on Experimental Anti-HCV Drugs ITMN-191/R7227, VCH-916, VCH-222, TMC435, ANA598,
MK-7009, GS-9450, Abbott/Enanta and Idenix Agents
therapy consisting of pegylated interferon
(Pegasys or PegIntron) plus ribavirin is the current standard of care for
chronic hepatitis C virus (HCV) infection, but this regimen causes difficult side
effects and does not produce a sustained response in about half of patients with
difficult-to-treat HCV genotype 1. Researchers are studying a number of oral drugs
that directly target various steps of the HCV lifecycle, an approach referred
to as "STAT-C."
Data on several such agents were presented at the 44th
Annual Meeting of the European Association for the Study of the Liver (EASL 2009)
last month in Copenhagen.
Vertex HCV NS3/4A serine protease inhibitor telaprevir
(formerly VX-950), now in Phase 3 studies, may be the first to exit the development
pipeline. Promising results from the Phase 2 PROVE 1 and PROVE 2 studies in treatment-naive
patients were published recently
in the New England Journal of Medicine, and, as previously reported, findings
from the PROVE 3 study were presented at EASL.
Researchers at EASL
good results from the SPRINT-1 trial of combination therapy containing Schering-Plough's
advanced HCV protease inhibitor candidate boceprevir,
as well as early
data on the company's newer HCV NS3 protease inhibitor SCH
presentation that garnered considerable attention looked at the first data
from a clinical trial (INFORM-1) of 2 directly-targeted oral agents -- the Roche
HCV polymerase inhibitor R7128
plus the InterMune/Roche HCV NS3/4A protease
inhibitor ITMN-191 (also known as R7227) -- without pegylated interferon or
is also being studied in combination with the current standard-of-care regimen.
Stefan Zeuzem presented findings from a double-blind, placebo-controlled, multiple
ascending dose study in which 191 treatment-naive genotype 1 chronic hepatitis
C patients were randomly assigned (8:2) to receive ITMN-191/R7227 (100 to 900
mg every 8 or 12 hours) or placebo in combination with standard doses of pegylated
interferon alfa-2a and weight-adjusted ribavirin for 14 days.
levels declined rapidly, with HCV RNA decreasing by about 5.5 log10, compared
with 2 log10 in the standard-of-care arm. At the end of dosing, 57% to 88% of
participants had HCV RNA < 25 IU/mL (compared with 8% in the standard therapy
arm) and 13% to 57% had undetectable HCV RNA < 9.3 IU/mL (vs none in the standard
therapy arm). Viral rebound did not occur in any of the treatment arms. Overall,
ITMN-191/R7227 was generally safe and well tolerated. There were no serious adverse
events (AEs) or laboratory abnormalities, and no AEs leading to treatment discontinuation.
InterMune is planning a Phase 2b trial of triple therapy using ITMN-191/R7227
at doses that appeared promising in this study (600 mg and 900 mg every 12 hours
and 300 mg every 8 hours).
"We believe that the viral kinetic and
safety results reported today provide evidence that ITMN-191 has the potential
to deliver superior sustained virologic response (SVR) rates in patients chronically
infected with the hepatitis C virus," said InterMune Chief Medical Officer
Steven Porter in a press release issued by the company.
As telaprevir moves toward the final stages of development, Vertex
is developing 2 new STAT-C agents, the non-nucleoside HCV RNA-dependent NS5B polymerase
inhibitors VCH-916 and VCH-222, which Vertex acquired from ViroChem Pharma when
it acquired the company in March 2009.
Eric Lawitz and colleagues presented
results from a study assessing the viral kinetics, pharmacokinetics, safety, and
tolerability of VCH-916 monotherapy, administered to 41 patients at doses of 100
and 200 mg every 8 hours for 14 days, and 300 and 400 mg twice-daily for 3 days
(or placebo). All participants had HCV genotype 1 and all but 2 were treatment-naive.
displayed linear pharmacokinetics with no accumulation upon repeated administration.
The maximal decline in HCV RNA ranged from 0.1 to 2.6 log10, generally rising
with higher doses. After 3 days of dosing, the maximal HCV RNA decrease was 1.5
log10 in the 3 highest dose arms.
