Ruxolitinib
Dr Viraj Ashok Shinde
Department of Pharmacology
Junior Resident 3

Overview
Introduction
Pharmacodynamics and Pharmacokinetics
Therapeutic efficacy and Tolerability
Dosage and administration
Place of ruxolitinib in management of polycythemia
vera

Introduction
 Polycythaemia vera (PV) - Myeloproliferative
neoplasm characterized by erythrocytosis, with
potential for leukocytosis &/or thrombocytosis
 Vascular complications
 Major cause of morbidity & mortality
 CVS events - Stroke & Coronary heart disease
 Main goal of therapy - Prevent thrombotic
complications by maintaining haematocrit at 45 %

Introduction
 Phlebotomy & low-dose aspirin - Used in
low-risk patients
 Addition of oral hydroxyurea - Greater
risk of thrombosis
 Interferon - firstline agent in high-risk
patients
 Good control of red blood cell counts is
generally achieved in 75–80 % of PV
patients treated with hydroxyurea

Introduction cont’d
 Patients responded inadequately to or are
intolerant of hydroxyurea (mucocutaneous
ulcers are main adverse effect), alternative
treatment options are needed ??
 Pathogenesis - Complex & not fully understood -
Involves dysregulation of Janus kinase (JAK)-signal
transducers & activators of transcription (STAT)
pathway

Pharmacodynamic Properties
of Ruxolitinib
 Potent & Selective inhibitor of JAK1 & 2
 Mediate signalling of several cytokines & growth factors -
important for haematopoiesis & immune function
 Main molecular abnormality of PV
 Somatic mutation in JAK2 gene (JAK2V617F)
 Present in 95 % patients
 Mouse model of JAK2V617F - Positive myeloproliferative
neoplasms, ruxolitinib associated with ↓ splenomegaly, ↓
levels of circulating inflammatory cytokines [e.g.
interleukin (IL)-6, tumour necrosis factor-a] & ↑ survival

Pharmacodynamic Properties
of Ruxolitinib
 Ruxolitinib inhibited
 Cytokine-induced phosphorylation of STAT3 (a substrate
of JAK1 & 2)
 Cellular proliferation in cellular models of cytokine-
dependent haematological malignancies, as well as
inducing apoptosis in cells harbouring JAK2V617F
mutation (e.g. JAK2V617F - Positive BaF3 cells)
 Single doses of ruxolitinib up to a supratherapeutic
dose of 200 mg had no effect on cardiac
repolarization, - No prolongation of corrected QT
interval

Pharmacokinetic Properties
of Ruxolitinib
 Oral administration - Well absorbed (≥ 95 %), with
maximum plasma concentrations (Cmax) achieved - 1–
2 h
 Pharmacokinetics not affected when administered
with high-fat meal - Drug may be administered with or
without food
 At steady state - Mean apparent volume of distribution
≈ 75 L

Pharmacokinetic Properties
of Ruxolitinib
 Drug is extensively bound (≈ 97 %) to plasma proteins
(primarily albumin) in vitro
 Metabolised by - Cytochrome P450 (CYP) 3A4 &
CYP2C9 isoenzyme
 Excreted – 74% - Urine
- 22 % - Faeces

Pharmacokinetic Properties
of Ruxolitinib
 Mean elimination half-life ≈ 3hrs
 Population pharmacokinetic analyses in patients
with myeloproliferative neoplasms indicate that
dosage adjustments are not required on basis of
gender, age, race or bodyweight

Therapeutic Efficacy of
Ruxolitinib
Phase III RESPONSE Trial
 Significantly (p < 0.001) greater proportion of patients
in ruxolitinib than best-available-therapy group
achieved composite primary endpoint at week 32
 Complete haematological response achieved by
significantly more patients in ruxolitinib group than in
best available-therapy group

Therapeutic efficacy cont’d
 Primary response to therapy at week 32 maintained
at week 48 -
Significantly more ruxolitinib than best available
therapy (19.1 vs. 0.9 % ; p < 0.0001)
 Probability that primary response to ruxolitinib would
be maintained from time of initial response to 1 year
was 94 %
Response rates for individual endpoints -
maintained over time - probabilities of
94 % for maintaining haematocrit control
100 % for maintaining a reduction of ≥ 35 % in spleen
volume at 1 year

Therapeutic efficacy cont’d
 Fewer patients in ruxolitinib group than
best available-therapy group - required
phlebotomies between week 8 and 32

Therapeutic efficacy cont’d
Symptoms and Patient-Reported Outcome
 Reduction (improvement) of ≥ 50 % from baseline to
week 32 in score of 14-item Myeloproliferative Neoplasm
Symptom Assessment Form (MPN-SAF)
Reported more in ruxolitinib [36 of 74
patients (49 %)] than best available-therapy [4 of 81 (5
%)] group
 At week 32, Patient Global Impression of Change scale -
much or very much improved from baseline
66 % patients - Ruxolitinib group
13 % patients - Best-available-therapy group

Therapeutic efficacy cont’d
Subgroup Analyses and Long-Term Follow-Up
 Subgroup analysis of RESPONSE data indicated that
efficacy of ruxolitinib was greater than that of best
available therapy irrespective of whether best available
therapy included (n = 66) or excluded (n = 45)
hydroxyurea
 Ruxolitinib treatment - Associated with normalization of
markers of iron deficiency resulting from frequent
phlebotomies

Therapeutic efficacy cont’d
 Switching from best available therapy to
ruxolitinib resulted in improved clinical outcomes
in subgroup analysis
 Most patients (84 %) in best-available-therapy
group switched to ruxolitinib between weeks 32
and 48

