Clinical Trials:
New treatments for
hepatitis C that have been studied in humans, and various drugs that
are in phase I, II and III development to treat hepatitis C
Most hepatitis C virus (HCV) infected
individuals seeking treatment are chronically infected. Treatment
goal is to achieve a sustained virological response (SVR), which is
the absence of serum HCV RNA up to 6 months after therapy is
concluded. To increase efficiency of interferon treatment, pegylated
interferon alpha (peg-IFN-alpha) therapy has been supplemented with
ribavirin. Combination therapy with peg-IFN-alpha and ribavirin has
resulted in a further increase in treatment efficiency with 54% of
HCV infected patients achieving SVR. The response and rate of SVR is
dependent on the genotype of HCV with only 30% of genotype 1
infected individuals achieving SVR, whereas greater than 80% of
genotype 2 or 3 achieve SVR with combination therapy. Combination
therapy treatment regiments are genotype dependent and the amount of
peg-IFN-α administered is dependent on the type used.
The suboptimal response has led to a
shift in the investigational focus for treatment of HCV toward
specifically targeted antiviral therapy for HCV agents. Moreover,
pegylated IFN alpha and/or ribavirin are associated with frequent
side effects and have a negative impact on the patient's quality of
life. Among the first wave of targeted HCV therapeutics are the NS3a
protease and NS5B RNA polymerase inhibitors with 25 different
compounds in clinical development and further 8 in the IND enabling
study phase. Development of HCV protease inhibitors is slightly
ahead of polymerase inhibitors. The first study combining HCV
protease and polymerase inhibitors was successfully completed.
At least 17 further distinct molecules
are in early clinical development and another five close to enter
clinical investigation which have novel mechanisms of action. Among
the targets are cyclophilin inhibitors, NS5A protein inhibitors,
NS4B-RNA binding inhibitors, viral entry and replication inhibitors.
Specific therapeutic vaccines and antibodies are included in those
novel targeted HCV treatment modalities. Other novel mechanism of
action agents are directed against host cell or viral structures.
The European equivalent of
the American Association for the Study of
Liver Diseases (AASLD) conference is the
European Association for the Study of the
Liver (EASL). This year’s EASL conference
included a wealth of information about
studies that have been conducted on drugs in
development to treat hepatitis C. This
article will focus on coverage of the drugs
furthest along in the development cycle—telaprevir
and boceprevir as well some exciting news on
the development of HCV therapeutic vaccines
that are in early clinical development.
Telaprevir
In previous Phase II studies of Vertex’s
telaprevir, an HCV protease inhibitor, it
has been reported that SVR rates have been
as high as 69% in people with HCV genotype 1
who have never been treated (treatment
naïve). Retreatment with pegylated
interferon plus ribavirin in people who did
not achieve a sustained virological response
(SVR-undetectable HCV RNA (viral load) 24
weeks post treatment) with a previous course
of pegylated interferon plus ribavirin is
very important because they constitute a
large group of people with HCV who are in
the most need for newer HCV medicines that
will improve the chances for successful
response to treatment. At EASL results of a
phase II study of patients who did not
achieve an SVR and who were treated with the
combination of telaprevir /Pegasys/
ribavirin were reported and the results are
very encouraging.
There were three
groups in the study:
Group A:
telaprevir, Pegasys, ribavirin for 12 weeks
followed by Pegasys plus ribavirin for an
additional 12 weeks (total treatment
duration = 24 weeks).
Group B:
telaprevir, Pegasys, ribavirin for 24 weeks
followed by Pegasys plus ribavirin for an
additional 24 weeks (total treatment
duration = 48 weeks).
Group C:
Pegasys plus ribavirin for a total
treatment duration of 48 weeks (standard of
care).
A total of 453 patients
were enrolled and received at least one dose
of the study drug. (See Table 1 for SVR
results)
Definitions
of Prior Non-Response
Non-responders: people
who never achieved an undetectable HCV RNA
(viral load) during or at the end of HCV
treatment.
Relapsers:
people who became HCV viral load
undetectable during to the end of the HCV
treatment period, but who later became HCV
RNA (viral load) positive during the
follow-up period.
Breakthroughs:
people who achieved an undetectable HCV
viral load during treatment, but who later
had detectable HCV viral load before the end
of the treatment period.
Table 1: SVR
results by type of prior response:
Group A (TVR12/PR24)
Group B (TVR24/PR48)
Group C (PR48)
Non-responders
39%
out of 66 patients
38%
out of 64 patients
9%
out of 68 patients
Relapsers
69%
out of 42 patients
76%
out of 41 patients
20%
out of 41 patients
Breakthroughs
57%
out of 7 patients
50%
out of 8 patients
40%
out of 5 patients
Total
51%
out of 115 patients
52%
out of 113 patients
14%
out of 114 patients
Safety
Vertex reported that the side effects were
consistent with prior studies of
telaprevir/Pegasys/ribavirin. Seventeen out
of 339 patients (5%) discontinued therapy
due to skin rash and three out of 339
patients (1%) due to anemia. Growth
factors were allowed in the study but only
two out of 339 patients in the telaprevir
groups were given growth factors to treat
anemia.
Comment: Even though the total number of
patients in the study was small, the overall
SVR rates are impressive. Another study,
the REALIZE study, has been
launched by Tibotec (Vertex’s European
partner) that will enroll about 650
treatment-experienced patients, and the
results should give us a better picture of
the effectiveness of a regime that includes
the combination of telaprevir, pegylated
interferon and ribavirin, as well as
hopefully confirm the prior results.
Boceprecir
The final results of the SPRINT-1
study of boceprevir, an HCV
protease inhibitor used in combination with
PegIntron plus ribavirin, were also released
at EASL. The patients in the study were HCV
genotype 1 patients who had never been
treated (treatment naïve) for hepatitis C.
The study had two
parts: Part 1: To evaluate
boceprevir (800 mg – three times a day),
PegIntron and ribavirin in standard doses
with different treatment durations. Total
of 5 different treatment groups – two of the
arms also had a lead-in phase with PegIntron
plus ribavirin (without boceprevir). In
this part of the study the various treatment
regimes were compared to PegIntron plus
ribavirin (standard of care (control group))
for 48 weeks. (520 patients total)
Part 2:
To evaluate boceprevir, PegIntron and
ribavirin treatment: two different doses of
ribavirin (800-1400 mg/day vs. 400-1000
mg/day); 48 weeks of treatment with the
triple combination of
boceprevir/PegIntron/ribavirin. No lead-in
phase. (75 patients total)
Part 1 Results
An SVR rate of 75% (77 out of 103
patients) was highest in the arm
that received the lead-in of PegIntron plus
ribavirin for 4 weeks followed by 44 weeks
of boceprevir /PegIntron/ ribavirin (total
treatment duration = 48 weeks) vs. an SVR of
38% in the group that received the current
standard of care therapy of PegIntron plus
ribavirin. In the group that received the
lead-in of PegIntron plus ribavirin for 4
weeks followed by 24 weeks of the triple
combination of
boceprevir/PegIntron/ribavirin (total
treatment duration = 28 weeks) the SVR rates
were only 56%, which confirmed that the
optimal treatment duration for the triple
combination (boceprevir, PegIntron,
ribavirin) therapy is 48 weeks.
