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Tofacitinib.
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PMID:  21171673     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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 specifically 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.
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Publication Detail:
Type:  Journal Article; Review    
Journal Detail:
Title:  Drugs in R&D     Volume:  10     ISSN:  1179-6901     ISO Abbreviation:  Drugs R D     Publication Date:  2010  
Date Detail:
Created Date:  2010-12-21     Completed Date:  2011-11-14     Revised Date:  2013-07-03    
Medline Journal Info:
Nlm Unique ID:  100883647     Medline TA:  Drugs R D     Country:  New Zealand    
Other Details:
Languages:  eng     Pagination:  271-84     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Clinical Trials as Topic
Drugs, Investigational / pharmacology,  therapeutic use*
Humans
Immunosuppressive Agents / pharmacology,  therapeutic use*
Janus Kinase 3 / antagonists & inhibitors*
Pyrimidines / pharmacology,  therapeutic use*
Pyrroles / pharmacology,  therapeutic use*
Chemical
Reg. No./Substance:
0/Drugs, Investigational; 0/Immunosuppressive Agents; 0/Pyrimidines; 0/Pyrroles; 87LA6FU830/tofacitinib; EC 2.7.10.2/Janus Kinase 3
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Drugs R D. 2012 Mar 1;12(1):41-3
Note: Dosage error in article text

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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Journal Information
Journal ID (nlm-ta): Drugs R D
Journal ID (iso-abbrev): Drugs R D
ISSN: 1174-5886
ISSN: 1179-6901
Publisher: Springer International Publishing, Cham
Article Information
© Adis Data Information BV 2010
Electronic publication date: Day: 25 Month: 11 Year: 2012
pmc-release publication date: Day: 25 Month: 11 Year: 2012
Print publication date: Month: 11 Year: 2010
Volume: 10 Issue: 4
First Page: 271 Last Page: 284
PubMed Id: 21171673
ID: 3585773
Publisher Id: 10040271
DOI: 10.2165/11588080-000000000-00000

Tofacitinib
Adis Editorial

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 re-treatment in 660 patients in the US.[1]

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).

In September 2008, Pfizer began two phase II clinical trials to assess the efficacy and safety of topical tofacitinib in 81 and 197 patients with plaque psoriasis, respectively (NCT00678561, NCT00678210). Both studies were completed in the US and Canada. Results from the second trial were presented in October 2010, showing a statistically significant response in patients receiving tofacitinib in the treatment of moderate to severe plaque psoriasis.[2]

1.1.4 Renal Transplant Rejection

A phase II trial evaluated the compound in combination with mycophenolate mofetil in 338 de novo renal allograft recipients (NCT00483756). This trial was conducted in the US, Australia, Brazil, Canada, EU, and South Korea, and was completed in April 2010. A phase II, 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).[3]

Tofacitinib was investigated in a 6-month phase II clinical trial in the US for the prevention of renal allograft rejection. Tofacitinib was administered with interleukin (IL)-2 antagonist induction therapy, mycophenolate mofetil, and corticosteroids. The trial enrolled 61 de novo renal allograft recipients and was completed in October 2006 (NCT00106639). This phase II trial was extended into a long-term post-transplant study for patients who respond well. Enrollment of 45 patients was completed into this extension study (NCT00263328), which began in December 2005 in the US and is expected to complete in 2014.

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. Pfizer was investigating the compound in psoriasis before proceeding to studies in patients with kidney transplants.[4]

1.1.5 Rheumatoid Arthritis

Pfizer commenced phase III development of tofacitinib in the treatment of rheumatoid arthritis in February 2009, with the initiation of its phase III ORAL trials program. The program includes six trials conducted in 35 countries worldwide.[57]

A 2-year, randomized, 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, Australia, Latin America, Canada, the EU, India, Japan, South Korea, and Taiwan (NCT00847613). 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.

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). The study is ongoing in the US.

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). This randomized, double-blind, parallel-group study is recruiting patients in the US, Canada, South Korea, Puerto Rico, Spain, and Taiwan.

