FDA Approves DOPTELET® for Thrombocytopenia in Chronic Liver Disease

SUMMARY: The FDA on May 21, 2018, approved DOPTELET® (Avatrombopag) for thrombocytopenia in adults with Chronic Liver Disease (CLD) scheduled to undergo a procedure. Thrombocytopenia is the most common hematological abnormality encountered in patients with Chronic Liver Disease (CLD), occurring in 65-85% of patients. Thrombocytopenia is an indicator of advanced disease and is associated with a poorer prognosis, and can impact routine care of patients with CLD, interfering with diagnostic and therapeutic interventions. Therefore treatment options that can safely and effectively raise platelet levels could have a significant impact on care of these patients.

The cause of thrombocytopenia in CLD is multifactorial and can be due to decreased production, splenic sequestration, and increased destruction. Thrombopoietin (TPO) regulates platelet production and maturation, and CLD is associated with depressed Thrombopoietin levels . Bone marrow suppression can be also be caused by alcohol, viruses, medications and iron overload. Hypersplenism causes splenic platelet sequestration. Increased platelet destruction in cirrhosis can be due to increased shear stress, increased fibrinolysis, increased platelet aggregation related to infections, or immune mediated platelet destruction secondary to antiplatelet antibodies.

DOPTELET® (Avatrombopag), a second generation orally administered Thrombopoietin Receptor Agonist (TPO-RA), designed to mimic the effects of TPO, the primary regulator of normal platelet production. DOPTELET® stimulates the proliferation and differentiation of megakaryocytes from bone marrow progenitor cells and results in increased production of platelets.

The approval of DOPTELET® by the FDA was based on two identically designed, international, randomized, double-blind, placebo-controlled phase III trials, ADAPT-1 (N=231) and ADAPT-2 (N=204). In these two studies totaling 430 patients with Chronic Liver Disease and thrombocytopenia (N=430), patients were randomized 2:1 to DOPTELET® (N=274) or placebo (N=156) daily for 5 days prior to a scheduled procedure, and had at least 1 post-dose safety assessment. Patients randomized to DOPTELET® received differential dosing based on mean platelet count at entry. Patients with a baseline platelet count less than 40,000/uL (low baseline platelet cohort) received DOPTELET® 60 mg orally once daily for 5 consecutive days. Those with a baseline platelet count of 40,000 to less than 50,000/uL (high baseline platelet cohort) received DOPTELET® 40 mg orally once daily for 5 consecutive days. Eligible patients were scheduled to undergo their procedure 5 to 8 days after the last dose of study drug. Patients were stratified according to HepatoCellular Cancer status and bleeding risk associated with the elective procedure (low, moderate, or high). The Primary efficacy endpoint was the proportion of patients, or responders, who did not require a platelet transfusion or any rescue procedure for bleeding after randomization, and for up to 7 days following an elective procedure.

In both trials, DOPTELET® exhibited superiority compared to placebo, in increasing the proportion of patients not requiring platelet transfusions or rescue procedures for bleeding up to 7 days, following a scheduled procedure. In the low baseline platelet cohort, 66% and 69% of patients treated with DOPTELET® responded in the ADAPT-1 and ADAPT-2 trials, respectively. For those receiving placebo, 23% (treatment difference 43%, P<0.0001) and 35% (treatment difference 34%, P=0.0006) responded in the ADAPT-1 and ADAPT-2 trials, respectively. In the high baseline platelet cohort, 88% of DOPTELET®-treated patients in both trials responded compared to 38% and 33% of placebo-treated patients. Treatment difference was 50% (P<0.0001) in the ADAPT-1 trial and 55% (P<0.0001) in the ADAPT-2 trial. Additionally, DOPTELET® was statistically superior to placebo at the two Secondary efficacy endpoints in each trial which included proportion of patients with platelet count of 50,000/uL or more by procedure day, and mean change in the platelet count from baseline to procedure day. The most common adverse reactions reported in at least 3% of patients were pyrexia, abdominal pain, nausea, headache, fatigue, and peripheral edema.

It was concluded that DOPTELET® is the first orally administered treatment option approved by the FDA for patients with Chronic Liver Disease who routinely undergo multiple, invasive procedures. The availability of this new oral agent can lead to a measured increase in platelets and minimize the risk of bleeding and need for platelet transfusions. https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm608323.htm