By
Liz Highleyman
Idenix
Pharmaceuticals is developing a set of directly targeted anti-HCV
agents that work by different mechanisms, and therefore have
the potential to be used together in all-oral combination regimens.
Combining drugs that target different steps of the viral lifecycle
may improve efficacy and reduce drug resistance.
IDX184
Jay Lalezari from Quest Clinical Research in San Francisco and
colleagues evaluated the safety, tolerability, antiviral activity,
and pharmacokinetics of IDX184, a liver-targeted nucleotide
analog prodrug that prevents the HCV polymerase from copying
viral genetic material.
In this double-blind Phase 2a ascending dose trial, sequential
groups of 20 previously untreated patients with genotype
1 chronic hepatitis C were (or will be) randomly assigned
(16:4) to receive IDX184 at doses of 50, 100, 150, or 200 mg
once or twice daily, or else placebo, for 14 days. All participants
also received standard therapy consisting of 180 mcg/week pegylated
interferon alfa-2a (Pegasys) plus 1000-1200 mg/day weight-adjusted
ribavirin during the IDX184 dosing period and for 14 additional
days thereafter.
Investigators reported interim results from the 50 mg and 100
mg cohorts at EASL; the study is continuing with the 150 mg
cohort and those data are expected later this year.
Results
 |
After
14 days, HCV viral load decreased more in the IDX184 arms
than in the placebo plus standard therapy arm: |
| |
 |
50
mg once-daily IDX184: -2.7 log IU/mL; |
|
50
mg twice-daily IDX184: -4.0 log IU/mL; |
|
100
mg once-daily IDX184: -4.2 log IU/mL; |
|
Placebo:
-1.2 log IU/mL; |
|
|
At
the end of dosing, 13% of participants in the 50 mg once-daily
IDX184 arm and 50% in both the 50 mg twice-daily and 100
mg once-daily groups achieved undetectable HCV viral load
(< 15 IU/mL), compared with none in the placebo arm. |
|
No
viral breakthrough (> 1 log above the nadir or lowest-ever
level) was observed during IDX184 dosing. |
|
HCV
viral load rebounded in most patients after the last day
of IDX184 dosing, even though they remained on pegylated
interferon/ribavirin. |
|
Mean
ALT and AST levels -- an indicator of liver inflammation
-- decreased markedly in patients receiving IDX184 at all
dose levels, but not in those receiving placebo plus standard
therapy. |
|
No
participants discontinued treatment early. |
|
No
treatment-emergent serious adverse events were reported
during the 14-day IDX184 dosing period. |
|
In
general, adverse events and laboratory profiles were consistent
with those of pegylated interferon/ribavirin, and similar
in the IDX184 and placebo arms. |
|
The
most common adverse events were fatigue, myalgia (muscle
aches), headache, and nausea. |
|
The
most common laboratory abnormality was neutropenia (low
white blood cell count, a known side effect of interferon). |
|
The
most common laboratory abnormality was neutropenia (low
white blood cell count, a known side effect of interferon). |
|
There
were no significant differences in efficacy or safety between
the IDX184 100 mg once-daily and 50 mg twice-daily doses. |
Based
on these findings, the researchers concluded, IDX184 "delivers
significant antiviral activity with low systemic exposures."
In addition, IDX184 was "generally safe and well tolerated,"
leading an external safety review committee to recommend that
the study should proceed to evaluate the 150 mg dose.
IDX320
Idenix researchers presented 2 posters on IDX320, an non-covalent
NS3/4A HCV protease inhibitor further back in the development
pipeline.
L.B. Lallos and colleagues reported that IDX320 interfered with
HCV protease activity in laboratory studies using purified proteases,
an HCV replicon model, and an infectious HCV virus in cell cultures.
IDX320 was found to bind tightly to the HCV NS3/4A protease,
with a dissociation half-life of more than 9 hours. The drug
inhibited the protease enzyme of HCV genotypes 1a, 1b, 2a, and
4a, as well as 3a at a higher concentration. In contrast, it
did not interfere with 9 human cellular proteases.
In cell assays, IDX320 inhibited genotype 1a and 1b replicons
and the genotype 2a JFH-1 HCV strain. Treatment of replicon
cells for 14 days produced a maximum reduction of 3.7 logs.
The NS3 mutation D168V was the signature resistance mutation
for IDX320, but HCV with this mutations remained fully susceptible
to interferon/ribavirin and different classes of direct-acting
antiviral agents. The investigators concluded that, "IDX320
is a potent inhibitor of HCV NS3/4A protease and HCV replication
in cell culture with broad genotypic coverage."
In the second poster, S.S. Good and colleagues reported preclinical
pharmacokinetic and safety data from laboratory and animal studies.
IDX320 had good bioavailability, with a mean plasma half-life
of 6 hours in mice and 10 hours in monkeys after a 2 mg/kg IV
dose. The drug was highly protein bound. Of the 8 human CYP450
enzymes that process drugs in the liver, only 3A4 metabolized
IDX320, and the drug in turn did not significantly inhibit 5
of these enzymes.
