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Drugs R D 2010; 10 (4): 271-284

1179-6901/10/0004-0271

ADIS R&D PROFILE

ª 2010 Adis Data Information BV. All rights reserved.

Tofacitinib
Abstract

Tofacitinib (CP-690,550; CP-690550; CP690550), an orally active immunosuppressant, is being developed by Pfizer for the treatment of rheumatoid
arthritis, inflammatory bowel disease, dry eyes, ankylosing spondylitis, psoriasis,
psoriatic arthritis, and for the prevention of transplant rejection. Tofacitinib
inhibits Janus activated kinase 3 (JAK3), which has a pivotal role in cytokine
signal transduction that governs lymphocyte survival, proliferation, differentiation, and apoptosis. This review discusses the key development milestones
and therapeutic trials of this drug.

1. Introduction
Pfizer is developing tofacitinib, an orally active immunosuppressant. The design of this agent
is based on the observation that congenital deficiency in Janus activated kinase 3 (JAK3) results
in severe combined immunodeficiency (SCID).
Tofacitinib specifically inhibits JAK3, which has
a pivotal role in cytokine signal transduction that
governs lymphocyte survival, proliferation, differentiation, and apoptosis. The product is being
evaluated in clinical trials for the treatment of
rheumatoid arthritis, inflammatory bowel disease,
dry eyes, ankylosing spondylitis, psoriasis, psoriatic arthritis, and for the prevention of transplant
rejection.
1.1 Key Development Milestones
1.1.1 Crohn Disease

A phase II trial was initiated in December
2007, which investigated tofacitinib in 150 patients
with Crohn disease in the US (NCT00615199).
The study evaluated the safety and efficacy of

tofacitinib, with the primary outcome measured
by decrease in Crohn disease activity index (CDAI)
score of at least 70 points from baseline, at week 4.
The study was completed in November 2009.
1.1.2 Dry Eyes

A prospective phase I/II dose-ranging trial was
initiated by Pfizer in November 2008 to evaluate
tofacitinib topical ophthalmic solution in 412 patients with dry eyes in the US (NCT00784719).
Patients were randomized to receive placebo,
ciclosporin 0.05%, or one of four doses of tofacitinib, administered at least once daily for 8
weeks. The study was completed in January 2010.
1.1.3 Plaque Psoriasis

In September 2010, Pfizer initiated a randomized
phase III trial to compare the efficacy responses
of oral tofacitinib with placebo in patients with
moderate to severe chronic plaque psoriasis
(NCT01186744). The trial will evaluate the effects of treatment, treatment withdrawal and retreatment in 660 patients in the US.[1]

This drug profile has been extracted from Wolters Kluwer’s Adis R&D Insight drug pipeline database.
R&D Insight tracks and evaluates drug development worldwide through the entire development process, from
discovery, through pre-clinical and clinical studies to market launch. This is an open access article published
under the terms of the Creative Commons License ‘‘Attribution-NonCommercial-NoDerivative 3.0’’ (http://
creativecommons.org/licenses/by-nc-nd/3.0/) which permits non-commercial use, distribution, and reproduction,
provided the original work is properly cited and not altered.

Malaysia. South Korea. and Taiwan (NCT00847613).[3] Tofacitinib was investigated in a 6-month phase II clinical trial in the US for the prevention of renal allograft rejection. Canada. A phase II. A phase III study has been completed that compared the safety and efficacy of tofacitinib (5 and 10 mg twice daily) as monotherapy in adult patients with moderate to severe rheumatoid arthritis (ORAL Solo. mycophenolate mofetil. South Korea. Drugs R D 2010. and Thailand (NCT00853385). Canada. Tofacitinib was administered with interleukin (IL)-2 antagonist induction therapy. Japan. Spain. and Taiwan. with the initiation of its phase III ORAL trials program.5 Rheumatoid Arthritis Pfizer commenced phase III development of tofacitinib in the treatment of rheumatoid arthritis in February 2009. Latin America. the Philippines. South Korea. Pfizer was investigating the compound in psoriasis before proceeding to studies in patients with kidney transplants. NCT00678210). and the Philippines. India. Approximately 900 patients with rheumatoid arthritis will be recruited in a phase III study that will compare the efficacy of two doses of tofacitinib with methotrexate over 24 months in the prevention of joint damage and improvement of symptoms of rheumatoid arthritis (NCT01039688). randomized. Latin America. India. and corticosteroids. NCT00814307).4 Renal Transplant Rejection A phase II trial evaluated the compound in combination with mycophenolate mofetil in 338 de novo renal allograft recipients (NCT00483756). the EU. parallel-group study is recruiting patients in the US. which began in December 2005 in the US and is expected to complete in 2014. Australia.[5-7] A 2-year.1. Enrollment of 45 patients was completed into this extension study (NCT00263328). Canada. open-label extension of this study has completed accrual and will follow 178 transplant patients for 3 years to assess the long-term safety and tolerability of tofacitinib (NCT00658359). Latin America. Pfizer began two phase II clinical trials to assess the efficacy and safety of topical tofacitinib in 81 and 197 patients with plaque psoriasis. showing a statistically significant response in patients receiving tofacitinib in the treatment of moderate to severe plaque psoriasis. double-blind. respectively (NCT00678561. This study has enrolled approximately 652 patients in the US. All rights reserved. and was completed in April 2010. In September 2008. Australia. 1. Results released in November 2010 showed that the trial had met two of three primary endpoints.[4] ª 2010 Adis Data Information BV. Results from the second trial were presented in October 2010. 10 (4) . EU. the EU. Both studies were completed in the US and Canada. Brazil. Another phase III study is assessing oral tofacitinib (5 and 10 mg twice daily) for 6 months in approximately 400 patients with active rheumatoid arthritis taking methotrexate with inadequate response to tumor necrosis factor inhibitors (NCT00960440).[5] Approximately 700 adult patients with active rheumatoid arthritis on background of methotrexate will receive tofacitinib 5 mg and 10 mg twice daily or adalimumab (Humira) as a comparator in a phase III study in the US. Australia. This trial was conducted in the US. The study is ongoing in the US. and South Korea. The trial enrolled 61 de novo renal allograft recipients and was completed in October 2006 (NCT00106639). double-blind trial is being conducted in patients with moderate to severe rheumatoid arthritis who are receiving background methotrexate at multiple centers in the US.1. The trial will compare the efficacy of two doses of tofacitinib versus placebo in 750 patients and is expected to be completed in February 2012. The program includes six trials conducted in 35 countries worldwide. Puerto Rico. This phase II trial was extended into a long-term post-transplant study for patients who respond well. This randomized. the EU.272 Adis R&D Profile Pfizer is planning to initiate a phase III trial to evaluate the long-term safety of tofacitinib in patients with moderate to severe chronic plaque psoriasis (NCT01163253).[2] 1. Canada. Tofacitinib was well tolerated in phase I safety studies in healthy volunteers. The agent has also been shown to prevent rejection in primates receiving kidney transplants with superior efficacy to that seen in parallel studies using ciclosporin.

