Antineoplastic agents, protein kinase inhibitors. ATC code:
Pharmacology: Pharmacodynamics: Mechanism of action:
Ruxolitinib is a selective inhibitor of the Janus Associated Kinases (JAKs) JAK1 and JAK2 (IC50
values of 3.3 nM and 2.8 nM for JAK1 and JAK2 enzymes, respectively). These mediate the signalling of a number of cytokines and growth factors that are important for haematopoiesis and immune function.
MF and PV are myeloproliferative neoplasms known to be associated with dysregulated JAK1 and JAK2 signalling. The basis for the dysregulation is believed to include high levels of circulating cytokines that activate the JAK-STAT pathway, gain-of-function mutations such as JAK2V617F, and silencing of negative regulatory mechanisms. MF patients exhibit dysregulated JAK signalling regardless of JAK2V617F mutation status. Activating mutations in JAK2 (V617F or exon 12) are found in >95% of PV patients.
Ruxolitinib inhibits JAK-STAT signalling and cell proliferation of cytokine-dependent cellular models of haematological malignancies, as well as of Ba/F3 cells rendered cytokine-independent by expressing the JAK2V617F mutated protein, with IC50
ranging from 80-320 nM.
Ruxolitinib inhibits cytokine-induced STAT3 phosphorylation in whole blood from healthy subjects, MF patients and PV patients. Ruxolitinib resulted in maximal inhibition of STAT3 phosphorylation 2 hours after dosing which returned to near baseline by 8 hours in both healthy subjects and MF patients, indicating no accumulation of either parent or active metabolites.
Baseline elevations in inflammatory markers associated with constitutional symptoms such as TNFα, IL-6 and CRP in subjects with MF were decreased following treatment with ruxolitinib. MF patients did not become refractory to the pharmacodynamic effects of ruxolitinib treatment over time. Similarly, patients with PV also presented with baseline elevations in inflammatory markers and these markers were decreased following treatment with ruxolitinib.
In a thorough QT study in healthy subjects, there was no indication of a QT/QTc prolonging effect of ruxolitinib in single doses up to a supratherapeutic dose of 200 mg, indicating that ruxolitinib has no effect on cardiac repolarisation.
Clinical efficacy and safety:
Myelofibrosis: Two randomised phase 3 studies (COMFORT-I and COMFORT-II) were conducted in patients with MF (primary MF, post-polycythaemia vera MF or post-essential thrombocythaemia MF). In both studies, patients had palpable splenomegaly at least 5 cm below the costal margin and risk category of intermediate-2 or high risk based on the International Working Group (IWG) Consensus Criteria. The starting dose of Jakavi was based on platelet count. Patients with platelet counts ≤100,000/mm3
were not eligible for enrolment in COMFORT studies but 69 patients were enrolled in the EXPAND study, a Phase Ib, open label, dose-finding study in patients with MF (primary MF, post-polycythaemia vera MF or post-essential thrombocythaemia MF) and baseline platelet counts ≥50,000 and <100,000/mm3
COMFORT-I was a double-blind, randomised, placebo-controlled study in 309 patients who were refractory to or were not candidates for available therapy. The primary efficacy endpoint was proportion of subjects achieving ≥35% reduction from baseline in spleen volume at week 24 as measured by Magnetic Resonance Imaging (MRI) or Computed Tomography (CT).
Secondary endpoints included duration of maintenance of a ≥35% reduction from baseline in spleen volume, proportion of patients who had ≥50% reduction in total symptom score, changes in total symptom scores from baseline to week 24, as measured by the modified MF Symptom Assessment Form (MFSAF) v2.0 diary, and overall survival.
COMFORT-II was an open-label, randomised study in 219 patients. Patients were randomised 2:1 to ruxolitinib versus best available therapy. In the best available therapy arm, 47% of patients received hydroxyurea and 16% of patients received glucocorticoids. The primary efficacy endpoint was proportion of patients achieving ≥35% reduction from baseline in spleen volume at week 48 as measured by MRI or CT.
Secondary endpoints included proportion of patients achieving a ≥35% reduction of spleen volume from baseline at week 24 and duration of maintenance of a ≥35% reduction from baseline spleen volume.
In COMFORT-I and COMFORT-II, patient baseline demographics and disease characteristics were comparable between the treatment arms. (See Table 1.)