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; NCT00814307). This study has enrolled approximately 652 patients in the US, Latin America, the EU, India, Malaysia, and the Philippines. Results released in November 2010 showed that the trial had met two of three primary endpoints.[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, Canada, Latin America, the EU, South Korea, the Philippines, and Thailand (NCT00853385).

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). Recruitment of 750 patients was completed in September 2010 at multiple centers in the US, Australia, Latin America, China, the EU, Malaysia, and Thailand.

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). Patients who have completed the qualifying study (NCT00603512) are eligible for enrollment in this study.

Two phase II trials (ORAL Sequel, NCT00413699 and NCT00414661) are evaluating the long-term efficacy and safety of tofacitinib in 4000 patients and 300 patients with rheumatoid arthritis, respectively, in the US, the EU, and Latin America (Argentina and Mexico). Preliminary results from ORAL Sequel have been reported.[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. 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. At week 6, 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.

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).

A phase I trial (NCT01143805) compared the bioavailability of oral and intravenous tofacitinib in volunteers. The trial was completed August 2010.

1.1.6 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.[8] This randomized, double-blind, placebo-controlled study recruited patients in the EU, Latin America, and South Africa.

1.1.7 Other Indications

According to Pfizer’s pipeline in January 2010, tofacitinib is being investigated in phase II trials for the treatment of ankylosing spondylitis and psoriatic arthritis.

1.1.8 Trials in Healthy Volunteers

In August 2010, Pfizer initiated a randomized, open-label, phase I trial (NCT01184092) to assess the pharmacokinetics of three different tablet formulations of tofacitinib under fasted conditions in healthy volunteers. The trial enrolled 24 subjects in Singapore and was completed in September 2010.[9]

In a phase I trial (NCT01185184) completed in August 2010, 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. Using a three-way crossover design, these were compared to a 10 mg immediate-release tablet formulation.[10]

Pfizer has completed enrollment in a phase I trial (NCT01101919) of tofacitinib in healthy volunteers in China. Approximately 12 subjects enrolled in the trial, which is evaluating the pharmacokinetics of the compound. Another phase I trial (NCT01184001), completed in October 2010, evaluated the effect of food on the pharmacokinetics of tofacitinib in 16 healthy volunteers in the US.[11]


2. Scientific Summary
2.1 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. Patients received multiple doses of tofacitinib (30 mg twice daily) and single doses of methotrexate (15–25 mg per week). Tofacitinib exposure was not affected by coadministration of methotrexate; the area under the concentration-time curve (AUC) from 0 to 12 hours (AUC12) ratio (tofacitinib plus methotrexate/tofacitinib) was 103.06% (90% CI 99.00, 107.29). Methotrexate exposure decreased by 10% on coadministration, with an AUC12 ratio (tofacitinib plus methotrexate/methotrexate) of 89.53% (90% CI 77.38, 103.57), which was not regarded as clinically significant. Dose adjustments should not be required when coadministering tofacitinib and methotrexate.[12]

2.2 Adverse Events
2.2.1 Psoriasis

In a phase II clinical trial involving 197 adult patients with moderate to severe plaque psoriasis, the most frequently reported treatment-related adverse events were upper respiratory tract infection and headache. Three patients experienced a total of five serious adverse events. Dose-dependent decreases in mean neutrophil counts and hemoglobin values, and increases in mean low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and total cholesterol levels were observed.[2]

Oral tofacitinib administered for 2 weeks resulted in adverse events in 10 of 59 adult patients with psoriasis who participated in a randomized placebo-controlled trial. During treatment with tofacitinib at dosages of 5, 10, 20, 30, or 50 mg twice daily, or 60 mg once daily, the most common adverse events were mild nausea and mild headache. Increases in total cholesterol, LDL-C and triglyceride levels occurred in patients in some of the tofacitinib groups, but no other changes in laboratory parameters were reported.[13]

2.2.2 Rheumatoid Arthritis

Phase III : Rates of discontinuation as a result of adverse events were low in the phase III ORAL Solo trial (Study 1045; NCT00814307), which evaluated tofacitinib monotherapy in patients with moderate to severe rheumatoid arthritis. A total of 611 patients who had an inadequate response to DMARDS were randomized to placebo, or to tofacitinib 5 or 10 mg twice daily. Adverse events were reported in 54% and 40% of patients during months 0–3 and months 3–6, respectively, and events leading to treatment withdrawal occurred in 2% of patients at 0–3 months and 1% of patients at 3–6 months. Over the 6-month study period, serious adverse events occurred in 25 patients (4.1%) and serious infections occurred in six patients. 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, but not during months 3–6. Elevated transaminase levels were rare and occurred at a similar frequency in all treatment groups.[5]

