Source: European Medicines Agency (EU) Revision Year: 2021 Publisher: Bristol-Myers Squibb Pharma EEIG, Plaza 254, Blanchardstown Corporate Park 2, Dublin 15, D15 T867, Ireland
Pharmacotherapeutic group: Antineoplastic agents, protein kinase inhibitors
ATC code: L01EJ02
Fedratinib is a 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. Fedratinib reduced JAK2-mediated phosphorylation of signal transducer and activator of transcription (STAT3/5) proteins, inhibited malignant cell proliferation in vitro and in vivo.
Fedratinib inhibits cytokine induced signal transducer and activator of transcription (STAT)3 phosphorylation in whole blood from myelofibrosis patients. A single dose administration of 300, 400, or 500 mg of fedratinib resulted in maximal inhibition of STAT3 phosphorylation approximately 2 hours after dosing, with values returning to near baseline at 24 hours. Similar levels of inhibition were achieved at steady state PK on cycle 1 day 15, after administration of 300, 400 or 500 mg of fedratinib per day.
Two key clinical studies (JAKARTA and JAKARTA2) were conducted in patients with myelofibrosis. JAKARTA was a randomised placebo-controlled Phase 3 study in patients who are JAK inhibitor naïve. JAKARTA2 was a single-arm study in patients who have been treated with ruxolitinib.
JAKARTA was a double-blind, randomised, placebo-controlled Phase 3 study in patients with intermediate-2 or high-risk myelofibrosis, post-polycythaemia vera myelofibrosis or post-essential thrombocythemia myelofibrosis with splenomegaly and platelet count ≥50 × 109/L. A total of 289 patients were randomised to receive either Inrebic 500 mg (N=97), 400 mg (n=96) or placebo (n=96) once daily for at least 24 weeks (6 × 28 day cycles). Placebo patients could cross-over after 24 weeks to active treatment. The 400 mg dose appeared to be better tolerated than the 500 mg dose with fewer patients in the 400 mg arm reporting Grade 3 or 4 treatment emergent adverse events (TEAEs), TEAEs leading to dose reduction or dose interruption, and TEAEs leading to permanent treatment discontinuation. Fifty-nine percent (59%) of patients were male and the median age was 65 years (range 27 to 86 years), with 40% of patients between 65 and 74 years and 11% of patients at least 75 years. Sixty-four percent (64%) of patients had primary MF, 26% had post-polycythaemia 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 haemoglobin count at baseline was 10.2 g/dL (range 4.5 to 17.4 g/dL). The median platelet count was 213.5 × 109/L (range 23.0 to 1155.0 × 109/L); 16.3% of patients had a platelet count <100 × 109/L and 83.7% of patients had a platelet count ≥100 × 109/L. Patients had a median palpable spleen length of 15 cm (range 4 to 40 cm) at baseline and a median spleen volume as measured by magnetic resonance imaging (MRI) or computed tomography (CT) of 2568.0 mL (range of 316 to 8244 mL) at baseline. (The median normal spleen volume is approximately 215 mL).
The primary efficacy endpoint was the proportion of patients achieving ≥35% reduction from baseline in spleen volume at week 24 (end of cycle 6) as measured by MRI or CT confirmed 4 weeks later.
The key secondary endpoint was the proportion of patients with a ≥50% reduction in Total Symptom Score (TSS) from baseline to the end of cycle 6 as measured by the modified Myelofibrosis Symptoms Assessment Form (MFSAF) v2.0 diary.
Analyses of reduction in spleen volume are presented in Table 3.
Table 3. Percentage of patients achieving spleen volume reduction from baseline to the end of cycle 6 in the Phase 3 study, JAKARTA (intent-to-treat (ITT) Population):
| Spleen volume and spleen size at the end of cycle 6 | Inrebic 400 mg N=96 n (%) | Εικονικό φάρμακο N=96 n (%) |
|---|---|---|
| Spleen volume | ||
| Number ( % ) of patients with spleen volume reduction by 35% or more at the end of cycle 6 | 45 (46,9) | 1 (1,0) |
| 95% confidence interval | 36,9, 56,9 | 0,0, 3,1 |
| p-value | p<0,0001 | |
| Number ( % ) of patients with spleen volume reduction by 35% or more at the end of cycle 6 (with a follow-up scan 4 weeks later) | 35 (36,5) | 1 (1,0) |
| 95% confidence interval | 26,8, 46,1 | 0,0, 3,1 |
| p-value | p<0,0001 | |
A higher proportion of patients in Inrebic 400 mg group achieved a ≥35% reduction from baseline in spleen volume regardless of the presence or absence of the JAKV617F mutation.
