Avatrombopag reduces preprocedure platelet needs in chronic liver disease

BOSTON – Avatrombopag, an investigational thrombopoietin receptor agonist, may reduce procedure-related bleeding risk in patients with chronic liver disease and thrombocytopenia, results of a phase II trial suggest.

Patients randomized to receive avatrambopag (E5501) before invasive surgical or diagnostic procedures had significantly more platelet count responses and required significantly fewer platelet transfusions than did patients randomized to placebo, Dr. Norah Terrault said at the annual meeting of the American Association for the Study of Liver Diseases.

"It was a well-tolerated drug with no dose-limiting adverse events," Dr. Terrault said, although she noted that one patient had a nonfatal episode of portal-vein thrombosis that may have been related to the drug.

Avatrombopag has been shown to mimic the effects of thrombopoietin both in vitro and in vivo, and in a phase II study it was shown to increase platelet counts in patients with chronic immune thrombocytopenia.

Dr. Terrault, associate professor of medicine in the division of gastroenterology at the University of California, San Francisco, and her colleagues tested the efficacy of short-course avatrombopag in 130 patients with chronic liver disease and thrombocytopenia prior to a planned invasive procedure. The patients were all adults with cirrhosis from viral hepatitis, nonalcoholic steatohepatitis, or alcoholic liver disease.

The trial, labeled E5501-G000-202, enrolled patients into two cohorts. In cohort A, 67 patients were randomly assigned to receive either placebo or a loading dose of a first-generation formulation of avatrombopag 100 mg on day 1, followed by a maintenance dose on days 2-7 of either 20, 40, or 80 mg daily.

In cohort B, 63 patients were randomized either to placebo or to a second-generation formulation of avatrombopag at 80 mg on day 1, followed by either 10 mg daily for days 2-7 or 20 mg/day for days 2-4 and placebo on days 5, 6, and 7.

Patients in both cohorts were scheduled for procedures 1-4 days after the end of drug dosing.

The primary end point was a platelet count response – defined as a platelet count increase from baseline of at least 20 × 10⁹/L and at least one count of greater than 50 × 10⁹/L during days 4-8 from the start of treatment. In an intention-to-treat analysis, the proportion of patients achieving the primary end point was significantly higher in each cohort compared with controls.

In cohort A, the respective responses in the 20- and 80-mg groups were seen in 7 of 18 patients on the 20-mg dose (38.9%) and in 13 of 17 on the 80-mg dose (76.5%), compared with 1 of 16 (6.3%) controls (P less than .05 for both comparisons). There was no significant difference between patients given a placebo vs. a 40-mg dose, however.

In cohort B, 9 of 21 patients on the 10-mg dose (42.9%) had a platelet count response, as did 11 of 21 (52.4%) in the 20-mg group, compared with 2 of 21 on placebo (9.5%; P less than .05 for both comparisons).

The investigators also performed an exploratory analysis looking at platelet transfusion requirements for 58 of the patients in cohort B and found that 7 of 20 (35%) controls needed preprocedure platelets, compared with 1 of 19 (5.3%) each in the 10- and 20-mg avatrombopag groups (P less than .05).

In the combined cohorts, 78 of 93 (83.9%) patients assigned to the drug had treatment-emergent adverse events, compared with 28 of 37 (75.7%) assigned to placebo. There were 15 grade-3 or -4 adverse events among avatrombopag patients (16.1%), compared with 5 among controls (13.5%).

There were three severe treatment-related events, all in patients who received the active drug, and 16 serious treatment-related events among those taking avatrombopag, compared with four on placebo (17.2% vs. 10.8%).

One patient – a 55-year-old with a history of cardiovascular disease, Child-Pugh class C cirrhosis, and a MELD (Model for End-Stage Liver Disease) score of 19 – died. The death was attributed to acute respiratory failure, cardiopulmonary arrest, and metabolic acidosis.

A 61-year-old man with Child-Pugh class C disease and a MELD score of 19 but no hepatocellular carcinoma had weight gain on study day 34, which was shown on Doppler ultrasound to be portal-vein thrombus. His peak platelet count was 199 × 10⁹/L on day 17. He was successfully treated with embolization and anticoagulation therapy.

Investigators are currently planning phase III trials with avatrombopag, Dr. Terrault said.

The study was funded by Eisai, maker of avatrombopag. Dr. Terrault receives grant and research support from the company and serves in an advisory capacity.

