Elevated
levels of the liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase
(AST) are markers of inflammation associated with liver damage. People with chronic
viral hepatitis often have increased hepatocyte apoptosis (programmed death of
liver cells) and elevated activation of caspases, enzymes that play a role in
inflammation and apoptosis.
Inhibition
of caspase activity may help reduce liver damage as reflected in lower ALT and
AST levels, according to a study presented at the 57th Annual Meeting of the American
Association for the Study of Liver Diseases (AASLD) last month in Boston.
Researchers
conducted a placebo-controlled, double-blind, parallel-group, dose-ranging study
to examine the efficacy and safety of the pancaspase inhibitor PF-03491390 in
reducing ALT and AST levels in patients with chronic hepatitis C virus (HCV) infection.
The
study included 204 participants with documented chronic hepatitis C and liver
fibrosis who did not achieve a virological response, relapsed, or were not able
to tolerate standard interferon-based therapy. All subjects had liver enzyme levels
at least 1.5 times the upper limit of normal.
Patients
were randomly assigned to receive either placebo or PF-03491390 at doses of 5,
25, or 50 mg orally twice daily (BID) for 12 weeks. If ALT and AST were still
elevated at Week 10, the PF-03491390 dose was doubled through Week 12.
Results
Median absolute ALT and AST values decreased from baseline to Week 10 in all treatment
groups, as shown in the table below.
AST declined by 28%-36% from baseline in the 3 PF-03491390 arms, while ALT declined
by 37%-48%.
Highly significant reductions in serum AST and ALT were observed for each PF-03491390
dose compared with placebo (P < 0.0001).
There were no significant differences in AST and ALT reduction between the dose
groups.
Reductions in ALT and AST were observed starting at Week 1 and were maintained
throughout the study.
By Week 10, ALT levels normalized in 15% of patients receiving the 5 mg dose,
35% in the 25 mg arm, and 19% in the 50 mg arm, compared with 3% in the placebo
group.
A few more patients experienced ALT normalization after the PF-03491390 dose was
doubled at Week 10 (although mean liver enzymes reductions did not change).
Liver enzymes returned to baseline levels after PF-03491390 was discontinued.
No changes
in HCV viral load were observed in any of the treatment groups (PF-03491390 is
not an antiviral agent). Most adverse events were of mild or moderate severity,
and occurred at similar rates in the PF-03491390 and placebo arms.
The most frequently reported treatment-emergent adverse events were headache (24
patients) and fatigue (22 patients).
Placebo
PF-03491390
5
mg BID
PF-03491390
25
mg BID
PF-03491390
50
mg BID
Number of patients
51
55
50
48
Mean baseline AST, IU/L
60
69
58
73
Mean AST reduction from baseline at Week 10, IU/L
-2
-17*
-23*
-25*
Mean baseline ALT, IU/L
101
103
98
115
Mean ALT reduction from Baseline at Week 10, IU/L
-2
-34*
-41*
-49*
*P < 0.0001 versus placebo
Conclusion
"PF-03491390
was well tolerated and effectively reduced ALT and AST in patients with chronic
HCV hepatitis during a 12-week treatment period," the researchers concluded.
"Further randomized trials are necessary to determine whether PF-03491390
may influence liver histology in patients with liver fibrosis."
Lead
investigator Mitchell Shiffman, MD, of Virginia Commonwealth University suggested
that PF-03491390 might also reduce liver inflammation associated with other conditions
such as chronic hepatitis B or non-alcoholic fatty liver disease, but noted that
there is a theoretical concern that inhibiting apoptosis could impair the immune
system's response to cancerous cells. Virginia Commonwealth University
Medical Center, Richmond, VA; University of Miami, Miami, FL; Scripps Clinic,
La Jolla, CA; Pfizer Ltd, Sandwich, U.K.; Duke University, Durham, NC.
11/10/06
Reference M
L Shiffman, E Schiff, P Pockros, and others. PF-03491390 (formerly IDN-6556),
a Pancaspase Inhibitor, is Well-Tolerated and Effectively Reduces Raised Aminotransferases
(ALT and AST) in Chronic Active Hepatitis C (HCV) Patients. 57th AASLD. Boston,
MA. October 27-31, 2006. Abstract 95.
Median absolute ALT and AST values decreased from baseline to Week 10 in all treatment
groups, as shown in the table below.
