Mechanism Of Action
Fedratinib is an oral kinase inhibitor with activity
against wild type and mutationally activated Janus Associated Kinase 2 (JAK2)
and FMS-like tyrosine kinase 3 (FLT3). Fedratinib is a JAK2-selective inhibitor
with higher inhibitory activity for JAK2 over family members JAK1, JAK3 and
TYK2. Abnormal activation of JAK2 is associated with myeloproliferative
neoplasms (MPNs), including myelofibrosis and polycythemia vera. In cell models
expressing mutationally active JAK2V617F or FLT3ITD,
fedratinib reduced phosphorylation of signal transducer and activator of
transcription (STAT3/5) proteins, inhibited cell proliferation, and induced
apoptotic cell death. In mouse models of JAK2V617F-driven
myeloproliferative disease, fedratinib blocked phosphorylation of STAT3/5, and
improved survival, white blood cell counts, hematocrit, splenomegaly, and
Fedratinib inhibited cytokine-induced STAT3
phosphorylation in whole blood from patients with myelofibrosis. The inhibition
of STAT3 phosphorylation was maximal approximately 2 hours after the first
dose, with values returning to near baseline at 24 hours. After daily
administration of fedratinib, levels of inhibition at steady state PK were
similar to the maximal inhibition reached after the first dose of 300 (0.75
times the recommended dose), 400 or 500 mg (1.25 times the recommended dose) of
The potential for QTc prolongation with fedratinib was
evaluated in 31 patients with solid tumors. No large mean increase in the QTc
interval (>20 ms) was detected with daily dosing of fedratinib 500 mg (1.25
times the recommended dose) for 14 days.
INREBIC at 300 mg to 500 mg once daily (0.75 to 1.25
times the recommended dose) results in a dose proportional increase in
geometric mean fedratinib peak concentrations (Cmax) and the area under the
plasma concentration time curve over the dosing interval (AUCtau). The mean
steady state levels are achieved within 15 days of daily dosing. The mean
accumulation ratio ranged between 3-to 4-fold.
At the dose of 400 mg once daily, the geometric mean
(coefficient of variation, %CV) fedratinib Cmax is 1804 ng/mL (49%) and AUCtau is
26870 ng•hr/mL (43%) in patients with myelofibrosis.
Following 400 mg once daily, fedratinib median time to
peak concentrations (Tmax) at steady-state is 3 hours (range: 2 to 4 hours).
Effect Of Food
A low-fat, low-calorie (total 162 calories: 6% from fat,
78% from carbohydrate and 16% from protein) or a high-fat, high-calorie (total
815 calories: 52% from fat, 33% from carbohydrate and 15% from protein) meal
increased area under the curve over time to infinity (AUCinf) up to 24% and Cmax
up to 14% of a single 500 mg dose of fedratinib.
The apparent volume of distribution of fedratinib at
steady-state is 1770 L in patients with myelofibrosis at 400 mg once daily
dose. Fedratinib is 92% or greater bound to human plasma proteins.
Fedratinib pharmacokinetics is characterized by a
biphasic disposition with an effective half-life of 41 hours, a terminal
half-life of approximately 114 hours, and apparent clearance (CL/F) (%CV) of 13
L/hr (51%) in patients with myelofibrosis.
Fedratinib is metabolized by CYP3A4, CYP2C19, and
flavin-containing monooxygenase 3 (FMO3). Fedratinib accounts for approximately
80% of total circulating drug in plasma after oral administration.
Following a single oral dose of radiolabeled fedratinib,
77% (23% unchanged) of the administered dose was excreted in feces and 5% (3%
unchanged) was eliminated in urine.
Age (20 years to 95 years), race (White, Asians), sex,
body weight (40 kg to 135 kg), mild [total bilirubin ≤upper limit of
normal (ULN) and AST >ULN or total bilirubin 1 to 1.5 times ULN and any AST]
or moderate (total bilirubin >1.5 to 3 times ULN and any AST) hepatic
impairment, and mild (CLcr 60 mL/min to 89 mL/min by C-G) renal impairment did
not have clinically meaningful effects on the pharmacokinetics of fedratinib.
The effect of severe (total bilirubin >3 times ULN and
any AST) hepatic impairment on fedratinib pharmacokinetics is unknown.