VCH-916 was generally well tolerated
over 14 days; while adverse effects were common, they were usually mild (93% mild,
7% moderate). The most frequently reported adverse events were gastrointestinal
symptoms (38%), throat irritation (25%), and central nervous system symptoms (19%)
in the three-times-daily cohorts. In the twice-daily groups, three-quarters reported
throat irritation and one-third reported nausea. However, no serious AEs, abnormal
laboratory findings, or ECG abnormalities were observed.
and colleagues looked at the safety, tolerability, and pharmacokinetics of VCH-222
in a Phase 1 double-blind, ascending dose trial. First, healthy HCV-uninfected
volunteers received single VCH-222 doses of 250, 500, 1000, and 1500 mg (500 mg
with food, the others fasting). VCH-222 was well tolerated at all doses tested,
with no serious AEs reported. Under fasting conditions, the rate and extent of
absorption appeared relatively proportional across the dose range and the half-life
was approximately 4 hours.
Next, 6 patients with HCV genotype 1 received
750 mg VCH-222 twice-daily for 3 days. Preliminary efficacy findings showed a
mean HCV RNA reduction of 3.2 log10 within 24 hours of dosing and 3.7 log10 on
"VCH-222 was safe and well tolerated up to 1,500 mg administered
as a single dose or at 750 mg bid for 3 days," the researchers concluded.
"In terms of exposure versus in vitro potency, excellent pharmacokinetic
properties were exhibited. In vivo, high HCV virological potency was demonstrated."
is an HCV NS3/NS4A protease inhibitor being developed by Tibotec in collaboration
with Medivir. Michael Manns and colleagues presented data from OPERA-1, an ongoing
double-blind, placebo-controlled Phase 2a trial to assess the antiviral activity,
safety, and pharmacokinetics of once-daily TMC435 in treatment-naive and treatment-experienced
genotype 1 patients.
Participants were randomly assigned to receive 7
days of monotherapy with TMC435 (25, 75, or 200 mg once-daily) or placebo, followed
by triple therapy with TMC435 or placebo plus pegylated interferon alfa-2a and
ribavirin for 21 or 28 days (patients thereafter continued on a standard course
of pegylated interferon/ribavirin).
Over 7 days of monotherapy, an antiviral
activity to dose relationship was observed. As part of triple therapy, the 75
mg and 200 mg TMC435 doses produced a similar antiviral effect. At week 4, HCV
RNA declined by 5.5 and 5.4 log10 IU/mL, respectively, in the 75 mg and 200 mg
triple-combination arms. 8 of 9 patients in the 75 mg group and 7 of 10 in the
200 mg group achieved undetectable viral load (< 10 IU/mL) at week 4; at week
12 (4 weeks on triple therapy followed by 8 on pegylated interferon/ribavirin),
6 of 9, 9 of 9 and 10 of 10 patients in the 25, 75, and 200 mg triple therapy
arms, respectively, still had HCV RNA < 10 IU/mL. No instances of viral breakthrough
were observed. TMC435 doses in combination with pegylated interferon/ribavirin
demonstrated antiviral activity superior to that of pegylated interferon/ribavirin
TMC435 was well tolerated at all doses. AST and ALT values improved
during therapy. There were no TMC435-related treatment discontinuations, serious
AEs, or clinically relevant detrimental changes in laboratory parameters, with
no evidence of hepatic, renal, cardiovascular, or hematopoietic toxicities.
a related report, Patrick Marcellin and colleagues presented results from previous
non-responders (n = 25) or relapsers (n = 12) in OPERA-1 who received once-daily
TMC435 (75, 150, 200 mg) or placebo plus pegylated interferon/ribavirin for 28
days, then continuing on pegylated interferon/ribavirin alone for up to 48 weeks.
The mean decreases in plasma HCV RNA at week 4 were 4.3, 5.5, and 5.3
log10 IU/mL, respectively, in patients receiving 75, 150 and 200 mg TMC435, versus
1.5 log10 IU/mL in the placebo group. At this time point, 44%, 78%, and 70% patients
in the 3 dose groups, respectively, achieved HCV RNA < 25 IU/mL, compared with
none in the placebo group; 22%, 56%, and 30%, respectively, had HCV RNA < 10
IU/mL. Only 3 instances of viral breakthrough were observed. Again, there were
no serious AEs or discontinuations due to AEs. ALT/AST levels decreased in all
TMC435 groups, but some patients -- mostly in the 200 mg group -- experienced
mild-to-moderate bilirubin increases.
also presented findings from a study of ANA598, a non-nucleoside HCV polymerase
inhibitor with potent in vitro antiviral activity being developed by Anadys Pharmaceuticals.