Safety Results
Treatment discontinuations due to side
effects in Part 1 of the study were between
9 and 19% in the boceprevir arms compared to
8% in the arm without boceprevir. The most
common side effects reported were fatigue,
anemia, nausea and headache.
Anemia (hemoglobin
decreasing to less than 10 g/dL) occurred in
about 50% of people in the boceprevir arms
compared to about 1/3 in the arm without
boceprevir. Erythropoietin (EPO-growth
factor) was allowed in the study—26% of
patients used EPO in the arm without
boceprevir compared to 39-51% who used EPO
in the groups that received boceprevir.
Part 2 Results
In Part 2 (low dose ribavirin) it was found
that the SVR rate was 36% vs. 50% in the
standard dose group (both in combination
with boceprevir and PegIntron). This
information confirms that standard doses of
ribavirin are needed to increase SVR rates
even with the addition of boceprevir.
Comments
The results are impressive—75% SVR rates.
However, the increase in anemia seen in the
patients who received boceprevir is a cause
for concern that could limit the usefulness
of boceprevir. Another concern is that EPO
was allowed and used in the clinical
trials. The use of EPO raises many concerns
including:
EPO is not currently
approved by the FDA to treat HCV
treatment-related anemia. It is
unlikely that the vast majority of
patients who develop anemia from HCV
treatment will be able to use EPO since
there are strong warnings about the use
of EPO that are now listed on the FDA
approved EPO package insert.
If EPO is used, will
it be covered by most insurance
companies? This seems highly unlikely
in the light of the warnings about and
the cost of EPO.
How did the use of EPO
affect the treatment outcome? Would
more patients have dropped out of the
study if EPO wasn’t used? If so, that
could decrease the listed SVR rates.
Does boceprevir now
have an advantage over the other
HCV drugs in development that have not
been able to or rarely used EPO?
Does boceprevir now
have a disadvantage over the
other HCV drugs in development because
EPO was used in the clinical trials?
Will physicians decide not to prescribe
boceprevir due to anemia if patients do
not have access to the use of EPO?
We may find out some of
the answers when phase III studies are
completed, but most likely the real answers
will come when and if boceprevir is approved
by the FDA to treat HCV.
Erythropoietin or EPO: Erythropoietin or EPO is a hormone that
is naturally produced by the kidneys, and to
a lesser extent by the liver, that helps
stimulate the bone marrow to produce red
blood cells that will increase the
oxygen-carrying capacity of the blood.
Synthetic EPO (brand name Epogen, Procrit)
is an injectible medicine that has been
approved by the Food and Drug Administration
(FDA) to treat anemia caused by kidney
failure, the HIV medication AZT, and
cancer. Most people have heard of EPO
related to its illegal use as a
performance-enhancing drug by some
athletes. In 2007, the FDA issued a Public
Health Advisory and required a black box
warning on the product information labeling
about the potential health risks of using
EPO.
Box
HCV Vaccines
The discovery of protective or therapeutic
vaccines has proven difficult, but reports
from EASL on various therapeutic vaccines
are encouraging. Therapeutic vaccines work
to stimulate the immune system to fight an
infection and may have a use in ‘boosting’
the effectiveness of current and future
medications to treat hepatitis C.
TG4040:
Results from a phase I study were released
and it was found that 6 out of 15 patients
given the therapeutic vaccine, TG4040, had a
viral load reduction of 0.5 to 1.4 log10
IU/mL from baseline. The next step in the
development process is a new clinical trial
of TG4040 in combination with pegylated
interferon plus ribavirin. The new trial is
expected to begin in 2010.
GI-5005:
Treatment with GI-5005, a therapeutic HCV
vaccine (plus pegylated interferon/ribavirin)
was compared to pegylated interferon/ribavirin
(without GI-5005). The combination that
included GI-5005 was found to produce 8% to
12% higher rates of HCV viral load
reductions at twelve weeks in HCV genotype 1
treatment-naïve patients compared to those
in the group who did not receive GI-5005.
ChronVac-C DNA
vaccine: Data on the first DNA
vaccine was released at EASL. In a proof of
concept study, 12 HCV genotype 1
treatment-naïve patients were given various
doses of the therapeutic vaccine. In 4 out
of 6 patients who received the two highest
doses there were viral load reductions
exceeding 0.5 log10 that lasted for 2 weeks
to greater than 10 weeks. The HCV viral
load reductions correlated with specific
immune response thereby satisfying the proof
of concept.
In the trials of HCV
vaccines listed above, the vaccines were
safe and well-tolerated.
In addition to the above
studies, there were many reports on drugs
being developed to treat hepatitis C. These
drugs are in very early development and a
summary of the results can be found on the
HCV Advocate Drug Pipeline web page.
2009 Annual
Meeting of the
European
Association for
the Study of the
Liver*
April 22-26,
2009 |
Copenhagen,
Denmark
*CCO is an
independent
medical
education
company that
provides
state-of-the-art
medical
information to
healthcare
professionals
through
conference
coverage and
other
educational
programs.
The European Association of the Study of
Liver Disease wrapped up on Sunday in Copenhagen. Here are some
of the hightlights of all things hepatitis C:
INFORM-1 Data
Roche, InterMune(ITMN
Quote) and Pharmasset(VRUS Quote) provided the most eagerly
anticipated clinical data of the conference Saturday with
results from a 14-day trial combining two experimental direct
antivirals -- InterMune's ITMN-191 with Pharmasset's R7128 --
given to patients with treatment-naïve hepatitis C. Roche is a
development partner on both drugs.
The companies called the INFORM-1 study
"ground breaking" and rightly so in that this trial was the
first time that two oral drugs -- both of which stop the
hepatitis C virus from replicating itself, albeit in different
ways -- were shown to be safe and effective in lowering viral
loads in patients when taken in combination.
However, the viral load reductions and number
of patients with undetectable levels of virus achieved by
various dose combinations of ITMN-191 and R7128 over 14 days
fell short of past studies combining a more potent oral drug
like Vertex Pharmaceuticals'(VRTX Quote) telaprevir with
standard of care for hepatitis C (long-acting injectable
interferon and ribavirin).
