An evaluation of fedratinib for adult patients with newly diagnosed and previously treated myelofibrosis

Introduction: : Myelofibrosis (MF) is a life shortening myeloproliferative neoplasm that has multiple features such as clonal proliferation, fibrosis and splenomegaly. Until recently, ruxolitinib, a Janus Kinase (JAK) 1/2 inhibitor was the only targeted therapy approved for transplant-ineligible patients with MF and who require treatment for symptoms and/or splenomegaly. However, the discontinuation rate with ruxolitinib at 3 to 5 years is high and mostly due to loss of response or toxicity and these patients had no subsequent treatment.

Areas covered: : Fedratinib, a selective JAK2 inhibitor, was approved by the Food and Drug Administration (FDA) in August 2019 for the treatment of intermediate-2 or high-risk primary or secondary MF regardless of prior JAK inhibitor treatment for the management of symptoms and splenomegaly. We discuss herein the development of fedratinib, its pharmacology and pharmacokinetics as well as the clinical development and the future directions. We used pubmed for the search of articles related to fedratinib and myelofibrosis.

Expert opinion: : Fedratinib provided a second-line treatment for patients with MF who failed or discontinued ruxolitinib. New combinations of JAK inhibitors with other targeted therapies are a must in order to improve the management of MF..

Comments：

Fedratinib is a selective inhibitor of JAK2, which is a key signaling molecule involved in the proliferation and survival of hematopoietic cells. It was initially developed by Sanofi and later acquired by Celgene. However, it was temporarily suspended from clinical trials due to concerns about Wernicke's encephalopathy, a rare but serious neurological side effect. Subsequent studies showed that the incidence of Wernicke's encephalopathy could be significantly reduced by prophylactic thiamine supplementation.

The FDA approval of fedratinib was based on the results of the JAKARTA-2 trial, which showed that fedratinib significantly improved spleen volume reduction and symptom response compared to best available therapy in patients with intermediate-2 or high-risk primary or secondary MF, regardless of prior JAK inhibitor treatment. The most common adverse events associated with fedratinib were diarrhea, nausea, vomiting, and anemia.

The development of fedratinib provides an important treatment option for patients with MF who fail or discontinue ruxolitinib. However, there is still a need for new combinations of JAK inhibitors with other targeted therapies in order to improve the management of MF. Ongoing clinical trials are exploring the efficacy and safety of combination therapy with JAK inhibitors and other agents, such as PI3K inhibitors, BET inhibitors, and hypomethylating agents.

Related Products

Cat.No.	Product Name	Information
S2736	Fedratinib (TG101348)	Fedratinib (SAR302503, TG101348) is a selective inhibitor of JAK2 with IC50 of 3 nM in cell-free assays, 35- and 334-fold more selective for JAK2 versus JAK1 and JAK3. Fedratinib also inhibits FMS-like tyrosine kinase 3 (FLT3) and RET (c-RET) with IC50 of 15 nM and 48 nM, respectively. Fedratinib has potential antineoplastic activity. Fedratinib inhibits proliferation and induces apoptosis. Phase 2.

Related Targets

FLT3 Apoptosis related JAK c-RET