Therapeutic efficacy cont’d
 Among these patients,
 79 % did not require phlebotomy during subsequent
treatment with ruxolitinib for 32 weeks
 Only 25 % had not required phlebotomy during initial 32
weeks’ treatment with best available therapy
 Haematological control achieved at week 32 was
maintained among ruxolitinib treated patients at week
80, with greatest reductions in white blood cell counts
& platelet levels achieved in patients with most
elevated levels at baseline

Symptom assessment in phase III RESPONSE trial

Tolerability of Ruxolitinib
Non-Haematological Adverse Events
 Ruxolitinib was generally well tolerated in phase III
RESPONSE trial
 Most frequent non-haematological adverse events in
ruxolitinib (n = 110) & best - available therapy (n = 111)
groups throughout 32 weeks’ treatment were
 Headache (16.4 vs. 18.9 % of patients)
 Diarrhoea (14.5 vs. 7.2 %)
 Fatigue (14.5 vs. 15.3 %)
 Pruritus (13.6 vs. 22.5 %)

Tolerability cont’d
 Severe adverse events - most common
 Ruxolitinib - dyspnoea [3 (2.7 %) vs. 0 patients
with best available therapy]
 Best available therapy - pruritus [4 (3.6 %) vs.
1 (0.9 %) with ruxolitinib]
 Adverse events - treatment discontinuation
 Ruxolitinib group -3.6 % patients
 Best-available-therapy group -1.8 % of patients

Tolerability cont’d
 JAK/STAT pathway - associated with immune function –
↑ risk of developing
 Serious bacterial
 Mycobacterial (i.e. tuberculosis)
 Fungal
 Viral infections
 Newly diagnosed non-melanoma skin cancer occurred in
 Four patients receiving ruxolitinib
 Two patients receiving best available therapy
Only one in best-available-therapy group – h/o non-
melanoma skin cancer or precancerous skin lesions

Tolerability cont’d
 Throughout 32 weeks’ therapy in RESPONSE trial, low-
grade elevations in
 Cholesterol
 Triglycerides
 ALT & AST, occurred in a numerically higher proportion of
patients receiving ruxolitinib than best available therapy
 Laboratory measures with highest proportion of patients
(>6%) with grade 3 or 4 elevations in either group were
 Potassium (7.3 % of patients in ruxolitinib group vs. 3.6 % in
best-available-therapy group)
 Gamma-glutamyl transferase (7.3 vs. 3.6 %)
 Lipase (6.4 vs. 2.7 %)
 Urate (2.7 vs.9.9 %)

Tolerability cont’d
 Thromboembolic events
 One patient - Ruxolitinib group compared
 Six patients - Best available-therapy group throughout 32
weeks’ treatment
 One additional event in ruxolitinib group after week 32
 Myelofibrosis developed
 Three patients - Ruxolitinib group
 One patient - Best-available-therapy group
 One patient in ruxolitinib group progressed to AML (at
day 56)

Tolerability cont’d
Haematological Adverse Events
 Reversible myelosuppression frequently occurs with
ruxolitinib - Inhibitory effect on JAK/STAT pathway
 Phase III RESPONSE trial, low-grade anaemia,
thrombocytopenia and lymphopenia were most frequent
haematological adverse events in ruxolitinib and best-
available-therapy groups

Tolerability cont’d
 During long-term (median of 19.5 months) therapy
in pooled analysis, grade 3 or 4 anaemia and
thrombocytopenia each occurred in 3.7 % of
patients receiving ruxolitinib
 Most common haematological adverse events in
ruxolitinib group in phase II trial
 Grade 1 anaemia - 53 %
 Thrombocytopenia - 27 % of patients

New or worsening haematological adverse events in 32-week,
phase III RESPONSE trial in patients Patients (%) with PV who had
previously had an inadequate response to or unacceptable
adverse effects from hydroxyurea . Θ indicates 0 %

Dosage and Administration of
Ruxolitinib
 Recommended starting dose - 10 mg twice
daily (maximum dose 25 mg twice daily)
 Complete blood count - Before therapy is
commenced
Every 2–4 weeks until doses are
stabilized & then as clinically indicated

Dosage and Administration of
Ruxolitinib
 If haemoglobin levels, platelet counts or
absolute neutrophil counts ↓ beyond
specified limits, recommendations for
dose reductions and interruptions are
provided in manufacturer’s prescribing
information
 Dose ↓ recommended in patients with
 Moderate or severe renal impairment
 Any degree of hepatic impairment

Place of Ruxolitinib in Management
of Polycythemia Vera
 Approved for treatment of PV patients with an
inadequate response to or intolerance of
hydroxyurea,
↓ haematocrit without phlebotomy & ↓ spleen
size
 By targeting mutations that lead to overactivity of
JAK-STAT pathway,
ruxolitinib first targeted approach in PV

Summary
Orally administered inhibitor of JAK 1 and 2 that
reduces hyperactive JAK/STAT signalling
Provides marked and durable reductions in haematocrit
without phlebotomy
Reduces spleen size, and improves symptoms and
health-related quality of life
Low grade anaemia, thrombocytopenia and
lymphopenia are common, but can usually be managed
with dosage modifications

References
 Ruxolitinib: A Review in Polycythaemia Vera , Kate
McKeage ; Drugs 2015
 Verstovsek S, Komrokji RS. Novel and emerging
therapies for the treatment of polycythemia vera.
Expert Rev Hematol. 2015;8(1):101–13