Janus Kinase Inhibitor

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Kim Papp - One of the best experts on this subject based on the ideXlab platform.

  • SAT0469 Integrated efficacy analysis of tofacitinib, an oral Janus Kinase Inhibitor, in patients with active psoriatic arthritis
    Annals of the Rheumatic Diseases, 2017
    Co-Authors: Peter Nash, Kim Papp, Cunshan Wang, Laura C Coates, Keith S Kanik, Thijs Hendrikx, Joe C Wu, Roy Fleischmann, Juan J. Gomez-reino, William C Ports
    Abstract:

    Background Tofacitinib is an oral Janus Kinase Inhibitor under investigation for treatment of psoriatic arthritis (PsA). Objectives To determine efficacy based on pooled data from 2 pivotal Phase 3 studies of tofacitinib in patients (pts) with active PsA. Methods Data were pooled from 2 placebo (PBO)-controlled, double-blind, multicentre, global Phase 3 studies (OPAL Broaden [N=422; 12 months; NCT01877668]; OPAL Beyond [N=394; 6 months; NCT01882439]). Pts had active PsA and either inadequate response (IR) to ≥1 conventional synthetic disease-modifying antirheumatic drug (csDMARD) and were tumour necrosis factor Inhibitor (TNFi)-naive (OPAL Broaden), or had IR to ≥1 TNFi (OPAL Beyond). Pts were randomised to tofacitinib 5 mg twice daily (BID), 10 mg BID, adalimumab 40 mg subcutaneous injection once every 2 weeks (OPAL Broaden only) or PBO, in addition to a single, stable background csDMARD. PBO pts advanced to tofacitinib 5 mg or 10 mg BID at Month (M)3. Endpoints included ACR20/50/70 response rates (≥20%, ≥50% and ≥70% improvement), change from baseline (Δ) in HAQ-DI (Health Assessment Questionnaire-Disability Index), HAQ-DI response (decrease from baseline [BL] of ≥0.35), PASI75 (≥75% improvement from BL in Psoriasis Area and Severity Index), ΔLEI (Leeds Enthesitis Index) and enthesitis absence, ΔDSS (Dactylitis Severity Score) and dactylitis absence and ΔDLQI (Dermatology Life Quality Index). Pooled data only included tofacitinib 5 mg and 10 mg BID (to M6) and PBO (to M3). Significance was declared for p≤0.05 without correction for multiplicity. Results For pooled data, pts were predominantly white (94.2%) and female (55.4%) with ≥5 peripheral swollen or tender joints (98.0%), enthesitis (LEI>0; 67.5%), dactylitis (DSS>0; 52.5%), psoriatic body surface area ≥3% (67.7%) and CRP levels above the upper limit of normal (>2.87 mg/L; 62.5%) at BL. Mean age was 49.1 years and PsA duration was 8.0 years. Significant improvements vs PBO at M3 were observed for peripheral arthritis and physical function endpoints for tofacitinib 5 mg and 10 mg BID: ACR20, ACR50, ACR70, ΔHAQ-DI (least squares mean [LSM]), and HAQ-DI response (Table 1). Significant improvements in psoriasis, enthesitis and dactylitis endpoints vs PBO were also observed for tofacitinib 5 mg and 10 mg BID at M3: PASI75, ΔLEI, enthesitis absence based on LEI, ΔDSS (LSM), dactylitis absence based on DSS and ΔDLQI (Table 1). Efficacy was maintained or further improved at M6. Conclusions In a pooled analysis of csDMARD-IR/TNFi-naive and TNFi-IR pts, tofacitinib 5 mg and 10 mg BID were superior to PBO at M3 across four PsA disease domains: peripheral arthritis, psoriasis, enthesitis and dactylitis. Acknowledgements This study was sponsored by Pfizer Inc. Editorial support was provided by K Haines of CMC and was funded by Pfizer Inc. Disclosure of Interest P. Nash Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Janssen, Eli Lilly, Novartis, Pfizer Inc, Roche, UCB, Consultant for: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Janssen, Eli Lilly, Merck, Novartis, Pfizer Inc, Sanofi, Roche, UCB, Speakers bureau: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Janssen, Novartis, Pfizer Inc, Roche, UCB, L. Coates Speakers bureau: Pfizer Inc, R. Fleischmann Grant/research support from: Abbott, Amgen, Astellas, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Genentech, Eli Lilly, Janssen, Novartis, Pfizer Inc, Regeneron, Sanofi Aventis, Roche, UCB, Consultant for: Abbott, Akros, Amgen, Bristol-Myers Squibb, Celgene, Genentech, Eli Lilly, Janssen, Novartis, Pfizer Inc, Sanofi Aventis, UCB, K. Papp Grant/research support from: Abbott, Amgen, Anacor, Astellas, Celgene, Celtic, Dow Pharma, Eli Lilly, Galderma, Janssen, Janssen Biotech (Centocor), Merck, Novartis, Pfizer Inc, Consultant for: 3M, Abbott, Akros, Alza, Amgen, Astellas, Baxter, Boehringer Ingelheim, Celgene, Cipher, Eli Lilly, Forward Pharma, Funxional Therapeutics, Galderma, Genentech, Isotechnika, Janssen, Janssen Biotech (Centocor), J&J, Kirin, Kyowa, Meiji Seika Pharma, Merck, Mitsubishi Pharma, Mylan, Novartis, Pfizer Inc, Regeneron, Sanofi Aventis, Serono, Stiefel, Takeda, UCB, Speakers bureau: 3M, Abbott, Amgen, Astellas, Boehringer Ingelheim, Celgene, Eli Lilly, Galderma, Janssen, Merck, Novartis, Pfizer Inc, J. Gomez-Reino Grant/research support from: AbbVie, Novartis, Pfizer Inc, Roche, UCB, Consultant for: Pfizer Inc, Speakers bureau: AbbVie, Bristol-Myers Squibb, Janssen, MSD, Pfizer Inc, Roche, UCB, K. Kanik Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, C. Wang: None declared, J. Wu Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, T. Hendrikx Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, W. Ports Shareholder of: Pfizer Inc, Employee of: Pfizer Inc

