Presented at Milan Conference, European Society for Diseases of the Liver
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cactus jammies
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Telaprevir (VX-950) with combo treatment, treatment-naive groups.

The first study we will look at is the PROVE 1 trial, which evaluated the
use of the HCV protease inhibitor telaprevir in combination with
peginterferon alfa-2a and ribavirin among treatment-naive, genotype 1
HCV-infected patients. PROVE 1 was a randomized, placebo-controlled, phase
II trial and its study design is illustrated on this slide.

In the first treatment arm, patients received standard-of-care HCV therapy
of peginterferon alfa-2a 180 µg/week and weight-based ribavirin and placebo.
The remaining 3 arms received telaprevir in combination with peginterferon
alfa-2a and ribavirin for 12 weeks; however, each regimen varied according
to the treatment duration of additional therapy with peginterferon alfa-2a
and ribavirin without telaprevir. For example, 1 arm underwent a 12-week
treatment phase with triple-combination therapy followed by 36 weeks of
peginterferon alfa-2a and ribavirin therapy. This is abbreviated as the 12
and 36 arm on the slide.

A second arm, shown here as the 12 and 12 arm, received triple-combination
therapy for 12 weeks and a subsequent 12 weeks of peginterferon alfa-2a and
ribavirin therapy for a total treatment period of 24 weeks. A third arm
received telaprevir in combination with peginterferon alfa-2a and ribavirin
for 12 weeks but did not receive additional peginterferon alfa-2a and
ribavirin therapy. The telaprevir dosage is also illustrated on this slide.
Participants received a 1250 mg loading dose of telaprevir followed by 750
mg every 8 hours.

ITT, intent to treat; pegIFN, peginterferon alfa; PROVE, Protease Inhibition
for Viral Evaluation; RBV, ribavirin; SVR, sustained virologic response;
TVR, telaprevir; wks, weeks.

This slide shows the PROVE 1 virologic response rates, based on an
intent-to-treat analysis. The percentages of patients with undetectable HCV
RNA at Week 4 and Week 12 are shown for each of the 4 treatment arms, as
well as the rates of sustained virologic response (SVR) and relapse.

A higher percentage of patients achieved undetectable HCV RNA in the
telaprevir-based regimens vs the control arm of standard-of-care treatment
peginterferon alfa-2a and ribavirin. Among patients who received
peginterferon alfa-2a and ribavirin in combination with placebo, the
proportions with undetectable HCV RNA by Week 4 and 12 were 11% and 45%,
respectively. The overall SVR rate in this arm was 41% and the relapse rate
was 23%.

Among patients who received the triple-combination therapy for 12 weeks
followed by 36 weeks of peginterferon alfa-2a and ribavirin therapy, 81% and
80% had undetectable HCV RNA at Week 4 and at Week 12, respectively. The
rates of SVR and relapse were 67% and 6%, respectively. Similarly, among
patients who received 12 weeks of triple-combination therapy followed by 12
weeks of peginterferon alfa-2a and ribavirin, 81% and 68% had undetectable
HCV RNA at Week 4 and Week 12, respectively. The overall SVR rate was 61%
and the relapse rate was 2%, which represented only 1 in 41 patients who
relapsed.

Lastly, among patients who received 12 weeks of triple-combination therapy
and no additional peginterferon alfa-2a and ribavirin therapy, the overall
SVR rate was only 35%. Therefore, there is a strong indication that both the
12 and 36 regimen and the 12 and 12 regimen are associated with a highly
significant increase in the rate of SVR compared with both the
standard-of-care therapy and the regimen that consisted of
triple-combination therapy for 12 weeks without any additional peginterferon
alfa-2a and ribavirin therapy.

abbreviations used:
AE, adverse event; PROVE, Protease Inhibition for Viral Evaluation; TVR,
telaprevir.

Adverse events associated with telaprevir therapy included gastrointestinal
events, skin events such as rash (moderate and severe) and pruritus, and
anemia. Each of these adverse events was more frequent in the
telaprevir-treated patients vs those who received the standard-of-care
treatment of peginterferon alfa-2a plus ribavirin. The incidence and
severity of all other adverse events was similar among the telaprevir-based
treatment arms and the control arm.

The cumulative rate of discontinuation due to adverse events by Week 12 was
18% among the telaprevir-treated arms compared with 4% in the control
peginterferon alfa-2a plus ribavirin arm. Also, lower hemoglobin levels were
observed in the telaprevir-treated arms vs control for the first 12 weeks of
therapy during which patients received triple-combination therapy with
peginterferon alfa-2a, ribavirin, and telaprevir.