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A significantly higher proportion of patients in the Jakavi group achieved ≥35% reduction from baseline in spleen volume (Table 1) regardless of the presence or absence of the JAK2V617F mutation or the disease subtype (primary MF, post-polycythaemia vera MF, post-essential thrombocythaemia MF). (See Table 2.)
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The probability of maintaining spleen response (≥35% reduction) on Jakavi for at least 24 weeks was 89% in COMFORT-I and 87% in COMFORT-II; 52% maintained spleen responses for at least 48 weeks in COMFORT-II.
In COMFORT-I, 45.9% subjects in the Jakavi group achieved a ≥50% improvement from baseline in the week 24 total symptom score (measured using MFSAF diary v2.0), as compared to 5.3% in the placebo group (p<0.0001 using chi-square test). The mean change in the global health status at week 24, as measured by EORTC QLQ C30 was +12.3 for Jakavi and -3.4 for placebo (p<0.0001).
In COMFORT-I, after a median follow-up of 34.3 months, the death rate in patients randomised to the ruxolitinib arm was 27.1% versus 35.1% in patients randomised to placebo; HR 0.687; 95% CI 0.459-1.029; p=0.0668.
In COMFORT-I, after a median follow-up of 61.7 months, the death rate in patients randomised to the ruxolitinib arm was 44.5% (69 of 155 patients) versus 53.2% (82 of 154) in patients randomised to placebo. There was a 31% reduction in the risk of death in the ruxolitinib arm as compared to placebo (HR 0.69; 95% CI 0.50-0.96; p=0.025).
In COMFORT-II, after a median follow-up of 34.7 months, the death rate in patients randomised to ruxolitinib was 19.9% versus 30.1% in patients randomised to best available treatment (BAT); HR 0.48; 95% CI 0.28-0.85; p=0.009. In both studies, the lower death rates noted in the ruxolitinib arm were predominantly driven by the results obtained in the post polycythaemia vera and post essential thrombocythaemia subgroups.
In COMFORT-II, after a median follow-up of 55.9 months, the death rate in patients randomised to the ruxolitinib arm was 40.4% (59 of 146 patients) versus 47.9% (35 of 73 patients) in patients randomized to best available therapy (BAT). There was a 33% reduction in risk of death in the ruxolitinib arm compared to the BAT arm (HR 0.67; 95% CI 0.44-1.02; p=0.062).
Polycythaemia vera: A randomised, open-label, active-controlled phase 3 study (RESPONSE) was conducted in 222 patients with PV who were resistant to or intolerant of hydroxyurea defined based on the European Leukemia Net (ELN) international working group published criteria. 110 patients were randomised to the ruxolitinib arm and 112 patients to the BAT arm. The starting dose of Jakavi was 10 mg twice daily. Doses were then adjusted in individual patients based on tolerability and efficacy with a maximum dose of 25 mg twice daily. BAT was selected by the investigator on a patient-by-patient basis and included hydroxyurea (59.5%), interferon/pegylated interferon (11.7%), anagrelide (7.2%), pipobroman (1.8%) and observation (15.3%).
Baseline demographics and disease characteristics were comparable between the two treatments arms. The median age was 60 years (range 33 to 90 years). Patients in the ruxolitinib arm had PV diagnosis for a median of 8.2 years and had previously received hydroxyurea for a median of approximately 3 years. Most patients (>80%) had received at least two phlebotomies in the last 24 weeks prior to screening. Comparative data regarding long-term survival and incidence of disease complications is missing.
The primary composite endpoint was the proportion of patients achieving both an absence of phlebotomy eligibility (HCT control) and a ≥35% reduction in spleen volume from baseline at week 32. Phlebotomy eligibility was defined as a confirmed HCT of >45%, i.e. at least 3 percentage points higher than the HCT obtained at baseline or a confirmed HCT of >48%, depending on which was lower. Key secondary endpoints included the proportion of patients who achieved the primary endpoint and remained free from progression at week 48, as well as the proportion of patients achieving complete haematological remission at week 32.
The study met its primary objective and a higher proportion of patients in the Jakavi group achieved the primary composite endpoint and each of its individual components. Significantly more patients treated with Jakavi (23%) achieved a primary response (p<0.0001) compared to BAT (0.9%). Haematocrit control was achieved in 60% of patients in the Jakavi arm compared to 18.8% in the BAT arm and a ≥35% reduction in spleen volume was achieved in 40% of patients in the Jakavi arm compared to 0.9% in the BAT arm (figure).
