FDA Drug Approvals: Oncology and Hematology — Year in Review 2018

Mary L Windle, PharmD


January 15, 2019

New Drugs for Hematology

Doptelet (avatrombopag)

Avatrombopag is an orally administered thrombopoietin receptor agonist (TPO-RA). It stimulates proliferation and differentiation of megakaryocytes from bone marrow progenitor cells, resulting in an increased production of platelets. Avatrombopag does not compete with TPO for binding to the TPO receptor and has an additive effect with TPO on platelet production. It is indicated for thrombocytopenia in adults with chronic liver disease who are scheduled to undergo a medical or dental procedure.

Approval was based on the ADAPT-1 and ADAPT-2 clinical trials (n=435). The primary endpoint was the proportion of patients not requiring platelet transfusions or rescue procedures for bleeding up to 7 days following the procedure. Patients who received avatrombopag met the primary endpoint at a rate of 65.6-68.6%, compared with 22.9-33.3% for those who received placebo. Patients who received avatrombopag 40 mg met the primary endpoint at a rate of 87.9-88.1%, compared with a rate of 38.2-33.3% for those who received placebo. (Gastroenterology. 2018 Sep;155(3):705-718)

Mulpleta (lusutrombopag)

Lusutrombopag is another orally bioavailable thrombopoietin receptor agonist (TPO-RA). It interacts with the transmembrane domain of human TPO receptors expressed on megakaryocytes to induce the proliferation and differentiation of megakaryocytic progenitor cells from hematopoietic stem cells and megakaryocyte maturation. Similar to avatrombopag, it is indicated for thrombocytopenia in adults with chronic liver disease who are scheduled to undergo a procedure.

In a phase 3, randomized trial (n=96) of patients with chronic liver disease and thrombocytopenia, 79.2% of patients administered lusutrombopag did not require preoperative platelet transfusion, compared with 12.5% given placebo (P<.0001). (Clin Gastroenterol Hepatol. 2018 Nov 28. pii: S1542-3565(18)31324-7)

Tavalisse (fostamatinib)

Fostamatinib is indicated for thrombocytopenia in adults with persistent or chronic immune thrombocytopenia (ITP). Fostamatinib is a tyrosine kinase inhibitor with demonstrated activity against spleen tyrosine kinase (SYK). The major metabolite of fostamatinib, R406, inhibits signal transduction of Fc-activating receptors and B-cell receptors, resulting in reduced antibody-mediated platelet destruction.

Approval was based on the FIT clinical program (n=150), which included two randomized, placebo-controlled, phase 3 trials and an open-label extension trial. The primary endpoint was stable response (platelets ≥50,000/μL at more than 4 of 6 biweekly visits, weeks 14-24, without rescue therapy). Baseline median platelet count was 16,000/μL, and median duration of ITP was 8.5 years. Stable responses occurred in 18% of patients on fostamatinib, compared with 2% on placebo (P=.0003). Overall responses (defined retrospectively as one or more platelet count >50,000/μL within the first 12 weeks on treatment) occurred in 43% of patients on fostamatinib compared with 14% on placebo (P=.0006). Median time to response was 15 days (on 100 mg bid), and 83% responded within 8 weeks. (Am J Hematol. 2018 Jul;93(7):921-930)

Ultomiris (ravulizumab)

Ravulizumab is indicated for paroxysmal nocturnal hemoglobinuria (PNH). It binds to complement protein C5, thereby inhibiting cleavage to C5a and C5b, which prevents generation of the terminal complement complex C5b9 that mediates hemolysis in patients with PNH.

Ravulizumab administered every 8 weeks was shown to be noninferior to eculizumab (another C5 inhibitor) given every 2 weeks for transfusion avoidance, lactate dehydrogenase normalization, breakthrough hemolysis, and hemoglobin stabilization in a phase 3 trial in patients (n=246) who had not received complement inhibitors. (Blood. 2018 Dec 3. pii: blood-2018-09-876136)

Ravulizumab was also examined in a second study of 195 patients with PNH who were clinically stable after treatment with eculizumab for at least the past 6 months. These patients were randomly assigned to continue eculizumab or switch to ravulizumab. Again, ravulizumab demonstrated similar effects to eculizumab (noninferior) based on several clinical measures, including hemolysis and avoiding transfusion. (Blood. 2018 Dec 3. pii: blood-2018-09-876805)


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