Fedratinib approved for for the treatment of adults with intermediate-2 or high-risk primary or secondary myelofibrosis.
An oral kinase inhibitor that has activity against JAK3 and FLT3.
It does not inhibit JAK1 very much but is more specific for JAK2.
It is used for patients with significant thrombocytopenia.
Approval is based on efficacy results from the JAKARTA trial, in which 289 patients with intermediate-2 or high-risk myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis with splenomegaly were randomized to receive fedratinib 500 mg, 400 mg or placebo once daily for 3 cycles.
The primary efficacy measure was the percentage of patients achieving ≥35% reduction in spleen volume from baseline at the end of cycle 6.
Spleen volume was measured by MRI or CT scan, with a follow-up scan after 4 weeks.
Of the patients treated ≥35% reduction in spleen volume, compared with only 1 patient who received placebo.
The median duration of response was 18.2 months.
40% of patients who received the recommended dose of fedratinib experienced a ≥50% reduction in myelofibrosis-related symptoms versus only 9% of patients who received placebo.
The most common (≥20%) adverse events related to fedratinib were diarrhea, nausea, and vomiting.
The drug has a black box warning for encephalopathy, particularly Wernicke encephalopathy.
Approximately 2/3 of patients get G.I. adverse events including nausea, vomiting, and diarrhea but are generally low-grade.
Fedratinib interferes with the uptake of thiamine from the G.I. tract and can, in rare cases lead to encephalopathy.