Based on Kaplan-Meier estimates, the median duration of spleen response was 18.2 months for the Inrebic 400 mg group.
The modified MFSAF included 6 key MF associated symptoms: night sweats, itching, abdominal discomfort, early satiety, pain under ribs on left side, and bone or muscle pain. The symptoms were measured on a scale from 0 (absent) to 10 (worst imaginable).
The percentage of patients (95% confidence interval) with a ≥ 50% reduction in TSS at the end of cycle 6 was 40.4% (36/89, 95% CI:30.3%, 50.6%) in the Inrebic 400 mg arm and 8.6% (7/81, 95% CI: 2.5%, 14.8%) in the placebo arm.
JAKARTA2, was a multicentre, open-label, single-arm study in patients previously exposed to ruxolitinib with a diagnosis of intermediate-1 with symptoms, intermediate-2 or high-risk primary myelofibrosis, post-polycythaemia vera myelofibrosis or post-essential thrombocythemia myelofibrosis with splenomegaly and platelet count ≥50 × 109/L. A total of 97 patients who were heavily pre-treated (79% of patients had received ≥2 prior therapies and 13% had received ≥ 4 prior therapies) were enrolled and started treatment with Inrebic 400 mg once daily with dose escalation up to 600 mg permitted. Fifty-five percent (55%) of patients were male and the median age was 67 years (range 38 to 83 years) with 46% of patients between 65 and 74 years and 17% of patients at least 75 years. Fifty-five percent (55%) of patients had primary MF, 26% had post-polycythaemia vera MF, and 19% had post-essential thrombocythemia MF. Sixteen percent (16%) of patients had intermediate1 with symptoms, 49% had intermediate-2, and 35% had high-risk disease. The median haemoglobin count was 9.8 g/dL (range 6.8 to 15.3 g/dL) at baseline. The median platelet count was 147.0 × 109/L (range 48.0 to 929.0 × 109/L) at baseline; 34.0% of patients had a platelet count <100 × 109/L, and 66.0% of patients had a platelet count ≥100 × 109/L. Patients had a median palpable spleen length of 18 cm (range 5 to 36 cm) at baseline and a median spleen volume as measured by magnetic resonance imaging (MRI) or computed tomography (CT) of 2893.5 mL (range of 737 to 7815 mL) at baseline.
The median duration of prior exposure to ruxolitinib was 10.7 months (range 0.1 to 62.4 months). Seventy-one percent (71%) of patients had received a dose of either 30 mg or 40 mg daily of ruxolitinib prior to study entry.
The primary efficacy endpoint was the proportion of patients achieving a ≥35% reduction in spleen volume from baseline to the end of cycle 6 as measured by MRI or CT.
For the primary endpoint, the percentage of patients (95% confidence interval) who achieved a ≥35% reduction in spleen volume by MRI or CT at the 400 mg dose at the end of cycle 6 was 22.7% (22/97, 95% CI: 14.8%, 32.3%)
The European Medicines Agency has waived the obligation to submit the results of studies with Inrebic in all subsets of the paediatric population for the treatment of myelofibrosis (MF) (see section 4.2 for information on paediatric use).
Fedratinib at 300 mg to 500 mg once daily (0.75 to 1.25 times the recommended dose of 400 mg) results in a dose proportional increase in geometric mean fedratinib 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 ratios are similar in adult patients with primary MF, post-PV MF or post-ET MF, ranging from 3- to 4-fold.
At the dose of 400 mg once daily, the geometric mean (coefficient of variation, CV) fedratinib Cmax,ss is 1804 ng/mL (49) and AUCtau,ss is 26870 ng.hr/mL (43%) in patients with myelofibrosis.
Following 400 mg once daily oral administration, fedratinib is rapidly absorbed, achieving Cmax at steady-state in 3 hours (range: 2 to 4 hours). Based on a mass balance study in humans, oral absorption of fedratinib is estimated to be approximately 63-77%.
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 AUCinf up to 24% and Cmax up to 14% of a single 500 mg dose of fedratinib. Thus, fedratinib can be taken with or without food since no clinically meaningful effect on the pharmacokinetics of fedratinib was observed with food. Administration with a high fat meal may reduce the incidence of nausea and vomiting and thus fedratinib is recommended to be taken with food.
The mean apparent volume of distribution of fedratinib at steady-state is 1770 L in patients with myelofibrosis at 400 mg once daily dose suggesting extensive tissue distribution. The human plasma protein binding of fedratinib is approximately 95%, mostly to α1-acid glycoprotein.
Fedratinib is metabolized by multiple CYPs in vitro, with the predominant contribution from CYP3A4, and with a lesser contribution from CYP2C19 and FMOs.
