 Cyclophilin
Inhibitor Debio-025 Demonstrates Potent Anti-HCV Activity in HIV-HCV Coinfected
Patients
By
Liz Highleyman
At
the 2006 annual meeting of the American Association for the Study of Liver Diseases
(AASLD), a Polish-Swiss research team reported that the cyclophilin inhibitor
Debio-025 demonstrated activity against both hepatitis
C virus (HCV) and HIV in vitro and
in pre-clinical studies of coinfected
individuals. Now,
in the March 2008 issue of Hepatology, the same researchers report data
from a randomized, double-blind, placebo-controlled trial of Debio-025.
Cyclophilins
are intracellular binding proteins involved in several cellular processes such
as immune response, protein secretion, and mitochondrial function. As background,
the study authors noted that prior research has shown that cyclophilin B (CypB)
is a functional regulator of HCV's NS5B RNA-dependent RNA polymerase, which is
required for viral replication.
The present study included 23 HIV-infected
participants (19 HIV-HCV coinfected, 4 with HIV alone). All were Caucasian and
most (18) were men. All had detectable HIV RNA > 5000 copies/mL and a CD4 cell
count > 250 cells/mm3. Coinfected individuals had detectable HCV RNA > 2000
copies/mL. Subjects were HBV negative and none had decompensated liver disease.
Participants were randomly assigned to receive 1200 mg Debio-025 (n =
19) or placebo (n = 4) administered orally twice-daily for 14 days, followed by
a 4-week washout period. The trial was designed as a proof-of-concept study with
a single regimen close to the anticipated maximum tolerated dose.
 Results
•
Among the 16 coinfected patients, mean HCV viral load decreased significantly
more after 14 days in the Debio-025 arm compared with the placebo arm (3.6 vs
0.73 log10; P < 0.0001).
•
All but one of the coinfected subjects (94%) experienced at least a 2 log10 drop
in HCV RNA.
•
Debio-025 was active against all 3 HCV genotypes represented in the study (1,
3, and 4).
•
However, response was greater in patients with genotype 3 (mean HCV RNA reduction
of 4.64 log10) than in those with genotypes 1 or 4 (mean reduction 3.19 log10).
•
3 patients (1 with each genotype) achieved undetectable HCV viral load by day
15.
•
HCV viral breakthrough was not observed during treatment, suggesting that Debio-025
has a relatively high barrier to resistance.
•
HIV viral load also decreased from baseline in patients taking Debio-025, although
the decline was not significantly greater compared with the placebo arm (mean
decrease 1.03 vs 0.56, respectively).
•
The overall incidence of adverse events (AEs) was similar in the Debio-025 and
placebo groups, at about 75% each.
•
The most common AEs in the Debio-025 arm were jaundice, abdominal pain, vomiting,
fatigue, and fever.
•
Fifteen patients (79%) in the Debio-025 arm experienced elevated total bilirubin
levels, half of whom developed jaundice, and 4 of whom discontinued treatment
for this reason.
•
No patients developed elevated ALT, AST, GGT, or alkaline phosphatase.
•
There were no laboratory signs of increased hemolysis (red blood cell destruction),
but 2 patients developed decreased platelet counts.
•
All AEs were mild-to-moderate and generally resolved after stopping the study
drug.
•
In patients treated with Debio-025, Cyp-B levels in peripheral blood mononuclear
cells decreased from 67 ng/mg protein at baseline to 5 ng/mg at day 15 (P <
0.01).
•
The single patient with a < 1 log10 decrease in HCV RNA did experience a reduction
in Cyp-B.
Conclusion
"Debio-025
induced a strong drop in Cyp-B levels, coinciding with the decrease in hepatitis
C viral load," the investigators concluded.
They added that, "These
are the first preliminary human data supporting the hypothesis that Cyp-B may
play an important role in hepatitis C virus replication and that Cyp inhibition
is a valid target for the development of anti-hepatitis C drugs."
Given
the high rate of elevated bilirubin seen in this trial, the authors suggested
that the 1200 mg twice-daily dose was "probably too high," and that
"future studies will have to establish significant anti-HCV effects at lower
doses without induction of clinically relevant hyperbilirubinemia."
Medical
University of Bialystok, Poland; Hospital of Infectious Diseases, Warsaw, Poland;
Children's Memorial Health Institute, Warsaw, Poland; Scripps Research Institute,
La Jolla, CA; Novartis Consumer Health SA, Nyon, Switzerland; Debiopharm SA, Lausanne,
Switzerland.
3/14/08
Reference
R Flisiak, A Horban,
P Gallay, and others. The cyclophilin inhibitor Debio-025 shows potent anti-hepatitis
C effect in patients coinfected with hepatitis C and human immunodeficiency virus.
Hepatology 47(3): 817-826. March 2008. |
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