The INFORM-1 study is a solid proof of concept
that an all-oral combination therapy for hepatitis C is
possible, but Roche, InterMune and Pharmasset are going to have
to show that higher doses of the drugs, especially of
InterMune's ITMN-191, produce stronger antiviral efficacy in
order to make it possible to eliminate the use of interferon and
ribavirin.
Vertex's Telaprevir
Vertex had a fairly quiet EASL conference,
mainly because telaprevir is in the middle of phase III studies
that won't have data available until next year. Still, the
company did present previously disclosed data showing that
telaprevir is capable of significantly improving cure rates in
the most difficult-to-treat patients who had failed prior
treatment with the current standard drug regimen for hepatitis C
-- a 48-week course of long-acting interferon plus ribavirin.
This data keeps telaprevir ahead of its
hepatitis C rivals because no other drug has yet shown the
ability to improve the cure rates for both patients new to
therapy as well as those who have failed prior therapy.
Telaprevir was the "butt" of some negative
EASL chatter due to an anecdotal report that the drug was
causing severe anal itching in patient(s). One EASL attendee
described the side effect as "fire in the hole."
All jokes aside, itchy rash is a well-known
and documented side effect of telaprevir, but there have been no
confirmed reports of anal pruritis (the medical term for anal
itching) in any of the telaprevir studies presented to date. In
fact, patient discontinuation rates due to telaprevir-induced
rash appear to be on the decline, as doctors and patients learn
how to better manage the side effect.
This should lead to higher cure rates for
telaprevir in the ongoing phase III studies compared to the
already high rates seen in the phase II trials.
New England Journal Of Medicine Publishes
Landmark Clinical Studies Of The Investigational
Hepatitis C Virus Protease Inhibitor Telaprevir
http://www.medicalnewstoday.com
Two clinical studies published
in this week's New England Journal of Medicine
demonstrate that treatment with the investigational oral
hepatitis C virus (HCV) protease inhibitor telaprevir dosed in
combination with pegylated-interferon (peg-IFN) and ribavirin (RBV)
as part of a 24-week treatment regimen resulted in a significant
improvement in the rate of sustained viral response (SVR),
considered a cure of the viral infection, in treatment-naïve
genotype 1 HCV patients, as compared with the SVR rate for
standard therapy dosed for 48 weeks. The data are from two Phase
2b (mid-stage) clinical trials of telaprevir known as PROVE 1
and PROVE 2. In these trials, patients who received a 24-week
telaprevir-based treatment regimen achieved SVR rates of up to
69 percent, as compared to SVR rates of up to 46 percent in
patients in the control arms of these trials who received peg-IFN
and RBV for a standard duration of 48 weeks. Telaprevir is being
developed by Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX)
in collaboration with Tibotec and Mitsubishi Tanabe Pharma.
Telaprevir is currently in Phase 3 (late-stage) clinical
development.
HCV is the most common
blood-borne infection in the U.S., four times more common than
HIV infection, and is the leading cause of liver
transplantations and liver cancer in the U.S.
"Currently available therapies
for patients infected with HCV can be difficult to tolerate and
less than half the patients who start the yearlong treatment
regimen achieve the ultimate goal of having an undetectable
level of virus in their bodies," said John McHutchison, M.D.,
Lead Investigator for the PROVE 1 trial and Associate Director
of the Duke Clinical Research Institute. "In these Phase 2
clinical trials, up to 69 percent of patients in the 24-week
telaprevir-based treatment arm had undetectable virus levels
after 24 weeks, and even though telaprevir does produce side
effects of its own, its addition to standard therapy allowed us
to shorten the duration of treatment. This 24-week regimen was
half the duration of currently approved therapies and, if
confirmed to be this effective in larger Phase 3 studies, could
one day become a very important treatment option for hepatitis C
patients."
"In the PROVE 1 and PROVE 2
trials, telaprevir significantly improved the proportion of
patients who were cured of their disease and also shortened the
duration of HCV therapy from 48 to 24 weeks for the majority of
treatment-naïve patients - an exciting achievement and a
potentially meaningful advance in the treatment of this
disease," said Robert Kauffman, M.D., Ph.D., Senior Vice
President of Clinical Development for Vertex. "Based on data
from these trials, as well as from the PROVE 3 trial in patients
who failed prior HCV therapy, telaprevir is being evaluated in a
comprehensive Phase 3 registration program in more than 2,200
treatment-naïve and treatment-failure patients. Assuming
successful completion of this program, we expect to file an
application for approval of telaprevir with the U.S. FDA in the
second half of 2010."
PROVE 1 and PROVE 2
Study Results
The primary endpoint of the PROVE 1 and PROVE 2 trials was the
proportion of patients who had no detectable hepatitis C virus
in their blood (undetectable plasma HCV RNA) 24 weeks after the
completion of therapy, also known as a sustained viral response
(SVR). Patients who achieve an SVR are considered to be cured of
their HCV infection.
Final results from the PROVE 1
and PROVE 2 trials showed that the 24-week treatment arm, which
consisted of 12 weeks of telaprevir dosed in combination with
peg-IFN and RBV followed by an additional 12 weeks of peg-IFN
and RBV alone, resulted in a significant improvement in SVR
rates, an increased rate of rapid virologic response (RVR,
defined as undetectable levels of HCV RNA by the end of week 4)
and low rates of viral relapse (defined in patients as
undetectable HCV RNA at the end of treatment but detectable
viral levels during the post-treatment follow-up period), as
compared with the SVR, RVR and relapse rates observed in
patients in the control arms who received peg-IFN and RBV for 48
weeks.
Of the small sub-group of
African American patients enrolled in PROVE 1, 44 percent
achieved an SVR in the telaprevir arms, while 11 percent
achieved an SVR in the control group. SVR rates in African
Americans are typically lower than in other ethnic groups.
African Americans are also disproportionately infected with HCV
as compared to other ethnic groups.
Together, these data suggest
that a 24-week telaprevir-based treatment regimen may be
sufficient for treatment-naïve patients who achieve an RVR.
These findings are being confirmed in Vertex's ADVANCE Phase 3
clinical trial in treatment-naïve patients, focusing on 24-week
response-guided regimens that consist of either 8 or 12 weeks of
telaprevir in combination with peg-IFN and RBV. Treatment-naïve
patients in the ADVANCE Phase 3 trial who achieve an RVR and who
stay undetectable through week 12 of treatment will receive 24
weeks of treatment. Patients who do not meet the RVR criteria
but are undetectable at week 24 will continue on peg-IFN and RBV
for a total duration of 48 weeks. This Phase 3 trial is designed
to maximize the number of patients who can achieve SVR while
offering a large proportion of treatment-naïve patients the
benefit of a 24-week treatment duration.
