Inrebic (fedratinib)

Over the past two decades, the field has progressed from the identification of early JAK2 inhibitors to the approval of several first-generation agents, including ruxolitinib, tofacitinib, baricitinib, and fedratinib, which validated the clinical feasibility of JAK blockade. Together, these multidisciplinary approaches have accelerated hit discovery, refined selectivity, and improved the pharmacokinetic and safety profiles of emerging JAK inhibitors. By consolidating progress across medicinal chemistry, structural biology, and computational design, this review outlines key opportunities and remaining challenges in developing next-generation JAK inhibitors with enhanced precision and therapeutic value for oncology, immunology, and chronic inflammatory diseases.

This study reveals that miR-500a-3p promotes proliferation and glycolysis while inhibiting apoptosis of HCC cells by negatively regulating SOCS2 and activating the JAK2/STAT5 pathway.

To explore therapeutic implications, transcriptomics-guided drug repositioning combined with molecular docking analysis identified five candidate compounds-celastrol, fedratinib, pevonedistat, tozasertib, and withaferin A-predicted to target key network hubs. Overall, this in silico study provides a ceRNA-centered regulatory framework for GC and prioritizes biologically informed biomarkers and repositioned drug candidates with potential applicability across other malignancies to converge precision oncology.

Fedratinib is the second drug approved by the FDA for adult patients with myelofibrosis (MF) following ruxolitinib; however, the mechanism of its dose-limiting toxicity, particularly hepatotoxicity, remains poorly unclear. The results of risk assessment indicated that clinically relevant doses of fedratinib could significantly increase the area under curve (AUC) of drugs mainly metabolized by UGT1A1 and UGT1A3, suggesting a potential risk of clinically significant drug-drug interactions (DDIs). The current research provides useful information for the possible hepatotoxicity mechanism and clinical safe medication of fedratinib.

This ox-LDL-induced upregulation of ACP5 was effectively reversed by the JAK2 inhibitor fedratinib...Conditional ablation of ACP5 significantly reduced aortic plaque area, decreased M1 macrophage proportion in peritoneal lavage fluid, diminished 4-HNE expression in the aortic root, reduced numbers of atrophic mitochondria, and increased aortic GPX4 expression. In conclusion, ACP5 exacerbates atherosclerosis by modulating macrophage polarization and promoting macrophage ferroptosis.

Similarly, ectopic expression of survivin, vimentin, or cyclin D1 partially rescued the phenotypic changes induced by fedratinib. Fedratinib exerts antitumor effects against ESCC in vitro, in vivo, and in patient-derived organoid models by suppressing the JAK2-STAT3 signaling axis and its downstream effectors, vimentin, survivin, and cyclin D1.

P2, N=30, Active, not recruiting, Institut für Klinische Krebsforschung IKF GmbH at Krankenhaus Nordwest | Trial primary completion date: Dec 2025 --> Mar 2026

Fedratinib exhibits therapeutic duality: inhibition of SRC and JAK2 attenuates fibrosis by inhibiting JAK-STAT/TGFβ/Smad3 pathways, while off-target binding to AKT1/EGFR drives renal injury and vitamin B1 depletion-related toxicity with black-box encephalopathy warning. Evidence suggests for CKD patients with estimated glomerular filtration rate (eGFR) <45 mL/min/1.73 m2 or age ≥70 years, a 50% dose reduction (200 mg/day) with renal function and thiamin monitoring (<30 nmol/L) may optimize risk-benefit profile.

P2, N=20, Recruiting, Fred Hutchinson Cancer Center | Suspended --> Recruiting

Equally, there is a major focus on next generation JAK inhibitors and mutant calreticulin antibodies. There is also increasing conversation around the need for novel endpoints, as the limitations of symptom assessment, in particular, become apparent and candidate biomarkers of disease modification emerge.

All JAKi reduced EC inflammation but most JAKi could not prevent the up-regulation of adhesion molecules or the increase in procoagulant and the decrease in anticoagulant factors triggered by proinflammatory cytokines. Peficitinib and fedratinib exhibited cytotoxic effects causing EC apoptosis.

Telmisartan was used as the internal standard (IS). Stability studies confirmed the analyte's integrity across multiple freeze-thaw cycles. The developed LC-MS/MS method is selective, sensitive, fully validated, and was successfully applied to pharmacokinetic studies.