273 Short Term Safety, Tolerability, Pharmacokinetics and Preliminary Activity of Gs-9450, a Selective Caspase Inhibitor, in Patients With Chronic HCV Infection

Manns, MP; Lawitz, Eric; Hoepelman, A. I. M.; Choi, Hong-Jo; Lee, J.Y.; Cornpropst, Melanie; Liang, W.; King, Bernard D.; Hirsch, Kenneth; Oldach, David; Rousseau, Franck

doi:10.1016/s0168-8278(10)60275-9

Cited by 9 publications

(4 citation statements)

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“…Nevertheless, there are several instances in which, regardless of whether caspases have been definitively implicated in the etiology or pathological consequences of a disease, caspase inhibition has ameliorated the symptoms of several conditions caused by inappropriate apoptotic cell death. For example, because chronic hepatitis virus C infection is accompanied by detrimental hepatocyte apoptosis, a recent clinical trial examined the therapeutic potential of a caspase inhibitor (Manns 2010). Similarly, the severity of ischemia reperfusion injury resulting from cell death that often follows a stroke (Renolleau et al 2007), traumatic brain injury (Knoblach et al 2004), or organ transplant (Baskin-Bey et al 2007) can be reduced by caspase inhibition.…”

Section: Inhibiting Caspases To Prevent Cell Deathmentioning

confidence: 99%

Caspase Functions in Cell Death and Disease

McIlwain

Berger

Mak

2013

Cold Spring Harbor Perspectives in Biology

1,876

1,358

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Caspases are a family of endoproteases that provide critical links in cell regulatory networks controlling inflammation and cell death. The activation of these enzymes is tightly controlled by their production as inactive zymogens that gain catalytic activity following signaling events promoting their aggregation into dimers or macromolecular complexes. Activation of apoptotic caspases results in inactivation or activation of substrates, and the generation of a cascade of signaling events permitting the controlled demolition of cellular components. Activation of inflammatory caspases results in the production of active proinflammatory cytokines and the promotion of innate immune responses to various internal and external insults. Dysregulation of caspases underlies human diseases including cancer and inflammatory disorders, and major efforts to design better therapies for these diseases seek to understand how these enzymes work and how they can be controlled.

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Section: Inhibiting Caspases To Prevent Cell Deathmentioning

confidence: 99%

Caspase Functions in Cell Death and Disease

McIlwain

Berger

Mak

2013

Cold Spring Harbor Perspectives in Biology

1,876

1,358

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“…Caspase‐8 is a key initiating caspase essential for apoptosis induced by all three death receptors (Fas, TNF‐R1, and TRAIL receptors 1 and 2) 10. Short‐term treatment with GS‐9450 can cause reductions in alanine aminotransferase (ALT) levels in patients with chronic hepatitis C virus (HCV) infection,11 which is also accompanied by increased hepatocyte apoptosis. Given the potential for GS‐9450 in treating apoptosis‐mediated liver injury, we sought to evaluate the safety and activity of GS‐9450 in a proof‐of‐concept, 4‐week pilot trial in subjects with NASH.…”

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confidence: 99%

A phase 2, randomized, double-blind, placebo-controlled study of GS-9450 in subjects with nonalcoholic steatohepatitis

et al. 2011

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In nonalcoholic steatohepatitis (NASH), the extent of hepatocyte apoptosis correlates with disease severity. Reducing hepatocyte apoptosis with the selective caspase inhibitor GS-9450 has a potential for altering the course of the liver disease. In this phase 2, double-blind study, 124 subjects with biopsy-proven NASH were randomized to once-daily placebo or 1, 5, 10, or 40 mg GS-9450 for 4 weeks. Absolute and percent changes from baseline in ALT levels, AST levels, and caspase-3–cleaved cytokeratin (CK)-18 fragments at week 4 were assessed by an analysis of covariance model with adjustment for baseline values. In the 40-mg group, mean (SD) ALT decreased by 47 (43) U/L from baseline to week 4 (P < 0.0001 versus placebo), and the proportion of subjects with normal ALT increased from 0% to 35% at week 4. In the 40-mg group, mean AST decreased by 13 U/L from baseline (not significant), and the proportion with normal AST increased from 20% at baseline to 48% at week 4. By week 4, mean CK-18 fragment levels had decreased to 393 (723) U/L in the GS-9450 10-mg group and 125 (212) U/L in the 40-mg group, but these reductions were not statistically significant. No serious adverse events were reported during treatment, and the percentage of subjects with at least one treatment-emergent grade 3 or 4 laboratory abnormality ranged from 11.5% to 17% across the GS-9450 treatment groups versus 35% in the placebo group. Conclusion GS-9450 treatment induced significant reductions in ALT levels in NASH patients. Reductions in CK-18 fragment levels also occurred, although they were not statistically significant. At appropriate therapeutic indices, selective caspase inhibitors may be a promising treatment option in patients with NASH.

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“…In a phase Ⅰ clinical trial, GS-9450 was well-tolerated when administered to healthy individuals [23] . In a doubleblind, placebo-controlled phase Ⅱa trial in patients with chronic hepatitis C, a disease also characterized by increased hepatocellular apoptosis, GS-9450 reduced serum ALT levels [24] . Moreover, in a substudy of the latter trial, GS-9450 induced a moderate reduction in caspase-8 expression and a strong reduction in caspase-3 expression in peripheral T-lymphocytes [25] .…”

Section: Commentary On Hot Topicsmentioning

confidence: 99%

“…However, most information about the safety of caspaseinhibitors is from experimental models and therefore it is difficult to reach definite conclusions about their safety in humans [21] . The existing clinical studies are small and short in duration [22,24,[28][29][30] ; accordingly, larger and longterm studies are required to evaluate the carcinogenic potential, if any, of caspase inhibitors.…”

Section: Commentary On Hot Topicsmentioning

confidence: 99%

Inhibition of apoptosis in the management of nonalcoholic fatty liver disease

Bouziana

Τζιόμαλος²

2013

WJGPT

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Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in the developed world. The pathogenesis of NAFLD is multifactorial, involving obesity, insulin resistance, inflammation and oxidative stress. Accordingly, several treatments targeting these pathways have been evaluated in patients with NAFLD but have either shown limited efficacy or an unfavorable safety profile. On the other hand, increased hepatocyte apoptosis also appears to be implicated in the development and progression of NAFLD and recent pilot studies suggest that inhibition of apoptosis might represent a useful approach in this disease. However, several issues pertaining both to the efficacy and safety of this new class of agents remain unresolved and larger studies are required to clarify the role of this therapeutic modality in the management of NAFLD.

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273 Short Term Safety, Tolerability, Pharmacokinetics and Preliminary Activity of Gs-9450, a Selective Caspase Inhibitor, in Patients With Chronic HCV Infection

Cited by 9 publications

References 0 publications

Caspase Functions in Cell Death and Disease

Caspase Functions in Cell Death and Disease

A phase 2, randomized, double-blind, placebo-controlled study of GS-9450 in subjects with nonalcoholic steatohepatitis

Inhibition of apoptosis in the management of nonalcoholic fatty liver disease

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