No new safety signals have emerged over 2 years in the ongoing ORAL Sequel phase II/III extension study (Study 1024; NCT00413699), which included 1077 patients treated with placebo or tofacitinib as monotherapy or in combination with methotrexate. The most frequently reported adverse events included urinary tract infections, bronchitis, and upper respiratory tract infections. The most common serious adverse events were infections, which occurred in 18% of patients (incidence rate 2.62 per 100 patient-years of tofacitinib therapy). There were two cases of tuberculosis, one in a patient treated with tofacitinib in addition to methotrexate, and another that occurred 2 months after tofacitinib withdrawal. Decreased neutrophil counts and increased LDL-C and HDL-C levels observed during the first 3 months of treatment did not worsen over the 2-year follow-up.[5]

Phase II : The most frequently reported treatment-emergent adverse events were urinary tract infections, headache, and diarrhea, according to final results from two phase IIb trials (NCT00550446, Study 1035, n = 384; NCT00413660, Study 1025, n = 507) of tofacitinib, as monotherapy or in combination with methotrexate, in patients with active rheumatoid arthritis. Most adverse events were mild to moderate in severity. Adverse events leading to treatment discontinuation and serious adverse events were infrequent. Dose-dependent increases in LDL-C, HDL-C, and total cholesterol, and decreases in mean neutrophil counts were consistent with reports from previous trials of tofacitinib in rheumatoid arthritis. In addition, the transaminase increases reported in patients receiving background methotrexate, were consistent with data from previous trials.[14,16]

After 1 year of an extension study that included patients enrolled in three phase II studies (Study 1019 6-week monotherapy; Study 1025 24-week background methotrexate; and Study 1035 24-week, monotherapy), most adverse events were mild to moderate in nature. Among reported adverse events, ten were rated as severe and included abdominal pain, acne, acute renal failure, diarrhea, disseminated tuberculosis, diverticulitis, herpes zoster, pneumonia, staphylococcal infection, and urinary tract infections. Most frequently reported adverse events were urinary tract infection, diarrhea, anaemia, nausea, and sinusitis.[17]

Twelve-week data from a phase II study in 136 Japanese patients with rheumatoid arthritis receiving stable background methotrexate showed that oral tofacitinib, at doses of 1–10 mg twice daily, was generally well tolerated. Most treatment-emergent adverse events were mild or moderate in intensity; the most commonly observed were nasopharyngitis, stomach discomfort, and increased levels of liver transaminases and blood cholesterol. Serious adverse events were observed in five patients.[18,19]

Phase I : Tofacitinib plus methotrexate was well tolerated in a fixed-sequence, drug-drug interaction, phase I study in patients with rheumatoid arthritis. There were no deaths, serious adverse events or discontinuations due to adverse events. 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. Patients were administered their weekly methotrexate dose on the morning of day 1. Tofacitinib was administered at 30 mg every 12 hours on days 3–6. On day 7, patients received their morning tofacitinib dose followed by their weekly methotrexate. No obvious trends in the incidence, severity, or type of adverse events were observed across treatment groups. Of 34 adverse events reported in the study, five patients had seven adverse events after methotrexate monotherapy, six patients had 15 adverse events after tofacitinib monotherapy, and five patients had 12 adverse events after combination treatment. Four treatment-related adverse events (dizziness, disorientation, headache, and hot flushes) were observed. Abnormal laboratory test values were reported, but were considered non-clinically significant. Two patients temporarily discontinued tofacitinib during the study, both missing one dose. One patient experienced mild leg pain and other experienced a mild vasovagal episode during a blood draw. Both cases were resolved and the patients continued dosing as scheduled.[12,20]

