The Effect of Fedratinib, a Selective Inhibitor of Janus Kinase 2 (JAK2), on Weight and Metabolic Parameters in Patients with Intermediate (INT)- or High-risk Myelofibrosis (MF)
Authors: Tremblay Douglas , Cavalli Lara , Banerjee Sibabrata Raja , Rose Shelonitda , Mascarenhas John 
Published: November 2020

BACKGROUND: MF is characterized by stem cell-derived clonal myeloproliferation, abnormal cytokine expression, marrow fibrosis, splenomegaly, and shortened survival. Fedratinib (FEDR) is an oral, selective JAK2 inhibitor approved in the United States (US) for treatment (Tx) of INT-2 or high-risk MF. Ruxolitinib (RUX) is a JAK1/2 inhibitor approved in the US and European Union for Tx of INT- or high-risk MF. Clinical experience indicates that weight gain during RUX Tx is both common and substantial (mean increase ~4 kg from baseline [BL] in the COMFORT-I and COMFORT-II studies); begins during early Tx (~6-8 weeks from initiation) and continues throughout the course of Tx; and cannot be solely attributable to resolution of MF symptoms (eg, early satiety, abdominal discomfort) or splenomegaly (Mesa 2015; Sapre 2019; Molle 2020). The impact of FEDR on weight and metabolic parameters is of interest. FEDR was investigated in the randomized, placebo (PBO)-controlled, phase III JAKARTA trial in patients (pts) with JAK-inhibitor-naïve MF, and in the single-arm, phase II JAKARTA2 trial in pts with MF previously treated with RUX.
OBJECTIVE: Evaluate changes in weight, BMI, and metabolic parameters in pts treated with FEDR 400 mg/day.
METHODS: JAKARTA enrolled pts with INT-2 or high-risk primary or post-ET/post-PV MF, platelet counts ≥ 50 ×109/L, palpable splenomegaly (≥ 5 cm below LCM), and ECOG PS ≤ 2. Pts were randomized 1:1:1 to FEDR 400 mg, FEDR 500 mg, or PBO, administered once-daily for at least 6 continuous 28-day Tx cycles (ie, 24 weeks). This analysis focuses on pts randomized to FEDR 400 mg/day (approved starting dose) or PBO. We assessed changes from BL in weight, BMI, albumin, fasting glucose, and systolic and diastolic blood pressure (SBP and DBP) at the end of cycle 6 (EOC6; PBO pts could crossover to FEDR after EOC6). Reported changes from BL at EOC6 are for pts who completed 6 Tx cycles. As a supporting analysis, we assessed changes in these parameters for pts in JAKARTA2, who all received FEDR 400 mg/day (starting dose).
RESULTS: In JAKARTA, 96 pts received FEDR 400 mg and 95 pts received PBO. Median age at BL was 63 years (range 39-86) in the FEDR arm and 66 (27-85) in the PBO arm, and mean [±SD] spleen volumes were 2755 [1353] mL and 2928 [1484] mL, respectively. In the FEDR arm, mean weight at BL was 69.4 kg, and remained relatively unchanged during FEDR Tx, increasing by 0.8 kg from BL to EOC6 (Figure). In the PBO arm, mean weight decreased by 0.1 kg from BL (68.6 kg) to EOC6. Mean BMI increased nominally by 0.3 in the FEDR arm (BL 24.0) and was unchanged from BL (24.3) in the PBO arm. In the FEDR arm, mean albumin level increased slightly by 0.24 g/dL from BL (4.14 g/dL) to EOC6, and fasting glucose was unchanged from BL (5.5 mmol/L). No clinically significant changes were observed in SBP or DBP during FEDR Tx, which were 124.5 and 70.6 mmHg at BL, respectively, and increased nominally at EOC6 by 1.7 and 0.1 mmHg. In the PBO arm, mean albumin level was 4.07 g/dL at BL and decreased by 0.09 g/dL at EOC6, fasting glucose was 5.6 mmol/L and decreased by 0.1 mmol/L, SBP was 124.3 mmHg and increased by 1.3 mmHg, and DBP was 70.6 mmHg and decreased by 1.3 mmHg.
JAKARTA2 included 97 pts with advanced MF previously treated with RUX. Median age at study entry was 67 years (range 38-83) and mean [±SD] spleen volume was 3095 [1459] mL. At BL, mean weight was 73.5 kg and BMI was 25.5; these decreased by 0.6 kg and 0.2, respectively, by EOC6. From BL to EOC6, mean albumin, fasting glucose, SBP, and DBP changed by +0.39 g/dL (BL 3.94 g/dL), -0.6 mmol/L (BL 6.6 mmol/L), +3.8 mmHg (BL 124.1 mmHg), and +2.9 mmHg (BL 66.7 mmHg), respectively.
Median spleen volume change from BL to EOC6 with FEDR 400 mg was -40% in JAKARTA and -34% in JAKARTA2. There was no apparent correlation between changes in weight and spleen volume in pts treated with FEDR 400 mg in either trial.
CONCLUSIONS: Disproportionate weight gain not correlating with MF symptom resolution is a concern with long-term RUX Tx. In JAKARTA, FEDR did not meaningfully increase pts' weight or BMI after 6 Tx cycles. Modest increases in albumin compared with BL suggest improved nutritional status during FEDR Tx, and there were no clinically relevant changes in fasting glucose or BP after 6 FEDR Tx cycles. Changes in weight and metabolic parameters in JAKARTA2 support findings with FEDR 400 mg from JAKARTA. Unlike observations in pts treated with RUX (Mesa 2015), spleen volume reductions during FEDR Tx were not associated with weight increases.

Disclosures
Cavalli: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Banerjee:Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Rose:Bristol-Myers Squibb Company: Current Employment, Current equity holder in publicly-traded company. Mascarenhas:Incyte, Kartos, Roche, Promedior, Merck, Merus, Arog, CTI Biopharma, Janssen, and PharmaEssentia: Other: Research funding (institution); Celgene, Prelude, Galecto, Promedior, Geron, Constellation, and Incyte: Consultancy.