  • Evaluating Dosage Optimality for Tofacitinib, an Oral Janus Kinase Inhibitor, in Plaque Psoriasis, and the Influence of Body Weight.
    CPT: pharmacometrics & systems pharmacology, 2017
    Co-Authors: Matthew M. Hutmacher, Kim Papp, Sriram Krishnaswami, Robert Wolk, Hernan Valdez, Charles A. Mebus, Scott T. Rottinghaus, Pankaj Gupta
    Abstract:

    Tofacitinib is an oral Janus Kinase Inhibitor. An integrated analysis was conducted to evaluate dosage optimality for tofacitinib in patients with moderate-to-severe plaque psoriasis and the impact of body weight on optimality in this patient population. Data were pooled from one phase IIb trial (2, 5, and 15 mg twice daily (b.i.d.)) and four phase III trials (5 and 10 mg b.i.d.). A longitudinal exposure–response model for Psoriasis Area and Severity Index (PASI) improvement (percent change from baseline) was established. Body weight influenced potency; heavier subjects require higher doses to achieve comparable benefit to lighter subjects. Disease severity, sex, and prior biologic usage were also predictive of response. The 10 and 5 mg doses were predicted to achieve 81% and 65%, respectively, of the maximum effect based on a 75% improvement in PASI. The greater efficacy of 10 mg over 5 mg was clinically meaningful.

  • treatment of plaque psoriasis with an ointment formulation of the Janus Kinase Inhibitor tofacitinib a phase 2b randomized clinical trial
    BMC Dermatology, 2016
    Co-Authors: Kim Papp, Robert Bissonnette, Melinda Gooderham, Steven R Feldman, Lars Iversen, Jennifer Soung, Zoe Diana Draelos, Carla Mamolo, Vivek S Purohit, Cunshan Wang
    Abstract:

    Background Most psoriasis patients have mild to moderate disease, commonly treated topically. Current topical agents have limited efficacy and undesirable side effects associated with long-term use. Tofacitinib is a small molecule Janus Kinase Inhibitor investigated for the topical treatment of psoriasis.

  • tofacitinib an oral Janus Kinase Inhibitor for the treatment of chronic plaque psoriasis long term efficacy and safety results from 2 randomized phase iii studies and 1 open label long term extension study
    Journal of The American Academy of Dermatology, 2016
    Co-Authors: Kim Papp, Steven R Feldman, Richard G. Langley, Robert Wolk, D Thaci, James G Krueger, Hideshi Torii, Stephen K Tyring, Annie Gardner, Charles Mebus
    Abstract:

    Background Tofacitinib is an oral Janus Kinase Inhibitor being investigated for psoriasis. Objectives We sought to report longer-term tofacitinib efficacy and safety in patients with moderate to severe psoriasis. Methods Data from 2 identical phase-III studies, Oral-treatment Psoriasis Trial Pivotal 1 and 2, were pooled with data from these patients in an ongoing open-label long-term extension study. Patients (n = 1861) were randomized 2:2:1 to tofacitinib 5 mg, 10 mg, or placebo twice daily (BID). At week 16, placebo patients were rerandomized to tofacitinib. Pivotal study participants could enroll into the long-term extension where they received tofacitinib at 10 mg BID for 3 months, after which dosing could be 5 or 10 mg BID. Results At week 28, the proportions of patients randomized to tofacitinib 5 and 10 mg BID achieving 75% or greater reduction in Psoriasis Area and Severity Index score from baseline were 55.6% and 68.8%, and achieving Physician Global Assessment of clear or almost clear were 54.7% and 65.9%. Efficacy was maintained in most patients through 24 months. Serious adverse events and discontinuations because of adverse events were reported in less than 11% of patients over 33 months of tofacitinib exposure. Limitations There was no dose comparison beyond week 52. Conclusions Oral tofacitinib demonstrated sustained efficacy in patients with psoriasis through 2 years, with 10 mg BID providing greater efficacy than 5 mg BID. No unexpected safety findings were observed.

  • tofacitinib an oral Janus Kinase Inhibitor for the treatment of chronic plaque psoriasis results from two randomized placebo controlled phase iii trials
    British Journal of Dermatology, 2015
    Co-Authors: Kim Papp, Steven R Feldman, Richard G. Langley, Marjorie Buonanno, M A Menter, Boni E Elewski, Alice B Gottlieb, Thomas A Luger, D Thaci, Pankaj Gupta
    Abstract:

    SummaryBackground Tofacitinib is an oral Janus Kinase Inhibitor being investigated for psoriasis. Objectives To determine the 16-week efficacy and safety of two oral tofacitinib doses vs. placebo in patients with moderate-to-severe chronic plaque psoriasis. Methods Patients in two similarly designed phase III studies (OPT Pivotal 1, NCT01276639, n = 901; OPT Pivotal 2, NCT01309737, n = 960) were initially randomized 2 : 2 : 1 to tofacitinib 10 or 5 mg or placebo, twice daily. Coprimary efficacy end points (week 16) included the proportion of patients achieving Physician's Global Assessment (PGA) of ‘clear’ or ‘almost clear’ (PGA response) and the proportion achieving ≥ 75% reduction in Psoriasis Area and Severity Index (PASI 75). Results Across OPT Pivotal 1 and OPT Pivotal 2, 745 patients received tofacitinib 5 mg, 741 received tofacitinib 10 mg and 373 received placebo. At week 16, a greater proportion of patients achieved PGA responses with tofacitinib 5 and 10 mg twice daily vs. placebo (OPT Pivotal 1, 41·9% and 59·2% vs. 9·0%; OPT Pivotal 2, 46·0% and 59·1% vs. 10·9%; all P < 0·001). Higher PASI 75 rates were observed with tofacitinib vs. placebo (OPT Pivotal 1, 39·9%, 59·2% and 6·2%, respectively, for tofacitinib 5 and 10 mg twice daily and placebo; OPT Pivotal 2, 46·0%, 59·6% and 11·4%; all P < 0·001 vs. placebo). Adverse event (AE) rates appeared generally similar across groups; rates of serious AEs, infections, malignancies and discontinuations due to AEs were low. Twelve patients reported herpes zoster across the tofacitinib treatment groups in both studies vs. none in the respective placebo groups. The most common AE across groups was nasopharyngitis. Conclusions Oral tofacitinib demonstrated significant efficacy vs. placebo during the initial 16 weeks of treatment in patients with moderate-to-severe psoriasis. Safety findings were consistent with prior studies.