Telaprevir Safety &
Tolerability Across PROVE 1 and PROVE 2
More than 400 patients received a telaprevir-containing regimen
as part of the PROVE 1 and PROVE 2 clinical trials, and the
adverse event profile was generally consistent across these
trials. Telaprevir was evaluated in combination with
Peginterferon alfa-2a and ribavirin. In these placebo-controlled
studies, the most common adverse events reported more frequently
in the telaprevir treatment arms compared to the placebo arms
were gastrointestinal events, skin events (rash, pruritus) and
anemia. Other adverse events reported were similar in type and
frequency to those seen with currently approved peg-IFN and RBV
treatment. The most common adverse event leading to
discontinuation in the telaprevir arms was rash in approximately
7 percent of patients across both PROVE 1 and PROVE 2.
Investigators have reported that rash adverse events were
reversible upon discontinuation of treatment, and a rash
management plan was implemented as part of subsequent telaprevir
clinical trials, including ongoing Phase 3 trials.
PROVE 1 Study Design
PROVE 1 was a Phase 2b, randomized, double-blind,
placebo-controlled trial that enrolled and treated 250
treatment-naïve genotype 1 HCV patients at 37 clinical trial
sites in the U.S. Of the patients enrolled in PROVE 1, the mean
age was 48.1 years, 63 percent were men and 77 percent were
white. Patients in PROVE 1 received 750mg of telaprevir (or
placebo) orally every eight hours, based on treatment arm, and a
once-weekly 180ug injection of Peginterferon alfa-2a, as well as
a 1,000mg or 1,200mg weight-based daily oral dose of ribavirin.
PROVE 1 consisted of four treatment arms: (1) a 24-week
telaprevir-based arm consisting of 12 weeks of telaprevir in
combination with peg-IFN and RBV, followed by an additional 12
weeks of peg-IFN and RBV alone, (2) a 48-week telaprevir-based
arm consisting of 12 weeks of telaprevir in combination with
peg-IFN and RBV, followed by an additional 36 weeks of peg-IFN
and RBV alone, (3) a 12-week telaprevir-based arm consisting of
12 weeks of telaprevir in combination with peg-IFN and RBV, and
(4) a control arm consisting of 12 weeks of placebo in
combination with peg-IFN and RBV, followed by 36 weeks of peg-IFN
and RBV alone.
PROVE 2 Study Design
PROVE 2 was a Phase 2b, randomized, partially double-blind,
placebo-controlled trial that enrolled and treated 323
treatment-naïve genotype 1 HCV patients at 28 clinical trial
sites in France, Germany, the United Kingdom and Austria. Of the
patients enrolled in PROVE 2, the mean age was 44.3 years, 59.4
percent were men and 94.1 percent were white. Patients in PROVE
2 received 750mg of telaprevir (or placebo) orally every eight
hours, based on treatment arm, a once-weekly 180ug injection of
Peginterferon alfa-2a, as well as a 1,000mg or 1,200mg
weight-based daily oral dose of ribavirin. PROVE 2 consisted of
four treatment arms: (1) a 24-week telaprevir-based arm
consisting of 12 weeks of telaprevir in combination with peg-IFN
and RBV, followed by an additional 12 weeks of peg-IFN and RBV
alone, (2) a 12-week telaprevir-based arm consisting of 12 weeks
of telaprevir in combination with peg-IFN and RBV, (3) a 12-week
telaprevir-based arm consisting of 12 weeks of telaprevir in
combination with peg-IFN (no RBV), and (4) a control arm
consisting of 12 weeks of placebo in combination with peg-IFN
and RBV, followed by 36 weeks of peg-IFN and RBV alone.
About Telaprevir and
Vertex's HCV Development Portfolio
Telaprevir (VX-950) is an investigational oral inhibitor of HCV
protease, an enzyme essential for viral replication, and is one
of the most advanced investigational antiviral agents in
development that specifically targets HCV. Telaprevir is being
evaluated as part of a global Phase 3 registration program in
more than 2,200 treatment-naïve and treatment-failure patients.
Vertex retains commercial
rights to telaprevir in North America. Vertex and Tibotec are
collaborating to develop and commercialize telaprevir in Europe,
South America, Australia, the Middle East and other countries.
Vertex is collaborating with Mitsubishi Tanabe Pharma to develop
and commercialize telaprevir in Japan and certain Far East
countries.
Vertex is also developing
VCH-222, an oral inhibitor of the HCV NS5B
polymerase. HCV polymerase inhibitors represent an additional
class of drug candidates that are aimed at inhibiting viral
replication.
Source: Vertex
Pharmaceuticals Incorporated
Anadys' ANA598 and Rash
Anadys Pharmaceuticals'(ANDS Quote) share
price has not yet recovered from the emergence last week of a
rash associated with its experimental drug ANA598. The company
contends that investors are more worried about rash than doctors
using the drug in clinical trials and the emergence of this
potential side effect will not derail the drug's development.
However, Anadys only has another quarter or
two of cash left and doesn't have enough money on hand to begin
the next round of ANA598 clinical trials. Anadys is negotiating
with potential partners for ANA598 but if talks are delayed, the
company could be forced to raise money though another dilutive
financing.
-- Highlights include
Anadys Pharmaceuticals Inc. (ANDS), Roche Holding AG (RHHBY),
Schering-Plough (SGP), Gilead Sciences (GILD), Vertex
Pharmaceuticals (VTRX) and Valeant Pharmaceuticals International
(VRX).
-- Strong efficacy data
observed in early phase Ib studies for ANA598, but a severe rash
raises safety concerns
ANA598
is Anadys’ (ANDS) lead anti-HCV (hepatitis C Virus) drug
candidate currently under phase I studies. The company’s share
price got a boost recently on its strong efficacy data from a
phase Ib study.
Anadys presented the final
antiviral and safety data from all three dose levels (200, 400
and 800 mg bid) at the 44th annual meeting of the European
Association for the Study of the Liver (EASL) on April 23, 2009.
The trial enrolled total 35 subjects. ANA598 treatment resulted
in rapid and sustained reductions in HCV RNA with median
reductions at end of treatment
(day 4) exceeding 2 log10
(>99%) at all dose levels.
At 200 mg bid, the median viral
load reduction was 2.4 log10 (range of 0.4 to 3.4); at 400 mg
bid, 2.3 log10 (range of 1.6 to 3.5); and at 800 mg bid, 2.9
log10 (range of 2.2 to 3.4). Genotype 1a patients demonstrated
median reductions of 1.4 log10, 1.8 log10, and 2.5 log10 at 200,
400 and 800 mg bid, respectively. Genotype 1b patients
demonstrated median reductions of 2.6 log10, 2.5 log10 and 3.2
log10, at 200, 400 and 800 mg bid, respectively. Genotype 1b is
the most common subtype of hepatitis C found in North America
and Europe.
