Celgene Announces FDA Approval of Inrebic (fedratinib), a Selective JAK2 Inhibitor, for Intermediate-2/High-Risk Primary and Secondary Myelofibrosis

On August 16, 2019, VCBeat (WeChat ID: vcbeat) learned from foreign media reports that Celgene announced the U.S. Food and Drug Administration (FDA) had approved its highly specific JAK2 inhibitor, Inrebic (fedratinib), for the treatment of patients with intermediate-2 and high-risk primary or secondary myelofibrosis.

Inrebic (fedratinib) is the second drug approved for the treatment of patients with myelofibrosis, an approval based on results from the Phase 2 JAKARTA2 trial and the pivotal Phase 3 JAKARTA trial.

Inrebic (fedratinib) is an oral kinase inhibitor active against both wild-type and mutationally activated Janus-associated kinase 2 (JAK2) and FMS-like tyrosine kinase 3 (FLT3). As a JAK2-selective inhibitor, it exhibits greater inhibitory activity against JAK2 compared with other family members, including JAK1, JAK3, and TYK2. Aberrant activation of JAK2 is associated with myeloproliferative neoplasms (MPNs), including myelofibrosis and polycythemia vera.

In cellular models expressing mutant-activated JAK2 or FLT3, fedratinib reduces phosphorylation of signal transducer and activator of transcription (STAT3/5) proteins, inhibits cell proliferation, and induces apoptotic cell death. In a mouse model of myeloproliferative neoplasms driven by JAK2V617F, fedratinib blocked STAT3/5 phosphorylation, improved survival rates, and alleviated disease-related symptoms, including leukocytosis, hematocrit abnormalities, splenomegaly, and fibrosis.

Myelofibrosis (MF), abbreviated as MF, is a myeloproliferative neoplasm caused by collagen proliferation in the bone marrow hematopoietic tissue, where fibrous tissue severely impairs hematopoietic function. Primary myelofibrosis is also known as "myelosclerosis" or "agnogenic myeloid metaplasia."

Myelofibrosis is characterized by varying degrees of fibrous tissue proliferation in the bone marrow and extramedullary hematopoiesis, primarily occurring in the spleen and secondarily in the liver and lymph nodes. Typical clinical manifestations include anemia with erythroblasts and myelocytes, along with a significant number of teardrop-shaped red blood cells. Bone marrow aspiration often results in a "dry tap." Patients frequently present with marked splenomegaly and varying degrees of osteosclerosis. Additional symptoms may include severe fatigue, shortness of breath, subcostal pain, fever, night sweats, pruritus, and bone pain.

Myelofibrosis is a rare disease, with an incidence rate of 0.2 to 2 per 100,000 individuals. The age of onset is mostly between 50 and 70 years, but it can also occur in infants and young children. The incidence is slightly higher in males than in females. Currently, only one approved drug is available for the treatment of myelofibrosis: Jakafi (ruxolitinib), a JAK1/JAK2 inhibitor that was launched in 2011.

Celgene, founded in 1986 and headquartered in San Diego, California, USA, is a global integrated biopharmaceutical company primarily dedicated to researching therapeutic approaches for diseases related to protein homeostasis, immuno-oncology, epigenetics, immunology, and neuroinflammation. It develops innovative therapies for the treatment of cancer and inflammatory diseases while advancing their commercialization.

Celgene is currently developing small-molecule drugs for the treatment of hematologic malignancies and solid tumors, with indications including multiple myeloma (MM), myelodysplastic syndromes (MDS), chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma (NHL), pancreatic cancer, non-small cell lung cancer, and melanoma.

(Compiled by Cheng Tao)