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Jakafi

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Jakafi

CLINICAL PHARMACOLOGY

Mechanism Of Action

Ruxolitinib, a kinase inhibitor, inhibits Janus Associated Kinases (JAKs) JAK1 and JAK2 which mediate the signaling of a number of cytokines and growth factors that are important for hematopoiesis and immune function. JAK signaling involves recruitment of STATs (signal transducers and activators of transcription) to cytokine receptors, activation and subsequent localization of STATs to the nucleus leading to modulation of gene expression.

Myelofibrosis (MF) and polycythemia vera (PV) are myeloproliferative neoplasms (MPN) known to be associated with dysregulated JAK1 and JAK2 signaling. In a mouse model of JAK2V617F-positive MPN, oral administration of ruxolitinib prevented splenomegaly, preferentially decreased JAK2V617F mutant cells in the spleen and decreased circulating inflammatory cytokines (eg, TNF-α, IL-6).

Pharmacodynamics

Ruxolitinib inhibits cytokine induced STAT3 phosphorylation in whole blood from healthy subjects and MF and PV patients. Jakafi administration resulted in maximal inhibition of STAT3 phosphorylation 2 hours after dosing which returned to near baseline by 10 hours in both healthy subjects and MF and PV patients.

Pharmacokinetics

Absorption

In clinical studies, ruxolitinib is rapidly absorbed after oral Jakafi administration with maximal plasma concentration (Cmax) achieved within 1 to 2 hours post-dose. Based on a mass balance study in humans, oral absorption of ruxolitinib was estimated to be at least 95%. Mean ruxolitinib Cmax and total exposure (AUC) increased proportionally over a single dose range of 5 to 200 mg. There were no clinically relevant changes in the pharmacokinetics of ruxolitinib upon administration of Jakafi with a high-fat meal, with the mean Cmax moderately decreased (24%) and the mean AUC nearly unchanged (4% increase).

Distribution

The mean volume of distribution at steady-state is 72 L in MF patients with an associated inter-subject variability of 29% and 75 L in PV patients with an associated inter-subject variability of 23%. Binding to plasma proteins in vitro is approximately 97%, mostly to albumin.

Metabolism

In vitro studies suggest that ruxolitinib is metabolized by CYP3A4 and to a lesser extent by CYP2C9.

Elimination

Following a single oral dose of [14C]-labeled ruxolitinib in healthy adult subjects, elimination was predominately through metabolism with 74% of radioactivity excreted in urine and 22% excretion via feces. Unchanged drug accounted for less than 1% of the excreted total radioactivity. The mean elimination half-life of ruxolitinib is approximately 3 hours and the mean half-life of ruxolitinib + metabolites is approximately 5.8 hours.

Effects of Age, Gender, or Race

In healthy subjects, no significant differences in ruxolitinib pharmacokinetics were observed with regard to gender and race. In a population pharmacokinetic evaluation in MF patients, no relationship was apparent between oral clearance and patient age or race, and in women, clearance was 17.7 L/h and in men, 22.1 L/h with 39% inter-subject variability. Clearance was 12.7 L/h in PV patients, with a 42% inter-subject variability, and no relationship was apparent between oral clearance and gender, patient age or race in this patient population.

Drug Interactions

Strong CYP3A4 inhibitors: In a trial of 16 healthy volunteers, a single dose of 10 mg of Jakafi was administered alone on Day 1 and a single dose of 10 mg of Jakafi was administered on Day 5 in combination with 200 mg of ketoconazole (a strong CYP3A4 inhibitor, given twice daily on Days 2 to 5). Ketoconazole increased ruxolitinib Cmax and AUC by 33% and 91%, respectively. Ketoconazole also prolonged ruxolitinib half-life from 3.7 to 6.0 hours [see DOSAGE AND ADMINISTRATION and DRUG INTERACTIONS].

Fluconazole: Simulations using physiologically-based pharmacokinetic (PBPK) models suggested that fluconazole (a dual CYP3A4 and CYP2C9 inhibitor) increases steady state ruxolitinib AUC by approximately 100% to 300% following concomitant administration of 10 mg of Jakafi twice daily with 100 mg to 400 mg of fluconazole once daily, respectively [see DOSAGE AND ADMINISTRATION and DRUG INTERACTIONS].

Mild or moderate CYP3A4 inhibitors: In a trial of 15 healthy volunteers, a single dose of 10 mg of Jakafi was administered alone on Day 1 and a single dose of 10 mg of Jakafi was administered on Day 5 in combination with 500 mg of erythromycin (a moderate CYP3A4 inhibitor, given twice daily on Days 2 to 5). Erythromycin increased ruxolitinib Cmax and AUC by 8% and 27%, respectively [see DRUG INTERACTIONS].

