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AASLD 2012: Avatrombopag Reduces Bleeding Risk for Liver Disease Patients Undergoing Surgery

The experimental thrombopoietin receptor agonist avatrombopag (E5501) effectively increased platelet counts in patients with chronic liver disease enough to enable them to safely undergo scheduled surgeries, according to data presented at the American Association for the Study of Liver Diseases Liver Meeting (AASLD 2012) this month in Boston.

People with advanced liver disease often develop thrombocytopenia, or low platelet levels. These cell fragments play a critical role in blood clotting, and platelet deficiency can lead to easy bruising and excessive bleeding. Thrombocytopenia can limit eligibility for invasive medical procedures, which may require platelet transfusions. Drugs like avatrombopag and eltrombopag (recently approved for managing thrombocytopenia in people with chronic hepatitis C) stimulate

proliferation of platelet precursor cells in the bone marrow.

Norah Terrault from the University of California at San Francisco and colleagues conducted a Phase 2, randomized, placebo-controlled trial to evaluate whether avatrombopag boosts platelet counts in patients with chronic liver disease prior to elective invasive procedures, as was previously shown for people with chronic immune thrombocytopenia.

Study 202 enrolled 130 participants with chronic viral hepatitis, non-alcoholic steatohepatitis, or alcoholic liver disease. They had low platelet levels at baseline (10-50 billion/L +15%). Elective invasive procedures were scheduled for 1 to 4 days after the last dose of the study drug. At baseline the average age was 55 years, the mean meld score was 13, and the mean platelet count was 40 billion/L.

Participants in Cohort A (n=67) were randomly assigned to receive a 100 mg loading dose of avatrombopag or placebo on day 1, followed by 20, 40, or 80 mg/day avatrombopag or placebo for 6 days. Cohort B (n=63) was added to evaluate a new formulation of avatrombopag. This group received a 80 mg loading dose of avatrombopag or placebo, then 10 mg/day for 6 days, 20 mg/day for 3 days and placebo for 3 days, or else placebo for all 6 days.

Results

• In an intent-to-treat analysis, significantly more people receiving avatrombopagexperienced good response, defined as a platelet count increase of at least 20 billion/L from baseline and at least 1 count > 50 billion between days 4 and 8:

o   Cohort A 80 mg avatrombopag: 77%;

o   Cohort B 20 mg avatrombopag: 52%;

o   Cohort B 10 mg avatrombopag: 43%;

• Placebo: 6% (Cohort A) to 10% (Cohort B).
• The highest response rates were observed 3 to 7 days after the final avatrombopag dose.
• Cohort B participants receiving either dose of avatrombopag required significantly fewer platelet transfusions before elective procedures compared with placebo recipients (5% vs 35%, respectively).
• Avatrombopag was generally safe and well-tolerated.
• The most common adverse events were nausea, fatigue, and headache in both avatrombopag and placebo arms, with no clear trends in frequency or severity.

Based on these findings, the researchers concluded, "In this Phase 2 study, avatrombopag was efficacious and well tolerated in patients with [liver disease and thrombocytopenia] scheduled for elective invasive procedures. Results suggest that avatrombopag can potentially replace transfusions in these patients."

11/27/12

Reference

N Terrault, T Hassanein, S Joshi, et al. Once-daily oral avatrombopag (E5501) prior to elective surgical or diagnostic procedures in patients with chronic liver disease and thrombocytopenia: results from a Phase 2, randomized, double-blind, placebo-controlled study (Study 202). 63rd Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2012). Boston, November 9-13, 2012. Abstract 122.