U.S. FDA Grants Priority Review for Fedratinib New Drug Application in Myelofibrosis

The U.S. Food and Drug Administration (FDA) will give a priority review to the experimental targeted drug fedratinib as a potential treatment for the blood cancer myelofibrosis.

The drug’s developer, Celgene Corporation, announced March 5 that the FDA had accepted its New Drug Application (NDA) for the priority review, which means that the agency will expedite its evaluation of the drug because there is evidence it could significantly improve treatment options for myelofibrosis. The FDA plans to issue a decision about whether it will approve the drug on or before Sept. 3.

The FDA has also granted fedratinib Orphan Drug designation for this indication because myelofibrosis is rare; this makes Celgene eligible for certain financial incentives as it develops the drug.

Fedratinib is a highly selective JAK2 inhibitor, a new member of an existing class of drugs. It works by inhibiting the activity of STAT 3 and 5 proteins, which slows the growth of, and may kill, cancer cells.

Myelofibrosis is a group of rare cancers in which bone marrow is progressively replaced by scar tissue so that it can’t generate healthy blood cells.

“The acceptance of the NDA and granting of priority review for fedratinib represent the first potential new treatment option after many years for patients affected by myelofibrosis,” said Jay Backstrom, M.D., chief medical officer for Celgene. “Patients with myelofibrosis, including the number who are ineligible for (or whose disease progressed while taking) existing therapy continues to increase, representing a well-defined unmet medical need. We believe fedratinib can play an important role in the treatment of myelofibrosis, and we look forward to working with the FDA as the review process advances.”

The evidence that the FDA will consider came from two clinical trials of fedratinib: a randomized, placebo-controlled, phase 3 trial called JAKARTA that included patients with primary or secondary myelofibrosis, and a single-arm, open-label phase 2 trial called JAKARTA2, which enrolled patients with primary or secondary myelofibrosis who had previously taken Jakafi (ruxolitinib), a drug in the same class as fedratinib and the only FDA-approved treatment for the disease.

The JAKARTA trial tested the efficacy of daily oral doses (400 mg or 500 mg) of fedratinib compared with placebo in patients with intermediate-2 or high-risk primary myelofibrosis; myelofibrosis that developed after polycythemia vera; or myelofibrosis with spleen enlargement that developed after essential thrombocythemia. The study included 289 subjects enrolled at 94 sites in 24 countries.

The study’s main measurement was the proportion of patients who experienced a reduction in spleen volume of at least 35 percent after six one-month treatment cycles, detected via MRI or CT scan four weeks after the conclusion of treatment. The trial also measured the proportion of patients with a reduction of 50 percent or more in Total Symptom Score after six one-month treatment cycles, as measured by the modified Myelofibrosis Symptoms Assessment Form (MFSAF) v2.0 diary.

Results of the 289-patient trial, reported in 2013, showed spleen response rates of 47 and 49 percent with the 400 and 500 mg doses, respectively, at week 24; four weeks later, the numbers had dropped to 36 and 40 percent.

JAKARTA2 evaluated the efficacy of a once-daily dose of fedratinib (400 mg starting dose) in patients previously treated with JAKAFI and with a diagnosis of intermediate-1 myelofibrosis with symptoms, intermediate-2 or high-risk primary myelofibrosis, post-polycythemia vera myelofibrosis or post-essential thrombocythemia myelofibrosis. The study included 97 subjects enrolled at 40 sites in 10 countries. The study’s measurement goals were the same as those in the JAKARTA study.

Results, reported in 2017, showed that, of 83 evaluable patients, 46 achieved a spleen response, the study’s authors reported. Common serious or severe side effects included anemia and thrombocytopenia (a low blood platelet count).

The FDA placed a clinical hold on the fedratinib program in November 2013 after potential cases of Wernicke’s encephalopathy, a thiamin deficiency that can cause confusion and other symptoms, were reported among approximately 1 percent of subjects in clinical trials, Celgene stated in a press release. The FDA removed the clinical hold in August 2017, the company said.

Celgene said it plans to launch future trials that will evaluate fedratinib in combination with luspatercept, designed to repair a defect in the maturation of red blood cells that causes chronic anemia.