Study ANA598-502, a randomized, double-blind, placebo-controlled, multiple ascending
dose trial, was designed to evaluate the safety, tolerability, and antiviral activity
of oral ANA598 in treatment-naive genotype 1 chronic hepatitis C patients. A total
of 35 participants were treated with ANA598 at doses of 200, 400, or 800 mg twice-daily,
or matching placebo, for 3 days.
produced rapid and sustained declines in HCV RNA, with median reductions at the
end of dosing exceeding 2 log10 in all dose groups. In the 200, 400, and 800 mg
arms, respectively, the median viral load reductions were 2.4, 2.3, and 2.9 log10.
Genotype 1a patients had median HCV reductions of 1.4, 1.8, and 2.5 log10, respectively,
and viral load was still declining at the end of the 3 days of treatment. Genotype
1b patients had larger median reductions of 2.6, 2.5, and 3.2 log10, respectively.
No viral rebound was observed while on ANA598. The drug was well-tolerated in
this short study with no serious AEs.
Anadys also recently completed dosing
in a 14-day study of ANA598 in 30 healthy HCV negative volunteers. Participants
received ANA598 (400 mg once-daily, 800 mg once-daily, or 600 mg twice-daily)
or placebo on day 1, followed by pharmacokinetic assessment on days 2-3, then
subsequent drug doses on days 4-14.
According to a company press release,
preliminary results indicate that ANA598 was generally well tolerated in all cohorts,
with no serious adverse events. However, 3 participants receiving ANA598 (2 in
the 800 mg once-daily arm and 1 in the 600 mg twice-daily arm) developed a grade
2 rash and discontinued treatment after 6-7 days of consecutive dosing. The company
said there were no other instances of rash in this or any other study of ANA598.
Data collection and analysis is ongoing.
also presented data from a randomized, placebo-controlled, double-blind Phase
2a study of MK-7009,
a HCV NS3/4A protease inhibitor being developed by Merck. A total of 95 treatment-naive
genotype 1 chronic hepatitis C patients received MK-7009 (600 or 800 mg once-daily
or 300 or 600 mg twice-daily) or placebo for 4 weeks with pegylated interferon/ribavirin;
participants then continued on pegylated interferon/ribavirin for an additional
The proportion of patients who achieved rapid virological response
(< 10 IU/mL at week 4) ranged from 69% to 82% in the MK-7009 arms, compared
with 6% in the placebo arm. Viral suppression continued after the end of MK-7009
dosing. At day 42, 77% to 94% in the MK-7009 arms still had undetectable HCV viral
load, compared with 12% in the placebo arm.
MK-7009 in combination with
pegylated interferon/ribavirin was well tolerated, with no serious AEs and no
discontinuations due to AEs. The most commonly reported AEs were nausea, headache,
and flu-like symptoms; the incidence of nausea and vomiting was higher in the
MK-7009 arms compared with the placebo arm, but did not require anti-emetic treatment
and did not lead to dose reduction or discontinuation of therapy.
this first study of MK-7009 in combination with [pegylated interferon/ribavirin],
MK-7009 is a well-tolerated and potent inhibitor of HCV," the researchers
concluded. "The results support further development of MK-7009 for HCV treatment."
Phase 2b study is underway to evaluate the safety, tolerability, and efficacy
of MK-7009 in combination with pegylated interferon/ribavirin in approximately
200 previously treated genotype 1 patients, according to a Merck press release.
Participants will receive MK-7009 at doses of 300 or 600 mg twice-daily or placebo
in combination with standard therapy.
researcher team presented data on EA-058 and EA-063, novel non-ketoamide HCV protease
inhibitors being developed through a collaboration of Abbott Laboratories and
Based on laboratory findings, these agents appear
highly potent against both wild-type HCV and virus that has developed resistance
mutations; it also appears to be active across HCV genotypes. In a comparative
study, the new agents were more potent than ITMN-191/R7227, MK-7009, and TMC 435350
against HCV genotypes 2 and 3a.
EA-058 and EA-063 had favorable pharmacokinetic
properties, suggesting they could potentially be administered once daily. In studies
of rats and dogs, the drugs reached high levels in the liver relative to blood
plasma, which the investigators suggested could "minimize extra-hepatic adverse
effects in humans."
