INREBIC (fédratinib)

Key points

Favourable opinion for reimbursement in the treatment of disease-related splenomegaly or symptoms in adult patients with primary myelofibrosis, post polycythaemia vera myelofibrosis or post essential thrombocythaemia myelofibrosis who are Janus Associated Kinase (JAK) inhibitor naïve or have been treated with ruxolitinib.  

What therapeutic improvement?

No clinical added value in the therapeutic strategy. 

Role in the care pathway?

Allogeneic haematopoietic stem cell transplantation (HSCT) is the only curative treatment usually indicated in patients with relatively advanced, intermediate or high-risk disease, but only the minority of patients are eligible for transplant (due to their age and/or general health status and the need to have a compatible donor available). For patients not eligible for transplant, treatment depends on the myelofibrosis risk level (IPSS score) and the patient’s symptoms. The objective is to improve the symptoms, whether they are constitutional or directly associated with splenomegaly and/or haematopoiesis abnormalities.

Apart from allogeneic transplantation, which concerns very few patients, there are no treatments available capable of inducing a constant and definitive regression of myelofibrosis. Treatment is primarily palliative, slowing down the progression of fibrosis or reducing splenomegaly and inflammatory symptoms, or compensating for the consequences of cytopenia. The medicinal products used are hydroxyurea, interferon alpha, corticosteroids, IMiD (lenalidomide, revlimid), and transfusions.

Hydroxyurea is used in routine practice based on a benefit that was inadequately established in old studies. Its use has been replaced by that of JAK inhibitors. 

JAKAVI (ruxolitinib) was the first JAK inhibitor to have obtained an MA in the treatment of myelofibrosis. Its efficacy in the treatment of patients with primary myelofibrosis, post polycythaemia vera myelofibrosis or post essential thrombocythaemia myelofibrosis has been established for reducing spleen volume and the resulting symptoms.

In the event of failure or intolerance to ruxolitinib, no second-line therapy previously had an MA or was recommended in the treatment of splenomegaly and symptoms associated with myelofibrosis.

Role of INREBIC (fedratinib) in the care pathway:

INREBIC (fedratinib) is the second representative of the Janus Associated Kinase (JAK) inhibitor class indicated in the treatment of disease-related splenomegaly or symptoms in adult patients with primary myelofibrosis, post polycythaemia vera myelofibrosis or post essential thrombocythaemia myelofibrosis who are JAK inhibitor naïve or have been treated with ruxolitinib (the other JAK inhibitor currently available). Its efficacy has been established for spleen volume reduction.

In JAK inhibitor naïve patients, in the absence of comparative data, the role of INREBIC (fedratinib) compared to JAKAVI (ruxolitinib) cannot be determined. 

In patients previously treated with ruxolitinib, INREBIC (fedratinib) is a treatment option but uncertainties remain concerning its contribution given the absence of a comparative approach and the non-consensual definition of ruxolitinib resistance.

Considering the risk of the development of Wernicke's encephalopathy (WE) identified during clinical studies with a dosage higher than that recommended (500 mg), the Committee highlights the importance of assessing then monitoring thiamine levels before initiating treatment with fedratinib then periodically during treatment. It also highlights that, as specified in the SPC, any change in mental status, confusion or memory impairment should raise concern for potential encephalopathy, including Wernicke's and prompt a full evaluation including a neurologic examination, assessment of thiamine levels and imaging (see sections 4.2 and 4.8 of the SPC).