RVR that is undetectable, HCV/RNA in week 4 of therapy which actually correlated week 8 of
the total therapy. The SVR rate was very high 97% in non-black patients who achieved an RVR and
discontinued therapy at week 28. SVR rates were slightly lower but again pretty high 87% in the
black population who had the same response.
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This slide basically summarizes the study design of the ADVANCE III trial. You clearly can study
this design in further detail and again to summarize the results of the ADVANCE trial are shown on
this slide, 69% of patients achieve an SVR in the 8 week telaprevir containing arm versus 75% in the
12 week arm. This compared to 44% in the control arm. The difference in the SVR rates in the
telaprevir containing arms versus the control arms was statistically significant. There was no
significant difference in SVR rates between week 8 and week 12. But there was a trend to a lower
response rate in the 8 week arm. The relapse rates are once again low in the telaprevir group, 9% in
both arms as compared to 28% in patients who did not receive telaprevir.
This slide represents the SVR rate in patients who qualified for shortened duration of therapy
meaning 24 weeks. A total of 57% and 58% of patients in week 8 and week 12 arms qualified for 24
weeks of therapy. Those patients who received shortened therapy, 83% in the 8 week arm and 89%
in the 12 week arm achieved and SVR. Once again, very impressive results.
This slide shows a response rate to race on the left and cirrhosis on the right. A total of 58% and
62% of black patients in the 8 and 12 week arms achieve and SVR versus 25% in the control arm.
Similarly 53% and 62% of patients with bridging fibrosis and cirrhosis in the 8 and 12 week arms
achieve an SVR versus 33% in the control arms.
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And this slide represents a study design of the ILLUMINATE trial. This slide just summarizes the
overall SVR rates. This included both patients who did and did not an achieve an eRVR and that
was about 72%. A total of 92% of patients who received 24 weeks of therapy after achieving an
eRVR achieve an SVR compared with 88% of those who were treated for 48 weeks after not
achieving an eRVR.
These results clearly show that 24 weeks of therapy is sufficient for patients who achieved and
eRVR using a triple combination of telaprevir, peginterferon and ribavirin. We’ve discussed adverse
effects and discontinuation rates and once again I would urge you to study these slides carefully and
familiarize yourself with the data. Anemia and dysgeusia were reported more frequently in
boceprevir as compared to control arms. And again as mentioned earlier pruritus, rash and anemia
were more frequent in the telaprevir arms.
So what do you know about resistance to protease inhibitors? I think it’s fair to say that minor
resistant populations are present even at baseline in virtually all Hepatitis C infected patients.
Secondly, resistant variants are rapidly selective in monotherapy. We also know that emergence of
resistance is reduced when protease inhibitors are combined with potent antiviral agents without
cross-resistance such as interferon ribavirin are used.
And lastly, failure to achieve and SVR during triple combination therapy is clearly associated with
the selection of resistant HCV variants. I think in the context of treatment failure on triple
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combination with the direct acting antiviral agent, the failure to achieve an SVR is primarily due to
insufficient response to peginterferon and ribavirin which causes the growth of these uncontrolled
HCV variants to direct acting antiviral agents.
How can we predict treatment failure? I think clearly predicting treatment failure depends on
making a good assessment of interferon and ribavirin responsiveness in patients who will receive
triple combinations. There are two ways to assess interferon responsiveness, one is to use a lead-in
phase as employed in the boceprevir trials and the second is to use various baseline predictors of
response.
And this leads to the topic of pharmacogenomics. To give you a little background this slide
illustrates the utility of the lead-in phase in predicting response in the SPRINT II trial. If you study
this carefully patients who achieved more than a 1 log decline in HCV/RNA from baseline during
the four weeks of therapy achieved an SVR of 82% in both boceprevir arms as compared to those
patients who achieved less than a one log decline in SVR in week 4 therapy. I’m going to do this
slide again.
This slide illustrates the utility of a lead-in phase in predicting response to therapy in the SPRINT II
trial. Patients who achieve a more than 1 log decline in HCV/RNA from baseline with peginterferon
riba alone during the four weeks of therapy achieve an SVR rate of 82% in both boceprevir
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containing arms versus only 29 to 39% of patients who achieve less than a 1 log drop in HCV/RNA
at week 4.
Now what is the significance of the interleukin 28B polymorphism. This basically is a single
nucleotide polymorphism, a snip which is detected on chromosome 19 and basically the interleukin
28B codes for interferon lambda. And interferon lambda has antiviral activity against Hepatitis C
genotype 1 both in vitro and in vivo basically working through downstream signaling of interferon
gamma which appears to involve interferon alpha.
The data comes from the IDEAL trial and this is basically - along with the lead-in phase it is also
possible that baseline parameters will be used to help keep in guidelines or decisions. And I think
what might become fashionable as a predictor is the interleukin B, 28B phenotype which is a genetic
marker for interferon responsiveness.
It has been clearly found that patients with a TT genotype will be poor responders to peginterferon
ribavirin with a 25% chance of achieving an SVR whereas a patient who’s heterozygous i.e. a CT
genotype has a 30 to 35% chance of SVR whereas the patients with the CC genotype will have a
response rate of up to as high as 80%.