IDX375, IDX136 & IDX316
researchers from Idenix presented data from studies of 4 investigational agents.
The furthest along in development, IDX184,
is a liver-targeted nucleotide analog pro-drug that is processed to its nucleoside
form in the liver, thus minimizing systemic exposure.
In HCV genotype
1-infected chimpanzees, once-daily oral administration of 10 mg/kg IDX184 for
4 days produced substantial decreases in HCV RNA. Maximal viral load declines
in all chimps studied ranged from 1.4 to 3.8 log10 copies/mL. Viral load reductions
of >1 log10 were associated with nucleoside metabolite levels > 2
ng/mL. "Oral administration of 10 mg/kg of IDX184 to HCV-infected chimpanzees
resulted in potent antiviral activity that was achieved with low systemic levels
of the parent drug and its nucleoside metabolite," the researchers concluded.
first clinical study of IDX184 in humans evaluated the safety and pharmacokinetics
of single ascending oral doses of IDX184 (5, 10, 25, 50, 75, and 100 mg) administered
sequentially to cohorts of 8 healthy HCV negative volunteers. IDX184 was rapidly
absorbed, but plasma concentrations of the nucleoside metabolite increased gradually.
The drug was well tolerated and there were no serious AEs, premature discontinuations,
or dose-limiting toxicities.
"IDX184 appeared to be safe and well
tolerated in this study," the investigators concluded. "Consistent with
a liver-targeting approach, systemic exposure of parent drug and metabolite was
low. The favorable safety and pharmacokinetic profiles warrant further clinical
development of IDX184 in HCV-infected patients."
is a potent and selective non-nucleoside HCV polymerase inhibitor. In a preclinical
study in mice, rats, and cynomolgus monkeys, IDX375 selectively concentrated in
the liver of all 3 species. After oral administration, high systemic exposures
were observed in rodents receiving doses up to 250 mg/kg and in monkeys receiving
up to 100 mg/kg.
No adverse effects were observed in monkeys given 10
or 100 mg/kg oral doses for 7 days. Furthermore, IDX375 showed no significant
inhibition of 5 major human cytochrome P450 enzymes, suggesting it may not interact
significantly with other drugs. Based on these findings, the researchers concluded,
"IDX375 is a promising clinical candidate based on its favorable safety profile
and preclinical pharmacokinetics that suggest once- or twice-daily dosing in humans."
and IDX316, 2 specific macrocyclic HCV protease inhibitor candidates, are
furthest back in the Idenix development pipeline. The antiviral activity and specificity
of these agents were evaluated using a variety of HCV replicon assays.
and IDX316 were found to be potent and selective inhibitors of protease enzymes
of HCV genotypes 1a, 1b, and 4, but with no activity against human cellular proteases.
Treatment of replicon cells for 14 days with each agent reduced HCV RNA by nearly
3 log10. IDX316 remained active against HCV with common NS3 mutations and exhibited
enhanced activity when combined with standard-of-care agents (pegylated interferon/ribavirin)
and IDX184 or IDX375.
In mice, rats, and monkeys given single oral doses
of 10 or 15 mg/kg IDX316, the "parent" drug selectively concentrated
in the liver, and plasma concentrations remained high after 24 hours. No AEs were
observed in rhesus macaque monkeys given 10 or 100 mg/kg oral doses of either
IDX136 or IDX316 for 7 days. Here too, neither drug significantly inhibited 5
major human cytochrome P450 enzymes.
Based on the favorable preclinical
safety profile and pharmacokinetics that suggest once- or twice-daily dosing,
the researchers said that IDX136 and IDX316 are currently undergoing further pharmacology
and toxicology studies to support initiating human studies.
Forestier, D Larrey, P Marcellin, S Zeuzem, and others. Antiviral Activity and
Safety of ITMN-191 in Combination with Peginterferon Alfa-2a and Ribavirin in
Patients with Chronic Hepatitis C Virus (HCV). 44th Annual Meeting of the European
Association for the Study of the Liver (EASL 2009). Copenhagen, Denmark. April
22-26, 2009. Abstract 85.
E Lawitz, C Cooper, M Rodriguez-Torres, and
others. Safety, Tolerability and Antiviral Activity of VCH-916, a Novel Non-Nucleoside
HCV Polymerase Inhibitor in Patients with Chronic HCV Genotype-1 Infection. EASL
2009. April 22-26, 2009. Abstract 92.
C Cooper, R. Larouche, B Bourgault,
and others. Safety, Tolerability and Pharmacokinetics of the HCV Polymerase Inhibitor
VCH-222 Following Single Dose Administration in Healthy Volunteers and Antiviral
Activity in HCV-Infected Individuals. EASL 2009. April 22-26, 2009.
