The FDA recently approved fedratinib for myelofibrosis, making it just the second drug approved for the disease, as well as the second approved JAK inhibitor. The approval was based on the phase III JAKARTA trial, in which the drug significantly reduced symptoms compared with a placebo. However, the drug comes with a Boxed Warning for encephalopathy.
The FDA recently greenlighted fedratinib (Inrebic; Celgene) for intermediate-2- or high-risk primary or secondary (post-polycythemia vera or post-essential thrombocythemia) myelofibrosis, making it just the second drug approved for the disease. The agency based its decision on a phase III trial in which the drug significantly reduced symptoms compared with a placebo. However, the drug comes with a Boxed Warning for encephalopathy.
Myelofibrosis is a rare blood cancer likely caused by abnormal blood stem cells in the bone marrow. Scar tissue then forms, impairing blood-cell production. This can cause the spleen to take over that task—and enlarge. Generally, patients at low risk require only surveillance, but those at intermediate and high risk of disease progression require treatment as symptoms—fatigue, weakness, shortness of breath, fever, and weight loss—worsen. The JAK1/2 inhibitor ruxolitinib (Jakafi; Incyte) has been the mainstay of treatment. Like ruxolitinib, fedratinib, a JAK2 inhibitor, disrupts JAK–STAT signaling, which becomes overactive in patients with myelofibrosis due to JAK2, CALR, or MPL mutations.
In the JAKARTA trial of 289 patients with newly diagnosed myelofibrosis, 37% of those treated with fedratinib had at least a 35% reduction in spleen volume, and 40% had at least a 50% improvement in symptoms, compared with 1% and 9%, respectively, of patients who received a placebo. In the phase II JAKARTA-2 trial, 55% of 83 patients resistant or intolerant to ruxolitinib had a splenic response.
However, side effects—namely encephalopathy—have been a concern: The FDA placed a clinical hold on fedratinib from 2013 to 2017 due to eight suspected cases of Wernicke's encephalopathy, a neurological disorder. The hold was lifted after a follow-up analysis confirmed only one case, but fedratinib now has a Boxed Warning for encephalopathy.
In JAKARTA, 21% of patients experienced serious side effects, most commonly cardiac failure and anemia, and 1% died from cardiogenic shock; 14% discontinued treatment due to side effects.
“Fedratinib has had a long road to get to this point, and I do think the approval is a positive development, particularly for patients who are resistant or intolerant to ruxolitinib,” says Ann Mullally, MD, of Dana-Farber/Harvard Cancer Center in Boston, MA, who was not connected to the trials.
Naveen Pemmaraju, MD, of The University of Texas MD Anderson Cancer Center in Houston, who was also not involved in the trials, notes that fedratinib's broad approval means it can be given to patients with different types of myelofibrosis and at different times.
As for encephalopathy, “I think it's appropriate to be concerned about it, and like any post-FDA drug approval, we should be vigilantly watching this to see what a real-world cohort of patients with myelofibrosis does,” Pemmaraju says.
Mullally agrees. “I think clinicians will be very aware of it, but I think it's a rare occurrence,” she says.
Pemmaraju now wonders whether fedratinib can be combined with other drugs, particularly those that have been used with ruxolitinib, and how it should be sequenced with ruxolitinib.
Mullally also sees a need for drugs specific to the JAK2 V617F mutation that leads to overactivity of the JAK–STAT pathway. “To have a big impact in this disease, we need potent selective drugs that can preferentially eradicate the cells that harbor the causative mutations, and then we'd have the potential to intervene earlier in the course of the disease,” she says. –Catherine Caruso
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