Fedratinib, the active ingredient in Inrebic®, is a potent oral kinase inhibitor with activity against wild-type and mutationally activated Janus kinase 2 (JAK2) and FMS-like tyrosine kinase 3 (FLT3). Inrebic is a JAK2-selective inhibitor with higher potency for JAK2 than for family members JAK1, JAK3, and tyrosine kinase 2 (TYK2).1 In MF, constitutive activation of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway causes cell proliferation, inhibition of cell death, and clonal expansion of myeloproliferative tumor cells. This leads to disease features such as extramedullary hematopoiesis, bone marrow fibrosis, and splenomegaly.2

The drug was approved by the US Food and Drug Administration (FDA) on August 16, 2019, and is indicated for the treatment of adults with intermediate-2 or high-risk primary myelofibrosis (MF) or MF secondary to polycythemia vera (PV) or essential thrombocythemia (ET). The safety and efficacy of Inrebic in children have not been established.3 Inrebic is a registered trademark of Impact Biomedicines and is under license by Celgene, a Bristol Myers Squibb Company.4 

The National Comprehensive Care Network clinical practice guidelines for the treatment of myeloproliferative neoplasms include Inrebic as a treatment option for patients who have intermediate-2 or high-risk MF with platelet counts of 50 × 109/L or higher, either as initial therapy or as second-line therapy for those previously treated with Jakafi® (ruxolitinib).2

Mechanism of Action

JAK2 plays a key role in the signaling of normal hematopoiesis. The somatic activating mutation JAK2 V617F is present in 50% to 60% of patients with primary MF or ET, and in 95% of patients with PV. JAK2 V617F constitutively activates the JAK/STAT signaling pathway, leading to cell proliferation and the clonal expansion of myeloid malignant cells.2,5,6 

Inrebic is a kinase inhibitor with activity against wild-type and mutationally activated JAK2 and FLT3. The drug has been found to decrease the phosphorylation of signal transducer and activator of transcription (STAT3/5) proteins, hinder cell growth, and trigger apoptotic cell death in cell models harboring mutationally active JAK2 V617F or FLT3 internal tandem duplication (ITD) mutations. In another study using in mouse models of JAK2 V617F-driven myeloproliferative disease, Inrebic reduced the phosphorylation of STAT3/5; increased survival, white blood cell counts, and hematocrit; and reduced splenomegaly and fibrosis.2,5,6 

Read more about MF pathophysiology

Administration 

Inrebic is available as 100-mg capsules. The recommended dosage for patients with a baseline platelet count of  50 × 109/L or higher is 400 mg taken orally once per day with or without food. The dose must be reduced if the patient is taking a strong CYP3A inhibitor or has severe kidney disease with creatinine clearance (ClCr) between 15 ml/min to 29 ml/min.5 The drug can be taken with a high-fat meal to reduce nausea and vomiting.7

Get full prescribing information for Inrebic at MPR

Adverse Effects

The most common side effects of Inrebic are diarrhea, nausea, vomiting, and anemia. Other possible side effects are thrombocytopenia, increased serum amylase and lipase levels, and liver problems.5,8

Read more about MF complications 

Warnings and Precautions

The most important warnings and precautions related to Inrebic use are described below:

Thiamine Deficiency 

Thiamine levels should be checked before initiating Inrebic therapy. Treatment should not be started if baseline thiamine levels are not normal. While the patient is being treated, thiamine levels should be checked monthly for the first 3 months and then every 3 months thereafter.4,5,8

Any disturbance in the patient’s mental state, such as drowsiness, confusion, or memory problems, should trigger a comprehensive evaluation that includes a neurological examination, measurement of the thiamine levels, and imaging to rule out any form of encephalopathy, which can be serious and fatal. This includes Wernicke encephalopathy, which is a neurologic emergency due to thiamine, or vitamin B1, deficiency. Ataxia, mental status disturbances, and ophthalmoplegia (eg, nystagmus, diplopia) are some of the signs and symptoms of Wernicke encephalopathy.4,5,8

If Wernicke encephalopathy is suspected, Inrebic should be discontinued immediately and parenteral thiamine started. The patient should be monitored until the symptoms disappear and the thiamine levels return to normal.4,5,8

Anemia and Thrombocytopenia

Treatment with Inrebic can cause anemia and thrombocytopenia. It is important for the patient to undergo a baseline complete blood cell count before and during treatment. If grade 4 anemia, neutropenia, or thrombocytopenia develops, dosage adjustment is advised.4,5,8

Severe Gastrointestinal Side Effects 

If severe nausea, vomiting, or diarrhea that does not respond to treatment develops, emergency medical treatment should be started immediately. Prophylaxis with medications for vomiting and diarrhea is recommended.4,5,8

Liver Toxicity 

Blood testing to evaluate liver function should be done before and during treatment with Inrebic. If the results are abnormal, the dose should be reduced or interrupted.4,5,8