H Reesink, C Moreno, and others. Opera-1
Trial: Interim Analysis of Safety and Antiviral Activity of TMC435 in Treatment-Naive
Genotype 1 HCV Patients. EASL 2009. April 22-26, 2009.
H Reesink, T Berg, and others. Antiviral
Activity and Safety of TMC435 Combined with Peginterferon Alpha-2a and Ribavirin
in Patients with Genotype 1 Hepatitis C Infection Who Failed Previous IFN-Based
Therapy. EASL 2009. April 22-26, 2009.
E Lawitz, M Rodriguez-Torres,
M DeMicco, and others. Antiviral Activity of ANA598, a Potent Non-nucleoside Polymerase
Inhibitor, in Chronic Hepatitis C Patients. EASL 2009. April 22-26, 2009.
Thompson, R Patel, K Steffy, and others. Preclinical Studies of ANA598 Combined
with Other Anti-HCV Agents Demonstrate Potential of Combination Treatment. EASL
2009. April 22-26, 2009.
M Manns, E Gane, M Rodriguez-Torres, and others.
Significantly Improves Rapid Viral Response (RVR) in Combination with Pegylated
Interferon Alfa-2a and Ribavirin in Patients with Chronic Hepatitis C (CHC) Genotype
1 Infection. EASL 2009. April 22-26, 2009. Abstract 2701.
Y Gai, T Middleton, and others. Potent HCV Protease Inhibitors with the Potential
for Once-Daily Dosing and Broad Genotype Coverage. EASL 2009. April 22-26, 2009.
Standring, R Lanford, B Li, and others. Antiviral
Activity of the Liver-Targeted Nucleotide HCV Polymerase Inhibitor IDX184 Correlates
with Trough Serum Levels of the Nucleoside Metabolite in HCV-Infected Chimpanzees.
EASL 2009. April 22-26, 2009.
X-J Zhou, K Pietropaolo, J Sullivan-Bolyai,
and others. IDX184,
a Liver-Targeted Nucleotide HCV Polymerase Inhibitor: Results of a First-in-Man
Safety and Pharmacokinetic Study. EASL 2009. April 22-26, 2009.
Good, C Bu, M Camire, and others. Preclinical
Pharmacokinetic and Safety Profile of IDX375, a Novel and Potent Non-nucleoside
HCV Polymerase Inhibitor. EASL 2009. April 22-26, 2009.
JP Bilello, MA Soubasakos, and others. Preclinical
Profiles of IDX136 and IDX316, Two Novel Macrocyclic HCV Protease Inhibitors.
EASL 2009. April 22-26, 2009.
Reports Presentation Of Triple Combination Study of ITMN-191 at European Association
for the Study of the Liver (EASL). Press release. April 24, 2009.
Pharmaceuticals. Vertex Pharmaceuticals Announces Acceptance of Telaprevir and
VCH-222 Abstracts for Presentation at EASL Annual Meeting. Press release.
March 18, 2009.
Medivir. New Phase IIa Data on TMC435 in Patients with
Hepatitis C Presented at the Ongoing EASL Meeting. Press release. April
Anadys Pharmaceuticals. ANA598 Demonstrates Potent Antiviral
Activity at All Dose Levels in Completed Phase Ib Study in Hepatitis C Patients.
Press release. April 24, 2009.
Merck & Co. Merck Announces Interim
Phase IIa Study Results of MK-7009, an Investigational Oral Hepatitis C Virus
Protease Inhibitor, in Patients with Chronic Hepatitis C. Press release.
April 23, 2009.
Idenix Pharmaceuticals. Idenix Pharmaceuticals Reports
Data from Three Hepatitis C Development Programs. Press release. April
2009 MAIN PAGE
Conference on Retroviruses and Opportunistic Infections (CROI 2009)
by HIV and Hepatitis.com - February 8 - 11, 2009, Montreal
HIV and AIDS Treatment
News, Experimental News, FDA-approved News
of the 15th Conference on Retroviruses and Opportunistic Infections (CROI 2009)
- Coverage by HIV and Hepatitis.com, February 8 - 11, 2009, Montreal