The FDA has granted a priority review designation to a new drug application (NDA) for fedratinib as a treatment for patients with myelofibrosis.
The designation is based on results from the phase III JAKARTA2 and phase II JAKARTA-2 trials3, which evaluated fedratinib in patients with primary or secondary myelofibrosis, and in those patients who were previously exposed to ruxolitinib (Jakafi), respectively. Results of both studies demonstrated a significant reduction in splenomegaly and symptom burden in patients with myelofibrosis.
Under the Prescription Drug User Fee Act, the FDA is expected to make a decision on the NDA by September 3, 2019, announced Celgene, the developer of the highly selective JAK2 inhibitor, in a press release. The FDA has also granted orphan drug designation for fedratinib for the treatment of patients with secondary and primary myelofibrosis.
“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, MD, chief medical officer of Celgene, in the press release. “Patients with myelofibrosis, including the number who are ineligible for or failed 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.”
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 36% (95% CI, 27%-46%) and 40% (95% CI, 30%-50%) of patients who received fedratinib at the 400- and 500-mg doses, respectively, compared with 1% of patients who were on the placebo arm (P <.001).
Additionally, symptom response rates at week 24 were 36% (95% CI, 26%-46%), 34% (95% CI, 24%-44%), and 7% (95% CI, 2%-13%) in the fedratinib at 400-mg, 500-mg, and placebo groups, respectively (P <.001).
Regarding safety, the common adverse events with fedratinib were anemia, gastrointestinal symptoms, and increased levels of liver transaminases, serum creatinine, and pancreatic enzymes. Four patients on the 500-mg daily dose had cases of encephalopathy; a diagnosis of Wernicke encephalopathy was diagnosed by magnetic resonance imaging in 3 patients and was suspected clinically in 1 patient.
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.
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.
In their statement, Celgene also said that the company plans to evaluate fedratinib in combination with luspatercept.
This article was originally published on OncLive as "FDA Grants Fedratinib Priority Review for Myelofibrosis."
1. U.S. FDA Grants Priority Review for Fedratinib New Drug Application in Myelofibrosis. Celgene. Published March 5, 2019. https://bit.ly/2H0Ec5i. Accessed March 5, 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.