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

ABSTRACT

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 and 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.

KEYWORDS:

• Myelofibrosis
• ruxolitinib
• fedratinib
• JAK2
• pacritinib
• momelotinib
• prelabresib
• navitoclax

Article highlights

• In the JAKARTA2 phase II trial, the spleen response was 55%.

• In the JAKARTA phase III trial, the spleen response was 40%.

• Fedratinib was approved for the treatment of intermediate-2 or high-risk MF as initial treatment or in patients previously treated with ruxolitinib.

• The clinical development of fedratinib was interrupted due to Wernicke’s Encephalopathy.

• Long-term AEs and durability of response is difficult to assess due to the clinical hold

• Pacritinib had been approved by the FDA for the treatment of patients with intermediate or high-risk primary or secondary MF and who have platelet levels below 50 x 10⁹/L.

• Momelotinib an oral JAK1/2 and Activin A receptor type 1 (ACVR1) inhibitor for patients who have symptomatic MF with anemia previously treated with a JAK inhibitor

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.