On September 15, 2023, the FDA approved momelotinib (Ojjaara; GlaxoSmithKline), a kinase inhibitor, for the treatment of adults with intermediate- or high-risk myelofibrosis, including primary or secondary myelofibrosis (post–polycythemia vera and post–essential thrombocythemia), and anemia. The FDA granted momelotinib an orphan drug designation.
Momelotinib is the first approved agent for the treatment of patients with myelofibrosis and anemia, and is the only approved medicine for newly diagnosed and previously treated patients with myelofibrosis and anemia that addresses the disease’s main manifestations of anemia, constitutional symptoms, and splenomegaly (enlarged spleen).
Momelotinib inhibits the 3 key signaling pathways of Janus kinase (JAK) 1; JAK2; and activin A receptor, type I (ACVR1). Although the inhibition of JAK1 and JAK2 may improve constitutional symptoms and splenomegaly, the inhibition of ACVR1 leads to a decrease in hepcidin, a protein that is elevated in patients with myelofibrosis and contributes to anemia. Approximately 40% of patients with myelofibrosis have moderate-to-severe anemia at diagnosis, and nearly all patients with myelofibrosis have anemia.
“We are thrilled to see momelotinib reach the clinic, giving patients and their physicians another option to help manage myelofibrosis. Any new treatment that takes steps toward unlocking the mysteries of this complex and chronic blood cancer represents great progress,” stated Kapila Viges, Chief Executive Officer, Myeloproliferative Neoplasms Research Foundation, in a press release.
This approval of momelotinib was based on the efficacy results of the phase 3 MOMENTUM clinical trial (NCT04173494) and data from a subpopulation of adults with myelofibrosis and anemia in the phase 3 SIMPLIFY-1 clinical trial (NCT01969838).
The global, randomized, double-blind MOMENTUM study compared momelotinib treatment with danazol treatment in 195 patients with myelofibrosis symptoms and anemia who previously received a JAK inhibitor. Efficacy assessments showed that 25% of patients who received momelotinib had a ≥50% reduction in the symptoms of myelofibrosis compared with 9% of patients who received danazol, for a difference of 16% (95% confidence interval [CI], 6-26; P<.01). In the momelotinib arm, 30% of the patients achieved transfusion independence compared with 20% of patients in the danazol arm, which translated to a noninferiority difference of 14% (95% CI, 2-25; P=.023). A spleen volume reduction of ≥25% was observed in 39% of the patients who received momelotinib and in 6% of patients who received danazol, for a difference of 33% (95% CI, 23-44; P<.0001).
The multicenter, randomized, double-blind SIMPLIFY-1 study compared the safety and efficacy of momelotinib with ruxolitinib in JAK inhibitor–naïve patients who had myelofibrosis. The efficacy and safety analyses of SIMPLIFY-1 were based on a subset of patients with myelofibrosis and anemia, which was defined as hemoglobin <10 g/dL at baseline. The primary efficacy end point was a reduction in spleen volume of ≥35%. In this study, 31% of the 86 patients who received momelotinib achieved this end point (95% CI, 22%-42%) compared with 33% of the 95 patients who received ruxolitinib (95% CI, 23%-43%).
“With momelotinib we have the potential to establish a new standard of care for myelofibrosis patients with anemia. Addressing key manifestations of myelofibrosis, including anemia, constitutional symptoms and splenomegaly, makes a significant difference in the treatment regimen for these patients who have limited options to address these aspects of the disease,” said Ruben A. Mesa, MD, FACP, President and Executive Director, Atrium Health Levine Cancer Center and Atrium Health Wake Forest Baptist Comprehensive Cancer Center, in a press release.
The most common (≥20% in either study) adverse events with momelotinib were thrombocytopenia, hemorrhage, bacterial infection, fatigue, dizziness, diarrhea, and nausea.
The recommended dose of momelotinib is 200 mg orally once daily with or without food.