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Abrocitinib is a Janus kinase 1-selective inhibitor for the treatment of moderate-to-severe atopic dermatitis. Abrocitinib is eliminated primarily by metabolism involving cytochrome P450 (CYP) enzymes. Abrocitinib pharmacologic activity is attributable to the unbound concentrations of the parent molecule and 2 active metabolites, which are substrates of organic anion transporter 3 (OAT3). The sum of potency-adjusted unbound exposures of abrocitinib and its 2 active metabolites is termed the abrocitinib active moiety. We evaluated effects of CYP inhibition, CYP induction, and OAT3 inhibition on the pharmacokinetics of abrocitinib, its metabolites, and active moiety.Three fixed-sequence, open-label, phase I studies in healthy adult volunteers examined the drug-drug interactions (DDIs) of oral abrocitinib with fluvoxamine and fluconazole, rifampin, and probenecid.Co-administration of abrocitinib with fluvoxamine or fluconazole increased the area under the plasma concentration-time curve from time 0 to infinity (AUCIt is important to consider the effects of DDIs on the abrocitinib active moiety when making dosing recommendations. Co-administration of strong CYP2C19/2C9 inhibitors or CYP inducers impacted exposure to the abrocitinib active moiety. A dose reduction by half is recommended if abrocitinib is co-administered with strong CYP2C19 inhibitors, whereas co-administration with strong CYP2C19/2C9 inducers is not recommended. No dose adjustment is required when abrocitinib is administered with OAT3 inhibitors.NCT03634345, NCT03637790, NCT03937258.

Objective To explore herpes zoster (HZ) rates and live zoster vaccine (LZV) safety in a subset of patients with rheumatoid arthritis who received LZV before tofacitinib ± methotrexate (MTX), or adalimumab (ADA) plus MTX in the ORAL Strategy. Methods ORAL Strategy was a 1‐year, phase IIIb/IV, randomized, triple‐dummy, active‐comparator–controlled study. MTX‐inadequate responder patients received tofacitinib 5 mg twice daily (BID), tofacitinib 5 mg BID plus MTX, or ADA 40 mg every other week plus MTX (1:1:1 randomization). Eligible patients age ≥50 years could opt to receive LZV 28 days before initiating study treatment. HZ incidence rates (IRs; patients with events per 100 patient‐years) were calculated. Opportunistic HZ infections (multidermatomal/disseminated), serious HZ events, and LZV‐related adverse events were monitored. Results In ORAL Strategy, 216 of 1,146 patients (18.8%) received LZV. Overall, 18 patients (1.6%) developed HZ (vaccinated: n = 3; nonvaccinated: n = 15). HZ IRs were 1.1 (95% confidence interval [95% CI] 0.3–2.9), 2.3 (95% CI 1.0–4.6), and 1.7 (95% CI 0.6–3.7) for tofacitinib monotherapy, tofacitinib plus MTX, and ADA plus MTX, respectively, and were generally similar between vaccinated and nonvaccinated patients. Three multidermatomal, 1 disseminated, and 2 serious HZ events occurred. No vaccinated patients had zoster‐like lesions within 42 days of vaccination; 1 patient had vaccination‐site erythema. Conclusion LZV was well tolerated, and HZ IRs were generally similar between treatment groups and vaccinated versus nonvaccinated patients. However, ORAL Strategy was not powered for comparisons between vaccinated and nonvaccinated patients because

