Pancaspase Inhibitor PF-03491390 Reduces ALT and AST Levels in Chronic Hepatitis

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Pancaspase Inhibitor PF-03491390 Reduces ALT and AST Levels in Chronic

Hepatitis C Patients

By Liz Highleyman

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 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.

http://www.hivandhepatitis.com/2006icr/aasld/docs/111006_e.html

_________________________________________________________________

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[Guest guest]

Pancaspase Inhibitor PF-03491390 Reduces ALT and AST Levels in Chronic

Hepatitis C Patients

By Liz Highleyman

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 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.

http://www.hivandhepatitis.com/2006icr/aasld/docs/111006_e.html

_________________________________________________________________

Stay in touch with old friends and meet new ones with Windows Live Spaces

http://clk.atdmt.com/MSN/go/msnnkwsp0070000001msn/direct/01/?href=http://spaces.\

live.com/spacesapi.aspx?wx_action=create & wx_url=/friends.aspx & mkt=en-us