Patients With Renal Impairment
Following a single 300 mg dose of INREBIC, the AUCinf of
fedratinib increased by 1.5-fold in subjects with moderate (CLcr 30 mL/min to
59 mL/min by C-G) renal impairment and 1.9-fold in subjects with severe (CLcr
15 mL/min to 29 mL/min by C-G) renal impairment, compared to that in subjects
with normal renal function (CLcr ≥90 mL/min by C-G) [see DOSAGE AND
ADMINISTRATION and Renal Impairment].
Drug Interaction Studies
Clinical Studies And Model-Informed Approaches
Effect Of Strong And Moderate CYP3A4 Inhibitors
Coadministration of ketoconazole (strong CYP3A4
inhibitor: 200 mg twice daily) with a single dose of INREBIC (300 mg) increased
fedratinib AUCinf by 3-fold [see DOSAGE AND ADMINISTRATION and DRUG
Based on modeling and simulation, coadministration of a
strong CYP3A4 inhibitor such as ketoconazole (400 mg once daily) with INREBIC
400 mg once daily is predicted to increase fedratinib AUC at steady state by 2Âfold
[see DOSAGE AND ADMINISTRATION and DRUG INTERACTIONS].
Based on modeling and simulation, coadministration of
moderate CYP3A4 inhibitors, erythromycin (500 mg three times daily) or
diltiazem (120 mg twice daily), with INREBIC 400 mg once daily is predicted to
increase fedratinib AUC at steady state by 1.2-, and 1.1-fold, respectively.
Effect Of Dual CYP3A4 And CYP2C19 Inhibitor
The effect of concomitant administration with a dual
CYP3A4 and CYP2C19 inhibitor on fedratinib pharmacokinetics is not known [see DRUG
Effect Of Strong And Moderate CYP3A4 Inducers
The effect of concomitant administration with a strong or
moderate CYP3A4 inducer on fedratinib pharmacokinetics is not known [see DRUG
Effect Of Gastric Acid Reducing Agents
Coadministration of pantoprazole (proton pump inhibitor:
40 mg once daily) with a single dose of INREBIC (500 mg) increased fedratinib
AUCinf by 1.2-fold.
Effect Of Fedratinib On Drugs That Are CYP3A, CYP2C19, Or
Coadministration of a single dose of midazolam (CYP3A
substrate: 2 mg), omeprazole (CYP2C19 substrate: 20 mg), and metoprolol (CYP2D6
substrate: 100 mg) increased midazolam, omeprazole, or metoprolol AUCinf by 4-,
3-, and 2-fold, respectively [see DRUG INTERACTIONS].
In Vitro Studies
Fedratinib As A Substrate For Transporters
Fedratinib is a substrate of P-glycoprotein (P-gp) but
not breast cancer resistance protein (BCRP), BSEP, multidrug resistance protein
(MRP), MRP2, and organic anion transporting polypeptide (OATP)1B1 and OATP1B3.
Effect Of Fedratinib On Transporter Substrates
Fedratinib inhibits P-gp, BCRP, OATP1B1, OATP1B3, organic
cation transporter (OCT)2, multidrug and toxin extrusion (MATE) protein 1, and
MATE-2K, but not BSEP, MRP2, and organic anion transporter (OAT)1 and OAT3 in
Animal Toxicology And/Or Pharmacology
The JAK/STAT pathway has been implicated in bone
formation and metabolism, and its inhibition may cause bone abnormalities, e.g.
in developing bone. There is currently no evidence of bone abnormalities in patients
who received INREBIC.