273 1. Methotrexate exposure decreased by 10% on coadministration. A phase II trial has been completed in Japan in 318 patients with rheumatoid arthritis who had previously had an inadequate response to DMARDs (NCT00687193). NCT 00413699 and NCT00414661) are evaluating the long-term efficacy and safety of tofacitinib in 4000 patients and 300 patients with rheumatoid arthritis. All rights reserved. Recruitment of 750 patients was completed in September 2010 at multiple centers in the US. Preliminary results from ORAL Sequel have been reported. Latin America. in the US. A phase III study in Japan was initiated in April 2008 to assess the efficacy and safety of tofacitinib for the treatment of rheumatoid arthritis (NCT00661661).6 Ulcerative Colitis The safety and efficacy of tofacitinib was investigated in a phase II trial (NCT00787202) completed in September 2010 in 197 patients with moderate to severe ulcerative colitis. completed in October 2010.1. Tofacitinib exposure was not affected by coadministration of methotrexate. and Latin America (Argentina and Mexico).8 Trials in Healthy Volunteers In August 2010.[5] Another phase II trial (NCT01059864) was initiated in February 2010 to assess the effects of tofacitinib and atorvastatin on lipids in patients with rheumatoid arthritis. the EU. phase I trial (NCT01184092) to assess the pharmacokinetics of three different tablet formulations of tofacitinib under fasted conditions in healthy volunteers. All patients will receive 12 weeks of open-label tofacitinib 10 mg oral tablets administered twice daily starting at day 0 through to week 12. Pfizer initiated a randomized. open-label. and South Africa. placebo-controlled study recruited patients in the EU. Malaysia. Using a three-way crossover design. 1. Two phase II trials (ORAL Sequel.00. respectively.[8] This randomized. the EU. which is evaluating the pharmacokinetics of the compound.[10] Pfizer has completed enrollment in a phase I trial (NCT01101919) of tofacitinib in healthy volunteers in China. double-blind.[11] 2. evaluated the effect of food on the pharmacokinetics of tofacitinib in 16 healthy volunteers in the US.1.29).1. ª 2010 Adis Data Information BV.7 Other Indications According to Pfizer’s pipeline in January 2010. 107. tofacitinib is being investigated in phase II trials for the treatment of ankylosing spondylitis and psoriatic arthritis. they will be randomized to receive double-blind treatment with once-daily atorvastatin 10 mg oral tablets or placebo up to week 12 in addition to tofacitinib.Tofacitinib Pfizer is conducting a phase III study comparing tofacitinib at 5 mg and 10 mg for use in combination with a variety of disease-modifying antirheumatic drugs (DMARDS) in adult patients with rheumatoid arthritis (NCT00856544). Latin America. and Thailand. Another phase I trial (NCT01184001). Patients received multiple doses of tofacitinib (30 mg twice daily) and single doses of methotrexate (15–25 mg per week). Scientific Summary 2. The trial was completed August 2010. A phase I trial (NCT01143805) compared the bioavailability of oral and intravenous tofacitinib in volunteers. Australia.06% (90% CI 99. with an AUC12 ratio (tofacitinib plus methotrexate/methotrexate) Drugs R D 2010. Patients who have completed the qualifying study (NCT00603512) are eligible for enrollment in this study. Approximately 12 subjects enrolled in the trial. At week 6. 1. the area under the concentration-time curve (AUC) from 0 to 12 hours (AUC12) ratio (tofacitinib plus methotrexate/tofacitinib) was 103. 10 (4) . China. these were compared to a 10 mg immediate-release tablet formulation. the behavior and safety of tofacitinib was explored following a single dose of two 20 mg osmotic capsules of the drug in 12 healthy volunteers.[9] In a phase I trial (NCT01185184) completed in August 2010. The trial enrolled 24 subjects in Singapore and was completed in September 2010.1 Pharmacokinetics No clinically relevant effects on the pharmacokinetics of tofacitinib or methotrexate was observed following short-term coadministration of the drugs in a phase I study in patients (n = 12) with rheumatoid arthritis.

R3 (Anti-Asthma and COPD Products). headache. Canada. 20. L4 (Immunosuppressive Agents).2 Rheumatoid Arthritis Phase III : Rates of discontinuation as a result of adverse events were low in the phase III ORAL Solo trial (Study 1045. according to phase II data of 89. nitriles. urinary tract infections Rare Abdominal pain. CP690550 Originator Pfizer Highest development phase III (Australia.[4-Methyl-3. 30. All rights reserved. L04A-A (Selective immunosupressants). the most frequently reported treatment-related adverse events were upper respiratory tract infection and headache. India.38.2 Adverse Events 2. but no other changes in laboratory parameters were reported. M1 (Anti-Inflammatory and Anti-Rheumatic Products). inhibits immune cell proliferation and T-cell activation in cynomolgus monkeys Drug interactions Fluconazole increases AUC and Cmax of tofacitinib in healthy subjects. D5 (Nonsteroidal Products for Inflammatory Skin Disorders). psoriatic arthritis. and increases in mean low-density lipoprotein cholesterol (LDL-C). which Drugs R D 2010.[2] Oral tofacitinib administered for 2 weeks resulted in adverse events in 10 of 59 adult patients with psoriasis who participated in a randomized placebocontrolled trial. Malaysia. Crohn disease. R03 (Drugs for Obstructive Airway Diseases). staphylococcal infections. protein cholesterol (HDL-C) and total cholesterol levels were observed. NCT00814307). methotrexate has no clinically relevant effect on the pharmacokinetics of CP 690550 in patients with rheumatoid arthritis ATC Codes WHO ATC code A03A (Drugs for Functional Bowel Disorders). diverticulitis.550. Taiwan. S01 (Ophthalmologicals) EphMRA ATC code A3A (Plain Antispasmodics and Anticholinergics).53% (90% CI 77. dry eyes. South Korea. renal transplant rejection. pyrroles. plaque psoriasis. M01 (Antiinflammatory and Antirheumatic Products). inhibits in vitro and in vivo JAK3 activity. sinusitis. suppresses in vivo allogenic response in a mouse model of organ transplantation. During treatment with tofacitinib at dosages of 5. Increases in total cholesterol. respiratory tract infections. lipid metabolism disorders. CP-690550.[12] 2. acne. ulcerative colitis Class 2-Ring-heterocyclic-compounds. the EU. nausea. 10 (4) . Features and properties Alternate names CP-690. Japan. the most common adverse events were mild nausea and mild headache. S1 (Ophthalmologicals) Adverse events Occasional Anaemia. Thailand. prolongs survival of transplanted organs in mice. small molecules Mechanism of action Janus kinase 3 inhibitors Chemical name 3. or 50 mg twice daily. pneumonia. D05 (Antipsoriatics). Dose-dependent decreases in mean neutrophil counts and hemoglobin values. herpes zoster. high-density lipoª 2010 Adis Data Information BV. A07E (Intestinal Antiinflammatory Agents). nasopharyngitis. 10. the US) Active development indications Ankylosing spondylitis. Latin America.1 Psoriasis In a phase II clinical trial involving 197 adult patients with moderate to severe plaque psoriasis.274 Adis R&D Profile Table I.[N-methyl-N-(7H-pyrrolo [2. tuberculosis Patient benefits Once-daily dosing at 20 mg appears effective in treating rheumatoid arthritis.[13] 2. or 60 mg once daily.57). elevated aminotransferase levels.2. renal failure. infections. which was not regarded as clinically significant.2. A7E (Intestinal Anti-Inflammatory Agents). LDL-C and triglyceride levels occurred in patients in some of the tofacitinib groups. 103. Three patients experienced a total of five serious adverse events. rheumatoid arthritis. Dose adjustments should not be required when coadministering tofacitinib and methotrexate. neutropenia. pyrimidines. Philippines.3-d] pyrimidin-4-yl)amino] piperidin-1-yl]-3-oxopropionitrile Molecular formula C16 H20 N6 O Pharmacodynamics Reduces IL-2-induced STAT5 phosphorylation in human cells. L4A (Immunosuppressive Agents). diarrhea.