Samuel H Zwillich - One of the best experts on this subject based on the ideXlab platform.

  • THU0238 Tofacitinib, an Oral Janus Kinase Inhibitor: Safety Comparison in Patients with Rheumatoid Arthritis and an Inadequate Response to Nonbiologic or Biologic Disease-Modifying Anti-Rheumatic Drugs
    Annals of the Rheumatic Diseases, 2020
    Co-Authors: G.-r. Burmester, Samuel H Zwillich, Thijs Hendrikx, Kenneth Kwok, C. Charles-schoemann, John D. Isaacs, R Riese
    Abstract:

    Background Tofacitinib is a novel, oral Janus Kinase Inhibitor for the treatment of rheumatoid arthritis (RA). Objectives This analysis provides comparative safety data on the incidence of safety events for patients (pts) with an inadequate response (IR) to a nonbiologic disease-modifying antirheumatic drug (DMARD)-IR versus pts with an IR to a biologic DMARD (bDMARD)-IR. Methods The primary comparison was performed on pooled data from 5 randomised, controlled Phase 3 (P3) studies in RA pts treated with tofacitinib 5 mg or 10 mg BID for 6 to 12 months. Supportive analyses were conducted on 2 pooled open-label long-term extension (LTE) studies. All pts enrolled were nonbiologic or biologic DMARD-IR. Results In the pooled P3 studies, 2389 tofacitinib-treated pts with 1783 pt-years (pt-yrs) of exposure were analysed in the DMARD-IR population and 641 pts with 315 pt-yrs of exposure in the bDMARD-IR group. Baseline demographics were generally similar, albeit the bDMARD-IR group was generally older, heavier and had fewer Asian pts. Compared with the DMARD-IR, the bDMARD-IR population exhibited increases in the rate (events/100 pt-yrs) of serious adverse events (SAE) (12.3 [95% confidence interval (CI) 9.0, 16.9] vs 9.9 [8.6, 11.5]) and discontinuations due to adverse events (AE DC) (15.0 [95% CI 11.3, 20.0] vs 9.6 [7.7, 12.1) in both tofacitinib treatment arms and in placebo. There were four adalimumab pts (and 0 events) that were bDMARD-IR. The rates of deaths, serious infections (SI), malignancies and major adverse cardiovascular events were similar across the populations (Table). LTE studies included 2715 pts with 3588 pt-yrs of exposure in the DMARD-IR population and 566 pts with 514 pt-yrs of exposure in the bDMARD-IR group. As compared with the DMARD-IR, the bDMARD-IR population showed increases (events/100 pt-yrs [95% CI]) in rates of SAEs (14.6 [11.6, 18.4] vs 10.2 [9.2, 11.3]); AE DC (10.0 [7.6, 13.1] vs 6.8 [6.0, 7.7]); and SI (4.7 [3.1, 7.0] vs 2.7 [2.2, 3.3]). The rates of the other safety events were similar. Image/graph Conclusions Event rates for important safety events for both DMARD-IR and bDMARD-IR pts are within the ranges observed with biologic therapies approved for treatment of RA with some differences noted in SI (LTE only), SAE and AE DC favouring the DMARD-IR population. Disclosure of Interest G. Burmester Grant/research support from: Abbott, BMS, MSD, Pfizer Inc., Roche, UCB, Consultant for: Abbott, BMS, MSD, Pfizer Inc., Roche, UCB, Speakers bureau: Abbott, BMS, MSD, Pfizer Inc., Roche, UCB, C. Charles-Schoemann Grant/research support from: Pfizer Inc., Consultant for: Pfizer Inc., Speakers bureau: Pfizer Inc., J. Isaacs Consultant for: Pfizer Inc., T. Hendrikx Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., K. Kwok Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., S. Zwillich Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., R. Riese Shareholder of: Pfizer Inc., Employee of: Pfizer Inc.

  • Switching from adalimumab to tofacitinib in the treatment of patients with rheumatoid arthritis
    Arthritis Research & Therapy, 2016
    Co-Authors: Mark C. Genovese, Samuel H Zwillich, David Gruben, Bethanie Wilkinson, Lisy Wang, R Riese, L. Takiya, Ronald F. Van Vollenhoven, Pinaki Biswas, Thomas V. Jones
    Abstract:

    Background Tofacitinib is an oral Janus Kinase Inhibitor for the treatment of rheumatoid arthritis (RA). The aim of this study was to explore the safety and efficacy of open-label tofacitinib following blinded treatment with adalimumab or tofacitinib for moderate to severe RA.

  • the mechanism of action of tofacitinib an oral Janus Kinase Inhibitor for the treatment of rheumatoid arthritis
    Clinical and Experimental Rheumatology, 2016
    Co-Authors: Jennifer Hodge, Martin E. Dowty, Sriram Krishnaswami, Manisha Lamba, Sujatha Menon, James D Clark, Thomas T Kawabata, Jeanbaptiste Telliez, Samuel H Zwillich
    Abstract:

    : Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterised by infiltration of immune cells into the affected synovium, release of inflammatory cytokines and degradative mediators, and subsequent joint damage. Both innate and adaptive arms of the immune response play a role, with activation of immune cells leading to dysregulated expression of inflammatory cytokines. Cytokines work within a complex regulatory network in RA, signalling through different intracellular Kinase pathways to modulate recruitment, activation and function of immune cells and other leukocytes. As our understanding of RA has advanced, intracellular signalling pathways such as Janus Kinase (JAK) pathways have emerged as key hubs in the cytokine network and, therefore, important as therapeutic targets. Tofacitinib is an oral JAK Inhibitor for the treatment of RA. Tofacitinib is a targeted small molecule, and an innovative advance in RA therapy, which modulates cytokines critical to the progression of immune and inflammatory responses. Herein we describe the mechanism of action of tofacitinib and the impact of JAK inhibition on the immune and inflammatory responses in RA.