ObjectiveTofacitinib is an oral Janus kinase for the treatment of rheumatoid arthritis (RA). This post hoc analysis assessed whether baseline body mass index (BMI) impacts tofacitinib efficacy in patients with RA.MethodsPooled data from six phase 3 studies in patients receiving tofacitinib 5 mg (N=1589) or 10 mg (N=1611) twice daily or placebo (advancing to active treatment at months 3 or 6; N=680), ±conventional synthetic disease-modifying antirheumatic drugs, were stratified by baseline BMI (2). Endpoints (through to month 6) were assessed descriptively: American College of Rheumatology 20/50/70 response rates; changes from baseline (∆) in Disease Activity Score in 28 joints, erythrocyte sedimentation rate (DAS28-4(ESR)), DAS28-4(C-reactive protein), Clinical Disease Activity Index (CDAI), Health Assessment Questionnaire-Disability Index (HAQ-DI) and pain; and proportions of patients achieving DAS28-4(ESR) ≥1.2 and HAQ-DI ≥0.22 decreases from baseline, low disease activity (DAS28-4(ESR) ≤3.2 or CDAI ≤10) and radiographic non-progression (Δmodified Total Sharp Score ≤0.5; months 12 and 24). Estimates were adjusted using multivariable models for selected outcomes. Univariate/multivariable regression analyses determined predictors of month 6 outcomes.ResultsOf 3880 patients included, 1690 (43.6%), 1173 (30.2%) and 1017 (26.2%) had baseline BMI 2, respectively. Tofacitinib showed greater efficacy improvements versus placebo in each BMI category. Differences in efficacy outcomes (adjusted and unadjusted) were generally not clinically meaningful across BMI categories within treatment groups. In regression analyses, BMI was not consistently associated with selected outcomes.ConclusionsBaseline BMI did not consistently affect tofacitinib response suggesting that tofacitinib is an effective oral treatment option for adults with moderate to severe RA regardless of baseline BMI, including patients with BMI ≥30 kg/m2.Trial registration numbersNCT00814307, NCT01039688; NCT00960440; NCT00847613; NCT00856544; NCT00853385.

Background\ud \ud Abrocitinib, an oral selective Janus kinase 1 inhibitor, was effective and well tolerated in adults with moderate-to-severe atopic dermatitis in a phase 2b trial. We aimed to assess the efficacy and safety of abrocitinib monotherapy in adolescents and adults with moderate-to-severe atopic dermatitis.\ud \ud \ud Methods\ud \ud In this multicentre, double-blind, randomised phase 3 trial (JADE MONO-1), patients (aged ≥12 years) with moderate-to-severe atopic dermatitis (Investigator Global Assessment score ≥3, Eczema Area and Severity Index [EASI] score ≥16, percentage of body surface area affected ≥10%, and Peak Pruritus Numerical Rating Scale score ≥4) with a bodyweight of 40 kg or more, were enrolled at 69 sites in Australia, Canada, Europe, and the USA. Patients were randomly assigned (2:2:1) to oral abrocitinib 100 mg, abrocitinib 200 mg, or placebo once daily for 12 weeks. Randomisation was done using an interactive response technology system, stratified by baseline disease severity and age. Patients, investigators, and the funder of the study were masked to study treatment. The coprimary endpoints were the proportion of patients who had achieved an Investigator Global Assessment response (score of 0 [clear] or 1 [almost clear] with a ≥2-grade improvement from baseline), and the proportion of patients who achieved at least a 75% improvement in EASI score from baseline (EASI-75) score, both assessed at week 12. Efficacy was assessed in the full analysis set, which included all randomised patients who received at least one dose of study medication. Safety was assessed in all randomised patients. This study is registered with ClinicalTrials.gov, NCT03349060.\ud \ud \ud Findings\ud \ud Between Dec 7, 2017, and March 26, 2019, 387 patients were enrolled: 156 were assigned to abrocitinib 100 mg, 154 to abrocitinib 200 mg, and 77 to placebo. All enrolled patients received at least one dose of study treatment and thus were evaluable for 12-week efficacy. Of the patients with available data for the coprimary endpoints at week 12, the proportion of patients who had achieved an Investigator Global Assessment response was significantly higher in the abrocitinib 100 mg group than in the placebo group (37 [24%] of 156 patients vs six [8%] of 76 patients; p=0·0037) and in the abrocitinib 200 mg group compared with the placebo group (67 [44%] of 153 patients vs six [8%] of 76 patients; p