and total cholesterol. the transaminase increases reported in patients receiving background methotrexate. as monotherapy or in combination with methotrexate. the most commonly observed were nasopharyngitis. NCT00413699). A total of 611 patients who had an inadequate response to DMARDS were randomized to placebo. nausea. Study 1025. headache. and increased levels of liver transaminases and blood cholesterol. most adverse events were mild to moderate in nature. n = 384. anaemia. Dose-dependent increases in LDL-C. and decreases in mean neutrophil counts were consistent with reports from previous trials of tofacitinib in rheumatoid arthritis. Decreased neutrophil counts and increased LDLC and HDL-C levels observed during the first 3 months of treatment did not worsen over the 2-year follow-up. ten were rated as severe and included abdominal pain. staphylococcal infection. which included 1077 patients treated with placebo or tofacitinib as monotherapy or in combination with methotrexate. Tofacitinib therapy was associated with significant decreases in neutrophil counts and significant increases in LDL-C and HDL-C levels during the first 3 months. No obvious trends Drugs R D 2010. according to final results from two phase IIb trials (NCT00550446. Most adverse events were mild to moderate in severity. and Study 1035 24-week. There were no deaths. NCT00413660. n = 507) of tofacitinib. phase I study in patients with rheumatoid arthritis. 275 tion and serious adverse events were infrequent. was generally well tolerated. HDL-C. bronchitis.[5] Phase II : The most frequently reported treatment-emergent adverse events were urinary tract infections. serious adverse events or discontinuations due to adverse events. patients received their morning tofacitinib dose followed by their weekly methotrexate.[5] No new safety signals have emerged over 2 years in the ongoing ORAL Sequel phase II/III extension study (Study 1024. drug-drug interaction. one in a patient treated with tofacitinib in addition to methotrexate.Tofacitinib evaluated tofacitinib monotherapy in patients with moderate to severe rheumatoid arthritis. but not during months 3–6. Over the 6-month study period. and events leading to treatment withdrawal occurred in 2% of patients at 0–3 months and 1% of patients at 3–6 months. disseminated tuberculosis. which occurred in 18% of patients (incidence rate 2. were consistent with data from previous trials. Study 1035. The most common serious adverse events were infections. diarrhea. and urinary tract infections.1%) and serious infections occurred in six patients. in patients with active rheumatoid arthritis. Study 1025 24-week background methotrexate. Adverse events were reported in 54% and 40% of patients during months 0–3 and months 3–6. Tofacitinib was administered at 30 mg every 12 hours on days 3–6. and another that occurred 2 months after tofacitinib withdrawal. Elevated transaminase levels were rare and occurred at a similar frequency in all treatment groups. There were two cases of tuberculosis. and diarrhea. and upper respiratory tract infections.19] Phase I : Tofacitinib plus methotrexate was well tolerated in a fixed-sequence. at doses of 1–10 mg twice daily. Among reported adverse events. Adverse events leading to treatment discontinuaª 2010 Adis Data Information BV. monotherapy).[17] Twelve-week data from a phase II study in 136 Japanese patients with rheumatoid arthritis receiving stable background methotrexate showed that oral tofacitinib. serious adverse events occurred in 25 patients (4. On day 7. diverticulitis. Patients were administered their weekly methotrexate dose on the morning of day 1. In addition. diarrhea.62 per 100 patient-years of tofacitinib therapy). acute renal failure. acne. or to tofacitinib 5 or 10 mg twice daily.[18. respectively. Serious adverse events were observed in five patients. pneumonia. Most frequently reported adverse events were urinary tract infection. and sinusitis. herpes zoster. stomach discomfort.[14-16] After 1 year of an extension study that included patients enrolled in three phase II studies (Study 1019 6-week monotherapy. The most frequently reported adverse events included urinary tract infections. All rights reserved. Most treatmentemergent adverse events were mild or moderate in intensity. Twelve patients diagnosed with rheumatoid arthritis at least 6 months prior to the study and receiving stable weekly doses of oral methotrexate (15–25 mg/week) for a minimum of 28 days were enrolled. 10 (4) .

and methotrexate had no clinically relevant effect on the pharmacokinetics of tofacitinib. Since JAK2 mediates signaling via many hematopoietic cytokines. both missing one dose. severity.3 Animal Toxicology No evidence of metabolic abnormalities.276 Adis R&D Profile in the incidence. Tofacitinib was administered at 30 mg every 12 hours on days 3–6. All rights reserved.2. and hot flushes) were observed. phase I study of tofacitinib in patients with rheumatoid arthritis. Previous studies showed that tofacitinib had 20-fold less inhibitory activity for JAK2 than JAK3. its inhibition could result in anemia. Patients were administered their weekly methotrexate dose on the morning of day 1. methotrexate did not change the pharmacokinetics of tofacitinib. The pharmacokinetic profile of tofacitinib was evaluated after the tofacitinib doses on period 1/day 1 and period 2/day 5. subjects received a single 30 mg dose of tofacitinib. these changes were not    Drugs R D 2010. crossover study in healthy subjects have shown that coadministration of tofacitinib and fluconazole increased mean tofacitinib AUC from time zero to infinity and Cmax values by approximately 79% and 27%. single fixed-sequence. respectively. day 7. patients received their morning tofacitinib dose followed by their weekly methotrexate dose.[21] 2. thrombocytopenia. headache. but were considered non-clinically significant. This event was restricted to four animals at the highest drug exposure accompanied by minor decreases in hemoglobin levels. 10 (4) . However. Two patients temporarily discontinued tofacitinib during the study. six patients had 15 adverse events after tofacitinib monotherapy. Four treatment-related adverse events (dizziness. On ª 2010 Adis Data Information BV.3 Drug Interactions In a fixed-sequence. tofacitinib was associated with transient dose-related anemia. in comparison with tofacitinib alone. and five patients had 12 adverse events after combination treatment.[22] Coadministration of tofacitinib and methotrexate in patients with rheumatoid arthritis appeared to be safe and well tolerated.[20] Data from an open-label. respectively. or type of adverse events were observed across treatment groups. however.20] 2. and leukopenia in vivo. One patient experienced mild leg pain and other experienced a mild vasovagal episode during a blood draw. Coadministration of tofacitinib with methotrexate did not have a clinically relevant effect on the mean AUC12 values of methotrexate (1720 ng h/mL for the combination therapy and 1850 ng h/mL for methotrexate monotherapy). On period 2/day 2 (72 hours after the first tofacitinib dose). drug-drug interaction. hypertension. The drug resulted in a 10% decrease in methotrexate AUC and a 13% decrease in methotrexate Cmax when coadministered. Both tofacitinib and fluconazole were safe and well tolerated when administered alone or in combination. or cases of post-transplant lymphoproliferative disease were detected in cynomolgus monkeys treated with tofacitinib. The mean AUC12 values were 1410 ng h/mL and 1370 ng h/mL for tofacitinib plus methotrexate combination therapy and tofacitinib monotherapy. Of 34 adverse events reported in the study. subjects received fluconazole 400 mg followed by 200 mg once daily for 6 additional days (days 2–7).[12. Mean maximum concentration (Cmax) values were 384 ng/mL and 375 ng/mL for the combination therapy and tofacitinib monotherapy. Abnormal laboratory test values were reported. respectively. Twelve patients diagnosed with rheumatoid arthritis at least 6 months prior to the study and receiving stable weekly doses of oral methotrexate (15–25 mg/week) for a minimum of 28 days were enrolled. disorientation. presumably due to inhibition of cytochrome P450 (CYP) 3A4 by fluconazole. This study was conducted to estimate the effect of multiple-dose fluconazole on the pharmacokinetics of single-dose tofacitinib in healthy subjects. two-period. On period 1/day 1. and a single 30 mg dose of tofacitinib on period 2/day 5. five patients had seven adverse events after methotrexate monotherapy. Both cases were resolved and the patients continued dosing as scheduled. These animals survived for 90 days with recovery to baseline values. The observed 13% decrease in the mean Cmax value of methotrexate (433 ng/mL for the combination therapy and 478 ng/mL for methotrexate monotherapy) was not considered clinically significant. believed to be linked to a low level of JAK2 inhibition.

