FDA Approves Inrebic (fedratinib) for the Treatment of Patients With Myelofibrosis

Celgene Corporation announced the U.S. Food and Drug Administration (FDA) has approved Inrebic (fedratinib) 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 of Inrebic is another important milestone for Celgene and underscores our commitment to people living with blood cancers," said Jay Backstrom, M.D., M.P.H., Chief Medical Officer for Celgene. "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."

"Myelofibrosis can cause patients to suffer in many ways, including experiencing debilitating symptoms," said Ruben Mesa, M.D., FACP, Director of the Mays Cancer Center at UT Health San Antonio Cancer Center MD Anderson. "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."

The Inrebic development program consisted of multiple studies (including JAKARTA and JAKARTA2) in 608 patients who received more than one dose (ranging from 30 mg to 800 mg),1 of whom 459 had myelofibrosis,1 including 97 previously treated with ruxolitinib.1 The JAKARTA study evaluated the efficacy and safety of once-daily oral doses of Inrebic compared with placebo in patients with intermediate-2 or high-risk, primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis who were previously untreated with a JAK inhibitor, had enlarged spleens (a condition known as splenomegaly), and had a platelet count of ≥50 x 109/L (median baseline platelet count was 214 x 109/L; 16% <100 x 109/L and 84% ≥100 x 109/L).1,2 In the JAKARTA study, spleen volume was reduced by 35% or greater, when assessed from baseline to the end of cycle 6 (week 24), with a 4-week follow-up scan, in 37% (35 of 96) of patients treated with INREBIC 400 mg versus 1% (1 of 96) of patients who received placebo (p<0.0001).1 INREBIC also improved the Total Symptom Score as measured by the modified Myelofibrosis Symptoms Assessment Form (MFSAF) v2.0 diary2 (night sweats, itching, abdominal discomfort, early satiety, pain under ribs on left side, bone or muscle pain) by 50% or greater when assessed from baseline to the end of cycle 6 in 40% of (36 of 89) patients treated with 400 mg, versus 9% (7 of 81) of patients who received placebo (p<0.0001).1

Inrebic has a Boxed Warning for serious and fatal encephalopathy, including Wernicke’s. Serious encephalopathy was reported in 1.3% (8 of 608) of patients treated with Inrebic in clinical trials and 0.16% (1 of 608) of the cases were fatal. Wernicke’s encephalopathy is a neurologic emergency resulting from thiamine (Vitamin B1) deficiency. Thiamine levels should be assessed in all patients prior to starting Inrebic, periodically during treatment, and as clinically indicated.1 Do not start Inrebic in patients with thiamine deficiency; replete thiamine prior to treatment initiation. If encephalopathy is suspected, immediately discontinue Inrebic and initiate parenteral thiamine. Monitor until symptoms resolve or improve and thiamine levels normalize.

In the JAKARTA study, serious adverse reactions occurred in 21% of patients treated with Inrebic 400 mg once daily (n=96), with the most common (≥2%) being cardiac failure (5%) and anemia (2%).1 Fatal adverse reactions of cardiogenic shock occurred in 1% of patients.1 Permanent discontinuation due to an adverse reaction occurred in 14% of patients. The most frequent reasons for permanent discontinuation in ≥2% of patients receiving Inrebic included cardiac failure (3%), thrombocytopenia, myocardial ischemia, diarrhea, and increased blood creatinine (2% each).1

Dosage interruptions due to an adverse reaction during the randomized treatment period occurred in 21% of patients who received Inrebic. Adverse reactions requiring dosage interruption in >3% of patients who received Inrebic included diarrhea and nausea. Dosage reductions due to an adverse reaction during the randomized treatment period occurred in 19% of patients who received Inrebic. Adverse reactions requiring dosage reduction in >2% of patients who received Inrebic included anemia (6%), diarrhea (3%), vomiting (3%), and thrombocytopenia (2%).

"Inrebic is a much-welcomed new treatment for the myelofibrosis community," said Ann Brazeau, Chief Executive Officer and Founder, MPN Advocacy and Education International. "This FDA approval marks an important milestone for people living with myelofibrosis as we embark on making greater strides in the diagnosis, understanding and treatment of this disease."

About Myelofibrosis

Myelofibrosis is a serious and rare bone marrow disorder that disrupts the body’s normal production of blood cells. Bone marrow is gradually replaced with fibrous scar tissue, which limits the ability of the bone marrow to make blood cells.3 The disorder can lead to anemia, weakness, fatigue and enlargement of the spleen and liver, among other symptoms.3 Myelofibrosis is classified as a myeloproliferative neoplasm, a group of rare blood cancers that are derived from blood-forming stem cells.4 In the U.S., between 16,000 and 18,500 are living with myelofibrosis,5 and 1.5 of every 100,000 people will be diagnosed with myelofibrosis each year.6 Both men and women are affected, and while the disease can affect people of all ages, the median age at diagnosis ranges from 60 to 67 years.7,8

About JAKARTA

JAKARTA was a pivotal Phase 3, multicenter, randomized, double-blind, placebo-controlled trial evaluating the efficacy of once-daily oral doses of Inrebic compared with placebo in patients with intermediate-2 or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis with splenomegaly and a platelet count of ≥50 x 109/L2 (median baseline platelet count was 214 x 109/L; 16% of patients had a platelet count <100 x 109/L and 84% of patients had a platelet count ≥100 x 109/L) who were previously untreated with a JAK inhibitor.1,2 The study included 289 patients randomized to receive either Inrebic 500 mg (n=97) or 400 mg (n=96) or placebo (n=96)1 across 94 sites in 24 countries.

The primary endpoint was spleen response rate, defined as the proportion of patients achieving greater than or equal to a 35% reduction from baseline in spleen volume at the end of cycle 6 as measured by magnetic resonance imaging (MRI) or computerized tomography (CT) with a follow-up scan 4 weeks later. Secondary endpoints included symptom response rate, defined as the proportion of patients with a 50% or greater reduction in Total Symptom Score when assessed from baseline to the end of cycle 6 as measured by the modified Myelofibrosis Symptoms Assessment Form (MFSAF) v2.0 diary2 (night sweats, itching, abdominal discomfort, early satiety, pain under ribs on left side, bone or muscle pain).1

About Inrebic

Inrebic (fedratinib) is an oral kinase inhibitor with activity against wild type and mutationally activated Janus Associated Kinase 2 (JAK2) and FMS-like tyrosine kinase 3 (FLT3). Inrebic is a JAK2-selective inhibitor with higher potency for JAK2 over family members JAK1, JAK3 and TYK2. Abnormal activation of JAK2 is associated with myeloproliferative neoplasms, including myelofibrosis and polycythemia vera. In cell models expressing mutationally active JAK2 or FLT3, Inrebic reduced phosphorylation of signal transducer and activator of transcription (STAT3/5) proteins, inhibited cell proliferation, and induced apoptotic cell death. In mouse models of JAK2V617F-driven myeloproliferative disease, Inrebic blocked phosphorylation of STAT3/5, increased survival and improved disease-associated symptoms, including reduction of white blood cells, hematocrit, splenomegaly and fibrosis.1

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