The document discusses tofacitinib, an oral JAK inhibitor drug used to treat rheumatoid arthritis. It provides background on arthritis, describing the signs and symptoms. It then discusses the mechanism of action of tofacitinib, inhibiting JAK-STAT pathways involved in inflammatory cytokine signaling. Data is presented from preclinical studies in animal models of arthritis showing tofacitinib reduced markers of inflammation and improved arthritis scores in a dose-dependent manner. Clinical trial results demonstrating the drug met efficacy endpoints at a 5 mg twice daily dose are also summarized.

1. PRESENTED BY
SWAROOP KUMAR K
Novel Drug Discovery and
Development (NDDD), Lupin
swaroopkumar@lupin.com
Meyer et al
Pfizer Global Research & Development, USA
Journal of Inflammation 2010, 7:41

2. ARTHRITIS and TOFACITINIB
Discussion
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3. Introduction
 Arthritis is the inflammation of one or
more joints, which results in soreness,
swelling, stiffness, discomfort, and
restricted movement.
 It involves the breakdown of cartilage.
 Cartilage normally protects the joint,
allowing for even movement.
 Without the usual amount of cartilage,
the bones rub together, causing soreness,
swelling and stiffness.
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4. Who is Affected?
 Men and women of all ages
 Most prominent in women
 1 out of every 7 people in America has arthritis of some kind
 Children, as young as infants, can also get autoimmune forms of
arthritis—Juvenile Rheumatoid Arthritis, also known as JRA
 Many people are misunderstand that arthritis only reserved for
older, overweight people, but children are just as susceptible.
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5. Arthritis is not
spread, nor is it
transmitted.
Many researchers
believe that
arthritis is genetic,
explaining why it is
possible for small
children to
develop the
disease.
Spread or Transmitted ?
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6. Signs
 Joint swelling,
 Redness of the skin
around a joint
Symptoms
 Joint pain,
 Minor aches and pains,
 Reduced ability to move
the joint,
 Stiffness particularly in
the morning,
 Fatigue, and warmth
around a joint
Signs Vs Symptoms
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7. Any 4 of the following must be present to allow diagnosis of
RA :-
 Morning stiffness  1h
 Three or more joints involved
 Arthritis of hand joints
 Symmetric arthritis
 Rheumatoid nodules
 Rheumatoid factor
 Radiographic changes (must show erosion/decalcification)
 Blood tests and x-rays
Diagnosis of rheumatoid arthritis
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8. Choy, E. H.S. et al. N Engl J Med 2001;344:907-916
Inflammed synovial tissue (synovitis)
• Villous hyperplasia
• Intimal cell proliferation
• Inflammatory cell infiltration
T cells, B cells, macrophages and
plasma cells
• Production of cytokines and
proteases
• Increased vascularity
• Self-amplifying process
Pathogenesis of Rheumatoid Arthritis
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9. http://www.nature.com/clpt/journal/v91/n1/fig_tab/clpt2011278f7.html
TREATMENT
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10. Current therapy : Limitations
 Currently used therapy carry the burden of major side effects such as GIT
Ulceration, infections, hepatotoxicity and nephrotoxicity.
 Not effective for all patients. Moreover some patients develop resistance .
 Drawback for Biologics is loss in efficacy during therapy& 30% of patients
fail to achieve an improvement 20% ACR 20.
 Moderately to severely active rheumatoid arthritis who have had an
inadequate response or intolerance to methotrexate
 Accordingly, a need exists for improved treatment for immune disorders
and inflammatory disorders.
Treating inflammation with the Janus Kinase inhibitor CP - 690,550, cell, 2011, vol-3227-07-2013

11. 27-07-2013
JAK – STAT INHIBITOR
CP-690550 (TOFACITINIB)

12. IUPAC NAME :- 3-[(3R,4R)-4-methyl-3-[methyl(7H-
pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]-3-
oxopropanenitrile
STRUCTURE OF CP-690550
CENTER FOR DRUG EVALUATION AND RESEARCH (NDA 213214)
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13. JAK-STAT Signaling Pathways
CP-690550,
(Tofacitinib)
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14. CP 690550 is a Selective Inhibitor of Janus Kinases
Cytokines Signaling Through
JAK 1/3
IL-2, IL-4, IL-7, IL-9, IL-15, IL-21
Cytokines Signaling Through
Other JAK 1 Combinations
IL-6, IFNγ, IFNα/β, IL-22, IL-34
Inhibiting downstream signaling of cytokine receptor
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15. 27-07-2013
Multiple cytokine activated JAK/ STAT signaling pathways were potently inhibited with
specific IC50 values.