2.2.3 Animal Toxicology

No evidence of metabolic abnormalities, hypertension, or cases of post-transplant lymphoproliferative disease were detected in cynomolgus monkeys treated with tofacitinib. However, tofacitinib was associated with transient dose-related anemia, believed to be linked to a low level of JAK2 inhibition. Previous studies showed that tofacitinib had 20-fold less inhibitory activity for JAK2 than JAK3. Since JAK2 mediates signaling via many hematopoietic cytokines, its inhibition could result in anemia, thrombocytopenia, and leukopenia in vivo. This event was restricted to four animals at the highest drug exposure accompanied by minor decreases in hemoglobin levels. These animals survived for 90 days with recovery to baseline values.[21]

2.3 Drug Interactions

In a fixed-sequence, drug-drug interaction, phase I study of tofacitinib in patients with rheumatoid arthritis, methotrexate did not change the pharmacokinetics of tofacitinib. 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. Patients were administered their weekly methotrexate dose on the morning of day 1. Tofacitinib was administered at 30 mg every 12 hours on days 3–6. On day 7, patients received their morning tofacitinib dose followed by their weekly methotrexate dose. The mean AUC12 values were 1410 ng · h/mL and 1370 ng · h/mL for tofacitinib plus methotrexate combination therapy and tofacitinib monotherapy, respectively. Mean maximum concentration (Cmax) values were 384 ng/mL and 375 ng/mL for the combination therapy and tofacitinib monotherapy, respectively. 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). 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.[20]

Data from an open-label, single fixed-sequence, two-period, 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%, respectively, in comparison with tofacitinib alone, presumably due to inhibition of cytochrome P450 (CYP) 3A4 by fluconazole. Both tofacitinib and fluconazole were safe and well tolerated when administered alone or in combination. This study was conducted to estimate the effect of multiple-dose fluconazole on the pharmacokinetics of single-dose tofacitinib in healthy subjects. On period 1/day 1, subjects received a single 30 mg dose of tofacitinib. On period 2/day 2 (72 hours after the first tofacitinib dose), subjects received fluconazole 400 mg followed by 200 mg once daily for 6 additional days (days 2–7), and a single 30 mg dose of tofacitinib on period 2/day 5. The pharmacokinetic profile of tofacitinib was evaluated after the tofacitinib doses on period 1/day 1 and period 2/day 5.[22]

Coadministration of tofacitinib and methotrexate in patients with rheumatoid arthritis appeared to be safe and well tolerated, and methotrexate had no clinically relevant effect on the pharmacokinetics of tofacitinib. The drug resulted in a 10% decrease in methotrexate AUC and a 13% decrease in methotrexate Cmax when coadministered; however, these changes were not considered clinically relevant. No dosage adjustment is deemed necessary when tofacitinib is coadministered with methotrexate. This single fixed-sequence study was conducted in 12 patients diagnosed with rheumatoid arthritis for at least 6 months. 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. Patients received their weekly methotrexate dose on the morning of day 1. Tofacitinib was administered to patients at 30 mg every 12 hours on days 3–6. On day 7, patients received the morning dose of tofacitinib followed by their methotrexate single dose. Pharmacokinetic evaluations were performed on days 1 and 7 for methotrexate, and on days 6 and 7 for tofacitinib.[23]

2.4 Pharmacodynamics
2.4.1 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. A maximal mean reduction in phosphorylation of 74% was achieved, while recovery to baseline was observed at day 57, following completion of treatment at day 29. Additionally, 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 γ-irradiated allogeneic PBMCs. The presence of P-STAT5 was mainly detected in alloactivated CD4+ and CD8+ T cells that expressed CD25 (IL-2Rα) and was inhibited by tofacitinib in both populations. Furthermore, at the functional level, the inhibitory effect of tofacitinib was demonstrated on the expression of IL-2 responsive target genes downstream of the JAK/STAT pathway, such as FOXP3, SOCS3, IL-2Rα, interferon (IFN)-γ and granzyme B.[24]

Preclinical Studies : Tofacitinib demonstrated high selectivity for JAK3 inhibition with an enzyme inhibitory potency of 1 nmol/L and showed 20- to 100-fold less selectivity for JAK2 and JAK1, respectively. In addition, tofacitinib did not exhibit potent inhibitory activity against 30 other kinases with a median 50% inhibitory concentration (IC50) >3000 nmol/L. This included Lck, a key T-lymphocyte signaling molecule downstream of the T-cell receptor.[21]