CYP3A4 inducers: In a trial of 12 healthy volunteers, a single dose of 50 mg of Jakafi was administered alone on Day 1 and a single dose of 50 mg of Jakafi was administered on Day 13 in combination with 600 mg of rifampin (a strong CYP3A4 inducer, given once daily on Days 3 to 13). Rifampin decreased ruxolitinib Cmax and AUC by 32% and 61%, respectively. In addition, the relative exposure to ruxolitinib's active metabolites increased approximately 100% [see DRUG INTERACTIONS].

In vitro studies: In vitro, ruxolitinib and its M18 metabolite do not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4. Ruxolitinib is not an inducer of CYP1A2, CYP2B6 or CYP3A4 at clinically relevant concentrations.

In vitro, ruxolitinib and its M18 metabolite do not inhibit the P-gp, BCRP, OATP1B1, OATP1B3, OCT1, OCT2, OAT1 or OAT3 transport systems at clinically relevant concentrations. Ruxolitinib is not a substrate for the P-gp transporter.

Thorough QT Study

The effect of single dose ruxolitinib 25 mg and 200 mg on QTc interval was evaluated in a randomized, placebo-, and active-controlled (moxifloxacin 400 mg) four-period crossover thorough QT study in 47 healthy subjects. In a study with demonstrated ability to detect small effects, the upper bound of the one-sided 95% confidence interval for the largest placebo adjusted, baseline-corrected QTc based on Fridericia correction method (QTcF) was below 10 ms, the threshold for regulatory concern. The dose of 200 mg is adequate to represent the high exposure clinical scenario.

Clinical Studies

Myelofibrosis

Two randomized Phase 3 studies (Studies 1 and 2) were conducted in patients with myelofibrosis (either primary myelofibrosis, post-polycythemia vera myelofibrosis or post-essential thrombocythemia-myelofibrosis). In both studies, patients had palpable splenomegaly at least 5 cm below the costal margin and risk category of intermediate 2 (2 prognostic factors) or high risk (3 or more prognostic factors) based on the International Working Group Consensus Criteria (IWG).

The starting dose of Jakafi was based on platelet count. Patients with a platelet count between 100 and 200 X 109/L were started on Jakafi 15 mg twice daily and patients with a platelet count greater than 200 X 109/L were started on Jakafi 20 mg twice daily. Doses were then individualized based upon tolerability and efficacy with maximum doses of 20 mg twice daily for patients with platelet counts between 100 to less than or equal to 125 X 109/L, of 10 mg twice daily for patients with platelet counts between 75 to less than or equal to 100 X 109/L, and of 5 mg twice daily for patients with platelet counts between 50 to less than or equal to 75 X 109/L.

Study 1

Study 1 was a double-blind, randomized, placebo-controlled study in 309 patients who were refractory to or were not candidates for available therapy. The median age was 68 years (range 40 to 91 years) with 61% of patients older than 65 years and 54% were male. Fifty percent (50%) of patients had primary myelofibrosis, 31% had post-polycythemia vera myelofibrosis and 18% had post-essential thrombocythemia myelofibrosis. Twenty-one percent (21%) of patients had red blood cell transfusions within 8 weeks of enrollment in the study. The median hemoglobin count was 10.5 g/dL and the median platelet count was 251 X 109/L. Patients had a median palpable spleen length of 16 cm below the costal margin, with 81% having a spleen length 10 cm or greater below the costal margin. Patients had a median spleen volume as measured by magnetic resonance imaging (MRI) or computed tomography (CT) of 2595 cm³ (range 478 cm³ to 8881 cm³). (The upper limit of normal is approximately 300 cm³).

Patients were dosed with Jakafi or matching placebo. The primary efficacy endpoint was the proportion of patients achieving greater than or equal to a 35% reduction from baseline in spleen volume at Week 24 as measured by MRI or CT.

Secondary endpoints included duration of a 35% or greater reduction in spleen volume and proportion of patients with a 50% or greater reduction in Total Symptom Score from baseline to Week 24 as measured by the modified Myelofibrosis Symptom Assessment Form (MFSAF) v2.0 diary.

Study 2

Study 2 was an open-label, randomized study in 219 patients. Patients were randomized 2:1 to Jakafi versus best available therapy. Best available therapy was selected by the investigator on a patient-by-patient basis. In the best available therapy arm, the medications received by more than 10% of patients were hydroxyurea (47%) and glucocorticoids (16%). The median age was 66 years (range 35 to 85 years) with 52% of patients older than 65 years and 57% were male. Fifty-three percent (53%) of patients had primary myelofibrosis, 31% had post-polycythemia vera myelofibrosis and 16% had post-essential thrombocythemia myelofibrosis. Twenty-one percent (21%) of patients had red blood cell transfusions within 8 weeks of enrollment in the study. The median hemoglobin count was 10.4 g/dL and the median platelet count was 236 X 109/L. Patients had a median palpable spleen length of 15 cm below the costal margin, with 70% having a spleen length 10 cm or greater below the costal margin. Patients had a median spleen volume as measured by MRI or CT of 2381 cm³ (range 451 cm³ to 7765 cm³).