Animals treated with vehicle alone rejected their allografts within 12 days. Animals in the higher dose groups had a median survival time of >60 days. tofacitinib did not exhibit potent inhibitory activity against 30 other kinases with a median 50% inhibitory concentration (IC50) >3000 nmol/L. Patients received their weekly methotrexate dose on the morning of day 1. flow cytometry confirmed the inhibitory effect of tofacitinib on IL-2-induced P-STAT5 in peripheral blood mononuclear cells (PBMCs) of patients that were activated by g-irradiated allogeneic PBMCs. This included Lck. a key T-lymphocyte signaling molecule downstream of the T-cell receptor. three animals were euthanized on postoperative days 69. A maximal mean reduction in phosphorylation of 74% was achieved. The IC90 for tofacitinib in this assay was 160 nmol/L and was established as the initial target exposure for in vivo efficacy. such as FOXP3.[23] 2. respectively. Consistent with its mechanism of action. Patients were receiving a stable weekly oral methotrexate dose (15–25 mg/week) for a minimum of 4 weeks and were stable on any approved concomitant medication that was continued throughout the study. monkey. and on days 6 and 7 for tofacitinib. A fourth animal was euthanized on postoperative day 63 with impaired renal function and BK Drugs R D 2010. these cellular activities correlated with the ability of tofacitinib to block IL-2-induced phosphorylation of JAK3 and one of its key substrates STAT5. the inhibitory effect of tofacitinib was demonstrated on the expression of IL-2 responsive target genes downstream of the JAK/ STAT pathway. IL-2Ra. at the functional level. and 90. 277 zyme inhibitory potency of 1 nmol/L and showed 20. 10 (4) .4. whereas tofacitinibtreated animals experienced a dose-dependent increase in survival of transplanted hearts. Tofacitinib was administered to patients at 30 mg every 12 hours on days 3–6. Animals in the high exposure group had a mean survival time of 83 – 6 days while the low exposure group had a mean survival time of 46 – 4 days. borderline.[21] Preclinial studies in a mouse model of heterotopic heart transplantation indicated that tofacitinib suppressed the in vivo allogenic response.1 Transplant Rejection Clinical Studies : A phase I trial in eight stable patients receiving mycophenolate mofetil plus steroids more than 1 year after renal transplantation demonstrated that treatment with tofacitinib 30 mg increasingly reduced IL-2-induced phosphorylation of STAT5 (P-STAT5) from day 15 to day 29 compared with pre-dose baseline. patients received the morning dose of tofacitinib followed by their methotrexate single dose.[21] Tofacitinib displayed potent inhibition in cellbased assays using murine. SOCS3.[21] Cynomolgus monkeys receiving tofacitinib following bilateral nephrectomy and allogenetic renal transplant had a significantly longer mean survival time of 66 – 8 days compared with 6 – 1 days in the control group which had graft loss on postoperative days 3.[24] Preclinical Studies : Tofacitinib demonstrated high selectivity for JAK3 inhibition with an enª 2010 Adis Data Information BV. Pharmacokinetic evaluations were performed on days 1 and 7 for methotrexate. the plasma drug concentration at which 50% of mice would maintain their graft for >28 days or 50% effective concentration was determined to be »60 ng/mL. 90. while recovery to baseline was observed at day 57. 7. On day 7.to 100-fold less selectivity for JAK2 and JAK1. In addition. or human cells. The presence of P-STAT5 was mainly detected in alloactivated CD4+ and CD8+ T cells that expressed CD25 (IL-2Ra) and was inhibited by tofacitinib in both populations. In the high exposure group. and Banff IB acute rejection respectively. A JAK3-dependent cellular assay in the presence of 40 mg/mL human serum albumin to predict exposures required for in vivo activity was established. and 8. No dosage adjustment is deemed necessary when tofacitinib is coadministered with methotrexate. with pathology graded as no graft rejection. 6. interferon (IFN)-g and granzyme B. Additionally.Tofacitinib considered clinically relevant. All rights reserved.4 Pharmacodynamics 2. This single fixed-sequence study was conducted in 12 patients diagnosed with rheumatoid arthritis for at least 6 months. Furthermore. On the basis of drug exposures measured in all groups. following completion of treatment at day 29.

4%). 15 mg twice daily. and ACR70 response rates showed a similar trend with significantly better rates in the 3. Tofacitinib treatment of mice receiving renal allografts significantly reduced expression of IFN-g (35% vs 14. and III.22 unit improvement from baseline) were significantly better in all tofacitinib dosage groups. PCNA (36.6 was not significantly different between the active and placebo groups (6% and 10% vs 4%). 10. and 121 ng/mL. or placebo.[16] Compared with placebo. IFN-g in cells treated with tofacitinib was 12%. The respective IC50 values for these parameters were 89. with significant improvements in ACR20. and CD-3/CD16+ (11% vs 4.19).278 Adis R&D Profile nephritis. except the 1 mg twice daily group. Inhibition was proportional to drug concentration (max at 160 ng/mL).57 vs -0. compared with placebo. Animals with low exposure rejected on postoperative day 40.6.[14] The proportions of patients who achieved a HAQ-DI response (‡0. Secondary endpoints included the ACR50 and ACR70 response rates and the mean change from ª 2010 Adis Data Information BV. A total of 611 patients were randomized to tofacitinib 5 or 10 mg twice daily or placebo for 6 months. All rights reserved.5 Therapeutic Trials 2. CD71).[5] In the ongoing 2-year ORAL Sequel extension study (Study 1024.6) was achieved in significantly greater proportions of patients in all tofacitinib groups.5. Furthermore. and were significantly better for all tofacitinib dosage groups except 1 mg twice daily.[25] Tofacitinib inhibited immune cell proliferation. 52. However. tofacitinib was also associated with significant improvements in pain at week 2. IIB. change in Health Assessment Questionnaire Disability Index (HAQ-DI) scores and remission rate defined as a Disease Activity Score (DAS) 28-4 (ESR) [DAS28] <2. The three primary endpoints were the American College of Rheumatology 20% (ACR20) response rates. ACR20 response rates appeared to improve slightly over time in patients treated with tofacitinib either as monotherapy or in combination with methotrexate. Outcomes at 24 weeks were similar to those at 12 weeks. expression of CD25. proliferating cell nuclear antigen (PCNA). The ACR20 response rates at 12 weeks ranged from 49% to 61% versus 38% for placebo. T-cell activation (CD25. or 15 mg twice daily. improvements from baseline in the mean HAQ-DI and DAS28 scores were maintained over 2 years. than the placebo group (62–69% vs 41%).6% vs 12. respectively. and 48. ACR50. the proportion of patients who achieved a DAS28 score <2. Furthermore. ACR50 response rates were significantly better with tofacitinib 5 and 15 mg twice daily and 20 mg once daily than with placebo (36–47% vs 17%). 5. DAS28 remission (based on DAS28-3 [CRP] score <2. IIA. and 45%. which were all significantly improved in the tofacitinib 5 and 10 mg twice daily groups at 3 months. NCT00413660) in patients with rheumatoid arthritis who had an inadequate response to methotrexate alone. with graft pathology were graded as Banff IIB. The ACR20 response rates in the tofacitinib 5 and 10 mg twice daily groups were significantly better than in the placebo group (60% and 66% vs 27%).[5] Phase II : The addition of tofacitinib to methotrexate significantly improved ACR20 response rates at 12 weeks (primary endpoint) in a phase IIb trial (Study 1025.[26] 2. 5. 178. and the changes from baseline in the HAQ-DI were also significantly better with tofacitinib (-0. or 20 mg once daily. compared with placebo (18–38% vs 9%). 121. CD25 (12% vs 6%). 3. and ACR70 response rates in the higher tofacitinib dosage groups than the placebo group. Compared with stimulated (PMA/ iono/IL-2 or Con A) untreated cells. baseline in DAS28 score.50 and -0. compared with the placebo group. 34.1 Rheumatic Disease Phase III : Tofacitinib significantly reduced the signs and symptoms of disease and improved physical function in patients with moderate to severe rheumatoid arthritis in the phase II/III ORAL Solo trial (Study 1045.7%). 10 (4) . NCT00814307). 41%. and 20 mg once daily groups than in the placebo group (18–25% vs 6%). respectively. 28%. NCT00413699). CD71. and T-cell IFN-g production in whole blood studies on samples from cynomolgus monkeys. A total of 507 patients were randomized to receive tofacitinib at dosages of 1. and Drugs R D 2010.1%) compared with naive untreated mice.