Both key secondary endpoints were also met. The proportion of patients achieving a complete haematological remission was 23.6% on Jakavi compared to 8.0% on BAT (p=0.0013) and the proportion of patients achieving a durable primary response at week 48 was 20% on Jakavi and 0.9% on BAT (p<0.0001). (See figure.)
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Symptom burden was assessed using the MPN-SAF total symptom score (TSS) electronic patient diary, which consisted of 14 questions. At week 32, 49% and 64% of patients treated with ruxolitinib achieved a ≥50% reduction in TSS-14 and TSS-5, respectively, compared to only 5% and 11% of patients on BAT.
Treatment benefit perception was measured by the Patient Global Impression of Change (PGIC) questionnaire. 66% of patients treated with ruxolitinib compared to 19% treated with BAT reported an improvement as early as four weeks after beginning treatment. Improvement in perception of treatment benefit was also higher in patients treated with ruxolitinib at week 32 (78% versus 33%).
Additional analyses from the RESPONSE study to assess durability of response were conducted at week 80 and week 256 following randomisation. Out of 25 patients who had achieved primary response at week 32, 3 patients had progressed by week 80 and 6 patients by week 256. The probability to have maintained a response from week 32 up to week 80 and week 256 was 92% and 74%, respectively (see Table 3).
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A second randomised, open label, active-controlled phase 3b study (RESPONSE 2) was conducted in 149 PV patients who were resistant to, or intolerant of, hydroxyurea but without palpable splenomegaly. The primary endpoint defined as the proportion of patients achieving HCT control (absence of phlebotomy eligibility) at week 28 was met (62.2% in the Jakavi arm versus 18.7% in the BAT arm). The key secondary endpoint defined as the proportion of patients achieving complete haematological remission at week 28 was also met (23.0% in the Jakavi arm versus 5.3% in the BAT arm).
Ruxolitinib is a Biopharmaceutical Classification System (BCS) class 1 compound, with high permeability, high solubility and rapid dissolution characteristics. In clinical studies, ruxolitinib is rapidly absorbed after oral administration with maximal plasma concentration (Cmax
) achieved approximately 1 hour post-dose. Based on a human mass balance study, oral absorption of ruxolitinib, as ruxolitinib or metabolites formed under first-pass, is 95% or greater. Mean ruxolitinib Cmax
and total exposure (AUC) increased proportionally over a single dose range of 5-200 mg. There was no clinically relevant change in the pharmacokinetics of ruxolitinib upon administration with a high-fat meal. The mean Cmax
was moderately decreased (24%) while the mean AUC was nearly unchanged (4% increase) on dosing with a high-fat meal.
The mean volume of distribution at steady state is approximately 75 litres in MF and PV patients. At clinically relevant concentrations of ruxolitinib, binding to plasma proteins in vitro
is approximately 97%, mostly to albumin. A whole body autoradiography study in rats has shown that ruxolitinib does not penetrate the blood-brain barrier.
Ruxolitinib is mainly metabolised by CYP3A4 (>50%), with additional contribution from CYP2C9. Parent compound is the predominant entity in human plasma, representing approximately 60% of the drug-related material in circulation. Two major and active metabolites are present in plasma representing 25% and 11% of parent AUC. These metabolites have one half to one fifth of the parent JAK-related pharmacological activity. The sum total of all active metabolites contributes to 18% of the overall pharmacodynamics of ruxolitinib. At clinically relevant concentrations, ruxolitinib does not inhibit CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4 and is not a potent inducer of CYP1A2, CYP2B6 or CYP3A4 based on in vitro studies. In vitro data indicate that ruxolitinib may inhibit P-gp and BCRP.
Ruxolitinib is mainly eliminated through metabolism. The mean elimination half-life of ruxolitinib is approximately 3 hours. Following a single oral dose of [14
C]-labelled ruxolitinib in healthy adult subjects, elimination was predominately through metabolism, with 74% of radioactivity excreted in urine and 22% via faeces. Unchanged parent substance accounted for less than 1% of the excreted total radioactivity.
Dose proportionality was demonstrated in the single and multiple dose studies.
