By SPC News Staff

The FDA today approved avatrombopag (Doptelet, Dova Pharmaceuticals) to treat thrombocytopenia in adults with chronic liver disease (CLD) who are scheduled to undergo a medical or dental procedure. 

This is the first thrombopoietin (TPO) receptor agonist approved for this use in the United States. Avatrombopag is designed to mimic the affects of TPO, the primary regulator of normal platelet production.

The safety and efficacy of avatrombopag were studied in two randomized, double-blind, placebo-controlled phase 3 trials (ADAPT-1 and ADAPT-2) involving 435 patients with CLD and severe thrombocytopenia who were scheduled to undergo a procedure that would typically require platelet transfusion. The trials investigated two dose levels of avatrombopag administered orally over five days compared with placebo. 

The trial results showed that for both dose levels of avatrombopag, a higher proportion of patients had increased platelet counts and did not require platelet transfusion or any rescue therapy on the day of the procedure and up to seven days after the procedure compared with those taking placebo.

Avatrombopag also was superior to placebo at the two secondary efficacy end points in each trial. In the avatrombopag treatment groups, there was an increased proportion of patients achieving the target platelet count of at least 50,000/mL on the procedure day, and a greater magnitude of the change in mean platelet count from baseline to the procedure day; all treatment differences between the avatrombopag and placebo treatment groups were highly significant (P<0.0001).

The most common adverse reactions with avatrombopag included pyrexia, abdominal pain, nausea, headache, fatigue and peripheral edema. 

TPO receptor agonists have been associated with thrombotic and thromboembolic complications in patients with CLD. Portal vein thrombosis has been reported in patients with CLD treated with TPO receptor agonists. One treatment-emergent event of portal vein thrombosis was reported in the ADAPT trials in an avatrombopag-treated patient.

Consider the potential increased thrombotic risk when administering avatrombopag to patients with known risk factors for thromboembolism, including genetic prothrombotic conditions (Factor V Leiden, prothrombin 20210A, antithrombin deficiency, or protein C or S deficiency). The full prescribing information is available here.

Thrombocytopenia, a reduction in the number of platelets in the blood, is a common complication in patients with CLD, with the extent of thrombocytopenia often worsening with the severity of liver disease. TPO, the principal physiologic regulator of platelet production, is made in the liver and stimulates bone marrow production of platelets, which are critical blood components for controlling bleeding. As a result of damage to the liver in patients with CLD, TPO production is reduced, which consequently results in decreased platelet production and thrombocytopenia.

About 70,000 patients with CLD have a platelet count of less than 50,000/mcL. These patients typically require one to three invasive diagnostic and therapeutic procedures per year; each of these procedures carries a risk for bleeding. If not effectively treated, thrombocytopenia can lead to serious uncontrolled bleeding, resulting in prolonged hospitalizations and other post-procedure complications.

“Given the need for patients with CLD to routinely undergo multiple, invasive procedures, the availability of an oral agent that can lead to a measured increase in platelets, to minimize the need for platelet transfusions and risk of bleeding, will facilitate the clinical management of these patients,” said Norah Terrault, MD, MPH, a professor of medicine in the Division of Gastroenterology at the University of California, San Francisco, and a principal investigator for the phase 3 trials.

This product was granted priority review.