In recent studies, clinical activity with fedratinib was reported in patients with myeloproliferative neoplasm (MPN)-associated myelofibrosis (MF), including those with JAK-inhibitor-naïve disease or with prior ruxolitinib failure. Pharmacology, efficacy, and safety results from clinical trials with fedratinib were described in a review in the journal Leukemia.
Fedratinib is a JAK2 inhibitor that received approval in August 2019 from the US Food and Drug Administration (FDA) for use in the treatment of adults with intermediate-2 or high-risk primary or secondary MF.
In 2 pivotal trials, fedratinib demonstrated efficacy in patients with MF. In the phase 3 JAKARTA study (ClinicalTrials.gov Identifier: NCT01437787), JAK-inhibitor-naïve patients were randomized into 3 groups of 96 patients each, including 2 dosage groups for fedratinib (400 or 500 mg/day) and a placebo group.
The primary endpoint of the JAKARTA trial was the spleen volume response rate (SVRR) at end of cycle 6 (EOC6) and confirmed 4 weeks later. In the 400-mg fedratinib group, this rate was 37%, compared with 1% for the placebo group (P <.0001). Results with the 400 mg dose of fedratinib in this trial supported the FDA approval of this drug for intermediate-2 or high-risk MF at this dose.
In the single-arm, pivotal phase 2 JAKARTA2 trial (NCT01523171), 97 patients with MF who were previously treated with ruxolitinib received a starting dose of fedratinib of 400 mg/day. A recent analysis of this trial showed an SVRR at EOC6 in the intention-to-treat population of 31%. This rate was 30% for patients meeting stringent criteria for ruxolitinib failure.
Grade 1 or 2 gastrointestinal events were the most commonly reported adverse events across these studies. However, the current FDA approval for treatment of MF includes a black box warning due to a potential for encephalopathy, including Wernicke encephalopathy, in patients treated with fedratinib.
The authors of the report concluded that fedratinib provides a promising treatment option for patients with advanced MF. Fedratinib continues to be evaluated in ongoing clinical trials with patients who previously received ruxolitinib.
Disclosure: The authors declared affiliations with or received funding from the pharmaceutical industry. Please refer to the original article for a full list of disclosures.
Talpaz M, Kiladjian JJ. Fedratinib, a newly approved treatment for patients with myeloproliferative neoplasm-associated myelofibrosis. Leukemia. 2021;35(1):1-17. doi:10.1038/s41375-020-0954-2