Effects of age, gender or race: Based on studies in healthy subjects, no relevant 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. The predicted oral clearance was 17.7 l/h in women and 22.1 l/h in men, with 39% inter-subject variability in MF patients. 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, based on a population pharmacokinetic evaluation in PV patients.
The safety and effectiveness of Jakavi in paediatric patients have not been established (see Pharmacodynamics as previously mentioned).
Renal function was determined using both Modification of Diet in Renal Disease (MDRD) and urinary creatinine. Following a single ruxolitinib dose of 25 mg, the exposure of ruxolitinib was similar in subjects with various degrees of renal impairment and in those with normal renal function. However, plasma AUC values of ruxolitinib metabolites tended to increase with increasing severity of renal impairment, and were most markedly increased in the subjects with severe renal impairment. It is unknown whether the increased metabolite exposure is of safety concern. A dose modification is recommended in patients with severe renal impairment and end-stage renal disease (see Dosage & Administration). Dosing only on dialysis days reduces the metabolite exposure, but also the pharmacodynamic effect, especially on the days between dialysis.
Following a single ruxolitinib dose of 25 mg in patients with varying degrees of hepatic impairment, the mean AUC for ruxolitinib was increased in patients with mild, moderate and severe hepatic impairment by 87%, 28% and 65%, respectively, compared to patients with normal hepatic function. There was no clear relationship between AUC and the degree of hepatic impairment based on Child-Pugh scores. The terminal elimination half-life
was prolonged in patients with hepatic impairment compared to healthy controls (4.1-5.0 hours versus 2.8 hours). A dose reduction of approximately 50% is recommended for patients with hepatic impairment (see Dosage & Administration).
Toxicology: Preclinical safety data:
Ruxolitinib has been evaluated in safety pharmacology, repeated dose toxicity, genotoxicity and reproductive toxicity studies and in a carcinogenicity study. Target organs associated with the pharmacological action of ruxolitinib in repeated dose studies include bone marrow, peripheral blood and lymphoid tissues. Infections generally associated with immunosuppression were noted in dogs. Adverse decreases in blood pressure along with increases in heart rate were noted in a dog telemetry study, and an adverse decrease in minute volume was noted in a respiratory study in rats. The margins (based on unbound Cmax
) at the non-adverse level in the dog and rat studies were 15.7-fold and 10.4-fold greater, respectively, than the maximum human recommended dose of 25 mg twice daily. No effects were noted in an evaluation of the neuropharmacological effects of ruxolitinib.
In juvenile rat studies, administration of ruxolitinib resulted in effects on growth and bone measures. Reduced bone growth was observed at doses ≥5 mg/kg/day when treatment started on postnatal day 7 (comparable to human newborn) and at ≥15 mg/kg/day when treatment started on postnatal days 14 or 21 (comparable to human infant, 1-3 years). Fractures and early termination of rats were observed at doses ≥30 mg/kg/day when treatment was started on postnatal day 7. Based on unbound AUC, the exposure at the NOAEL (no observed adverse effect level) in juvenile rats treated as early as postnatal day 7 was 0.3-fold that of adult patients at 25 mg twice daily, while reduced bone growth and fractures occurred at exposures that were 1.5- and 13-fold that of adult patients at 25 mg twice daily, respectively. The effects were generally more severe when administration was initiated earlier in the postnatal period. Other than bone development, the effects of ruxolitinib in juvenile rats were similar to those in adult rats. Juvenile rats are more sensitive than adult rats to ruxolitinib toxicity.
Ruxolitinib decreased foetal weight and increased post-implantation loss in animal studies. There was no evidence of a teratogenic effect in rats and rabbits. However, the exposure margins compared to the highest clinical dose were low and the results are therefore of limited relevance for humans. No effects were noted on fertility. In a pre- and post-natal development study, a slightly prolonged gestation period, reduced number of implantation sites, and reduced number of pups delivered were observed. In the pups, decreased mean initial body weights and short period of decreased mean body weight gain were observed. In lactating rats, ruxolitinib and/or its metabolites were excreted into the milk with a concentration that was 13-fold higher than the maternal plasma concentration. Ruxolitinib was not mutagenic or clastogenic. Ruxolitinib was not carcinogenic in the Tg.rasH2 transgenic mouse model.