IDX320 produced "negligible cytotoxicity" in laboratory
cell cultures, and no adverse effects were observed in either
mice or monkeys, including blood chemistry or organ abnormalities.
The researchers concluded that, "IDX320 is a promising
clinical candidate based on its favorable preclinical safety
profile, with pharmacokinetics that suggest potential once-daily
dosing in humans."
In the first clinical studied in healthy HCV negative volunteers,
IDX320 continued to demonstrate a favorable pharmacokinetic
profile. According to a press release issued by Idenix, the
Phase 1 single and multiple ascending dose clinical study in
healthy volunteers is now complete, and a 3-day proof-of-concept
study in people with HCV is expected to begin in the second
quarter of 2010.
Combination
Therapy
Finally, M. La Colla and colleagues evaluated various 2- and
3-drug regimens containing IDX184, IDX320, the non-nucleoside
NS5B HCV polymerase inhibitor IDX375, and a prototype HCV NS5A
inhibitor (IDX-NS5A). This laboratory study exposed genotype
1b HCV replicons to the drugs alone or in combination.
During 3 days of exposure, treatment with IDX320 + IDX375 demonstrated
additive activity (the level expected if adding the effects
of each drug used alone), while IDX320 + IDX-NS4A produced additive
to synergistic activity (greater than the expected additive
effect). Triple combinations of IDX184 + IDX320 + either IDX375
or IDX-NS4A produced clear synergistic activity.
Over 14 days, exposure to IDX184, IDX320, or IDX375 individually
produced viral load reductions of approximately 0.5 to 1.5 logs.
Treatment with any 2-drug combination demonstrated additive
activity, with reductions of about 2 logs. But combining all
3 drugs produced enhanced activity, with a viral load decrease
of nearly 4 logs. No cytotoxic effects were observed during
this period.
"This effect, coupled with the different resistance profiles
of the 3 agents, suggests the potential value of triple combination
regimens in future HCV clinical studies," the investigators
concluded.
"The in vitro combination data presented today continue
to support our belief that the future of HCV treatment will
be a combination of direct-acting antivirals from different
drug classes," said Idenix CEO Jean-Pierre Sommadossiin
a company press release. "We are pursuing a drug development
strategy to achieve that goal."
Researcher affiliations:
Lalezari study: Researcher affiliations: Quest Clinical Research,
San Francisco, CA; Cedars-Sinai Medical Center, Los Angeles,
CA; StudySite, Tuan Trong Nguyen, MD, San Diego, CA; Orlando
Immunology Center, Orlando, FL; University Hepatitis Center
at Bach & Godofsky, M.D., P.A., Sarasota, FL; Idenix Pharmaceuticals,
Inc., Cambridge, MA.
Lallos study: Idenix Pharmaceuticals, Inc., Cambridge, MA; Idenix
Pharmaceuticals, Inc., Cagliari, Italy; Idenix Pharmaceuticals,
Inc., Montpellier, France.
Good study: Idenix Pharmaceuticals, Inc., Cambridge, MA; Idenix
Pharmaceuticals, Inc., Montpellier, France.
La Colla study: Idenix Pharmaceuticals, Inc., Cambridge, MA.
5/4/10
References
J
Lalezari, F Poordad, P Mehra, and others (IDX-08C-004 Investigator
Group). Antiviral activity, pharmacokinetics and safety of IDX184
in combination with pegylated interferon (pegIFN) and ribavirin
(RBV) in treatment-naive HCV genotype 1-infected subjects. 45th
Annual Meeting of the European Association for the Study of
the Liver (EASL 2010). Vienna, Austria. April 14-18, 2010. (Abstract).
LB
Lallos, J Mccarville, B Li, and others. In vitro antiviral
activity of IDX320, a novel and potent macrocyclic HCV protease
inhibitor. 45th Annual Meeting of the European Association for
the Study of the Liver (EASL 2010). Vienna, Austria. April 14-18,
2010. (Abstract).
S.S.
Good, X-R Pan-Zhou, M Larsson, and others. Preclinical pharmacokinetic
profile of IDX320, a novel and potent HCV protease inhibitor.
45th Annual Meeting of the European Association for the Study
of the Liver (EASL 2010). Vienna, Austria. April 14-18, 2010.
(Abstract).
La Colla, LB Lallos, I Serra, and others. A triple combination
of direct-acting antiviral agents demonstrates robust anti-HCV
activity in vitro. 45th Annual Meeting of the European
Association for the Study of the Liver (EASL 2010). Vienna,
Austria. April 14-18, 2010. (Abstract).
Other sources
Idenix. Idenix Pharmaceuticals Reports Positive Results With
IDX184 From Interim Analysis of Phase IIa Hepatitis C Study.
Press release. April 15, 2010.
Idenix. Idenix Pharmaceuticals Reports Favorable Pharmacokinetic
Data for IDX320, a Potent, Multi-Genotypic Protease Inhibitor
for the Treatment of Hepatitis C. Press release. April 16, 2010.