Norway. Belgium. Australia.18.27. Australia. China. Brazil. Italy. the Netherlands. and Malaysia 5 August 2010 3 June 2010 Trial update Pfizer initiates enrollment in a phase II trial in rheumatoid arthritis in Japan 22 June 2010 1 April 2010 Trial update Pfizer completes enrollment in its phase III trial for rheumatoid arthritis (NCT00856544) 7 April 2010 1 February 2010 Scientific update Final pharmacokinetics data from a phase I trial in rheumatoid arthritis published in the British Journal of Clinical Pharmacology[12] 30 March 2010 27 January 2010 Phase change Phase II clinical trials in ankylosing spondylitis in the US (PO) 1 June 2010 27 January 2010 Phase change Phase II clinical trials in dry eyes in the US (ophthalmic) 9 February 2010 27 January 2010 Phase change Phase II clinical trials in psoriatic arthritis in the US (PO) 1 June 2010 7 December 2009 Trial update Pfizer completes enrollment in a phase III trial in rheumatoid arthritis 11 March 2010 20 October 2009 Scientific update Final efficacy and adverse events data from two phase IIb trials in rheumatoid arthritis presented at the 44th Annual Meeting of the Association of Rheumatology Health Professionals (ACR/ARHP2009)[14. Latin America. Drugs R D 2010.29] data from phase IIb trials in rheumatoid arthritis presented at the 10th Annual congress of the European League Against Rheumatism (EULAR-2009) 9 July 2009 13 April 2009 Phase change Phase III clinical trials in rheumatoid arthritis in Australia (PO) 9 February 2010 13 April 2009 Phase change Phase III clinical trials in rheumatoid arthritis in India (PO) 9 February 2010 13 April 2009 Phase change Phase III clinical trials in rheumatoid arthritis in Malaysia (PO) 9 February 2010 13 April 2009 Phase change Phase III clinical trials in rheumatoid arthritis in the Philippines (PO) 9 February 2010 13 April 2009 Phase change Phase III clinical trials in rheumatoid arthritis in Taiwan (PO) 9 February 2010 13 April 2009 Phase change Phase III clinical trials in rheumatoid arthritis in Thailand (PO) 9 February 2010 13 April 2009 Phase change Phase III clinical trials in rheumatoid arthritis in the US (PO) 16 April 2009 Continued next page ª 2010 Adis Data Information BV. and Thailand 8 September 2010 31 August 2010 Phase change Phase I clinical trials in rheumatoid arthritis in Singapore (PO) 20 September 2010 25 July 2010 Trial update Pfizer completes a phase II trial in rheumatoid arthritis in Japan 25 August 2010 8 July 2010 Trial update Pfizer completes a phase III monotherapy trial (NCT00814307) in rheumatoid arthritis in the US. History Event date Update type Comment Update date 8 November 2010 Scientific update Efficacy and adverse events data from the phase II/III ORAL Solo and Oral Sequel trials in rheumatoid arthritis released by Pfizer[5] 9 November 2010 12 October 2010 Trial update Pfizer completes a phase I trial (NCT01184001) in healthy volunteers in Singapore 27 October 2010 7 October 2010 Scientific update Efficacy and adverse events data from a phase II trial in plaque psoriasis released by Pfizer[2] 8 October 2010 6 October 2010 InThought forecasts inThought analysis for dry eyes updated 6 October 2010 6 October 2010 InThought forecasts inThought analysis for plaque psoriasis updated 6 October 2010 6 October 2010 InThought forecasts inThought analysis for rheumatoid arthritis updated 6 October 2010 1 October 2010 Phase change Phase I clinical trials in rheumatoid arthritis in China (PO) 9 November 2010 30 September 2010 Trial update Pfizer completes a phase I trial in healthy volunteers in Singapore 29 October 2010 21 September 2010 Trial update Pfizer completes enrollment in its phase II extension study (NCT00658359) for renal transplant rejection in the US.18] and efficacy[15. Portugal. Latin America. Poland. and South Africa 1 October 2010 16 September 2010 Phase change Phase III clinical trials in plaque psoriasis in the US (PO) 6 October 2010 1 September 2010 Trial update Pfizer completes enrollment in its phase III trial for rheumatoid arthritis in the US. the EU. Malaysia.17. Latin America. Czech Republic. South Korea. Germany. India.17. Europe. France. and Spain 7 October 2010 21 September 2010 Trial update Pfizer completes a phase II trial in ulcerative colitis in the EU. Canada. All rights reserved.28] 20 October 2009 13 June 2009 Scientific update Safety[15. 10 (4) .Tofacitinib 279 Table II.