Tofacitinib displayed potent inhibition in cell-based assays using murine, monkey, or human cells. Consistent with its mechanism of action, these cellular activities correlated with the ability of tofacitinib to block IL-2-induced phosphorylation of JAK3 and one of its key substrates STAT5. 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. The IC90 for tofacitinib in this assay was 160 nmol/L and was established as the initial target exposure for in vivo efficacy.[21]

Preclinial studies in a mouse model of heterotopic heart transplantation indicated that tofacitinib suppressed the in vivo allogenic response. Animals treated with vehicle alone rejected their allografts within 12 days, whereas tofacitinib-treated animals experienced a dose-dependent increase in survival of transplanted hearts. Animals in the higher dose groups had a median survival time of >60 days. On the basis of drug exposures measured in all groups, 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.[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, 6, 7, and 8. 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. In the high exposure group, three animals were euthanized on postoperative days 69, 90, and 90, with pathology graded as no graft rejection, borderline, and Banff IB acute rejection respectively. A fourth animal was euthanized on postoperative day 63 with impaired renal function and BK nephritis. Animals with low exposure rejected on postoperative day 40, 52, 34, and 48, with graft pathology were graded as Banff IIB, IIB, IIA, and III, respectively.[25]

Tofacitinib inhibited immune cell proliferation, T-cell activation (CD25, CD71), and T-cell IFN-γ production in whole blood studies on samples from cynomolgus monkeys. Inhibition was proportional to drug concentration (max at 160 ng/mL). Compared with stimulated (PMA/iono/IL-2 or Con A) untreated cells, expression of CD25, CD71, proliferating cell nuclear antigen (PCNA), IFN-γ in cells treated with tofacitinib was 12%, 41%, 28%, and 45%, respectively. The respective IC50 values for these parameters were 89, 121, 178, and 121 ng/mL. Tofacitinib treatment of mice receiving renal allografts significantly reduced expression of IFN-γ (35% vs 14.4%), CD25 (12% vs 6%), PCNA (36.6% vs 12.7%), and CD-3/CD16+ (11% vs 4.1%) compared with naive untreated mice.[26]

2.5 Therapeutic Trials
2.5.1 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; NCT00814307). A total of 611 patients were randomized to tofacitinib 5 or 10 mg twice daily or placebo for 6 months. The three primary endpoints were the American College of Rheumatology 20% (ACR20) response rates, change in Health Assessment Questionnaire Disability Index (HAQ-DI) scores and remission rate defined as a Disease Activity Score (DAS) 28-4 (ESR) [DAS28] <2.6. 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%), and the changes from baseline in the HAQ-DI were also significantly better with tofacitinib (-0.50 and -0.57 vs -0.19). However, the proportion of patients who achieved a DAS28 score <2.6 was not significantly different between the active and placebo groups (6% and 10% vs 4%). Secondary endpoints included the ACR50 and ACR70 response rates and the mean change from baseline in DAS28 score, which were all significantly improved in the tofacitinib 5 and 10 mg twice daily groups at 3 months, compared with the placebo group.[5]