16. 27-07-2013
Multiple cytokine are inhibited in different species by specific IC 50
Value

17. Parameters Rat Dog Monkey
i.v Oral i.v Oral i.v Oral
Dose
(mg/kg)
3 10 3 5 3 5
C
max(ng/ml) 261±90 1020 ± 255 791 ± 157
T max (h)
0.5± 0.3 0.5 ± 0.4 1.1 ± 0.9
AUC
840 ± 184 462±143 3250 ± 1610 2330± 423 2850 ± 543 2280 ±338
T ½ (h)
0.6 ± 0.1 ND 1.2 ± 0.1 ND 2.1 ± 0.4 ND
F(%)
16.5 43.0 48.0
CL(mL/
min/kg) 62 ± 14 19 ± 10 18 ± 4
Vss(L/kg)
2.6 ± 1.3 1.8 ± 0.8 1.7± 0.2
Pharmacokinetic profile of CP-690550
CENTER FOR DRUG EVALUATION AND RESEARCH (NDA 213214)
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18. Two animal models were used
• Collagen-induced arthritis in male DBA/1J mice (CIA model)
• M. butyricum -induced arthritis model in Lewis rats (AIA model)
CIA model - Booster injection (mice), Scoring, Histology
Day 0 Day 21 Day- 29, 34, 43,
48 &55
Immunization
(Collagen)
Booster Challenge of
emulsion
Scoring
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19. Score 1 2 3
NORMAL WRIST SWOLLEN WRIST + PAD
SWOLLEN
WRIST + PAD + DIGITS
SWOLLEN
0
Scoring presentation of CIA DBA/1j Mice
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20. Summary of CP-690550 Efficacy (Arthritis Scores)
data in CIA induced DBA/1J Mice
CENTER FOR DRUG EVALUATION AND RESEARCH (NDA 213214)
There were also observe dose-dependent decreases in paw arthritic score27-07-2013

21. ADJUVANT INDUCED ARTHRITIES(AIA)
Method of induction 15 mg/mL Mycobacteria butyricum suspension 50 μL injected 3 sites at
the base of the tail.
Strain Lewis rats (female)
Duration 16 to day 21
Readouts Body weight, Paw volume & Clinical score etc.,
Compound CP-690550
Dose of test compound 0.1,1,3 & 10 mg/kg/day ,oral, bid.
Dose-dependent response was observed in Paw Volume 27-07-2013

22. Peripheral blood neutrophil count and the inflammatory
cytokines IL-6 and IL-17 increase in the rat AIA model
Hind paw volume , IL-6 significantly increased & On day 7 Significantly increased IL-17 ,
neutrophils , peaked on day 14 and decreased on day 21 27-07-2013

23. Estimation of Hind paw edema, PBNC, and serum inflammatory
cytokine levels in the rat AIA model.
CP-690550 Dose –Dependently inhibits the above parameters in Rat AIA Model
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24. (CP-690550)Dry Eyes
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25. Marketed &
Phase IV Phase II Phase II Phase III Phase II
IL-2, IL-4, IL-7, IL-9, IL-15, IL-21 & IL-6, IFNγ, IFN α/β, IL-22, IL-34
CP-690,550 is Being Evaluated in a Number of
Inflammatory and Immunologic Diseases
Phase III
(Oral)
Phase II
(Top)
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26. 27-07-2013
Modeled Human Pharmacokinetic Parameters and JAK1/3 and JAK2
IC50 Coverage for CP-690,550
 At doses from 5 to 10 mg BID, JAK2 IC50 coverage is insignificant in comparison to JAK1/3
IC50 coverage
 Doses as low as 5 mg BID are well-tolerated and efficacious in moderate to severe RA ,
suggesting the importance of JAK1 and JAK3 target coverage in the absence of JAK2
inhibition
A) JAK1/3 human whole blood IC50 (IL-21 dependent pSTAT3) = 25 ± 6 nM; B) Range based on the upper and lower error around the IC50
where available; C ) JAK2 human whole blood IC50 (GM-CSF dependent pSTAT5) = 1377 ± 185 nM; D) GM-CSF stimulated myelomonocytic
HUO3 cell JAK2 IC50 = 324 nM [1].