Mexico. and Turkey 7 November 2008 4 June 2008 Scientific update Pharmacodynamics data from a phase I trial in renal transplant rejection presented at the 8th Joint Congress of the American Society of Transplant Surgeons (ASTS) and the American Society of Transplantation (AST)[24] 1 August 2008 5 April 2008 Scientific update Drug interactions data from two phase I trials in healthy subjects and rheumatoid arthritis presented at the 109th Annual Meeting of the American Society for Clinical Pharmacology and Therapeutics (ASCPT-2008)[22.23] 1 May 2008 28 February 2008 Phase change Phase I clinical trials in asthma in the US (PO) 14 March 2008 28 February 2008 Phase change Phase I clinical trials in psoriasis in the US (PO) 10 March 2008 28 February 2008 Phase change Phase II clinical trials in irritable bowel syndrome in the UK (PO) 11 August 2008 31 January 2008 Phase change Phase II clinical trials in rheumatoid arthritis in Japan (PO) 14 March 2008 31 December 2007 Phase change Phase II clinical trials in Crohn disease in the US (PO) 14 March 2008 30 September 2007 Phase change Phase II clinical trials in rheumatoid arthritis in Mexico (PO) 18 February 2009 30 September 2007 Phase change Phase II clinical trials in rheumatoid arthritis in South Korea (PO) 18 February 2009 30 September 2007 Phase change Phase II clinical trials in rheumatoid arthritis in the Ukraine (PO) 18 February 2009 31 July 2007 Phase change Phase II clinical trials in renal transplant rejection in Australia (PO) 16 November 2007 31 July 2007 Phase change Phase II clinical trials in renal transplant rejection in Brazil (PO) 9 February 2010 31 July 2007 Phase change Phase II clinical trials in renal transplant rejection in Canada (PO) 9 February 2010 31 July 2007 Phase change Phase II clinical trials in renal transplant rejection in the EU (PO) 9 February 2010 31 July 2007 Phase change Phase II clinical trials in renal transplant rejection in South Korea (PO) 9 February 2010 31 July 2007 Phase change Phase II clinical trials in renal transplant rejection in Spain (PO) 16 November 2007 22 June 2007 Scientific update Data presented at the Annual European Congress of Rheumatology (EULAR-2007) added to the rheumatic disease therapeutic trials section[30.31] 22 June 2007 28 February 2007 Phase change Phase II clinical trials in rheumatoid arthritis in the EU (PO) 16 November 2007 Continued next page ª 2010 Adis Data Information BV. and the Ukraine 18 February 2009 30 November 2008 Phase change Phase I/II clinical trials in dry eyes in the US (ophthalmic) 24 April 2009 6 November 2008 Phase change Phase II clinical trials in ulcerative colitis in the US (PO) 9 February 2010 29 October 2008 Scientific update Efficacy. the EU. All rights reserved. Drugs R D 2010. given in combination with methotrexate. and drug interactions data from phase I. in rheumatoid arthritis in the US.280 Adis R&D Profile Table II. South Korea. the EU. Mexico. II.20] 7 November 2008 30 September 2008 Phase change Phase II clinical trials in plaque psoriasis in Canada (PO) 3 October 2008 30 September 2008 Phase change Phase II clinical trials in plaque psoriasis in Canada (Topical) 9 February 2010 30 September 2008 Phase change Phase II clinical trials in plaque psoriasis in the US (PO) 3 October 2008 30 September 2008 Phase change Phase II clinical trials in plaque psoriasis in the US (Topical) 9 February 2010 31 August 2008 Trial update Pfizer completes a phase IIb trial. adverse events. 10 (4) . Contd Event date Update type Comment Update date 10 March 2009 Scientific update Efficacy and adverse events data from a trial in psoriasis presented at the 67th Annual Meeting of the American Academy of Dermatology (AAD-2009)[13] 2 April 2009 28 February 2009 Phase change Phase III clinical trials in rheumatoid arthritis in Canada (PO) 9 February 2010 28 February 2009 Phase change Phase III clinical trials in rheumatoid arthritis in the EU (PO) 9 February 2010 28 February 2009 Phase change Phase III clinical trials in rheumatoid arthritis in Japan (PO) 9 February 2010 28 February 2009 Phase change Phase III clinical trials in rheumatoid arthritis in Latin America (PO) 9 February 2010 28 February 2009 Phase change Phase III clinical trials in rheumatoid arthritis in South Korea (PO) 9 February 2010 10 February 2009 Trial update Pfizer completes a phase II trial in rheumatoid arthritis in the US.19. South America. and IIb trials in rheumatoid arthritis presented at the 72nd Annual Scientific Meeting of the American College of Rheumatology and the 43rd Annual Meeting of the Association of Rheumatology Health Professionals (ACR/ARHP-2008)[16.

at doses of 1–10 mg twice daily. all p < 0. fatigue. double-blind. or 15 mg/day) or adalimumab. phase II study. 15. and healthrelated quality-of-life parameters. ACR20 response rates with tofacitinib were similar to those achieved in patients treated with adalimumab (47%).[14] Tofacitinib was also associated with rapid and sustained improvement in pain. Mean HAQ-DI scores decreased from baseline over time and with increasing doses of the drug and these scores were also statistically significant compared with placebo. NCT00147498) that compared tofacitinib monotherapy (5.29] The addition of tofacitinib to background methotrexate significantly improved ACR response rates at 6 weeks in a phase II trial (Study 1019.[27] ACR response rates were significantly better among patients treated with tofacitinib than in those who received placebo at 12 weeks (49– 75% vs 29%) in a phase II trial (Study 1035. and DAS28 remission rates (15–21% vs 2%). The mean change from baseline in the secondary efficacy measure of Patient’s Assessment of Pain (PAIN) improved statistically significantly with tofacitinib compared with placebo.001).[15. at week 12. or 15 mg/day significantly increased ACR20 response rates compared with placebo (51–67% vs 25%). NCT00550446) in 384 patients with active rheumatoid arthritis. was effective and associated with dose-dependent increases in response in 136 Japanese patients with active rheumatoid arthritis receiving stable background methotrexate. In this 3-month. than with placebo (64–96% vs 14% of patients. Furthermore. Contd Event date Update type Comment Update date 31 January 2007 Phase change Phase II clinical trials in rheumatoid arthritis in Argentina (PO) 16 November 2007 31 January 2007 Phase change Phase II clinical trials in rheumatoid arthritis in Poland (PO) 16 November 2007 30 June 2005 Phase change Phase II clinical trials in renal transplant rejection in the US (PO) 19 October 2005 31 December 2004 Phase change Phase II clinical trials in rheumatoid arthritis in Belgium (PO) 30 March 2006 31 December 2004 Phase change Phase II clinical trials in rheumatoid arthritis in Brazil (PO) 30 March 2006 31 December 2004 Phase change Phase II clinical trials in rheumatoid arthritis in Canada (PO) 30 March 2006 31 December 2004 Phase change Phase II clinical trials in rheumatoid arthritis in Germany (PO) 30 March 2006 31 December 2004 Phase change Phase II clinical trials in rheumatoid arthritis in Italy (PO) 30 March 2006 31 December 2004 Phase change Phase II clinical trials in rheumatoid arthritis in Mexico (PO) 30 March 2006 31 December 2004 Phase change Phase II clinical trials in rheumatoid arthritis in Slovakia (PO) 30 March 2006 31 December 2004 Phase change Phase II clinical trials in rheumatoid arthritis in Spain (PO) 30 March 2006 31 December 2004 Phase change Phase II clinical trials in rheumatoid arthritis in the US (PO) 30 March 2006 28 November 2003 Scientific update Preclinical data has been added to the adverse events and transplant rejection pharmacodynamics sections[21] 2 December 2003 30 October 2003 Phase change Phase I clinical trials in immunosuppression in the US (PO) 4 November 2003 23 June 2003 Scientific update Data presented at the 4th Annual Meeting of the American Transplant Congress (ATC-2003) have been added to the transplant rejection pharmacodynamics section[25] 23 June 2003 19 June 2003 Phase change Preclinical trials in renal transplant rejection in the US (PO) 19 June 2003 physical functioning and several domains of the SF-36 quality-of-life questionnaire at week 12. 10 (4) .28. ACR70 response rates (20–38% vs 7%). 5. 10. All rights reserved.[19. ACR50 response rates (35–54% vs 10%). physical functioning.[30] The same study also showed statistically significant increases in the DAS.Tofacitinib 281 Table II. at dosages of 2–20 mg/day.31] Tofacitinib. in 264 patients with moderate to severe rheumatoid arthritis. without background methotrexate. At 24 weeks. tofacitinib 5. Clinically meaningful reductions in the HAQ-DI at week 6 were achieved in 31% of patients who received placebo compared with 57–71% of patients who received tofacitinib. patients were randomized to receive placebo.[18] Drugs R D 2010. tofacitinib (1. and 30 mg twice daily) with placebo ª 2010 Adis Data Information BV. randomized. 10. In this study. 3. placebo-controlled.and jointremission rates with the 15 and 30 mg dose levels of tofacitinib compared with placebo by week 2 and in the CDAI remission rates by week 4. ACR 20 response rates (primary endpoint) were dose dependent and higher with tofacitinib.