Fedratinib was the predominant entity (approximately 80% of plasma radioactivity) in systemic circulation after oral administration of radiolabelled fedratinib. None of the metabolites contribute greater than 10% of total parent substance-related exposure in plasma.
Following a single oral dose of radiolabelled fedratinib, elimination was primarily through metabolism with approximately 77% of radioactivity excreted in faeces and only approximately 5% of the excreted in urine. Unchanged parent substance was the major component in excreta, accounting on average for approximately 23% and 3% of the dose in faeces and urine, respectively. Fedratinib pharmacokinetics is characterised 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.
In a population pharmacokinetics analysis of cumulative data from 452 patients, no clinically meaningful effect on the pharmacokinetics of fedratinib was observed with regard to age (analysis including 170 patients with age 65-74 years, 54 with age 75-84 years and 4 with age 85+ years), body weight (40 to 135 kg), gender (analysis including 249 males and 203 females) and race (analysis including 399 White, 7 Black, 44 Asian and 2 other).
Following a single 300 mg dose of fedratinib, the AUCinf of fedratinib increased by 1.5-fold in subjects with moderate renal impairment (CLcr 30 mL/min to 59 mL/min by C-G) and 1.9-fold in subjects with severe renal impairment (CLcr 15 mL/min to 29 mL/min by C-G), compared to that in subjects with normal renal function (CLcr ≥90 mL/min by C-G).
In a population pharmacokinetics analysis of cumulative data from 452 patients, no clinically meaningful effect on the pharmacokinetics of fedratinib was observed with regard to mild renal impairment (defined as 60 ≤CLcr <90 mL/min).
The safety and pharmacokinetics of a single oral 300 mg dose of fedratinib were evaluated in a study in subjects with normal hepatic function and with mild hepatic impairment (Child-Pugh class A). No clinically meaningful effect on the pharmacokinetics of fedratinib was observed in subjects with mild hepatic impairment compared to that in subjects with normal hepatic function.
In a population pharmacokinetics analysis of cumulative data from 452 patients, no clinically meaningful effect on the pharmacokinetics of fedratinib was observed with regard to mild (defined as total bilirubin ≤ ULN and AST > ULN or total bilirubin 1 to 1.5 times ULN and any AST increase; n=115) or moderate (defined as total bilirubin >1.5 to 3 times ULN and any AST; n=17) hepatic impairment.
Fedratinib pharmacokinetics has not been evaluated in patients with severe hepatic impairment (Child-Pugh Class C) (see section 4.2).
Fedratinib has been evaluated in safety pharmacology, repeated dose toxicity, genotoxicity and reproductive toxicity studies and in a carcinogenicity study. Fedratinib was not genotoxic and not carcinogenic in the 6-month Tg.rasH2 transgenic mouse model. Preclinical studies have demonstrated that at clinically relevant doses, fedratinib does not inhibit thiamine transport in the gastrointestinal tract or the brain (see sections 4.2 and 4.8).
In repeat-dose toxicity studies of up to 9 months in length, in mice, rats and dogs, the main toxicities observed included bone marrow hypoplasia; bile duct hypertrophy, necrosis and proliferation; lymphoid atrophy/depletion; renal tubular degeneration/necrosis; gastrointestinal tract inflammation; degeneration/necrosis of skeletal and cardiac muscle; histiocytic infiltration of the lung; and evidence of immunosuppression including pneumonia and/or abscesses. The highest plasma exposures achieved in the repeat-dose toxicology studies were associated with significant toxicity, including mortality, and were below the tolerated plasma exposures in patients at the highest recommended dose of 400 mg, suggesting humans are less sensitive than preclinical species to the toxicities of fedratinib. Clinically relevant exposures were not attained in the species used in the toxicology studies, therefore these studies have a limited value in producing clinically relevant safety data on fedratinib.
Fedratinib had no effect on the oestrous cycle parameters, mating performance, fertility, pregnancy rate or reproductive parameters in male or female rats. The exposure (AUC) was approximately 0.10 to 0.13 times the clinical exposure at the recommended dose of 400 mg once daily. In a repeat-dose toxicity study, at exposures approximately equivalent to human clinical exposure, fedratinib caused aspermia, oligospermia and seminiferous tubule degeneration in male dogs (see section 4.6).
Fedratinib administered to pregnant rats during organogenesis (gestation days 6 to 17) was associated with adverse embryo-foetal effects including post-implantation loss, lower foetal body weights, and skeletal variations. These effects occurred in rats at approximately 0.1 times the clinical exposure at the recommended human daily dose of 400 mg/day. In rabbits, fedratinib did not produce developmental toxicity at the highest dose level tested (exposure approximately 0.08 times the clinical exposure at the recommended human daily dose).
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