This is very accurate as a marker of the likelihood of response of therapeutic response to the
administration of interferon and ribavirin. And if you look at the multivariate analyses of baseline
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predictors clearly the interleukin 28B genotype is the strongest predictor of response to interferon
and ribavirin. There are several others as listed in the above slide and clearly combinations of these
different parameters will help us in fine tuning this predictive modeling.
So take home messages with respect to baseline predictors of response I think treatment failure with
peginterferon ribavirin and a protease inhibitor for genotype 1 Hepatitis C is likely due to an
insufficient response to interferon and ribavirin therefore predictors of treatment failure will likely be
the same that we use for standard therapy which is interferon ribavirin. Clearly more data needs to
be seen with newer direct acting antiviral agents.
A lead-in phase of 4 weeks with peg-riba alone before starting the protease inhibitor is one way to
help assess responsiveness to interferon ribavirin and this may also help guide treatment decision
making. And finally algorithms that use baseline factors to predict responsiveness expected to be
inferred from future Phase III trial designs. And we should clearly stay tuned for more data in this
area.
There are several remaining issues for the use of protease inhibitors in treatment- experienced
patients.
It is clear that patients who are poorly responsive to interferon whether observed
historically or through the lead-in phase are not going to do well. And these patients are not
optimally served by either regime and will need better therapies for these poorly responsive patients.
We also need a better understanding of resistance, it’s clinical impact, what does it really mean. And
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finally we need to learn what baseline predictors of response will tell us including the interleukin
28B genotype and will these baseline predictors factor into our decisions as to who to treat and what
regime to choose.
So I think in conclusion in 2012 the next first line treatment for genotype 1 Hepatitis C infection
will be a triple combination of either boceprevir or telaprevir in combination with peginterferon
ribavirin. Treatment prediction based on lead-in or baseline parameters will help drive treatment
decisions. Unfortunately, these agents have not been studied in other genotypes and right now there
is no alternative to peginterferon ribavirin in these patients at this time. However stay tuned. There
were be new data emerging very shortly.
Now moving on to what I call the future which is the investigational therapies for Hepatitis C. And
these could be broadened looked at in the following categories. I think we’re not far away from
interferon free regimes. There’s triple therapy, there’s quadruple therapy and then there are other
therapies which I will address.
This slide basically elucidates the life cycle of the Hepatitis C virus and it was the elucidation of the
life cycle of the Hepatitis C virus that allowed for identification of potential targets of antiviral
agents that directly interrupt the HCV replication. So right from binding of the virus to the plasma
membrane and its endocytosis to the membrane all the way through uncoating and generating the
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KAPIL BRIJMOHAN CHOPRA
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membranous web to translation and replication, viral assembly and transport and release again into
the extracellular space, one may envision a variety of potential targets.
The most obvious targets are the NS3/4 serine protease and the NS5B HCV polymerase and
therefore the first generation of the DAAs have been the protease inhibitors and the nucleoside or
nonnucleoside polymerase inhibitors.
However, there will be newer therapies as you will see in studies that have already been presented.
This again illustrates the HCV life cycle and the various potential targets for antiviral therapy.
Clearly each drug has several unique features and these are well summarized over here. Besides
having a higher efficacy the different group of drugs have different genetic barriers to resistance and
these have all now been studied in various Phase I and Phase II trials moving on to Phase III.
We talked about the evolution of Hepatitis C therapy and it’s fair to say at this time the new agents
will generally maintain or improve upon the efficacy that we see in genotype 1 treatment naïve
patients. And this basically is a snapshot of all the different new drugs out there. Clearly these are
not head to head comparisons but gives you a flavor of what to expect in the future. And I’ll
summarize some of these studies on the next few slides.
These are some of the interferon-free regimes. Thus you have a nucleotide analog with or without
ribavirin, with or without peginterferon for genotype 2 or 3. You have an NS5A inhibitor combined
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with an NS3 protease inhibitor plus peginterferon ribavirin. You have protease inhibitors,
nonnucleoside polymerase inhibitors in combination with ribavirin.
Another group of drugs called the oral cyclophyllin inhibitors such as alisporivir plus minus ribavirin
plus minus ribavirin has also been tried in genotype 2 and 3 patients. Stay tuned for data on these
exciting therapies.
To give you an idea of what’s going on in triple therapy, once again this slide illustrates some of the
triple therapy studies that are already underway and have already been presented at some of our
national meetings. And this basically summarizes, this gives you an idea of the quadruple therapy
out there.
Some of the other therapies that are currently still in the proof of concept are summarized on these
slides. You clearly have the NS3/4A protease inhibitor, you have a nucleotide polymerase inhibitor
and then of course an oligonucleotide targeting miR-122 for genotype 1 treatment naïve patients.
I think with the above presentation you have a very good overview of what to expect for the
treatment of Hepatitis C. Clearly this represents a new era for the treatment of Hepatitis C for our
patients and I would clearly look forward to the results of some of these newer studies. Thank you
very much for you attention.