compared with 2% in patients receiving placebo. Mixed-Blind. and other factors specific to the individual agent. such that the current points of a drug relate to its probability of approval. or 60 mg once daily for 2 weeks. 10. novelty. At week 12. Randomized. the trial achieved its primary endpoint. ‘C’ indicating average. 10 (4) . ParallelGroup Treatment Withdrawal And Re-Treatment Study Of The Efficacy And Safety Of 2 Oral Doses Of CP-690. but without analyses of clinical data. The mean reduction from baseline in the mPASI score in the tofacitinib 50 mg twice-daily group was 71. and phase. and other factors in each phase of clinical development. evaluating strength of clinical data and trial design. a letter grade is assigned and reflects the momentum of a drug candidate in its current phase.’ indicating that the probability of approval is based on historical approval rates for similar drugs according to indication. except the 5 mg twice-daily group. ª 2010 Adis Data Information BV. In addition.[2] Oral tofacitinib significantly improved modified PASI (mPASI) scores compared with placebo in a randomized trial in 59 adults with psoriasis.7% respectively. Immunohistochemical analysis revealed normalization of keratin 16 expression in the skin biopsies from three out of four evaluable patients.2 Skin Disorders In a phase II clinical trial involving 197 adult patients with moderate to severe plaque psoriasis. 40. 2.8%. and ‘F’ indicating significantly below average/unlikely to progress. PASI 75 responses for tofacitinib 2. treatment with 5 mg and 15 mg twice daily of tofacitinib significantly improved patient reported health-related quality-of-life outcomes. 30. efficacy. 20. the proportion of patients who had an improvement from baseline of at least 2 points in the Physician Global Assessment (PGA) score. Possible points total 100 upon drug approval. ‘NYR’ stands for ‘Not Yet Rated. benchmarked against historical parameters and likelihood to maintain forward momentum. trial design. A Phase 3. as a result. Improvements in mPASI scores from baseline to day 14 were dose-dependent. with ‘A’ indicating significantly above average/likely to progress. with significantly greater improvements seen in all tofacitinib dosage groups.8% versus 11. Patients received tofacitinib at dosages of 5. and. Points are assigned for specific line items relating to safety. NE = no estimate.[13] References 1. or 50 mg twice daily. was significantly higher in the tofacitinib 50 mg twice-daily group than the placebo group. a statistically significant greater proportion of patients achieved at least a 75% reduction from baseline in PASI (Psoriasis Area and Severity Index) at week 12.550 In Subjects With Moderate To Severe Chronic Plaque Psoriasis. compared with placebo.282 Adis R&D Profile Table III. Forecasts InThought Probability of Approvala Indication Approval Date Estimate inThought Approvability Index Last Update Ankylosing spondylitis NE 29% (NYR) 9 Nov 2010 Crohn disease NE 28% (NYR) 27 Jul 2009 Dry eyes NE 28% (NYR) 6 Oct 2010 Plaque psoriasis NE 62% (NYR) 6 Oct 2010 Psoriatic arthritis NE 29% (NYR) 9 Nov 2010 Renal transplant rejection NE 28% (NYR) 27 Jul 2009 Rheumatoid arthritis NE 62% (NYR) 6 Oct 2010 Ulcerative colitis NE 28% (NYR) 9 Nov 2010 InThought Worldwide Revenueb Indication 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 Last Update Rheumatoid arthritis 0 0 0 0 0 7 64 218 422 599 24 Jul 2009 a The Wolters Kluwer Health Approvability Index is a dynamic tool that assesses the progress of a drug candidate through clinical development. molecule type. and 66.0%. and a lesional PGA response defined as clear or almost clear. and are allocated in each phase according to the historical approval rate of similar drugs. As early as week 4. Furthermore. Clinical Trial Profile Drugs R D 2010. All rights reserved. and 15 mg twice daily groups were 25.5% for placebo.5. Multi-Site. b All numbers in $US millions. 5.