No patient showed evidence of
viral rebound while on ANA598. The drug seemed well-tolerated in
this short-term study and there were no serious adverse events
reported.
However, later in a separate
study from healthy volunteers in a 14-day study conducted to
extend the safety and pharmacokinetic profile of ANA598, a
severe rash was observed in some ANA598 treated subjects. Thirty
subjects participated in the study, with eight subjects
receiving ANA598 and two subjects receiving placebo at each dose
level (400 mg once-daily, 800 mg once-daily and 600 mg bid).
Preliminary results from the
study suggested that ANA598 was generally well-tolerated in all
cohorts with no serious adverse events, but three subjects (two
subjects in the 800 mg once-daily cohort and one subject in the
600 mg bid cohort) developed grade II rash and discontinued
treatment after either six or seven days of consecutive dosing.
Competition is fierce
in anti-HCV market
Although ANA598 showed encouraging efficacy, this was only
conducted in an early phase I trial with a very small number of
patients. We remind investors that competition will be fierce in
the anti-HCV market.
HCV is a serious infection
afflicting about 3.2 million people in the U.S. and
approximately 170 million people worldwide -- fatal in some
cases -- and is the primary cause of liver transplants in the
U.S. and Europe. This market is currently dominated by two
players: Roche (RHHBY), which commands a majority of the U.S.
and global pegylated interferon market share through the sale of
Pegasys/Copegus, and Schering-Plough (SGP), through the sale of
Peg-Intron / Rebetrol. The global HCV market in 2008 was between
$2 and $3 billion and is expected to grow to $4.4 billion in
2010 and $8.8 billion in 2015.
Due to the asymptomatic nature
of HCV infection, it often goes undetected for up to 20 years
following the initial infection. Each year, 8,000 to 10,000
people in the U.S. die from complications of HCV. The current
standard of care is a combination of pegylated interferon and
ribavirin.
Even if Anadys is able to bring
ANA598 to the market, it will face tough competition from other
big players like Schering Plough, Roche, and Gilead (GILD) in
the HCV market. In addition, a number of companies are
developing oral formulations for the treatment of HCV.
Vertex (VTRX) has set a new
benchmark for the treatment of HCV. Its HCV candidate,
Telaprevir, demonstrated significant reduction in viral load
with 4.4-log reduction in viral load compared to 1-2 log
reduction seen in other standard of care interferon therapy.
We believe that this data sets
the bar very high, and we are unsure whether Anadys can reach
it. Currently, Telaprevir is undergoing phase III studies.
Valeant’s (VRX) Taribavirin (previously known as Viramidine) is
in advanced clinical development.
Meanwhile, Schering’s
Boceprevir is in phase III. Hence, they are already ahead of
Anadys in terms of development. So we believe competition will
remain a challenge for Anadys in the years to come.
Cash burn is a matter
of concern
The company is still in the development stage, with no products
on the market.
Net cash burn in the first
quarter of 2009 was $7.1 million. The company had only $21
million in cash, cash equivalents and investment as of March 31,
2009, which should last for about three quarters, according to
our model. Anadys, therefore, needs to enter into an agreement
on a partnership or acquisition relatively quickly otherwise it
will have to raise additional cash to fund its operations in
2009.
Currently all eyes are on the
ANA598 data and potential partnership agreement the company may
enter into in the near future. We are happy to see the very
positive efficacy data in the phase Ib trial, but are concerned
about the severe rash side effect. Since the phase I trial is
only tested in a small number of subjects, we remain skeptical
if the company can find a partner with favorable terms.
Schering-Plough's(SGP Quote) boceprevir made
some headlines last week with phase II cure rates numerically
higher than what's been reported by Vertex's telaprevir in its
phase II studies. But boceprevir still doesn't look competitive
because the drug is causing significant rates of anemia in
patients and requires dosing up to 48 weeks compared to 24-week
dosing for telaprevir. Boceprevir is also ineffective for
patients who have failed prior treatment.
The other challengers to telaprevir also
presented new data at the EASL conference, but none seemed ready
yet for a full fight. Johnson & Johnson's(JNJ Quote) TMC-435
appears to have at least a signal for liver toxicity;
Merck's(MRK Quote) MK-7009 reported high rates of vomiting;
while InterMune's ITMN-191 isn't very potent on its own,
especially when dosed twice daily.
Experimental Therapies: New
treatments for hepatitis C including pre-clinical development
that have not yet been studied in humans, and various drugs that
are in phase I, II and III development to treat hepatitis C.
New Study:
Telaprevir in Treatment Experienced Patients —Alan Franciscus, Editor-in-Chief
On
October 15, 2008 Tibotec announced that it
will begin screening patients for a large
phase III study to evaluate the combination
of telaprevir, pegylated interferon plus
ribavirin in treatment experienced patients
who did not achieve a sustained virological
response to a previous course of treatment
with pegylated interferon plus ribavirin.
Tibotec is Vertex’s commercial partner that
is conducting clinical trials outside of the
United States, Canada and Mexico.
This
worldwide study will enroll about 650 HCV
patients. According to the company press
release the U.S. centers have begun
screening patients, and other global study
centers are expected to begin the screening
process within the next couple of weeks.
The study will include null responders,
partial responders and relapsers.
The REALIZE Study
The
study will include 3 arms:
1. Telaprevir dosed at
750 mg q8h (every eight hours) for 12 weeks
in combination with standard doses of
pegylated interferon plus ribavirin,
followed by 36 weeks of treatment with
pegylated interferon plus ribavirin alone;
2. Delayed start arm – 4
weeks of treatment with pegylated interferon
plus ribavirin, followed by telaprevir dosed
at 750 mg q8h for 12 weeks in combination
with standard doses of pegylated interferon
and ribavirin, followed by another 32 weeks
of pegylated interferon and ribavirin alone;
3. Control Arm – standard
doses of pegylated interferon plus ribavirin
dosed for 48 weeks.
The
study has been named REALIZE (Re-treatment
of Patients with Telaprevir-based Regimen to
Optimize Outcomes).
Currently, Vertex is conducting another
large phase III study of telaprevir in
combination with pegylated interferon plus
ribavirin for the treatment of genotype 1
treatment naïve patients called the ADVANCE
trial. The ADVANCE trial is expected to
enroll about 1050 patients in the U.S.,
Europe and certain other countries. It is
expected that the results from the ADVANCE
study will be used to apply to the Food and
Drug Administration for marketing approval
of telaprevir in the U.S.