  • tofacitinib an oral Janus Kinase Inhibitor as monotherapy or with background methotrexate in japanese patients with rheumatoid arthritis an open label long term extension study
    Arthritis Research & Therapy, 2016
    Co-Authors: Hisashi Yamanaka, Yoshiya Tanaka, Tsutomu Takeuchi, Naonobu Sugiyama, Hirotoshi Yuasa, Shigeyuki Toyoizumi, Yosuke Morishima, Tomohiro Hirose, Samuel H Zwillich
    Abstract:

    Background Tofacitinib is an oral Janus Kinase Inhibitor for the treatment of rheumatoid arthritis. Here, tofacitinib safety and efficacy data from a long-term extension study in Japanese patients are presented.

  • Effects of tofacitinib monotherapy on patient-reported outcomes in a randomized phase 3 study of patients with active rheumatoid arthritis and inadequate responses to DMARDs
    Arthritis Research & Therapy, 2015
    Co-Authors: Vibeke Strand, Samuel H Zwillich, Keith S Kanik, David Gruben, Gene V. Wallenstein, Joel M. Kremer, Carol A. Connell, Roy Fleischmann
    Abstract:

    Introduction Tofacitinib is an oral Janus Kinase Inhibitor for the treatment of rheumatoid arthritis.

Sriram Krishnaswami - One of the best experts on this subject based on the ideXlab platform.

  • Evaluating Dosage Optimality for Tofacitinib, an Oral Janus Kinase Inhibitor, in Plaque Psoriasis, and the Influence of Body Weight.
    CPT: pharmacometrics & systems pharmacology, 2017
    Co-Authors: Matthew M. Hutmacher, Kim Papp, Sriram Krishnaswami, Robert Wolk, Hernan Valdez, Charles A. Mebus, Scott T. Rottinghaus, Pankaj Gupta
    Abstract:

    Tofacitinib is an oral Janus Kinase Inhibitor. An integrated analysis was conducted to evaluate dosage optimality for tofacitinib in patients with moderate-to-severe plaque psoriasis and the impact of body weight on optimality in this patient population. Data were pooled from one phase IIb trial (2, 5, and 15 mg twice daily (b.i.d.)) and four phase III trials (5 and 10 mg b.i.d.). A longitudinal exposure–response model for Psoriasis Area and Severity Index (PASI) improvement (percent change from baseline) was established. Body weight influenced potency; heavier subjects require higher doses to achieve comparable benefit to lighter subjects. Disease severity, sex, and prior biologic usage were also predictive of response. The 10 and 5 mg doses were predicted to achieve 81% and 65%, respectively, of the maximum effect based on a 75% improvement in PASI. The greater efficacy of 10 mg over 5 mg was clinically meaningful.

  • the mechanism of action of tofacitinib an oral Janus Kinase Inhibitor for the treatment of rheumatoid arthritis
    Clinical and Experimental Rheumatology, 2016
    Co-Authors: Jennifer Hodge, Martin E. Dowty, Sriram Krishnaswami, Manisha Lamba, Sujatha Menon, James D Clark, Thomas T Kawabata, Jeanbaptiste Telliez, Samuel H Zwillich
    Abstract:

    : Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterised by infiltration of immune cells into the affected synovium, release of inflammatory cytokines and degradative mediators, and subsequent joint damage. Both innate and adaptive arms of the immune response play a role, with activation of immune cells leading to dysregulated expression of inflammatory cytokines. Cytokines work within a complex regulatory network in RA, signalling through different intracellular Kinase pathways to modulate recruitment, activation and function of immune cells and other leukocytes. As our understanding of RA has advanced, intracellular signalling pathways such as Janus Kinase (JAK) pathways have emerged as key hubs in the cytokine network and, therefore, important as therapeutic targets. Tofacitinib is an oral JAK Inhibitor for the treatment of RA. Tofacitinib is a targeted small molecule, and an innovative advance in RA therapy, which modulates cytokines critical to the progression of immune and inflammatory responses. Herein we describe the mechanism of action of tofacitinib and the impact of JAK inhibition on the immune and inflammatory responses in RA.

  • Safety, tolerability, and pharmacokinetics of single oral doses of tofacitinib, a Janus Kinase Inhibitor, in healthy volunteers.
    Clinical pharmacology in drug development, 2014
    Co-Authors: Sriram Krishnaswami, Vincent Chow, Gary Chan
    Abstract:

    Tofacitinib is an oral Janus Kinase Inhibitor. This randomized, double-blind, parallel-group, placebo-controlled study was the first evaluation of tofacitinib in humans. The objectives were to characterize the safety and tolerability, pharmacokinetics (PK), and pharmacodynamics of escalating single tofacitinib doses in healthy subjects. Tofacitinib (0.1, 0.3, 1, 3, 10, 30, 60, and 100 mg) or placebo was administered as oral powder for constitution. For each dose, 7-9 subjects were randomized to tofacitinib and 3-5 subjects to placebo. Ninety-five males and females (age range 19-45) completed the study. Forty-nine treatment-emergent all-causality adverse events (AEs) were observed; nausea and headache were the most frequently reported. Tofacitinib PK was characterized by rapid absorption (time to peak serum concentration [Tmax ] 0.5-1 hour), rapid elimination (mean terminal half-lives 2.3-3.1 hours), and dose-proportional systemic exposures (peak serum concentration [Cmax ] and area under the serum concentration-time curve from time zero to infinity [AUC0-∞ ]). No appreciable correlation was observed between tofacitinib dose and lymphocyte subset counts. Single-dose tofacitinib up to 100 mg in healthy subjects had a safety profile of mostly mild AEs, and no deaths, serious AEs, severe AEs or discontinuations due to AEs.