27. At 5 mg BID Dose Patient Responding Rate is 67% of ACR 20, 40% of ACR 50 &
15 % of ACR 70
CENTER FOR DRUG EVALUATION AND RESEARCH (NDA 213214)
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28. 27-07-2013

29. Tofacitinib is a noval first oral JAK inhibitor that is investigated as a
targeted immunomodulator & Disease – modifying therapy for RA
Neutrophils infiltrating into an arthritic joint can release proteolytic
enzymes and ROS which can increase inflammation and accelerate
the destruction of the bone and cartilage.
Present study suggested that inhibition of neutrophilia by
CP-690550, as observed in both human RA patients and in the rat
AIA model
In pre clinical excellent efficacy showing in Rats than Mice &
Clinical ACR 20 score improved 67% of patients versus 25% who
received placebo
It is currently approved for the treatment of moderate to severe
rheumatoid arthritis (RA) in the United States and in clinical trials for
treatment of psoriasis, inflammatory bowel disease, and other
immunological diseases
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30. Xeljanz will have a wholesale acquisition cost
of $2,055.13 for a 30-day supply (or $24,666 per
year).
Marketed April 03 2013 .
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31. The Sun is Rising for Patients with Rheumatic Diseases: The
Future is Bright
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32. 27-07-2013

33. Back up slides
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34. 1994
Dr. Paul
1993
2011 filed a NDA to
FDA
November 23, 2001
( Phase 1 in US)
December 31, 2004 (Phase 2
in US, Spain, Canada,
Germany etc.,)
February 28, 2009
( Phase 3 in US, South
Korea, Canada,
Germany etc.,)
FDA approved
November 6th, 2012
April 03 2013
Marketed
History Of Tofacitinib
2000 (Preclinical
completed & Monkeys in
Stanford University)
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35. Ex- 55 % 0f patients achieved
ACR20, that means 55 percent
of patients in the study
achieved a 20 percent
improvement
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36. What was Pfizer's response on Arthritis Drug Xeljanz (tofacitinib) Receives A Negative
Opinion In Europe
Dr. Yvonne Greenstreet, senior vice president and the head of the Medicines
Development Group for Pfizer Specialty Care, said:
"We have confidence in XELJANZ and believe our application to the EMA demonstrates
that XELJANZ has a favorable risk:benefit profile.
XELJANZ's safety profile is well-characterized, and the issues raised by the EMA, including
serious infections, gastrointestinal perforations and malignancies, are familiar to
rheumatologists who are experienced working with treatments for patients to manage
this difficult disease.
Each regulatory authority will review and interpret applications individually and different
assessments are not uncommon.
The re-examination process will enable us to seek to address the CHMP's questions, and
we will continue to work closely with the EMA with the goal of making this medicine
available to appropriate patients in Europe."
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37. S.No Species Study Details
1. Spague-Dawley
rats
Pivotal GLP Toxicolgocial studies in rats were 6-weeks & 6-months
duration repeated dosing studies .
Doses - 0 ,1, 10, or 100, 500, 1000 and 2000 mg/kg/day (q.d., PO)
2. Cynomolgus
monkeys
Two pivotal studies
1.One(1) month repeated oral administration study with a 1-month
Recovery
Doses - 0,10,50 & 100 mg/kg/day
split doses
TID (0, 3.33, 16.67, & 33.33 mg/kg) 1-month Study
2. Nine (9) months repeated oral administration study
Doses - 0, 0.5, 2, and 10 mg/kg/day
split doses
BID (0, 0.25, 1, and 5 mg/kg/day)9-month duration study
Toxicology
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38. S.no Results
1 One month
repeated oral
administration
1. Secondary infections of open wounds /
2. Gastrointestinal erosions or ulcers
2
Nine months
repeated oral
administration
study
3 lymphomas
(100 mg Group)
Day 21
Euthanized
High dose group
Day 214
2 B cell origin
1 T cell origin
Lymphoma
Lymphoma
Two Animal
9 month scheduled
One Animal
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39. Tissue Distribution of CP-690550 (Pyrrolo[2,3-d]pyrimidine) in Long-
Evans Male Rats
Post Dosing in each time point One rat was euthanized by CO2 asphyxiation at
0.5, 1, 2, 4, 8, 12, 24, 72, 168, and 504 hr
Key Study Findings
The distribution of [14C]CP-690550 in blood and 57 tissues of male rats was studied
up to 504 hr following oral administration of 10.0 mg/kg (454 μCi/kg).
Maximum concentrations of [14C]CP-690550 occurred at 0.5 hr for 43 tissues, 1 hr
for 10 tissues and the whole-body, and 12 hr for the uvea.
It across the BBB by 0.5 hr and persisted in all CNS tissues for at least 4 hr.
It distributed into and was eliminated from 47 of 57 tissues by 24 hr following oral
administration.
By 72 hr, only the intervertebral discs, liver, vessel walls, kidneys, and ocular tissues
impregnated with melanin contained measurable levels of [14C]CP- 690550.
By168 and 504, only vessel walls and ocular tissues impregnated with melanin still
had measurable concentrations of [14C]CP-690550.27-07-2013

