Background
Phase 3, double-blind, randomized, placebo-controlled trial. 289 patients with intermediate-2 or high-risk primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF. Randomized to fedratinib 400 mg/day, 500 mg/day, or placebo (≥6 consecutive 4-week cycles). Fedratinib is a JAK2-selective inhibitor distinct from ruxolitinib (which inhibits JAK1 and JAK2 equally). 94 sites in 24 countries.
Interventions and follow up
Arm A: Fedratinib 400 mg orally once daily (n=96)
Arm B: Placebo orally once daily (n=96)
Note: a 500 mg arm (n=97) was also included but is not the approved dose; key results below are for 400 mg vs placebo
Primary endpoint: Spleen response (≥35% spleen volume reduction, confirmed 4 weeks later) at week 24
mFollow up: Primary analysis at week 24
Arm B: Placebo orally once daily (n=96)
Note: a 500 mg arm (n=97) was also included but is not the approved dose; key results below are for 400 mg vs placebo
Primary endpoint: Spleen response (≥35% spleen volume reduction, confirmed 4 weeks later) at week 24
mFollow up: Primary analysis at week 24
Results
Spleen response (fedratinib 400 mg vs placebo): 36% (35/96) vs 1% (1/96), P<.001
Spleen response (fedratinib 500 mg): 40% (39/97), P<.001 vs placebo
Symptom response ≥50% TSS reduction (TSS50, 400 mg): 36% (33/91) vs 7% (6/85), P<.001
Symptom response ≥50% TSS reduction (500 mg): 34%
Spleen response (fedratinib 500 mg): 40% (39/97), P<.001 vs placebo
Symptom response ≥50% TSS reduction (TSS50, 400 mg): 36% (33/91) vs 7% (6/85), P<.001
Symptom response ≥50% TSS reduction (500 mg): 34%
Adverse events
Hematologic/GI: common AEs included anemia, GI symptoms (nausea, vomiting, diarrhea), and elevated transaminases, creatinine, and pancreatic enzymes
Neurologic (serious): Wernicke encephalopathy occurred in 4 women in the 500 mg arm (MRI-confirmed in 3, clinically suspected in 1); no cases in the 400 mg arm
Program impact: the Wernicke signal led the original sponsor (Sanofi) to discontinue development following JAKARTA
Neurologic (serious): Wernicke encephalopathy occurred in 4 women in the 500 mg arm (MRI-confirmed in 3, clinically suspected in 1); no cases in the 400 mg arm
Program impact: the Wernicke signal led the original sponsor (Sanofi) to discontinue development following JAKARTA
Conclusions
Fedratinib 400 mg significantly improved spleen volume and symptom burden in treatment-naïve intermediate/high-risk MF versus placebo, with results comparable to ruxolitinib benchmark data. Wernicke encephalopathy at the 500 mg dose, later attributed to thiamine depletion, required protocol amendment and ultimately a program pause and reformulation with mandatory thiamine monitoring.
Key Limitations
Wernicke encephalopathy at the 500 mg dose is a serious class-specific concern linked to thiamine depletion; it was absent at 400 mg but requires ongoing pharmacovigilance. No head-to-head comparison with ruxolitinib in this trial. The program pause and ownership transfer (Sanofi → Impact Biomedicines → Celgene/BMS) created a gap in clinical development. Long-term OS data were not reported. The 500 mg dose was abandoned; 400 mg with a thiamine supplementation protocol became the approved regimen.
Clinical Context
Based on JAKARTA and JAKARTA-2 data, fedratinib (Inrebic) received FDA approval in August 2019 for intermediate-2 or high-risk primary or secondary MF, at 400 mg daily with mandatory thiamine replacement. Fedratinib is positioned as an alternative first-line JAK inhibitor and as second-line after ruxolitinib exposure. It preferentially inhibits JAK2 over JAK1 (ruxolitinib inhibits both), with theoretical benefits for anemia and platelet preservation that have been modest in practice. ESMO and ELN guidance recognize fedratinib among JAK inhibitor options for MF.