The primary efficacy endpoint was the proportion of patients achieving 35% or greater reduction from baseline in spleen volume at Week 48 as measured by MRI or CT.

A secondary endpoint in Study 2 was the proportion of patients achieving a 35% or greater reduction of spleen volume as measured by MRI or CT from baseline to Week 24.

Study 1 and 2 Efficacy Results

Efficacy analyses of the primary endpoint in Studies 1 and 2 are presented in Table 14 below. A significantly larger proportion of patients in the Jakafi group achieved a 35% or greater reduction in spleen volume from baseline in both studies compared to placebo in Study 1 and best available therapy in Study 2. A similar proportion of patients in the Jakafi group achieved a 50% or greater reduction in palpable spleen length.

Table 14: Percent of Patients with Myelofibrosis Achieving 35% or Greater Reduction from Baseline in Spleen Volume at Week 24 in Study 1 and at Week 48 in Study 2 (Intent to Treat)

  Study 1 Study 2
Jakafi
(N=155)
Placebo
(N=154)
Jakafi
(N=146)
Best Available Therapy
(N=73)
Time Points Week 24 Week 48
Number (%) of Patients with Spleen Volume Reduction by 35% or More 65 (42) 1 ( < 1) 41 (29) 0
P-value < 0.0001 < 0.0001

Figure 1 shows the percent change from baseline in spleen volume for each patient at Week 24 (Jakafi N=139, placebo N=106) or the last evaluation prior to Week 24 for patients who did not complete 24 weeks of randomized treatment (Jakafi N=16, placebo N=47). One (1) patient (placebo) with a missing baseline spleen volume is not included.

Figure 1: Percent Change from Baseline in Spleen Volume at Week 24 or Last Observation for Each Patient (Study 1)

Percent Change from Baseline in Spleen Volume at Week 24 or Last Observation for Each Patient - Illustration

In Study 1, myelofibrosis symptoms were a secondary endpoint and were measured using the modified Myelofibrosis Symptom Assessment Form (MFSAF) v2.0 diary. The modified MFSAF is a daily diary capturing the core symptoms of myelofibrosis (abdominal discomfort, pain under left ribs, night sweats, itching, bone/muscle pain and early satiety). Symptom scores ranged from 0 to 10 with 0 representing symptoms “absent” and 10 representing “worst imaginable” symptoms. These scores were added to create the daily total score, which has a maximum of 60.

Table 15 presents assessments of Total Symptom Score from baseline to Week 24 in Study 1 including the proportion of patients with at least a 50% reduction (ie, improvement in symptoms). At baseline, the mean Total Symptom Score was 18.0 in the Jakafi group and 16.5 in the placebo group. A higher proportion of patients in the Jakafi group had a 50% or greater reduction in Total Symptom Score than in the placebo group, with a median time to response of less than 4 weeks.

Table 15: Improvement in Total Symptom Score in Patients with Myelofibrosis

  Jakafi
(N=148)
Placebo
(N=152)
Number (%) of Patients with 50% or Greater Reduction in Total Symptom Score by Week 24 68 (46) 8 (5)
P-value < 0.0001

Figure 2 shows the percent change from baseline in Total Symptom Score for each patient at Week 24 (Jakafi N=129, placebo N=103) or the last evaluation on randomized therapy prior to Week 24 for patients who did not complete 24 weeks of randomized treatment (Jakafi N=16, placebo N=42). Results are excluded for 5 patients with a baseline Total Symptom Score of zero, 8 patients with missing baseline and 6 patients with insufficient post-baseline data.

Figure 2: Percent Change from Baseline in Total Symptom Score at Week 24 or Last Observation for Each Patient (Study 1)

Percent Change from Baseline in Total Symptom Score at Week 24 or Last Observation for Each Patient - Illustration

Figure 3 displays the proportion of patients with at least a 50% improvement in each of the individual symptoms that comprise 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 Jakafi.

Figure 3: Proportion of Patients With Myelofibrosis Achieving 50% or Greater Reduction in Individual Symptom Scores at Week 24

Proportion of Patients With Myelofibrosis Achieving 50% or Greater Reduction in Individual Symptom Scores at Week 24 - Illustration

Overall survival was a secondary endpoint in both Study 1 and Study 2. Patients in the control groups were eligible for crossover in both studies, and the median times to crossover were 9 months in Study 1 and 17 months in Study 2.

