FDA Approves Fedratinib for Myelofibrosis

The FDA has approved fedratinib (Inrebic) for the treatment of adult patients with intermediate-2 or high-risk primary or secondary myelofibrosis.

The FDA has approved fedratinib (Inrebic) for the treatment of adult patients with intermediate-2 or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis.1

The approval is based on findings from the phase III JAKARTA2 study, which evaluated fedratinib in patients with primary or secondary myelofibrosis; results demonstrated a significant reduction in splenomegaly and symptom burden in patients with myelofibrosis. Safety data were also examined from the phase II JAKARTA-2 trial3, which evaluated the agent in patients with myelofibrosis who were previously exposed to ruxolitinib (Jakafi).

“Myelofibrosis can cause patients to suffer in many ways, including experiencing debilitating symptoms,” Ruben Mesa, MD, FACP, director of the Mays Cancer Center at UT Health San Antonio Cancer Center MD Anderson, stated in a press release. “There has not been a new treatment approved for this disease in nearly a decade. With Inrebic, physicians and patients now have another option available for myelofibrosis.”

In the double-blind, placebo-controlled phase III JAKARTA trial, 289 patients with intermediate-2 or high-risk primary myelofibrosis, post-polycythemia vera (PV) myelofibrosis, or post-essential thrombocytopenia (ET) myelofibrosis were randomized to receive fedratinib orally at 400 (n = 96) or 500 mg daily (n = 97), or placebo (n = 96), for at least 6 consecutive 4-week cycles. The primary endpoint was spleen response, specifically a ≥35% reduction in spleen volume from baseline; a key secondary endpoint was symptom response, determined as ≥50% reduction in total symptom score assessed via the modified Myelofibrosis Symptom Assessment Form.

Results showed that spleen response was achieved by 37% of patients who received fedratinib at the 400-mg dose compared with 1% of patients who were on the placebo arm (P <.0001). Additionally, fedratinib improved the Total Symptom Score by ≥50% when assessed from baseline to the end of cycle 6 in 40% of patients treated with the 400-mg dose of fedratinib versus 9% of those on the placebo arm (P <.0001).

Regarding safety, the common adverse events (AEs) with fedratinib were anemia, gastrointestinal symptoms, and increased levels of liver transaminases, serum creatinine, and pancreatic enzymes. Serious AEs occurred in 21% of patients on the 400-mg daily fedratinib dose, with the most common being cardiac failure (5%) and anemia (2%). Fatal adverse reactions of cardiogenic shock occurred in 1% of patients, and AEs that led to treatment discontinuation occurred in 14% of patients. Such AEs included cardiac failure (3%), thrombocytopenia, myocardial ischemia, diarrhea, and increased blood creatinine (2% each).

AEs that led to dose interruptions during the randomized portion of the study, the most common of which were diarrhea and nausea, occurred in 21% of fedratinib-treated patients. Moreover, dose reductions to an AE (≥2%) included anemia (6%), diarrhea (3%), vomiting (3%), and thrombocytopenia (2%); such reductions were reported in 19% of those on the fedratinib arm.

In the single-arm, open-label, multicenter phase II JAKARTA-2 trial, investigators evaluated fedratinib in patients with primary or secondary myelofibrosis who previously received ruxolitinib and were resistant or intolerant after ≥14 days of treatment. Patients had intermediate- or high-risk primary myelofibrosis, post-PV myelofibrosis, or post-ET myelofibrosis. Oral fedratinib was administered at 400 mg daily for 6 consecutive 28-day cycles.

The trial enrolled 97 patients across 40 sites in 10 countries. To be eligible for enrollment, patients also had to have palpable splenomegaly at ≥5 cm below the left costal margin, an ECOG performance status of 0 to 2, and a life expectancy of 6 months or less.

The primary endpoint was spleen response; secondary endpoints included symptom response rate, duration of spleen response, and safety.

With 83 evaluable patients, results showed that 55% 46 (95% CI 44%—66%) achieved a spleen response, suggesting that patients with ruxolitinib-resistant or -intolerant myelofibrosis could achieve a significant clinical benefit with fedratinib.

Regarding safety, the most common grade 3/4 AEs included anemia (38%) and thrombocytopenia (22%). Nineteen percent of patients discontinued due to AEs. There were 7 deaths on the study, though none of them were treatment related. However, suspected cases of Wernicke's encephalopathy in other fedratinib trials led to study termination.

The FDA approval for fedratinib comes with a Boxed Warning for serious and fatal encephalopathy, including Wernicke’s encephalopathy, stating that thiamine levels should be assessed in all patients prior to fedratinib therapy, periodically during treatment, and as clinically indicated. It should not be started in patients with thiamine deficiency.

In November 2013, the FDA placed a clinical hold on the fedratinib program following the potential cases of Wernicke’s encephalopathy that were reported in these and other related clinical trials. The clinical hold was removed by the FDA in August 2017.

“The approval of Inrebic is another important milestone for Celgene and underscores our commitment to people living with blood cancers,” said Jay Backstrom, MD, MPH, chief medical officer for Celgene, the developer of the JAK2 inhibitor, in a press release. “We are excited to provide Inrebic as a new treatment option that may be used in patients with myelofibrosis, including patients previously treated with ruxolitinib.”


  1. U.S. FDA Approves INREBIC® (Fedratinib) as First New Treatment in Nearly a Decade for Patients With Myelofibrosis. Celgene Corporation. Published August 16, 2019. https://bit.ly/2ZbYLjH. Accessed August 16, 2019.
  2. Pardanani A, Harrison C, Cortes JE, et al. Safety and efficacy of fedratinib in patients with primary or secondary myelofibrosis: a randomized clinical trial. JAMA Oncol. 2015;1(5):643-651. doi: 10.1001/jamaoncol.2015.1590.
  3. Harrison CN, Schaap N, Vannucchi AM, et al. Janus kinase-2 inhibitor fedratinib in patients with myelofibrosis previously treated with ruxolitinib (JAKARTA-2): a single-arm, open-label, non-randomised, phase 2, multicentre study. Lancet Haematology. 2017;4(7):PE317-E324. doi: 10.1016/S2352-3026(17)30088-1.