Preclinical
Study Shows ITMN-191 Plus Pegasys is Active against HCV In Vitro
ITMN-191
is potent oral HCV NS3/4A protease inhibitor being developed by InterMune. As
presented at the 57th Annual Meeting of the American Association for the Study
of Liver Diseases (AASLD) last month in Boston, researchers conducted a study
to evaluate the in vitro antiviral activity of ITMN-191 in combination
with pegylated interferon alfa-2a (Pegasys).
The
study employed 2 replicon systems (laboratory models of replicating HCV) to study
drug interactions: the HCV genotype-1b replicon K2040, and a derivative of K2040
(R191M320) with reduced sensitivity to ITMN-191.
Results
The combination
of ITMN-191 plus Pegasys synergistically inhibited HCV replication in Huh7 cells
(a liver tumor cell line).
Analysis of fixed-dose ratios by the Loewe additivity model showed that combining
the 2 drugs yielded combination index values indicative of synergy at EC50, EC75,
and EC90 (0.3, 0.4 and 0.4, respectively).
Drug reduction index values were > 1, suggesting a potential clinical benefit
when ITMN-191 is administered in combination with Pegasys.
Analysis of variable-ratio drug combinations by the Bliss independence model indicated
that the synergy volumes observed in ITMN-191 combinations were significant (>
50 uM2).
Peak synergy volumes occurred at low concentrations, all of which may be therapeutically
relevant.
The extent of synergy observed by either method is quantitatively larger than
that observed for the experimental HCV protease inhibitors VX-950 and SCH 503034.
The
human minimum plasma concentration (Cmin) of Pegasys greatly improved ITMN-191
potency in a replicon model fully sensitive to ITMN-191 and in a replicon with
reduced sensitivity to ITMN-191.
The replicon with reduced sensitivity to ITMN-191 was hypersensitive to Pegasys
relative to the parental replicon (> 10-fold).
Conclusion
In
conclusion, the researchers wrote, "these data suggest synergistic antiviral
activity of the combination of ITMN-191 and [Pegasys] in vitro. Future clinical
study is warranted to address whether the combination will yield a greater virologic
response in HCV patients than either ITMN-191 or [Pegasys] alone.
"We
anticipate that future therapeutic approaches to the treatment of chronic hepatitis
C will involve multiple agents, likely in combination with interferon, and we
are hopeful that these combinations will lead to improved, sustained virologic
responses for patients who are in need of more optimal therapies," said InterMune
Chief Scientific Officer Lawrence M. Blatt, PhD. InterMune, Inc., Brisbane,
CA.
11/10/06
References
H
Tan, S D Seiwert, L M Blatt, and others. In Vitro Synergistic Antiviral Activity
of ITMN-191, an Orally Active Inhibitor of the Hepatitis C Virus (HCV) NS3/4A
Protease, in Combination with PEG-Interferon Alfa-2a. 57th AASLD. Boston, MA.
October 27-31, 2006. Abstract 933.
InterMune, Inc. InterMune Presents at
Two Liver Disease Conferences Research on ITMN-191 in Hepatitis C. Press release.
October 30, 2006.
The combination
of ITMN-191 plus Pegasys synergistically inhibited HCV replication in Huh7 cells
(a liver tumor cell line). 