On August 4, 2008,
Schering-Plough released the top-line results from their phase II clinical
study of boceprevir, an HCV protease inhibitor, in combination with
PegInterferon plus ribavirin in HCV genotype 1 treatment-naïve patients.
The treatment arms and response rates are listed below.
This study included 595
patients divided into 6 treatment arms*: Arm 1: 107 patients – triple therapy with no lead-in
phase. Triple therapy = PegIntron (1.5 mcg/kg) plus ribavirin 800-1400
mg daily (based on body weight), and boceprevir 800 mg three times a day.
Total treatment duration = 28 weeks. SVR 24 = 55%
Arm 2:
103 patients – 4 week lead-in phase of PegIntron (1.5 mcg/kg) plus ribavirin
800-1400 mg daily (based on body weight) followed by an additional 24 weeks
of triple therapy. Triple therapy = PegIntron (1.5 mcg/kg)
plus ribavirin 800-1400 mg daily (based on body weight), boceprevir 800 mg
three times a day. Total treatment duration = 28 weeks. SVR 24 = 56%
Arm 3:
103 patients – triple therapy with no lead-in phase. Triple therapy =
PegIntron (1.5 mcg/kg) plus ribavirin 400-1400 mg daily (based on body
weight) boceprevir 800 mg three times a day. Total treatment duration
= 48 weeks. SVR 12 = 66%
Arm 4:
103 patients – 4 week lead-in phase with PegIntron (1.5 mcg/kg) plus
ribavirin 800-1400 mg daily (based on body weight) followed by an additional
44 weeks of triple therapy. Triple therapy = PegIntron (1.5 mcg/kg)
plus ribavirin 400-1400 mg daily (based on body weight), boceprevir 800 mg
three times a day. Total treatment duration = 48 weeks. SVR 12 = 74%
Arm 5 (Control
Arm): 104 patients – combination therapy = PegIntron
(1.5 mcg/kg) plus ribavirin 400-1400 mg daily (based on body weight). Total
treatment duration = 48 weeks. SVR 12 = 38%
*There was another arm
that was added to the study that didn’t start enrollment until after the
other arms had begun enrollment. In the new arm, patients received
boceprevir in combination with low-dose ribavirin plus PegIntron for a
treatment duration of 48 weeks. These results are expected later in the
year.
The most common adverse
events (side effects) reported in the boceprevir arms were fatigue, anemia,
nausea and headache. The press release noted that there were no
increases in dermatological (skin) adverse events (rash and itching) that
are usually seen in patients treated with PegIntron plus ribavirin.
The treatment discontinuations due to adverse events were between 9 and 19%
in the boceprevir arms vs. 8% in the control arm (without boceprevir).
Comments:
The results of this study are encouraging, but they should be interpreted
with a bit of caution. First, the results reported here are
top-line numbers so there will be much more information released later in
the year at the American Association for the Study of Liver Diseases (AASLD)
conference about the patient characteristics, dose reductions (if any), and
side effects. Secondly, this is a small phase II study that included
five treatment arms ranging from 103 to 107 patients in each arm. A
small sample size of patients doesn’t give us a clear picture of the
effectiveness or side effect profile of a study drug. Finally, some of
these results are SVR12 so there is a possibility that the SVR 24 rates
could be a bit lower than listed here. Schering began recruitment into
a phase III study of boceprevir in combination with PegIntron plus ribavirin
earlier this year and that study will include many more patients – which
should give us a better understanding of the patient population, drug
effectiveness, side effect profile and other important issues.
This year’s
EASL (European Association for the Study of Liver Disease)
conference was held in Milan, Italy. EASL is becoming
one of the premiere liver disease conferences and is
comparable in its scope and importance to the AASLD
(American Association for the Study of Liver Disease)
Conference held in the United States. This article
will review the data presented on HCV drugs being developed
to treat hepatitis C.
Telaprevir
is an HCV protease inhibitor that is being developed by
Vertex. It is currently the furthest along in clinical
development among the new antivirals. Of note, it was
recently announced that the phase 3 clinical trial had
enrolled the first patients. At EASL two key phase II
study results were presented: final results from the PROVE1,
and SVR12 data from the PROVE2 trials, as well as
preliminary data from Study 107 – a study that is
investigating the treatment of prior non-responders, null
responders and relapsers from the PROVE1, 2 and 3 clinical
trials.
Telaprevir
PROVE1
The final results of the PROVE1 trial were presented at EASL.
In this trial there were 250 genotype 1 treatment-naïve
patients. The patients were divided into 4 treatment
arms and the patient characteristics were fairly balanced
between the arms. A description of the treatment arms
and the intent to treat (ITT) SVR rates are listed below.*
Arm
A: 75 patients treated with Pegasys plus
ribavirin for 48 weeks (control arm). SVR =
41%
Arm
B: 79 patients treated with telaprevir plus
Pegasys/ribavirin for 12 weeks, then treated for an
additional 36 weeks with Pegasys plus ribavirin.
SVR = 67%
Arm
C: 79 patients treated with telaprevir plus
Pegasys/ribavirin for 12 weeks followed by an additional 12
weeks of treatment with Pegasys/ribavirin.
SVR=61%
Arm
D: 17 patients treated telaprevir plus
Pegasys/ribavirin for 12 weeks – no further treatment.
SVR=35%
*Medication doses:
Telaprevir (750 mg or placebo) TID, Pegasys (180 ug injected
once weekly), and ribavirin (dosed by body weight at either
1000 or 1200 mg a day).
Importantly, these results confirm early data that the
optimal treatment duration is 24 weeks – the relapse
rate in the arms that included telaprevir was significantly
lower (0-2%) in those who were HCV RNA negative at weeks 4
and 12.
The most
common types of serious side effects reported were skin
rashes, gastrointestinal events, and anemia. The
incidents of overall serious side effects were higher in the
telaprevir arms: 11% in the telaprevir groups compared to 5%
in the group that received pegylated interferon and
ribavirin only. Treatment discontinuation rates
through week 12 due to adverse events were higher in the
telaprevir arms (18%) compared to those who did not receive
telaprevir (4%). The incidence of severe rash was 7%
in the participants who received telaprevir.
PROVE2
The PROVE2 study design is similar to that of PROVE1 and has
enrolled 323 HCV genotype 1 treatment naïve patients.
The clinical trial is being conducted in Europe. The
trial also included an arm of telaprevir and Pegasys, but
without ribavirin. The interim results were similar to
PROVE1 with 68% SVR12 in the arm that received 24 weeks of
treatment. Final results are expected later this year.
