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Fedratinib in myelofibrosis. | LitMetric

Fedratinib in myelofibrosis.

Blood Adv

Mays Cancer Center, UT Health San Antonio MD Anderson, San Antonio, TX.

Published: April 2020

AI Article Synopsis

  • Fedratinib was developed as a targeted treatment for myeloproliferative neoplasms after the discovery of the JAK2V617F mutation in 2005, showing strong activity against JAK2 with a 50% inhibitory concentration of only 3 nM.
  • Clinical trials demonstrated its effectiveness in reducing spleen size and improving symptoms of myelofibrosis (MF), with significant studies conducted from 2008 to 2012.
  • Despite a pause in clinical development due to concerns over Wernicke encephalopathy, fedratinib was eventually approved by the FDA in August 2019, accompanied by a warning about potential serious neurological risks.

Article Abstract

Following the discovery of the JAK2V617F mutation in myeloproliferative neoplasms in 2005, fedratinib was developed as a small molecular inhibitor of JAK2. It was optimized to yield low-nanomolar activity against JAK2 (50% inhibitory concentration = 3 nM) and was identified to be selective for JAK2 relative to other JAK family members (eg, JAK1, JAK3, and TYK2). It quickly moved into clinical development with a phase 1 clinical trial opening in 2008, where a favorable impact on spleen and myelofibrosis (MF) symptom responses was reported. A phase 3 trial in JAK2 inhibitor treatment-naive MF patients followed in 2011 (JAKARTA); a phase 2 trial in MF patients resistant or intolerant to ruxolitinib followed in 2012 (JAKARTA-2). Clinical development suffered a major setback between 2013 and 2017 when the US Food and Drug Administration (FDA) placed fedratinib on clinical hold due to the development of symptoms concerning for Wernicke encephalopathy (WE) in 8 of 608 subjects (1.3%) who had received the drug. It was ultimately concluded that there was no evidence that fedratinib directly induces WE, but clear risk factors (eg, poor nutrition, uncontrolled gastrointestinal toxicity) were identified. In August 2019, the FDA approved fedratinib for the treatment of adults with intermediate-2 or high-risk MF. Notably, approval includes a "black box warning" on the risk of serious and fatal encephalopathy, including WE. FDA approval was granted on the basis of the JAKARTA studies in which the primary end points (ie, spleen and MF symptom responses) were met in ∼35% to 40% of patients (JAKARTA) and 25% to 30% of patients (JAKARTA-2), respectively.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7189288PMC
http://dx.doi.org/10.1182/bloodadvances.2019000954DOI Listing

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