Elevated Levels of Serum Amylase and Lipase 

Increased levels of serum amylase or lipase during Inrebic treatment indicate a pancreatic problem. Blood should be tested to measure levels of amylase or lipase before and during treatment with Inrebic. If the levels rise, the dose should be reduced or interrupted.4,5,8

Major Adverse Cardiac Event (MACE)

Patients taking Inrebic should be monitored for the development of a MACE. Before Inrebic therapy is started or continued, especially if the patient is a current or past smoker or has other cardiovascular risk factors, the advantages and risks of Inrebic administration should be considered. Patients should be educated about the signs and symptoms of significant cardiovascular events and the steps to be taken if these occur.4,5,8

Possibility of Thrombosis

If symptoms of thrombosis develop, including deep venous thrombosis, pulmonary embolism, and arterial thrombosis, the patient should be evaluated immediately and appropriate treatment initiated.4,5,8

Possibility of Secondary Malignancies 

Patients on Inrebic should be monitored for the development of secondary malignancies, especially those who are current or past smokers.4,5,8

Read more about MF prognosis

Safety and Efficacy in Trials

The FDA approval of Inrebic was based on multiple trials, including the JAKARTA trial (NCT01437787), a multicenter, randomized, double-blind, placebo-controlled phase 3 clinical trial that evaluated the safety and efficacy of Inrebic.6  

JAKARTA

Patients were randomly assigned to Inrebic at a dose of 400 or 500 mg or to placebo once daily for at least 6 cycles.The primary outcome was the proportion of patients whose spleen volume had decreased by at least 35% from baseline after 6 cycles of treatment. A 35% reduction in spleen volume occurred in 35 of the 96 patients (36%) who received 400 mg of Inrebic, as compared to 1 of the 96 patients who received placebo. Additionally, a greater than 50% reduction in MF-related symptoms was noted in 40% of those who received the 400 mg of Inrebic vs 9% of the patients who received placebo.9

JAKARTA2

JAKARTA2 (NCT01523171) was a multicenter, open label, single-arm phase 2 study that evaluated the efficacy of a once-daily dose of Inrebic (400-mg starting dose) in patients previously treated with Jakafi and with a diagnosis of intermediate-1 with symptoms, intermediate-2, or high-risk primary MF or a diagnosis of secondary (post-PV or post-ET) MF. An updated analysis of the study data used the intent-to-treat (ITT) principles and narrower definitions of relapse on Jakafi treatment, Jakafi-refractory disease, and Jakafi intolerance.10 

At the end of cycle 6, the spleen volume of 31% of patients in the ITT population (n=97) had decreased by 35% or more. The analysis found that 79 of the 97 patients (81%) met the narrower criteria for Jakafi resistance or intolerance. Within this group, 30% of the 79 patients showed a 35% or greater volume reduction in spleen volume at the end of cycle 6: a response rate comparable with the response rate in the ITT population.10 

Additionally, a symptom response rate of 50% or higher was observed in 27% of patients in both the ITT group and the group analyzed with the stricter criteria. The new findings support the promise of Inrebic in the treatment of patients whose disease no longer responds to Jakafi by demonstrating clinically significant decreases in spleen volume and symptoms.10

Read more about MF clinical trials

References

  1. FDA approves Inrebic. Drugs.com. August 2019. Accessed December 26, 2022.
  2. Talpaz M, Kiladjian JJ. Fedratinib, a newly approved treatment for patients with myeloproliferative neoplasm-associated myelofibrosis. Leukemia. 2021;35(1):1-17. doi:10.1038/s41375-020-0954-2
  3. FDA approves fedratinib for myelofibrosis. News release. US Food and Drug Administration; August 16, 2019.
  4. Product monograph including patient medication information. INREBIC® fedratinib capsules. Celgene. Revised September 13, 2022. Accessed December 26, 2022.
  5. INREBIC® (fedratinib) capsules, for oral use. Highlights of prescribing information. Revised August 2019. Accessed December 26, 2022.
  6. Inrebic (fedratinib). CenterWatch. Updated August 1, 2019. Accessed December 26, 2022.
  7. Cunha JP. INREBIC. RxList.com. Updated June 16, 2022. Accessed December 26, 2022.
  8. Another treatment option in the fight against myelofibrosis. Inrebic. Accessed December 26, 2022.
  9. Inrebic receives FDA approval for adults with myelofibrosis. TOP. The Oncology Pharmacist. Updated July 22, 2021. Accessed December 26, 2022.
  10. Celgene updated analysis of JAKARTA2 fedratinib study shows clinically meaningful responses in patients previously treated for myelofibrosis with ruxolitinib. Drugs.com. Updated August 16, 2019. Accessed December 26, 2022.

Reviewed by Debjyoti Talukdar, MD, on 12/29/2022.