Bottom Line
The final
results from PROVE1 and the SVR12 results from PROVE2 have
confirmed that 24 weeks of treatment produced comparable
sustained virological response rates when the same treatment
regime was given for 48 weeks.
There have
been some concerns raised about anemia, but the incidence of
anemia was only slightly higher in the telaprevir arms and
resolved after treatment was discontinued. The severe
rash is also another concern, but the rate of treatment
discontinuation due to the rash was relatively low, and the
rash also resolved after treatment was discontinued.
Study 107
The preliminary results from Study 107 on the retreatment of
the people in the PROVE1, PROVE2, and PROVE3 control arms
who did not receive telaprevir were included in this study.
Participants from the PROVE studies were eligible for Study
107 if they were either null responders, partial responders
or relapsers. Participants who discontinued treatment
because of side effects were not eligible for Study 107.
The
dosing of this study is as follows:
12 weeks of
telaprevir (750 mg TID), Pegasys (180 ug-injected weekly)
plus ribavirin (1000/1200 mg/day) followed by 12 weeks of
Pegasys plus ribavirin alone (24 week treatment duration)
Included in
the study design was a stopping rule: if HCV RNA was higher
than 25 IU/mL at weeks 4 and 12, the treatment was stopped.
Interim Analysis
A total of
72 patients have received at least one dose of the study
medicines. Of these, 63 are currently on treatment –
for this analysis there were 60 patients who completed 4
weeks of therapy, 36 patients who completed 8 weeks of
therapy and 16 patients who completed 12 weeks of therapy.
The preliminary results found that at week 4, 83% achieved
HCV RNA less than 25 IU/mL and that all the patients who
continued treatment beyond week 4 maintained their viral
responses by weeks 8 and 12. The range of viral
breakthrough was very low (3%), and those who developed
viral breakthrough were identified early on. Based on
these positive treatment response rates, the protocol has
been amended so that the relapsers and partial responders
will receive 12 weeks of telaprevir in combination with 24
or 48 weeks of Pegasys plus ribavirin. The patients
who were previous non-responders will receive telaprevir,
Pegasys and ribavirin for 12 weeks followed by 48
weeks of Pegasys plus ribavirin therapy.
The side
effect profile was similar to what has been previously
reported in telaprevir, Pegasys and ribavirin therapy.
Two patients discontinued treatment due to
pleuritis/costochondritis (inflammation and pain in the
lungs and chest), and a generalized rash.
Bottom Line
These
results, although very preliminary, are encouraging because
the early response rates are the highest yet seen in a
population of HCV patients who are in the greatest need of
treatment. It is hoped that this positive trend of
improved treatment outcomes will carry over to the PROVE3
study that is retreating HCV genotype 1 prior
non-responders. The PROVE3 study is a blinded study so
no preliminary or interim results have been announced.
But stay tuned – the results from PROVE3 are expected
mid-2008. This study will give us a much better
picture of the effectiveness of telaprevir, Pegasys, and
ribavirin therapy in a non-responder group of genotype 1
patients. It is definitely the ONE to watch.
Boceprevir
Boceprevir
is an HCV protease inhibitor that is being developed by
Schering Plough. Of note, on May 21, 2008 Schering announced
the initiation of 2 phase III studies of
boceprevir/PegIntron and ribavirin. Interim results from the
SPRINT-1 study were released at EASL. The study aim
was to evaluate the most effective treatment strategy for
HCV genotype 1 treatment-naïve patients. The aims
included determining the most optimal treatment duration (28
vs. 48 weeks), the dose of ribavirin (800-1300 mg/daily vs.
400-1000 mg/daily), whether treatment would benefit from a
lead-in phase (PegIntron plus ribavirin) before beginning
boceprevir (800 mg TID), or if the triple combination of
boceprevir, PegIntron, and ribavirin from the beginning of
therapy produced the best treatment results. The baseline
characteristics were similar across the treatment arms
except that more males were included in the PegIntron plus
ribavirin control group than in the boceprevir arms.
The SVR12
data from the two 28-week boceprevir arms was presented.
In the group that received the PegIntron plus ribavirin
(lead-in phase), followed by the addition of boceprevir
there was a 57% SVR12 compared to 55% of the group who
received boceprevir, PegIntron and ribavirin (triple
therapy) from the beginning of treatment. In those
patients who achieved a rapid virological response (HCV RNA
negative after 4 weeks of treatment), the lead-in group, 86%
achieved an SVR12 compared to 74% achieving an SVR12 in the
group that received the triple therapy from the beginning.
The side
effect profile between the boceprevir and the PegIntron arms
were similar except there was more anemia and dysgeusia
(taste changes) in the boceprevir arm. The
discontinuation rates were higher in the boceprevir arms (11
and 15%) compared to the PegIntron plus ribavirin control
arm (8%).
The interim
results suggest that a shorter duration of treatment (28
weeks total) that includes a lead-in phase with PegIntron
plus ribavirin prior to the introduction of boceprevir
produces higher treatment response rates and that a rapid
virological response is a good predictor of treatment
response.
Bottom Line
These are
also very encouraging early results. The final results
of all of the treatment arms will give us a much better idea
of the effectiveness of boceprevir compared to PegIntron
plus ribavirin therapy. The good news about this study
is that the design of the phase III study will include a
lead-in phase and a shorter duration of treatment.
Boceprevir in Null Responders
The results
from another study using boceprevir in combination with
PegIntron plus ribavirin yielded less promising outcomes.
However, this trial was more about establishing the most
effective dose of boceprevir, treatment duration, safety
issues and if ribavirin was needed to maximize treatment
response rates.
In the
study there were 357 genotype 1 patients enrolled who were
deemed prior null responders – defined as either less than a
2 log10 drop in HCV RNA after 12 weeks of therapy with
pegylated interferon/ribavirin therapy or who did not
achieve undetectable HCV RNA if treated longer than 12
weeks. There were 7 arms in this study – with or
without different doses of boceprevir (100, 200, 400, 800
mg), and with and without ribavirin. This study had a
lead-in phase using PegIntron alone.
The authors
found that boceprevir is safe and well-tolerated. The
overall intent-to-treat sustained virological response rates
were 2% in the group that only received PegIntron plus
ribavirin and up to 14% in the groups that received triple
combination of PegIntron, ribavirin and boceprevir. It
was found that the most effective dose of boceprevir was 800
mg TID and that the use of ribavirin would be required to
optimize treatment outcome. The treatment duration
would include an additional 24 weeks after HCV RNA became
undetectable.
Bottom Line
It is hard
to draw any concrete conclusions because of the small
patient population and the many different treatment arms.