  • The effect of mild and moderate hepatic impairment on the pharmacokinetics of tofacitinib, an orally active Janus Kinase Inhibitor
    Clinical pharmacology in drug development, 2014
    Co-Authors: Nervin Lawendy, Manisha Lamba, Gary Chan, Rong Wang, Christine Alvey, Sriram Krishnaswami
    Abstract:

    Tofacitinib is an oral Janus Kinase Inhibitor for the treatment of rheumatoid arthritis. We report here an evaluation of the pharmacokinetics of a single 10 mg dose of tofacitinib in healthy volunteers (n = 6) and subjects with mild (n = 6) or moderate (n = 6) hepatic impairment. Compared to healthy volunteers, tofacitinib area under the plasma concentration-time profile from time 0 to infinity (AUCinf ) and maximum observed concentration (Cmax ) in subjects with mild hepatic impairment were not altered. In subjects with moderate hepatic impairment, the geometric mean AUCinf and Cmax of tofacitinib were increased (90% confidence intervals of percentage increase) by approximately 65% (25%, 117%) and 49% (12%, 97%), respectively. A single dose of tofacitinib 10 mg resulted in two treatment-emergent adverse events (AE) in the mild hepatic impairment group, and one in the moderate hepatic impairment group; they were not considered related to study treatment. There were no deaths, serious AEs, discontinuations due to AEs, or dose reductions due to AEs. Data from this study were critical to deriving dose adjustments for subjects with hepatic impairment.

  • The Pharmacokinetics, Metabolism, and Clearance Mechanisms of Tofacitinib, a Janus Kinase Inhibitor, in Humans
    Drug Metabolism and Disposition, 2014
    Co-Authors: Martin E. Dowty, Tim F. Ryder, Weiwei Wang, Gregory S. Walker, Gary L. Chan, Sriram Krishnaswami, Chandra Prakash
    Abstract:

    Tofacitinib is a novel, oral Janus Kinase Inhibitor. The objectives of this study were to summarize the pharmacokinetics and metabolism of tofacitinib in humans, including clearance mechanisms. Following administration of a single 50-mg 14C-labeled tofacitinib dose to healthy male subjects, the mean (standard deviation) total percentage of administered radioactive dose recovered was 93.9% (±3.6), with 80.1% (±3.6) in the urine (28.8% parent), and 13.8% (±1.9) in feces (0.9% parent). Tofacitinib was rapidly absorbed, with plasma concentrations and total radioactivity peaking at around 1 hour after oral administration. The mean terminal phase half-life was approximately 3.2 hours for both parent drug and total radioactivity. Most (69.4%) circulating radioactivity in plasma was parent drug, with all metabolites representing less than 10% each of total circulating radioactivity. Hepatic clearance made up around 70% of total clearance, while renal clearance made up the remaining 30%. The predominant metabolic pathways of tofacitinib included oxidation of the pyrrolopyrimidine and piperidine rings, oxidation of the piperidine ring side-chain, N-demethylation and glucuronidation. Cytochrome P450 (P450) profiling indicated that tofacitinib was mainly metabolized by CYP3A4, with a smaller contribution from CYP2C19. This pharmacokinetic characterization of tofacitinib has been consistent with its clinical experience in drug-drug interaction studies.

R Riese - One of the best experts on this subject based on the ideXlab platform.

  • THU0131 Tofacitinib (CP-690,550), an oral Janus Kinase Inhibitor: Analysis of malignancies across the rheumatoid arthritis clinical programme
    Annals of the Rheumatic Diseases, 2020
    Co-Authors: Xavier Mariette, Jeffrey R Curtis, Irina Kaplan, Jamie Geier, Lisy Wang, R Riese, R. Chew, John S. Bradley
    Abstract:

    Background Tofacitinib (CP-690,550) is a novel, oral Janus Kinase Inhibitor that is being investigated as a targeted immunomodulator and disease-modifying therapy for rheumatoid arthritis (RA). Objectives To evaluate the malignancies that occurred in the tofacitinib RA programme from the Phase (P) 2, 3, and long-term extension (LTE) studies up to 29 March 2011. Methods Data were pooled from 6 randomized P2, 5 randomized P3 studies and 2 open-label LTE studies. Patients (pts) in P3 and LTE studies were treated with tofacitinib 5 or 10 mg twice daily. Analyses included malignancy data from 1608 pts in P2, 3315 pts in P3, and 3227 pts in LTE studies (LTE pts rolled over from the P2 and P3 studies). Results A total of 4789 patients (5651 pt-yr) received tofacitinib in the P2, P3 and LTE studies. Fifty pts receiving tofacitinib (all doses) reported malignancies (excluding non-melanoma skin cancer [NMSC]); the most common were lung (12 cases) and breast cancer (9 cases). There were 3 lymphoma cases. The overall incidence rate (IR, events per 100 pt-yr) for all malignancies (excluding NMSC) was 0.89 (95% confidence interval [CI]: 0.67,1.17). The IRs (95% CI) of all malignancies (excluding NMSC) broken down into 0-6, 6-12, 12-18, 18-24 and >24 months based on exposure to study drug were 0.75 (0.46,1.23), 0.73 (0.41,1.28), 0.97 (0.48,1.94), 1.28 (0.53,3.08), and 1.37 (0.71,2.63), respectively. The number of cases in each time interval was small, with resultant wide CIs. The standardised incidence ratio (SIR) (95% CI) (as compared with the Surveillance Epidemiology and End Result database covering the general population) for all malignancies (excluding NMSC), lung, breast cancer and lymphomas in the tofacitinib group were 1.11 (0.82-1.47), 2.16 (1.12,3.77), 0.82 (0.38,1.56) and 1.74 (0.36,5.10), respectively. Twenty-one pts experienced NMSCs, for an IR of 0.37 (95% CI: 0.24,0.57). By comparison, the IR of NMSC in patients treated with anti-TNF was 0.47 (0.37-0.59) in a meta-analysis of randomized controlled trials and ranged from 0.23 to 0.35 in a meta-analysis of registries. 1,2 Conclusions The malignancies that occurred in the tofacitinib RA programme are consistent with the type and distribution of malignancies expected for patients with moderate to severe RA. The IRs for all malignancies (excluding NMSC), lung cancer, breast cancer and lymphomas are consistent with published estimates in RA patients treated with biologic and non-biologic DMARDs. 3-6 Longer follow-up is necessary to further evaluate the potential risk of malignancies in the CP RA programme. References Askling J, et al. Pharmacoepidemiol Drug Saf 2011;20:119-30. Mariette X, et al. Ann Rheum Dis 2011;70:1895-904. Carmona L, et al. Semin Arthritis Rheum 2011;41:71-80. Pallavicini FB, et al. Autoimmun Rev 2010;9:175-80. Simon TA, et al. Ann Rheum Dis 2009;68:1819-26. Wolfe F, Michaud K. Arthritis Rheum 2007;56:2886-95. Disclosure of Interest X. Mariette Consultant for: Pfizer Inc, J. Curtis Grant/Research support from: Pfizer Inc, Consultant for: Pfizer Inc, E. Lee Consultant for: Pfizer Inc, R. Riese Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, I. Kaplan Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, R. Chew Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, J. Geier Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, L. Wang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, J. Bradley Shareholder of: Pfizer Inc, Employee of: Pfizer Inc