BOSTON – Avatrombopag, an investigational thrombopoietin receptor agonist, may reduce procedure-related bleeding risk in patients with chronic liver disease and thrombocytopenia, results of a phase II trial suggest.

Patients randomized to receive avatrambopag (E5501) before invasive surgical or diagnostic procedures had significantly more platelet count responses and required significantly fewer platelet transfusions than did patients randomized to placebo, Dr. Norah Terrault said at the annual meeting of the American Association for the Study of Liver Diseases.

"It was a well-tolerated drug with no dose-limiting adverse events," Dr. Terrault said, although she noted that one patient had a nonfatal episode of portal-vein thrombosis that may have been related to the drug.

Avatrombopag has been shown to mimic the effects of thrombopoietin both in vitro and in vivo, and in a phase II study it was shown to increase platelet counts in patients with chronic immune thrombocytopenia.

Dr. Terrault, associate professor of medicine in the division of gastroenterology at the University of California, San Francisco, and her colleagues tested the efficacy of short-course avatrombopag in 130 patients with chronic liver disease and thrombocytopenia prior to a planned invasive procedure. The patients were all adults with cirrhosis from viral hepatitis, nonalcoholic steatohepatitis, or alcoholic liver disease.

The trial, labeled E5501-G000-202, enrolled patients into two cohorts. In cohort A, 67 patients were randomly assigned to receive either placebo or a loading dose of a first-generation formulation of avatrombopag 100 mg on day 1, followed by a maintenance dose on days 2-7 of either 20, 40, or 80 mg daily.

In cohort B, 63 patients were randomized either to placebo or to a second-generation formulation of avatrombopag at 80 mg on day 1, followed by either 10 mg daily for days 2-7 or 20 mg/day for days 2-4 and placebo on days 5, 6, and 7.

Patients in both cohorts were scheduled for procedures 1-4 days after the end of drug dosing.

The primary end point was a platelet count response – defined as a platelet count increase from baseline of at least 20 × 10⁹/L and at least one count of greater than 50 × 10⁹/L during days 4-8 from the start of treatment. In an intention-to-treat analysis, the proportion of patients achieving the primary end point was significantly higher in each cohort compared with controls.

In cohort A, the respective responses in the 20- and 80-mg groups were seen in 7 of 18 patients on the 20-mg dose (38.9%) and in 13 of 17 on the 80-mg dose (76.5%), compared with 1 of 16 (6.3%) controls (P less than .05 for both comparisons). There was no significant difference between patients given a placebo vs. a 40-mg dose, however.

In cohort B, 9 of 21 patients on the 10-mg dose (42.9%) had a platelet count response, as did 11 of 21 (52.4%) in the 20-mg group, compared with 2 of 21 on placebo (9.5%; P less than .05 for both comparisons).

The investigators also performed an exploratory analysis looking at platelet transfusion requirements for 58 of the patients in cohort B and found that 7 of 20 (35%) controls needed preprocedure platelets, compared with 1 of 19 (5.3%) each in the 10- and 20-mg avatrombopag groups (P less than .05).

In the combined cohorts, 78 of 93 (83.9%) patients assigned to the drug had treatment-emergent adverse events, compared with 28 of 37 (75.7%) assigned to placebo. There were 15 grade-3 or -4 adverse events among avatrombopag patients (16.1%), compared with 5 among controls (13.5%).

There were three severe treatment-related events, all in patients who received the active drug, and 16 serious treatment-related events among those taking avatrombopag, compared with four on placebo (17.2% vs. 10.8%).

One patient – a 55-year-old with a history of cardiovascular disease, Child-Pugh class C cirrhosis, and a MELD (Model for End-Stage Liver Disease) score of 19 – died. The death was attributed to acute respiratory failure, cardiopulmonary arrest, and metabolic acidosis.

A 61-year-old man with Child-Pugh class C disease and a MELD score of 19 but no hepatocellular carcinoma had weight gain on study day 34, which was shown on Doppler ultrasound to be portal-vein thrombus. His peak platelet count was 199 × 10⁹/L on day 17. He was successfully treated with embolization and anticoagulation therapy.

Investigators are currently planning phase III trials with avatrombopag, Dr. Terrault said.

The study was funded by Eisai, maker of avatrombopag. Dr. Terrault receives grant and research support from the company and serves in an advisory capacity.