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Non-responders and relapsers with Telaprevir (VX-950) and combo treatment.

abbreviations used:
pegIFN, peginterferon alfa; PROVE, Protease Inhibition for Viral Evaluation;
RBV, ribavirin; RVR, rapid virologic response; TVR, telaprevir.

An interim analysis of a clinical trial by Poordad and colleagues evaluated
the use of telaprevir in combination with peginterferon alfa-2a plus
ribavirin among patients who were previous nonresponders and relapsers.

These patients were originally from the control arms of the PROVE 1-3 trials
who did not achieve SVR with peginterferon alfa-2a and ribavirin. Therefore,
the participants of this trial had never received telaprevir. The previous
suboptimal virologic responses among these patients were carefully
characterized.

Patients were categorized as Week 4 null responders (< 1 log10 IU/mL drop in
HCV RNA at Week 4), Week 12 null responders (< 2 log10 IU/mL drop in HCV RNA
at Week 12), partial responders (= 2 log10 IU/mL drop in HCV RNA at Week 12
and detectable HCV RNA at Week 24), Week 20 breakthrough patients (achieved
undetectable HCV RNA on treatment but subsequently experienced virologic
breakthrough during treatment), and standard relapsers (achieved
undetectable HCV RNA on treatment but the virus rebounded after treatment
ended).

All 5 groups were treated with a triple-combination therapy of telaprevir
750 mg every 8 hours, 180 µg/week peginterferon alfa-2a, and 1000
mg/day-1200 mg/day ribavirin for 48 weeks. The proportions of patients with
undetectable HCV RNA levels at Week 4 (RVR) and at Week 12 (EVR) are shown
in this bar graph; the RVR rate is represented by the blue columns and the
EVR by the orange columns. Almost all groups demonstrated excellent
virologic responses, with 89% to 100% achieving EVR. Interestingly, even the
patients who were Week 4 null responders or Week 12 null responders to
previous therapy, who typically are the hardest to treat successfully,
achieved RVR rates of 33% and 50%, respectively, and EVR rates of 89% and
100%, respectively.

I would have expected the previous partial responders, Week 20 breakthrough
patients, and the relapsers to have good responses to this
triple-combination therapy, and the bar graphs confirm that the rate of Week
12 negativity was 100% across these 3 treatment groups. However, it had been
postulated that nonresponder patients might be in some way nonresponsive to
the antiviral effects of interferon and ribavirin and as a result
combination therapy with peginterferon alfa, ribavirin, and a STAT-C agent
might essentially amount to STAT-C monotherapy, with associated development
of viral resistance. But the results of this small study suggest otherwise.
Therefore, this early, open-label trial provided promising data which
suggest that triple-combination therapy with telaprevir, peginterferon
alfa-2a, and ribavirin is associated with excellent EVR in previous
nonresponders and relapsers to peginterferon alfa-2a and ribavirin. I look
forward to final SVR data in this group.

abbreviations used:
ITT, intent to treat; pegIFN, peginterferon alfa; PROVE, Protease Inhibition
for Viral Evaluation; RBV, ribavirin; SVR, sustained virologic response;
TVR, telaprevir; wks, weeks.

This table illustrates the response rates for the PROVE 2 trial. The
response rates among the standard-of-care control arm are similar to those
seen in the PROVE 1 trial. Specifically, among patients who received
peginterferon alfa-2a and ribavirin and placebo, the rate of undetectable
HCV RNA at Week 4 and 12 was 12% and 41%, respectively. The rates of SVR and
relapse were 48% and 20%, respectively. Among patients who received
telaprevir and peginterferon alfa-2a and ribavirin for 12 weeks followed by
12 weeks of peginterferon alfa-2a and ribavirin therapy, the rates of
undetectable HCV RNA at Weeks 4 and 12 were 69% and 73%, respectively. The
rates of SVR and relapse were 68% and 14%, respectively. These results are
very similar to those reported in the PROVE 1 trial.

High rates of HCV RNA undetectability at Weeks 4 and 12 weeks were achieved
in the third arm, which received triple-combination therapy for 12 weeks
with no additional peginterferon alfa-2a and ribavirin treatment-80% and
79%, respectively. In addition, an overall SVR rate of 62% was achieved in
this arm. All of these results are superior to those observed in the
standard-of-care control arm. However, the relapse rate in this arm was
higher than that seen among patients who received the triple-combination
therapy for 12 weeks followed by 12 weeks of peginterferon alfa-2a and
ribavirin therapy-29% vs 14%. The overall SVR rates were comparable between
these 2 study arms-62% in the 12-week triple-combination arm and 68% in the
12 and 12 arm.