40. 1. White blood cell Lymphocyte counts (rat, monkey)
Eosinophil, basophil, large unstained cells
2. Red blood cell Anemia
Hemoglobin
3. Lymphoid organs lymph nodes,
Thymus,
Spleen
Reductions in bone marrow cellularity
4. Clinical chemistry
(6 month)
Total protein(Albumin)
Calcium
Dehydration , changes in glucose, triglycerides, and
alkaline phosphatase
moncytes
Rat
Atrophy
Toxicology Results
Studies Conducted in Rats &
Monkeys
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41. Safety Pharmacology
1. Cardiovascular
Assessments
No effect on cardiovascular System included
1. In vitro hERG channel current, or In situ electrophysiological
characteristics of cardiac Purkinjie fibers
2. In vivo assessment of cardiovascular effects in rats.
2. Neurobehavioral
assessments
In mice found a reduction in spontaneous activity
3. Respiratory
assessments
No significant effects
4. Kidney function
assessments
No significant effects
5. Gastrointestinal
transit time
No significant effects
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42. Oxidation
pyrrolopyrimidine ring (M9)
Oxidation piperidine ring
(M6 and M18),
N-demethylation
M1
Oxidation
piperidine ring side chain (M2)
Glucuronidation
M20
Metabolism
( Mice, Rats , Rabbits &
Monkeys)
S.no Species Metabolites
1 Mice M29(Plasma & urine). M2 , M4/M18 (Plasma& feces).
2 Rat M1, M2, M4, M5, M6, M9, M13, M21, and M29
3 Rabbits M4,M28,M29 &M20.
4 Monkeys M9,M2,M29,M28,M29,M23,M11&M20.
5 Healthy
Male Subjects
M1, M2, M29, M4 M9, M11, and M14, M20
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43. Absorption  Absolute bioavailability(10 Mg)-74%
 Systemic exposure (AUC0-∞) & peak plasma concentration (Cmax) increased in
proportion to the dose in the dose range of 1 to 100 mg
 Tmax(Oral)-0.5-1 hours
 Coadministration with food –(32%.)
 Upon multiple dosing, steady-state was reached by 24-48 hours with negligible
accumulation
 Tofacitinib is a substrate of P-gp transporter
Distribution  Total plasma protein binding (39%)
 Binds moderately to albumin ( √ )
Does not bind to alpha-1 acid glycoprotein (×)
Volume of distribution (Vdss) (iv infusion) - 87 L.
Metabolism
and
Transporters
Extensively metabolized, primarily by CYP3A4 with minor
contribution from CYP2C19.
All metabolites have less than <8% of total drug exposure and their potency was
reported to be <10% of the potency of tofacitinib for JAK1/3 inhibition.
Not a substrate of BCRP transporter(In vitro)
Elimination parent drug -29%
Metabolites- 51%
Urine
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