  • THU0238 Tofacitinib, an Oral Janus Kinase Inhibitor: Safety Comparison in Patients with Rheumatoid Arthritis and an Inadequate Response to Nonbiologic or Biologic Disease-Modifying Anti-Rheumatic Drugs
    Annals of the Rheumatic Diseases, 2020
    Co-Authors: G.-r. Burmester, Samuel H Zwillich, Thijs Hendrikx, Kenneth Kwok, C. Charles-schoemann, John D. Isaacs, R Riese
    Abstract:

    Background Tofacitinib is a novel, oral Janus Kinase Inhibitor for the treatment of rheumatoid arthritis (RA). Objectives This analysis provides comparative safety data on the incidence of safety events for patients (pts) with an inadequate response (IR) to a nonbiologic disease-modifying antirheumatic drug (DMARD)-IR versus pts with an IR to a biologic DMARD (bDMARD)-IR. Methods The primary comparison was performed on pooled data from 5 randomised, controlled Phase 3 (P3) studies in RA pts treated with tofacitinib 5 mg or 10 mg BID for 6 to 12 months. Supportive analyses were conducted on 2 pooled open-label long-term extension (LTE) studies. All pts enrolled were nonbiologic or biologic DMARD-IR. Results In the pooled P3 studies, 2389 tofacitinib-treated pts with 1783 pt-years (pt-yrs) of exposure were analysed in the DMARD-IR population and 641 pts with 315 pt-yrs of exposure in the bDMARD-IR group. Baseline demographics were generally similar, albeit the bDMARD-IR group was generally older, heavier and had fewer Asian pts. Compared with the DMARD-IR, the bDMARD-IR population exhibited increases in the rate (events/100 pt-yrs) of serious adverse events (SAE) (12.3 [95% confidence interval (CI) 9.0, 16.9] vs 9.9 [8.6, 11.5]) and discontinuations due to adverse events (AE DC) (15.0 [95% CI 11.3, 20.0] vs 9.6 [7.7, 12.1) in both tofacitinib treatment arms and in placebo. There were four adalimumab pts (and 0 events) that were bDMARD-IR. The rates of deaths, serious infections (SI), malignancies and major adverse cardiovascular events were similar across the populations (Table). LTE studies included 2715 pts with 3588 pt-yrs of exposure in the DMARD-IR population and 566 pts with 514 pt-yrs of exposure in the bDMARD-IR group. As compared with the DMARD-IR, the bDMARD-IR population showed increases (events/100 pt-yrs [95% CI]) in rates of SAEs (14.6 [11.6, 18.4] vs 10.2 [9.2, 11.3]); AE DC (10.0 [7.6, 13.1] vs 6.8 [6.0, 7.7]); and SI (4.7 [3.1, 7.0] vs 2.7 [2.2, 3.3]). The rates of the other safety events were similar. Image/graph Conclusions Event rates for important safety events for both DMARD-IR and bDMARD-IR pts are within the ranges observed with biologic therapies approved for treatment of RA with some differences noted in SI (LTE only), SAE and AE DC favouring the DMARD-IR population. Disclosure of Interest G. Burmester Grant/research support from: Abbott, BMS, MSD, Pfizer Inc., Roche, UCB, Consultant for: Abbott, BMS, MSD, Pfizer Inc., Roche, UCB, Speakers bureau: Abbott, BMS, MSD, Pfizer Inc., Roche, UCB, C. Charles-Schoemann Grant/research support from: Pfizer Inc., Consultant for: Pfizer Inc., Speakers bureau: Pfizer Inc., J. Isaacs Consultant for: Pfizer Inc., T. Hendrikx Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., K. Kwok Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., S. Zwillich Shareholder of: Pfizer Inc., Employee of: Pfizer Inc., R. Riese Shareholder of: Pfizer Inc., Employee of: Pfizer Inc.

  • cardiovascular safety findings in patients with rheumatoid arthritis treated with tofacitinib an oral Janus Kinase Inhibitor
    Seminars in Arthritis and Rheumatism, 2016
    Co-Authors: Christina Charlesschoeman, Kenneth Kwok, Jamie Geier, Koshika Soma, Pierre Wicker, Miguel A Gonzalezgay, Andrea Zuckerman, R Riese
    Abstract:

    Abstract Objectives Tofacitinib is an oral Janus Kinase Inhibitor for the treatment of rheumatoid arthritis (RA). The implications of treatment with tofacitinib on cardiovascular (CV) risk in RA are unknown. Therefore, CV adverse events (AEs), and blood pressure and lipid level changes, in tofacitinib-treated patients with RA were evaluated. Methods Data were pooled from six Phase (P)3 studies (24 months) and two open-label long-term extension (LTE) studies (60 months) of tofacitinib in patients with RA and inadequate response to DMARDs. Tofacitinib was administered alone or with non-biologic DMARDs. CV events, including major adverse CV events (MACE: CV death and non-fatal CV events) and congestive heart failure (CHF), were assessed by a blinded adjudication committee. Results Overall, 4271 patients from P3 studies and 4827 enrolled from P2/P3 studies into LTE studies were evaluated, representing 3942 and 8699 patient-years of exposure to tofacitinib, respectively. Blood pressure remained stable over time across studies. The number of investigator-reported hypertension-related AEs in tofacitinib-treated patients was low in P3 studies (Months 0–3: 2.8%; Months 3–6: 1.4%; >6 months: 2.8%). Across studies, lipid level increases were generally observed within 1–3 months of treatment and stabilized thereafter. Patients with events (incidence rate [IR]/100 patient-years) for MACE and CHF, respectively, were: 23 (0.58) and 9 (0.23) in P3 studies, and 32 (0.37) and 8 (0.09) in LTE studies; IRs were comparable with placebo (P3) and did not increase over time (LTE). Conclusions Tofacitinib was associated with a low incidence of CV events in a large Phase 3 program, including LTE studies. Further long-term studies are underway.

  • Switching from adalimumab to tofacitinib in the treatment of patients with rheumatoid arthritis
    Arthritis Research & Therapy, 2016
    Co-Authors: Mark C. Genovese, Samuel H Zwillich, David Gruben, Bethanie Wilkinson, Lisy Wang, R Riese, L. Takiya, Ronald F. Van Vollenhoven, Pinaki Biswas, Thomas V. Jones
    Abstract:

    Background Tofacitinib is an oral Janus Kinase Inhibitor for the treatment of rheumatoid arthritis (RA). The aim of this study was to explore the safety and efficacy of open-label tofacitinib following blinded treatment with adalimumab or tofacitinib for moderate to severe RA.

  • tofacitinib an oral Janus Kinase Inhibitor analysis of malignancies across the rheumatoid arthritis clinical development programme
    Annals of the Rheumatic Diseases, 2016
    Co-Authors: Jeffrey R Curtis, Irina Kaplan, Kenneth Kwok, Jamie Geier, B Benda, Koshika Soma, Lisy Wang, R Riese
    Abstract:

    Objectives Tofacitinib is an oral Janus Kinase Inhibitor for the treatment of rheumatoid arthritis (RA). To further assess the potential role of Janus Kinase inhibition in the development of malignancies, we performed an integrated analysis of data from the tofacitinib RA clinical development programme. Methods Malignancy data (up to 10 April 2013) were pooled from six phase II, six Phase III and two long-term extension (LTE) studies involving tofacitinib. In the phase II and III studies, patients with moderate-to-severe RA were randomised to various tofacitinib doses as monotherapy or with background non-biological disease-modifying antirheumatic drugs (DMARDs), mainly methotrexate. The LTE studies (tofacitinib 5 or 10 mg twice daily) enrolled patients from qualifying prior phase I, II and III index studies. Results Of 5671 tofacitinib-treated patients, 107 developed malignancies (excluding non-melanoma skin cancer (NMSC)). The most common malignancy was lung cancer (n=24) followed by breast cancer (n=19), lymphoma (n=10) and gastric cancer (n=6). The rate of malignancies by 6-month intervals of tofacitinib exposure indicates rates remained stable over time. Standardised incidence ratios (comparison with Surveillance, Epidemiology and End Results) for all malignancies (excluding NMSC) and selected malignancies (lung, breast, lymphoma, NMSC) were within the expected range of patients with moderate-to-severe RA. Conclusions The overall rates and types of malignancies observed in the tofacitinib clinical programme remained stable over time with increasing tofacitinib exposure.

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  • Efficacy of tofacitinib, an oral Janus Kinase Inhibitor, on clinical signs of moderate-to-severe plaque psoriasis in different body regions.
    Journal of Drugs in Dermatology, 2014
    Co-Authors: Alan Menter, Kim Papp, Robert Wolk, Steve Tyring, Marjorie Buonanno
    Abstract:

    INTRODUCTION: Tofacitinib is a novel, oral Janus Kinase Inhibitor currently under investigation for plaque psoriasis. METHODS: This exploratory analysis of a Phase IIb, 12-week, dose-ranging study (clinicaltrials.gov identifier: NCT00678210) evaluated tofacitinib efficacy in four body regions of patients with moderate-to-severe chronic plaque psoriasis. Patients (n=197) were randomized to tofacitinib 2, 5, or 15 mg, or placebo, twice daily (BID). Psoriasis Area and Severity Index (PASI) score, body surface area values and change from baseline to week 12 were measured according to body region (head/neck, upper limbs, trunk and lower limbs). Change in Target Plaque Severity Score (TPSS) from baseline to week 12 was measured according to typically responsive as well as non-responsive treatment areas. RESULTS: At week 12, mean improvements in PASI and body surface area values were significantly greater with tofacitinib doses vs placebo across all four body regions measured (P

  • tofacitinib cp 690 550 an oral Janus Kinase Inhibitor improves patient reported outcomes in a phase 2b randomized double blind placebo controlled study in patients with moderate to severe psoriasis
    Journal of The European Academy of Dermatology and Venereology, 2014
    Co-Authors: Carla Mamolo, J. Harness, Alan Menter
    Abstract:

    Background Psoriasis is a chronic, inflammatory skin disease with a significant impact on health–related quality of life (HRQoL). Tofacitinib (CP-690,550) is a novel, oral Janus Kinase Inhibitor that is being investigated as a targeted immunomodulator. Objective This Phase 2b study assessed three tofacitinib dosage regimens vs. placebo to characterize the efficacy and safety of tofacitinib in patients with moderate–to-severe chronic plaque psoriasis. We report the patient-reported outcome (PRO) data. Methods A total of 197 patients were randomized to tofacitinib 2, 5, 15 mg twice daily or placebo for 12 weeks. Six PRO questionnaires were completed during the study: Dermatology Life Quality Index, Itch Severity Score (ISS), Short Form-36 questionnaire, version 2 (SF-36), Pain/Discomfort Assessment (PDA), Patient Satisfaction with Study Medication (PSSM) item and Patient Global Assessment of psoriasis. Results Treatment with tofacitinib resulted in significant, dose-dependent improvements in several PROs vs. placebo from week 2 onwards. At week 12, least squares mean changes from baseline for Dermatology life quality index, ISS and SF-36 mental component scores were significantly greater for all active drug arms vs. placebo (P < 0.05), and significantly greater for tofacitinib 5 and 15 mg for SF-36 physical component scores vs. placebo (P < 0.05). At week 12, all dose groups had significantly greater numbers of patients reporting ‘Clear’ or ‘Almost clear’ on the PtGA vs. placebo. Conclusion In patients with moderate–to–severe chronic plaque psoriasis, short-term (12–week) treatment with oral twice-daily tofacitinib improves HRQoL outcomes and patient assessment of disease severity and symptoms, with an early onset noted.

  • effect of tofacitinib a Janus Kinase Inhibitor on haematological parameters during 12 weeks of psoriasis treatment
    British Journal of Dermatology, 2013
    Co-Authors: Bruce E. Strober, Alan Menter, Richard G. Langley, Marjorie Buonanno, Robert Wolk, J. Harness, Hernan Valdez, James D Clark, Thomas T Kawabata, Kim Papp
    Abstract:

    SummaryBackground The Janus Kinase (JAK) Inhibitor, tofacitinib, has shown efficacy for the treatment of psoriasis in a phase IIb trial (A3921047; NCT00678210). Objectives To report haematology data from the phase IIb trial, given the importance of JAK-dependent signalling in haematopoiesis. Methods Patients with moderate-to-severe chronic plaque psoriasis were randomized to receive tofacitinib 2, 5 or 15 mg, or placebo, twice daily over 12 weeks. Blood samples were collected at screening, baseline, weeks 2, 4, 8 and 12 during treatment, and weeks 14 and 16 during off-treatment follow-up. Results Baseline haematology was similar across patients receiving tofacitinib 2 mg (n = 49), 5 mg (n = 49) or 15 mg (n = 49), or placebo (n = 50). Tofacitinib conferred dose-dependent decreases in haemoglobin, haematocrit and red blood cell counts, while reticulocyte counts initially declined, before recovering by week 8, and exceeding baseline levels after treatment cessation. With regard to white blood cells, tofacitinib had no clear dose-dependent effects on basophils or monocytes, but appeared to be associated with transient or reversible dose-dependent decreases in neutrophil and eosinophil counts and transient increases in lymphocyte counts, which were primarily attributable to increases in B-cell counts. Natural killer cell counts declined with tofacitinib. Conclusions Tofacitinib conferred tolerable, dose-dependent changes in haematological parameters during short-term administration in patients with psoriasis. The effects did not appear to be progressive, and were often transient or reversible.

  • dose response and pharmacokinetics of tofacitinib cp 690 550 an oral Janus Kinase Inhibitor in the treatment of chronic plaque psoriasis
    CPT: Pharmacometrics & Systems Pharmacology, 2013
    Co-Authors: Pankaj Gupta, Sriram Krishnaswami, Alan Menter, Bruce E. Strober, Richard G. Langley, Robert Wolk, J. Harness, S Chapel, Kim Papp
    Abstract:

    Tofacitinib (CP-690,550) is a novel, oral Janus Kinase Inhibitor that is currently being investigated as a targeted immunomodulator for the treatment of several autoimmune diseases such as psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, inflammatory bowel disease, and dry eye disease, and for prophylaxis of renal transplant rejection. Tofacitinib has demonstrated efficacy in a 14-day study in patients with psoriasis.1 An exploratory phase IIb study (A3921047; ClinicalTrials.gov NCT00678210) was designed using a modeling and simulation approach (results on file). The goal was to evaluate the dose response and pharmacokinetics (PK) of tofacitinib in patients with chronic plaque psoriasis together with its correlation with clinical efficacy responses over 12 weeks of treatment. An Emax (maximum effect) model with Bayesian estimation was used to characterize the dose–response profile. In addition, PK was characterized using a population-based approach. The model-based approaches enabled an understanding of the PK and pharmacodynamic profiles of tofacitinib in patients with chronic plaque psoriasis and allowed the identification of clinically meaningful efficacious dose(s) with acceptable safety profile(s) for further development in confirmatory phase III clinical trials.

  • Tofacitinib (CP-690,550), an oral Janus Kinase Inhibitor, improves patient-reported outcomes in a phase 2b, randomized, double-blind, placebo-controlled study in patients with moderate-to-severe psoriasis.
    Journal of The European Academy of Dermatology and Venereology, 2013
    Co-Authors: Carla Mamolo, J. Harness, Alan Menter
    Abstract:

    Background Psoriasis is a chronic, inflammatory skin disease with a significant impact on health–related quality of life (HRQoL). Tofacitinib (CP-690,550) is a novel, oral Janus Kinase Inhibitor that is being investigated as a targeted immunomodulator. Objective This Phase 2b study assessed three tofacitinib dosage regimens vs. placebo to characterize the efficacy and safety of tofacitinib in patients with moderate–to-severe chronic plaque psoriasis. We report the patient-reported outcome (PRO) data. Methods A total of 197 patients were randomized to tofacitinib 2, 5, 15 mg twice daily or placebo for 12 weeks. Six PRO questionnaires were completed during the study: Dermatology Life Quality Index, Itch Severity Score (ISS), Short Form-36 questionnaire, version 2 (SF-36), Pain/Discomfort Assessment (PDA), Patient Satisfaction with Study Medication (PSSM) item and Patient Global Assessment of psoriasis. Results Treatment with tofacitinib resulted in significant, dose-dependent improvements in several PROs vs. placebo from week 2 onwards. At week 12, least squares mean changes from baseline for Dermatology life quality index, ISS and SF-36 mental component scores were significantly greater for all active drug arms vs. placebo (P