Bloom B. placebo-controlled. Double Blind. Clinical Trial Profile 10. 18 Oct 2009 Media Release 15. May 2008.690 550 in Subjects With Moderate to Severe Ulcerative Colitis. et al. Pfizer Inc.eular. Phase 2B dose ranging monotherapy study of the oral JAK inhibitor CP690. safe and well tolerated in patients with active rheumatoid arthritis with an inadequate response to methotrexate alone.pfizer. 17. Parallel Group Multi-Center Study in Order to Investigate Safety and Efficacy of CP. A Phase 2 Randomized. Single Dose. New Pfizer Pipeline Shows Progress And Growth In Vaccines.550 and Mycophenolate Mofetil/ Mycophenolate Sodium in De Novo Renal Allograft Recipients. Cohen S. 72nd Annual Scientific Meeting of the American College of Rheumatology and the 43rd Annual Meeting of the Association of Rheumatology Health Professionals: abstr. 3-Period. 10th Annual Congress of the European League Against Rheumatism: abstr. USA [English] Chow V. OP-0159. Randomized. 2): 387 abstr.550) Under Fasted Conditions. www. USA [English] 13.550. dose-escalation study to evaluate the pharmacologic effects of CP-690. 72nd Annual Scientific Meeting of the American College of Rheumatology and the 43rd Annual Meeting of the Association of Rheumatology Health Professionals: abstr.org/annual/index. van Gurp E. Japan [English] Silverfield J. www. Nakamura H. Bioequivalence Study Comparing Phase 2b.eular. 24. Fleischmann R. Pfizer Inc. 10 Jun 2009. Long-term follow-up of patients with moderate to severe rheumatoid arthritis treated with the oral JAK inhibitor CP-690. 782. Open label study to estimate the effect of fluconazole on the pharmacokinetics of a JAK3 antagonist (CP-690. is a well-tolerated and effective long-term treatment for patients with moderate to severe rheumatoid arthritis.550. Clucas A.2009. Chow V. In First Phase 3 Trial.1111/j.org. Phase 1. Connell C. Cohen S. A Phase 1. 2-Period. Pfizer Development Pipeline Shows Advances In High-Priority Disease Areas. Mar 2008. Open-Label. 353. 3-Treatment.1365-2125. an oral JAk inhibitor. Cross-Over Study To Evaluate The Effect Of Food On Pharmacokinetics Of Tasocitinib (CP-690.550 and methotrexate is well tolerated in patients with rheumatoid arthritis without need for dose adjustment. Available from URL: http://www. Reduces Signs and Symptoms of Active Rheumatoid Arthritis and Improves Physical Function.pfizer. USA [English] Quaedackers M. 03 Apr 2009 Media Release 8. CP-690.rheumatology.asp. The oral JAK inhibitor CP-690. A Phase 1. 10 Jun 2009. et al. L13.550) in healthy adult subjects.pfizer. Clinical Pharmacology and Therapeutics. 30 Oct 2003 Media Release 5. Available from URL: http://www. The oral Jak inhibitor CP-690.rheumatology. 10 Jun 2009. Single-Dose.550.com. Placebo Controlled. Pfizer Inc. Pfizer’s Oral JAK Inhibitor. 283 16. Ni G. USA [English] Connell CA. www. Available from URL: http://www. CP-690. Double-blind.com. 72nd Annual Scientific Meeting of the American College of Rheumatology and the 43rd Annual Meeting of the Association of Rheumatology Health Professionals (Late Breaking Abstr. Randomized. et al.org/ annual/index. Clinical Trial Profile 12.org/10. British Journal of Clinical Pharmacology. Biologics And High-Priority Disease Areas.eular. et al. Demonstrates Response Both Alone And In Combination With Methotrexate At 24 Weeks In Patients With Active Rheumatoid Arthritis. Prevention of organ allograft rejection by a specific Janus kinase 3 inhibitor. Co-administration of the JAK inhibitor CP-690.550. A Randomized. Labadie R. 18. 10th Annual Congress of the European League Against Rheumatism: abstr. Suzuki M.550) and single doses of oral methotrexate in rheumatoid arthritis subjects. 6 Mar 2009. 1): 36.org/annual/ index. Clinical Trial Profile 9. 31 Oct 2003. et al. Wilkinson B.com. et al. an Oral JAK Inhibitor. Available from URL: http://www. 22. 83 (Suppl. Tasocitinib (CP-690. Forejtova S.550 in combination with methotrexate is efficacious. Flanagan ME. 716. Available from URL: http://www. Mar 2008.org. Clinical Pharmacology and Therapeutics. Active ComparatorControlled Trial to Evaluate the Safety and Efficacy of CoAdministration of CP-690. Cutolo M. Science.com. Zwillich SH. 24 Oct 2008. Open Label. Pfizer Inc.550 in stable kidney transplant patients. Administered as Monotherapy. Co-administration of an oral JAK inhibitor CP-690. et al.): abstr.550) Tablets In Healthy Subjects.pfizer. The Netherlands [English] Drugs R D 2010. Kanik K. rheumatology. Multicenter. www. SAT0157.asp. 83 (Suppl. Randomized. 10th Annual Congress of the European League Against Rheumatism: abstr. 24 Oct 2008. Silverfield J.550 in subjects with psoriasis. 2-Sequence. www. 69: 143-51. 3-Period. Clinical Trial Profile 4. Phase 3 And Commercial Image Tablet Formulations Of Tasocitinib (CP-690. 8 (Suppl. Available from URL: http://www.com.550 in combination with methotrexate (MTX) is efficacious.550). Labadie R. Mol W.pfizer. rheumatoid arthritis with an inadequate response to DMARDs.com. 20. All rights reserved. American Journal of Transplantation. Chow V. P3339. 302: 875-878. Labadie R. Open Label. Available from URL: http://dx.03570. 07 Oct 2010 Media Release 3. Open label study of the pharmacokinetics of a JAK3 antagonist (CP-690. USA [English] Wilkinson B. Pfizer. Single Dose. USA [English] Kremer J. www. 28 Jan 2010 Media Release 7. et al. 24 Oct 2008. Potential New Pfizer Medicine Reduces Transplant Rejection Rates in Animal Studies.Tofacitinib 2. 1): 36.pfizer. Cross-Over. 5646. et al. et al. 21.x. USA [English] Changelian PS. Pfizer Inc. et al. et al. 2. Cross Over Study To Evaluate The Pharmacokinetics And Safety Of Two Controlled Release Formulations Of CP690. USA [English] Tanaka Y. 10 (4) .550 or adalimumab vs placebo in patients with active ª 2010 Adis Data Information BV. Ball DJ. Krueger J. Harness J. 08 Nov 2010 Media Release 6. 23. No. USA [English] 14. OP-0181.doi. safe and well tolerated in Japanese patients with active rheumatoid arthritis with an inadequate response to MTX alone. 19. Pharmacodynamic monitoring of the immunosuppressive drug CP-690. 67th Annual Meeting of the American Academy of Dermatology: 171 abstr. No. Without Side Effects of Current Therapies.550 and methotrexate is well tolerated in patients with rheumatoid arthritis. Clinical Trial Profile 11. Oral Tasocitinib Demonstrates Statistically Significant Response by 12 Weeks in Phase 2 Study of People With Moderate to Severe Plaque Psoriasis. 1 Feb 2010. USA [English] Chow V. Wilkinson B.asp.org.

Improvements in pain. is associated with dose-dependent increases in remission rates and improvement in the CDAI and SDAI. Kanik K. Physical Functioning (PF). 73rd Annual Scientific Meeting of the American College of Rheumatology and the 44th Annual Meeting of the Association of Rheumatology Health Professionals: ª 2010 Adis Data Information BV. 10 Jun 2009. Borie DC. Results of two phase IIB studies of the oral JAK inhibitor CP-690. USA [English] 27.org. USA [English] 30. Aalami O. Available from URL: http://www. Cohen S. The JAK3 inhibitor CP-690. Bloom BJ. Paniagua R. Results of two phase IIB studies of the oral JAK inhibitor CP-690. function. 2003. et al. Wallenstein G. American Journal of Transplantation. Available from URL: http://www. Kanik K. Summary in 2 parts (Part B). 3 (Suppl. et al. USA [English] 26.eular. Cutolo M. 2007 Annual European Congress of Rheumatology: abstr. 13 Jun 2007. Breedveld FC. double-blind. SAT0136. Holm B.550 significantly inhibits immune responses in vivo as revealed by pharmacodynamic monitoring of naive and transplanted cynomolgus monkeys. Targeted inhibition of JAK3 with CP-690. 5): 257 (plus poster) abstr.284 25. Coombs J. SAT0136. Wilkinson B. Available from URL: http://www. 10 Jun 2009. et al.org. Wallenstein G. Summary in 2 parts (Part A). an orally active inhibitor of Janus kinase 3: results from a randomized. Breedveld FC. Wilkinson B. Bloom BJ. Fatigue. 3 (Suppl. et al. physical functioning. 2007 Annual European Congress of Rheumatology: abstr.550 (CP) On Pain. and health status in patients taking CP690. 2003. THU0428.550 and its effects on pain. 412. Effects of the Oral JAK Inhibitor CP-690. Larson MJ. 10th Annual Congress of the European League Against Rheumatism: abstr. 418. Coombs JH. and Health-Related Quality of Life (HRQoL) in Patients (pts) with Active Rheumatoid Arthritis (RA). The Netherlands [English] Drugs R D 2010. and health-related quality of life.550. and health-related quality of life. Wallenstein G. 6 weeks of treatment of active rheumatoid arthritis with an orally active inhibitor of Janus kinase 3. et al. All rights reserved. Adis R&D Profile abstr. 10 (4) .org. American Journal of Transplantation. 16 Oct 2009. 10th Annual Congress of the European League Against Rheumatism: abstr. et al. physical functioning. rheumatology. USA [English] 31. 13 Jun 2007. Changelian P.550 and its effects on pain. 5): 152-153.550 significantly prolongs allograft survival in a nonhuman primate model of renal transplantation.eular. placebo-controlled trial in the treatment of active rheumatoid arthritis.550. USA [English] 28. Summary in 2 parts (Part A). CP-690. SAT0040. et al. Unknown [English] 29.