Figure 4 and Figure 5 show Kaplan-Meier curves of overall survival at prospectively planned analyses after all patients remaining on study had completed 144 weeks on study.

Figure 4: Overall Survival - Kaplan-Meier Curves by Treatment Group in Study 1

Overall Survival - Kaplan-Meier Curves by Treatment Group in Study 1 - Illustration

Figure 5: Overall Survival - Kaplan-Meier Curves by Treatment Group in Study 2

Overall Survival - Kaplan-Meier Curves by Treatment Group in Study 2 - Illustration

Polycythemia Vera

Study 3 was a randomized, open-label, active-controlled Phase 3 study conducted in 222 patients with polycythemia vera. Patients had been diagnosed with polycythemia vera for at least 24 weeks, had an inadequate response to or were intolerant of hydroxyurea, required phlebotomy and exhibited splenomegaly. All patients were required to demonstrate hematocrit control between 40-45% prior to randomization. The age ranged from 33 to 90 years with 30% of patients over 65 years of age and 66% were male. Patients had a median spleen volume as measured by MRI or CT of 1272 cm³ (range 254 cm³ to 5147 cm³) and median palpable spleen length below the costal margin was 7 cm.

Patients were randomized to Jakafi or best available therapy. The starting dose of Jakafi was 10 mg twice daily. Doses were then individualized based upon tolerability and efficacy with a maximum dose of 25 mg twice daily. At Week 32, 98 patients were still on Jakafi with 8% receiving greater than 20 mg twice daily, 15% receiving 20 mg twice daily, 33% receiving 15 mg twice daily, 34% receiving 10 mg twice daily, and 10% receiving less than 10 mg twice daily. Best available therapy (BAT) was selected by the investigator on a patient-by-patient basis and included hydroxyurea (60%), interferon/pegylated interferon (12%), anagrelide (7%), pipobroman (2%), lenalidomide/thalidomide (5%), and observation (15%).

The primary endpoint was the proportion of subjects achieving a response at Week 32, with response defined as having achieved both hematocrit control (the absence of phlebotomy eligibility beginning at the Week 8 visit and continuing through Week 32) and spleen volume reduction (a greater than or equal to 35% reduction from baseline in spleen volume at Week 32). Phlebotomy eligibility was defined as a confirmed hematocrit greater than 45% that is at least 3 percentage points higher than the hematocrit obtained at baseline or a confirmed hematocrit greater than 48%, whichever was lower. Secondary endpoints included the proportion of all randomized subjects who achieved the primary endpoint and who maintained their response 48 weeks after randomization, and the proportion of subjects achieving complete hematological remission at Week 32 with complete hematological remission defined as achieving hematocrit control, platelet count less than or equal to 400 X 109/L, and white blood cell count less than or equal to 10 X 109/L.

Results of the primary and secondary endpoints are presented in Table 16. A significantly larger proportion of patients in the Jakafi group achieved a response for the primary endpoint compared to best available therapy at Week 32 and maintained their response 48 weeks after randomization. A significantly larger proportion of patients in the Jakafi group compared to best available therapy also achieved complete hematological remission at Week 32.

Table 16: Percent of Patients with Polycythemia Vera Achieving the Primary and Key Secondary Endpoints (Intent to Treat)

  Jakafi
(N=110)
Best Available Therapy
(N=112)
Number (%) of Patients Achieving a Primary Response at Week 32 23 (21%) 1 ( < 1%)
95% CI of the response rate (%) (14%, 30%) (0%, 5%)
P-value < 0.0001
Number (%) of Patients Achieving a Durable Primary Response at Week 48 21 (19%) 1 ( < 1%)
95% CI of the response rate (%) (12%, 28%) (0%, 5%)
P-value < 0.0001
Number (%) of Patients Achieving Complete Hematological Remission at Week 32 26 (24%) 10 (9%)
95% CI of the response rate (%) (16%, 33%) (4%, 16%)
P-value 0.0034
Primary Response defined as having achieved both the absence of phlebotomy eligibility beginning at the Week 8 visit and continuing through Week 32 and a greater than or equal to 35% reduction from baseline in spleen volume at Week 32.

For the proportion of patients achieving each of the individual components that make up the primary endpoint at Week 32, there were 60% of the patients with hematocrit control in the Jakafi group vs. 20% of the patients in the best available therapy group. There were 38% of the patients with spleen volume reduction from baseline greater than or equal to 35% at Week 32 in the Jakafi group vs. less than 1% of the patients in the best available therapy group.

Last reviewed on RxList: 12/15/2014
This monograph has been modified to include the generic and brand name in many instances.

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