In the final arm, which received telaprevir and peginterferon alfa-2a
without ribavirin, the Week 4 and 12 HCV RNA undetectable rates were
somewhat lower at 51% and 62%, respectively. The overall SVR rate was only
36%, which was less than the overall SVR rate among patients who received
the standard of care. Moreover, there was a high relapse rate of 48%. These
results strongly suggest that ribavirin is essential for treatment success
with this particular therapeutic regimen.

Adverse events in the PROVE 2 trial were very similar to those which
occurred in the PROVE 1 trial. In PROVE 2, a macropapular-type skin rash was
the most common reason for treatment discontinuation in the study arms
receiving telaprevir, with 12 (7%) of 163 patients discontinuing therapy.
The cumulative discontinuation rate due to adverse events was 12% for the
arm receiving the triple combination for 12 weeks with no additional
peginterferon alfa-2a and ribavirin therapy. This was comparable to the 10%
seen in both the standard-of-care arm and the 12-week telaprevir and
peginterferon alfa-2a arm. All treatment arms experienced comparable mean
decreases in hemoglobin levels in the first 12 weeks and there was no effect
on neutrophils or platelets in the telaprevir-treated arms.

Therefore, it can deduced from the adverse event profile of both PROVE 1 and
PROVE 2 that skin rash is the most frequent adverse event among
telaprevir-treated patients. However it remains debatable whether there is
an increased rate of anemia in patients receiving telaprevir.

For more information, go online to:
http://clinicaloptions.com/Hepatitis/Conference%20Coverage/Milan%202008/Tracks/I
nvestigational%20HCV/Capsules/1000.aspx
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Milk Thistle derivative   THIS IS BIG NEWS

Silibinin
Ferenci and colleagues presented a very interesting and provocative study
that evaluated the use of silibinin in combination with peginterferon alfa
and ribavirin among previous peginterferon alfa and ribavirin nonresponders.
Silibinin is the major active isomer of silymarin or milk thistle. It is the
active component that is thought to provide much of the antioxidant effect
of silymarin. There is significant debate as to whether silibinin is
associated with any antiviral efficacy.

In this study, it was hypothesized that intravenous silibinin would have
potential antiviral activity against HCV. The study design is illustrated in
this slide. A total of 20 peginterferon alfa and ribavirin nonresponders
were randomized to receive 1 of 4 different weight-based intravenous
infusions of silibinin daily for 1 week. The doses were 5 mg/kg/day, 10
mg/kg/day, 15 mg/kg/day, and 20 mg/kg/day.

The majority of the patient population was infected with genotype 1 HCV, and
7 of the patients had significant fibrosis. Thirteen of the patients
previously achieved < 2 log10 IU/mL reduction in HCV RNA on peginterferon
alfa and ribavirin treatment, and all of the patients had detectable HCV RNA
at Week 24 of previous therapy. After Week 1, patients continued silibinin
and initiated peginterferon alfa and ribavirin. After Week 2, patients were
switched from intravenous silibinin to oral silymarin 280 mg, 3 times daily,
in combination with peginterferon alfa and ribavirin for a total of 13
weeks.

This slide illustrates the interim results achieved with the use of
silibinin in combination with peginterferon alfa and ribavirin. The blue
columns represent the results following 1 week of silibinin monotherapy.
There was a dose-dependent increase in the HCV RNA decline from baseline
following 1 week of intravenous silibinin. Patients who received silibinin
20 mg/kg/day achieved nearly a 4 log10 IU/mL reduction in HCV RNA compared
with the 0.5 log10 IU/mL reduction achieved in the silibinin 5 mg/kg/day
group.

The orange columns represent the decline in HCV RNA from baseline following
the addition of peginterferon alfa and ribavirin at Week 2 of treatment.
There was an incremental decrease in HCV RNA among patients who received
silibinin 10 mg/kg/day, 15 mg/kg/day, and 20 mg/kg/day. In fact, 2 patients
in the silibinin 15 mg/kg/day arm and 4 patients in the silibinin 20
mg/kg/day arm achieved undetectable HCV RNA.

These findings are surprising and strongly suggestive that there is a direct
antiviral effect associated with the use of intravenous silibinin. However,
further evaluation is clearly needed. Obviously, one of the issues concerns
the use of intravenous, high-dose, purified silibinin rather than standard,
oral silymarin. The intravenous administration assured high concentrations
of the drug in these patients. Although this study is provocative, further
validation is required to determine whether there is a potential for this
type of therapy with milk thistle in HCV-infected patients.

For more information, go online to:
http://clinicaloptions.com/Hepatitis/Conference%20Coverage/Milan%202008/Tracks/I
nvestigational%20HCV/Capsules/63.aspx

- cactus jammies