The regulatory saga of fedratinib

Abstract

Fedratinib is an oral Janus Associated Kinase 2 (JAK2) inhibitor that became the second-ever drug to gain FDA approval for treatment of myelofibrosis (MF) in August of 2019. Specifically, fedratinib gained approval in patients with intermediate-2 or high-risk primary or secondary myelofibrosis. Ruxolitinib is the first JAK2 inhibitor that gained approval for this indication in November 2011. The sequence of events for approval of fedratinib, raises concerns about the appropriateness of controls in clinical trials. The purpose of this paper is to discuss the timeline for approval of each of these agents for myelofibrosis. Ruxolitinib was compared to placebo in the COMFORT-I trial, showing 35% reduction of spleen volume in 65 of 155 (41.9%) patients compared with 0.7% in the placebo group (p< 0.001). Ruxolitinib also achieved 50% reduction in total symptom score in 45.9% of patients, versus 5.3% in the placebo group (p< 0.001). Ruxolitinib was then compared to the standard of care at the time (i.e., hydroxyurea, glucocorticoids) in the COMFORT-II trial. Positive results of the COMFORT-I and COMFORT-II trials were announced in press releases in December 2010 and March 2011 respectively, which eventually led to its approval for treatment of MF in November 2011 (Figure 1). One month later enrollment for JAKARTA began in December 2011. Fedratinib received approval for treatment of MF based on the results of the JAKARTA study, a phase III trial that showed fedratinib was able achieve a 35% reduction in spleen volume in 35 of 96 (36%) patients compared to 1 of 96 (1%) patients in the placebo group (p< 0.001). It also yielded a 50% reduction in total modified Myelofibrosis Symptom Assessment Form symptom score in MF patients over placebo. Common adverse events included anemia, gastrointestinal symptoms, and increased levels of liver transaminases, serum creatinine, and pancreatic enzymes. That the JAKARTA trial lead to FDA approval of fedratinib as a first-line agent for MF without an active comparator speaks to the ongoing issue of the use of substandard control arms in trials testing new anticancer medications. In a recent analysis of control arm quality in randomized controlled trials leading to anticancer drug approvals between 2013 and 2018, Hilal et. al. found that 16 of 95 (17%) trials were conducted using suboptimal control arms. With regard to fedratinib, an appropriate control arm would have been the active treatment ruxolitinib, whose results were known and approval granted prior to enrollment. It can be argued that randomizing to placebo was in fact unethical. This is especially concerning given the toxicities of