The group of patients in this study are some of the most
difficult to treat and most did not receive the most
effective dose of boceprevir. The newly announced
phase 3 studies will hopefully answer the question of the
role of boceprevir in the retreatment of prior
non-responders.
R1626
R1626 is a
polymerase inhibitor that is being developed by Roche, and
in previous studies it has been shown to have potent
antiviral activity against hepatitis C. Prior
treatment data has suggested that there was a lack of viral
resistance to R1626. At the AASLD 2007 Conference
4-week data that was presented was very encouraging.
At EASL 2008 more information was released that included the
end-of-treatment response rates (total treatment duration =
48 weeks) of the entire Phase 2 clinical trial.
All study
participants were HCV genotype 1 treatment-naïve. A
total of 104 patients were randomized into 4 treatment arms:
Arm
A: R1626 (1500 mg bid-twice a day) plus Pegasys
for 4 weeks followed by Pegasys plus ribavirin for an
additional 44 weeks. (21 patients)
Arm
B: R1626 (3000 mg bid) plus Pegasys for 4 weeks
followed by Pegasys and ribavirin for an additional 44
weeks. (32 patients)
Arm
C: R1626 (1500 mg bid) plus Pegasys and ribavirin
for 4 weeks followed by Pegasys plus ribavirin for an
additional 44 weeks. (31 patients)
Arm
D: Pegasys plus ribavirin for 48 weeks (control
arm) (20 patients)
The patient
characteristics were fairly well-matched except that arm A
had a higher percentage of males (81%) compared to the other
arms (41%, 39% and 40% respectively). The fibrosis
scores were fairly well-matched and all fell within the
F0-F2 range.
The highest
end-of-treatment response rates were in Arm C – 84% which is
slightly higher than the treatment response rates reported
after 4 weeks of treatment. There were 7 patients who
initially were HCV RNA negative after the 4-week lead-in,
but became HCV RNA positive (rebounded) during therapy.
In all of the patients who rebounded, they rebounded after
R1626 was discontinued. As reported with the 4-week
data at AASLD 2007, there was no drug resistance to R1626
found in this study. The safety profile was similar
between the arms with the exception of grade 4 neutropenia
and other lab abnormalities in the R1626 arms. After
treatment was discontinued all lab values returned to
normal.
Bottom LIne
Even though
this is a small patient population, the lack of drug
resistance and very high end-of-treatment response rates are
very encouraging. Due to the high incidence of grade 4
neutropenia during the period that R1626 was taken, Roche
has launched a phase 2b dose ranging study to determine the
most optimal dose of R1626 that has lower rates of lab
abnormalities.
R7128
R7128 is an
HCV polymerase inhibitor that is being developed by
Pharmasset and Roche. At AASLD 2007 it was reported
that R7128 alone for treatment of HCV genotype 1
treatment-naïve patients for 4 weeks achieved an average of
2.7 log10 decline in HCV RNA with a maximum decline of 4.2
log10. It was also found that twice a day dosing was
the most effective.
At EASL
2008, Pharmasset presented results from another trial of
R7128 in combination with Pegasys and ribavirin for 4 weeks.
In this trial, 50 HCV genotype 1, treatment-naïve patients
were enrolled. The treatment arms* and the results
after 4 weeks of treatment are listed below.
Group A: R7128 500 mg BID plus Pegasys and
ribavirin (20 patients). 30% were HCV RNA negative;
mean HCV RNA reduction was -3.82 log10.
Group B: R7128 1500 mg BID plus Pegasys and
ribavirin (20 patients). 85% HCV RNA negative; mean
HCV RNA reduction was -5.12 log10
Group C: Placebo plus Pegasys and ribavirin
(10 patients) – control arm. 10% were HCV RNA
negative; mean HCV RNA reduction was -2.95 log10
*After
initial treatment of R7128 (at various doses) combined with
Pegasys and ribavirin for 4 weeks, trial participants
were then treated for another 4 weeks with Pegasys plus
ribavirin – then all the study participants were rolled over
to receive an additional 40 weeks with Pegasys plus
ribavirin (total duration of treatment was 48 weeks).
The safety
and tolerability was similar between the 3 arms including
the arm that did not include R7128.
Bottom Line
The data is
very impressive, but more long-term data is needed before
any conclusions can be drawn. It was announced at EASL
that Pharmasset will conduct new studies to evaluate R7128
at 1500 mg BID in HCV genotype 2 & 3 patients who did not
achieve a sustained virological response to a previous
course of interferon based therapy, as well as testing R7128
at 1000 mg BID.
In a
related development, on May 19, 2008 Pharmasset announced
that a new compound designated as PSI-7851 will be advanced
into animal toxicity studies and that Pharmasset will apply
to the Food and Drug Administration for an Investigational
New Drug (IND) designation. PSI-7851 is an HCV
polymerase inhibitor that has demonstrated in vitro (test
tube) a potency that is about 15- to 20 fold greater than
R7128.
More New Drugs in Development
There was
more news from EASL on drugs in early development including
the following studies:
•
VCH-916 is a HCV polymerase inhibitor being
developed by ViroChem. In a study of healthy
volunteers who received up to a single dose of 600 mg,
VCH-916 was found to be generally safe and well-tolerated
and achieved plasma concentrations proportional to the dose
given. Based on these results a 14-day study of HCV
genotype 1 treatment-naïve subjects is being planned.
•
TMC435350 is an HCV protease inhibitor being
developed by Medivir and Tibotec. In the study there were 52
healthy volunteers and 6 patients with HCV. Once a day
dosing with TMC435350 at 200 mg was given to all study
participants. The drug was found to be safe and
well-tolerated in both the healthy and the HCV-positive
participants. In the 6 patients with HCV genotype 1,
TMC435350 was found to have strong and rapid antiviral
activity with a median viral load reduction of -3.9 log10.
Further studies are being planned.
•
Nitazoxanide is a broad spectrum antiviral that is
being tested for the treatment of hepatitis C by Romark
Laboratories. In a previous study released at AASLD
2007, nitazoxanide used in combination with pegylated
interferon and ribavirin for the treatment of HCV genotype 4
patients produced an SVR12 of 79% compared to 43% in the
group that received pegylated interferon plus ribavirin but
without nitazoxanide. The prior study had a 12 week
lead-in of nitazoxanide. In this study a 4 week
lead-in phase using nitazoxanide alone was studied.
The authors found that the SVR12 rates were similar between
the different lead-in phases (80% for the 4-week lead-in vs.
79% for the 12-week). This is one to keep track of
since the potential for increased response rates by adding
nitazoxanide to the current standard of care of pegylated
interferon plus ribavirin is encouraging.
http://www.hcvadvocate.org/news/newsLetter/2008/advocate0608.html#1