BOSTON – Avatrombopag, an investigational thrombopoietin receptor agonist, may reduce procedure-related bleeding risk in patients with chronic liver disease and thrombocytopenia, results of a phase II trial suggest.

Patients randomized to receive avatrambopag (E5501) before invasive surgical or diagnostic procedures had significantly more platelet count responses and required significantly fewer platelet transfusions than did patients randomized to placebo, Dr. Norah Terrault said at the annual meeting of the American Association for the Study of Liver Diseases.

"It was a well-tolerated drug with no dose-limiting adverse events," Dr. Terrault said, although she noted that one patient had a nonfatal episode of portal-vein thrombosis that may have been related to the drug.

Avatrombopag has been shown to mimic the effects of thrombopoietin both in vitro and in vivo, and in a phase II study it was shown to increase platelet counts in patients with chronic immune thrombocytopenia.

Dr. Terrault, associate professor of medicine in the division of gastroenterology at the University of California, San Francisco, and her colleagues tested the efficacy of short-course avatrombopag in 130 patients with chronic liver disease and thrombocytopenia prior to a planned invasive procedure. The patients were all adults with cirrhosis from viral hepatitis, nonalcoholic steatohepatitis, or alcoholic liver disease.

The trial, labeled E5501-G000-202, enrolled patients into two cohorts. In cohort A, 67 patients were randomly assigned to receive either placebo or a loading dose of a first-generation formulation of avatrombopag 100 mg on day 1, followed by a maintenance dose on days 2-7 of either 20, 40, or 80 mg daily.

In cohort B, 63 patients were randomized either to placebo or to a second-generation formulation of avatrombopag at 80 mg on day 1, followed by either 10 mg daily for days 2-7 or 20 mg/day for days 2-4 and placebo on days 5, 6, and 7.

Patients in both cohorts were scheduled for procedures 1-4 days after the end of drug dosing.

The primary end point was a platelet count response – defined as a platelet count increase from baseline of at least 20 × 10⁹/L and at least one count of greater than 50 × 10⁹/L during days 4-8 from the start of treatment. In an intention-to-treat analysis, the proportion of patients achieving the primary end point was significantly higher in each cohort compared with controls.

In cohort A, the respective responses in the 20- and 80-mg groups were seen in 7 of 18 patients on the 20-mg dose (38.9%) and in 13 of 17 on the 80-mg dose (76.5%), compared with 1 of 16 (6.3%) controls (P less than .05 for both comparisons). There was no significant difference between patients given a placebo vs. a 40-mg dose, however.

In cohort B, 9 of 21 patients on the 10-mg dose (42.9%) had a platelet count response, as did 11 of 21 (52.4%) in the 20-mg group, compared with 2 of 21 on placebo (9.5%; P less than .05 for both comparisons).

The investigators also performed an exploratory analysis looking at platelet transfusion requirements for 58 of the patients in cohort B and found that 7 of 20 (35%) controls needed preprocedure platelets, compared with 1 of 19 (5.3%) each in the 10- and 20-mg avatrombopag groups (P less than .05).

In the combined cohorts, 78 of 93 (83.9%) patients assigned to the drug had treatment-emergent adverse events, compared with 28 of 37 (75.7%) assigned to placebo. There were 15 grade-3 or -4 adverse events among avatrombopag patients (16.1%), compared with 5 among controls (13.5%).

There were three severe treatment-related events, all in patients who received the active drug, and 16 serious treatment-related events among those taking avatrombopag, compared with four on placebo (17.2% vs. 10.8%).

One patient – a 55-year-old with a history of cardiovascular disease, Child-Pugh class C cirrhosis, and a MELD (Model for End-Stage Liver Disease) score of 19 – died. The death was attributed to acute respiratory failure, cardiopulmonary arrest, and metabolic acidosis.

A 61-year-old man with Child-Pugh class C disease and a MELD score of 19 but no hepatocellular carcinoma had weight gain on study day 34, which was shown on Doppler ultrasound to be portal-vein thrombus. His peak platelet count was 199 × 10⁹/L on day 17. He was successfully treated with embolization and anticoagulation therapy.

Investigators are currently planning phase III trials with avatrombopag, Dr. Terrault said.

The study was funded by Eisai, maker of avatrombopag. Dr. Terrault receives grant and research support from the company and serves in an advisory capacity.