In the ongoing 2-year ORAL Sequel extension study (Study 1024; NCT00413699), ACR20 response rates appeared to improve slightly over time in patients treated with tofacitinib either as monotherapy or in combination with methotrexate. Furthermore, improvements from baseline in the mean HAQ-DI and DAS28 scores were maintained over 2 years.[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; NCT00413660) in patients with rheumatoid arthritis who had an inadequate response to methotrexate alone. A total of 507 patients were randomized to receive tofacitinib at dosages of 1, 3, 5, 10, or 15 mg twice daily, or 20 mg once daily, or placebo. The ACR20 response rates at 12 weeks ranged from 49% to 61% versus 38% for placebo, and were significantly better for all tofacitinib dosage groups except 1 mg twice daily, compared with placebo. 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%), and ACR70 response rates showed a similar trend with significantly better rates in the 3, 5, 15 mg twice daily, and 20 mg once daily groups than in the placebo group (18–25% vs 6%). Outcomes at 24 weeks were similar to those at 12 weeks, with significant improvements in ACR20, ACR50, and ACR70 response rates in the higher tofacitinib dosage groups than the placebo group.[14] The proportions of patients who achieved a HAQ-DI response (≥0.22 unit improvement from baseline) were significantly better in all tofacitinib dosage groups, than the placebo group (62–69% vs 41%). Furthermore, DAS28 remission (based on DAS28-3 [CRP] score <2.6) was achieved in significantly greater proportions of patients in all tofacitinib groups, except the 1 mg twice daily group, compared with placebo (18–38% vs 9%).[16] Compared with placebo, tofacitinib was also associated with significant improvements in pain at week 2, and physical functioning and several domains of the SF-36 quality-of-life questionnaire at week 12.[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; NCT00550446) in 384 patients with active rheumatoid arthritis. Furthermore, ACR20 response rates with tofacitinib were similar to those achieved in patients treated with adalimumab (47%). In this study, patients were randomized to receive placebo, tofacitinib (1, 3, 5, 10, or 15 mg/day) or adalimumab, without background methotrexate. At 24 weeks, tofacitinib 5, 10, or 15 mg/day significantly increased ACR20 response rates compared with placebo (51–67% vs 25%), ACR50 response rates (35–54% vs 10%), ACR70 response rates (20–38% vs 7%), and DAS28 remission rates (15–21% vs 2%).[14] Tofacitinib was also associated with rapid and sustained improvement in pain, physical functioning, fatigue, and health-related quality-of-life parameters.[15,28,29]

The addition of tofacitinib to background methotrexate significantly improved ACR response rates at 6 weeks in a phase II trial (Study 1019; NCT00147498) that compared tofacitinib monotherapy (5, 15, and 30 mg twice daily) with placebo in 264 patients with moderate to severe rheumatoid arthritis. 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. 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. 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.[30] The same study also showed statistically significant increases in the DAS- and joint-remission 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.[19,31]

Tofacitinib, at doses of 1–10 mg twice daily, 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, randomized, double-blind, placebo-controlled, phase II study, at week 12, ACR 20 response rates (primary endpoint) were dose dependent and higher with tofacitinib, at dosages of 2–20 mg/day, than with placebo (64–96% vs 14% of patients; all p < 0.001).[18]

2.5.2 Skin Disorders

In a phase II clinical trial involving 197 adult patients with moderate to severe plaque psoriasis, 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, and, as a result, the trial achieved its primary endpoint. At week 12, PASI 75 responses for tofacitinib 2, 5, and 15 mg twice daily groups were 25.0%, 40.8%, and 66.7% respectively, compared with 2% in patients receiving placebo. As early as week 4, treatment with 5 mg and 15 mg twice daily of tofacitinib significantly improved patient reported health-related quality-of-life outcomes.[2]

Oral tofacitinib significantly improved modified PASI (mPASI) scores compared with placebo in a randomized trial in 59 adults with psoriasis. Patients received tofacitinib at dosages of 5, 10, 20, 30, or 50 mg twice daily, or 60 mg once daily for 2 weeks. Improvements in mPASI scores from baseline to day 14 were dose-dependent, with significantly greater improvements seen in all tofacitinib dosage groups, compared with placebo, except the 5 mg twice-daily group. The mean reduction from baseline in the mPASI score in the tofacitinib 50 mg twice-daily group was 71.8% versus 11.5% for placebo. Furthermore, the proportion of patients who had an improvement from baseline of at least 2 points in the Physician Global Assessment (PGA) score, and a lesional PGA response defined as clear or almost clear, was significantly higher in the tofacitinib 50 mg twice-daily group than the placebo group. Immunohistochemical analysis revealed normalization of keratin 16 expression in the skin biopsies from three out of four evaluable patients.[13]


Notes

An Erratum for this chapter can be found at http://dx.doi.org/10.1007/BF03259723

This drug profile has been extracted from Wolters Kluwer’s AdisR&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.

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Figures

[Figure ID: Tab1]
Table I 

Features and properties



[Figure ID: Tab2]
Table II 

History



[Figure ID: Tab3]
Table III 

Forecasts



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