JAKARTA (NCT01437787) was a double-blind, randomized,
placebo-controlled trial in patients with intermediate-2 or high-risk
myelofibrosis, post-polycythemia vera myelofibrosis or post-essential thrombocythemia
myelofibrosis with splenomegaly. A total of 289 patients were randomized to
receive either INREBIC 500 mg (N=97), 400 mg (n=96) or placebo (n=96) once
daily for at least 6 cycles. The median age was 65 years (range 27 to 86
years), 47% of patients were older than 65 years and 59% were male. Sixty-four
percent (64%) of patients had primary MF, 26% had post-polycythemia vera MF,
and 10% had post-essential thrombocythemia MF. Fifty-two percent (52%) of
patients had intermediate-2 risk, and 48% had high-risk disease. The median
baseline hemoglobin level was 10.2 g/dL. The median baseline platelet count was
214 x 109/L; 16% of patients had a platelet count <100 x 109/L and 84% of
patients had a platelet count ≥100 x 109/L. Patients had a baseline median
palpable spleen length of 15 cm. Patients had a baseline median spleen volume
as measured by magnetic resonance imaging (MRI) or computed tomography (CT) of
2568 mL (range of 316 to 8244 mL) (the upper limit of normal is approximately
300 mL). Patients underwent MRI or CT spleen volume assessment (after the third
and sixth cycle) with a follow-up scan 4 weeks after Cycle 6.
The efficacy of INREBIC in the treatment of patients with
primary or secondary myelofibrosis was established based upon the proportion of
patients achieving greater than or equal to a 35% reduction from baseline in
spleen volume at the End of Cycle 6 as measured by MRI or CT with a follow-up
scan 4 weeks later.
Efficacy analyses are presented in Table 5.
Table 5: Percent of Patients Achieving 35% or Greater
Reduction from Baseline in Spleen Volume at the End of Cycle 6 in the Phase 3
Study, JAKARTA (ITT Population)
|Spleen Response by MRI/CT at the End of Cycle 6 with a Follow-up Scan 4 Weeks Later
||INREBIC 400 mg
N=96 n (%)
N=96 n (%)
|Number (%) of Patients with Spleen Volume Reduction by 35% or More
Figure 1 shows the percent change in spleen volume from
baseline for patients who have an evaluable MRI/CT at the End of Cycle 6.
Figure 1: Percent Change in Spleen Volume from
Baseline at the End of Cycle 6 for Each Patient in the Phase 3 Study, JAKARTA
N*: Subjects with available percent change in spleen
volume at EOC6.
Based on Kaplan-Meier estimates, the median duration of
spleen response was 18.2 months for the INREBIC 400 mg group.
Additional outcomes included the proportion of patients
with a 50% or greater reduction in Total Symptom Score from baseline to the End
of Cycle 6 as measured by the modified Myelofibrosis Symptom Assessment Form
(MFSAF) v2.0 diary.
The modified MFSAF v2.0 is a patient diary capturing the
6 core symptoms of MF: night sweats, itching, abdominal discomfort, early
satiety, pain under ribs on left side, and bone or muscle pain. The modified
MFSAF diary was completed daily during the week prior to Day 1 of each
treatment cycle, and at the End of Cycle 6. Symptom scores ranged from 0
(“absent”) to 10 (“worst imaginable”). These scores were added to create the
Total Symptom Score, which has a maximum score of 60. At baseline, the mean Total
Symptom Score was 17.95 in the 400 mg group and 15.45 in the placebo group.
The proportion of patients with a 50% or greater
reduction in Total Symptom Score was 40% in the INREBIC 400 mg group and 9% in
the placebo group (Table 6). Results are excluded for 22 patients: 6 patients
with a baseline Total Symptom Score of zero (2 in the INREBIC 400 mg group and
4 in the placebo group) and 16 patients with missing baseline (5 in the INREBIC
400 mg group and 11 in the placebo group).
Table 6: Improvement in Total Symptom Score in
Patients with Myelofibrosis in the Phase 3 Study, JAKARTA
||INREBIC 400 mg
(N=89) n (%)
(N=81) n (%)
|Number (%) of Patients with 50% or Greater Reduction in Total Symptom Score at the End of Cycle 6
Figure 2 shows the percent change in Total Symptom Score
from baseline at the End of Cycle 6 for each patient.
Figure 2: Percent Change from Baseline in Total
Symptom Score at the End of Cycle 6 for Each Patient in the Phase 3 Study,
N*: Subjects with available percent change in Total
Symptom Score at EOC6.
Figure 3 displays the proportion of patients with at
least a 50% improvement in each of the individual symptoms that comprised the
Total Symptom Score indicating that all 6 of the symptoms contributed to the
higher Total Symptom Score response rate in the group treated with INREBIC.
Figure 3: Proportion of Patients Achieving 50% or
Greater Reduction in Individual Symptom Scores at the End of Cycle 6 with
Non-Zero Baseline Scores