Fedratinib, an oral JAK2 inhibitor, has emerged as a significant treatment option for patients with intermediate-2 or high-risk myelofibrosis (MF). Approved by the FDA in August 2019, fedratinib offers a new approach for managing this life-threatening condition, particularly for those who are either treatment-naïve or have previously been treated with ruxolitinib. This article provides a comprehensive overview of fedratinib's pharmacology, clinical development, efficacy, safety, and adverse event management strategies.
Mechanism of Action and Selectivity
Fedratinib was designed as a JAK2-selective inhibitor, demonstrating higher potency for JAK2 over other closely related kinase family members. Structural modeling reveals dual binding in the kinase domain at both the ATP and peptide-substrate binding sites, potentially explaining the lack of genetic resistance observed. In vitro studies have shown that fedratinib is effective against ruxolitinib-resistant JAK2 variants. Specifically, fedratinib has an IC50 value of 3 nM for both wild-type JAK2 and JAK2V617F, which is significantly lower than for JAK1 (>35 times), JAK3 (>300 times), and TYK2 (>100 times).
Off-Target Inhibition: FLT3 and BRD4
Beyond JAK2 inhibition, fedratinib also exhibits off-target inhibition of mutant and wild-type FLT3, a tyrosine kinase involved in cell survival and proliferation. Additionally, fedratinib inhibits BRD4, a bromodomain protein implicated in various cancers. This dual targeting of JAK2 and bromodomains may contribute to fedratinib's therapeutic efficacy. Inhibition of BRD4 can attenuate NF-κB hyperactivation and inflammatory cytokine production, potentially reversing bone marrow fibrosis in myeloproliferative neoplasms (MPNs).
Impact on JAK/STAT Signaling and Cytokine Expression
Fedratinib reduces phosphorylation of downstream STAT3/5 proteins (pSTAT3/pSTAT5), inhibits cell proliferation, and induces apoptotic cell death in cell models expressing mutationally active JAK2 or FLT3-ITD. In a phase II dose-finding study (NCT01420770), fedratinib reduced pSTAT3 levels at all dose levels (300, 400, and 500 mg) within 2 hours of the first dose. Patients with greater reductions in pSTAT3 levels were more likely to achieve a spleen response during treatment.
Abnormal cytokine expression is a hallmark of MF. Fedratinib modulates plasma levels of various cytokines, with the highest upregulation observed in erythropoietin, ferritin, adiponectin, and leptin, and the greatest downregulation in C-reactive protein, RANTES, and EN-RAGE. Notably, patients with a spleen response at 12 weeks showed similar patterns of cytokine regulation within the first 4 weeks of treatment. Significant downregulation of TNF-α and upregulation of adiponectin were also observed, potentially contributing to reduced spleen volume and improved symptom burden.
Clinical Efficacy: JAKARTA and JAKARTA2 Trials
The pivotal phase III JAKARTA trial evaluated fedratinib in JAK-inhibitor-naïve patients with MF. The study demonstrated a spleen volume response rate (SVRR) of 37% in the fedratinib 400 mg arm compared to 1% in the placebo arm (P < 0.0001). Symptom response rate was also significantly higher in the fedratinib arm (40%) compared to placebo (9%) (P < 0.001).
The open-label, single-arm, phase II JAKARTA2 study assessed fedratinib in patients previously treated with ruxolitinib. An updated analysis, employing ITT principles, showed an SVRR of 31% (95% CI 22%, 41%) at EOC6. In a subset of patients meeting stringent criteria for ruxolitinib failure, SVRR was 30% (95% CI 21%, 42%). These results suggest that fedratinib can provide clinical benefit to patients who have failed ruxolitinib treatment.
Safety and Adverse Event Management
The most common treatment-emergent adverse events (TEAEs) associated with fedratinib include diarrhea, nausea, anemia, vomiting, fatigue, thrombocytopenia, and constipation. Gastrointestinal TEAEs tend to occur early in treatment and decrease over time. Hematologic events, such as anemia and thrombocytopenia, are anticipated with JAK2 inhibitors and typically occur within the first 3-4 months of treatment.
The fedratinib development program was temporarily placed on clinical hold due to suspected cases of Wernicke’s encephalopathy (WE). However, the clinical hold was lifted after additional safety information was provided to the FDA. The prescribing information now includes a black box warning regarding the potential for encephalopathy, including WE. Proactive management of gastrointestinal events and routine monitoring of thiamine levels are recommended to mitigate this risk.
Fedratinib in Context: Unmet Needs and Future Directions
Fedratinib addresses a critical unmet need for patients with MF, particularly those who are transplant-ineligible and have limited treatment options. Compared to other JAK inhibitors, fedratinib has demonstrated more potent therapeutic activity in patients previously exposed to ruxolitinib. Preclinical data suggest that fedratinib's dual activity against JAK2 and BRD4 may offer additional benefits beyond JAK2 inhibition alone.
Ongoing clinical trials, such as FREEDOM (NCT03755518) and FREEDOM2 (NCT03952039), are evaluating the long-term safety, efficacy, and effect on overall survival of fedratinib in patients with intermediate-2 or high-risk MF previously treated with ruxolitinib. These studies will further define the role of fedratinib in the treatment landscape of myelofibrosis.