Background: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Glucocorticoids (GC) are an established therapy in RA that are often used to rapidly reduce pain and inflammation while awaiting the effects of disease-modifying antirheumatic drugs. Objectives: A post hoc analysis to describe the impact of background GC on the efficacy and safety of tofacitinib with and without methotrexate (MTX) and adalimumab (ADA) with MTX in ORAL Strategy. Methods: ORAL Strategy (NCT02187055) was a 1-year, double-blind, Phase 3b/4, head-to-head, non-inferiority randomised controlled trial in adult patients (pts) with active RA despite MTX therapy. Pts were randomised 1:1:1 to receive tofacitinib 5 mg twice daily (BID; tofa mono), tofacitinib 5 mg BID + MTX (tofa+MTX) or subcutaneous ADA 40 mg every other week + MTX (ADA+MTX). Pts receiving low-dose GC (≤10 mg/day prednisone or equivalent) before enrolment maintained a stable dose throughout the study period. The following efficacy endpoints were assessed through Month 12 for pts receiving tofa mono, tofa+MTX and ADA+MTX with/without GC: ACR20, ACR50 and ACR70 response rates, proportions of patients achieving low disease activity (LDA; DAS28–4[ESR]≤3.2) and remission (DAS28–4[ESR] Results: 1146 patients were randomised and treated; low-dose BL GC were received by 228/384 (59.4%) pts receiving tofa mono (mean [SD] BL GC dose: 7.5 [13.7] mg/day), 215/376 (57.2%) pts receiving tofa+MTX (mean [SD] BL GC dose: 6.5 [2.5] mg/day) and 223/386 (57.8%) pts receiving ADA+MTX (mean [SD] BL GC dose: 6.4 [2.6] mg/day). BL demographics and disease characteristics were generally similar across treatment groups, regardless of BL GC use. Efficacy endpoints (ACR50 response rate, LDA and remission rates, ΔHAQ-DI) were generally similar for each treatment group when stratified by GC use (figure 1, table 1; similar results were seen for ACR20/70 response rates – data not shown). GC use did not appear to be associated with higher rates of AEs, discontinuations due to AEs, SIEs and SAEs; some AE rates were higher with MTX than without MTX (table 2). SIEs in pts using GC included herpes zoster (HZ; tofa mono, n=2) and tuberculous meningitis (tofa+MTX, n=1); in pts not using GC, there was 1 event each of cytomegalovirus chorioretinitis (tofa+MTX), pulmonary TB (tofa+MTX), HZ (ADA+MTX) and varicella (ADA+MTX). Conclusions: In pts with RA, concomitant stable GC use did not appear to impact the efficacy of tofacitinib 5 mg BID±MTX or ADA+MTX. The finding that GC use was not associated with higher AE rates was unexpected and of interest. Acknowledgements: Study sponsored by Pfizer Inc. Medical writing support was provided by C Viegelmann of CMC and funded by Pfizer Inc. Disclosure of Interest: R. Fleischmann Grant/research support from: AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Celltrion, Eli Lilly, Genentech, GSK, Janssen, Novartis, Pfizer Inc, Sanofi-Aventis, UCB, Consultant for: AbbVie, Amgen, AstraZeneca, Bristol-Myers Squibb, Celltrion, Eli Lilly, Genentech, GSK, Janssen, Novartis, Pfizer Inc, Sanofi-Aventis, UCB, J. Wollenhaupt Consultant for: Pfizer Inc, Speakers bureau: Pfizer Inc, S. Cohen Grant/research support from: AbbVie, Amgen, Astellas, Bristol-Meyers Squibb, Eli Lilly, Genentech, Gilead, Janssen, Novartis, Pfizer Inc, Roche, Sandoz, Consultant for: AbbVie, Amgen, Astellas, Bristol-Meyers Squibb, Eli Lilly, Genentech, Gilead, Janssen, Novartis, Pfizer Inc, Roche, Sandoz, J. Smolen Grant/research support from: AbbVie, Eli Lilly, Janssen, MSD, Pfizer Inc, Roche, Consultant for: AbbVie, Amgen, AstraZeneca, Astro, Celgene, Celltrion, Eli Lilly, GSK, ILTOO, Janssen, MedImmune, MSD, Novartis-Sandoz, Pfizer Inc, Roche, Samsung, Sanofi, UCB, Speakers bureau: AbbVie, Amgen, AstraZeneca, Astro, Celgene, Celltrion, Eli Lilly, GSK, ILTOO, Janssen, MedImmune, MSD, Novartis-Sandoz, Pfizer Inc, Roche, Samsung, Sanofi, UCB, P. Dahl Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, N. Iikuni Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, H. Shi Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, S. Tatulych Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, L. Takiya Shareholder of: Pfizer Inc, Employee of: Pfizer Inc

Background Tofacitinib is anoral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA). Objectives This post hoc analysis aims to explore the efficacy of tofacitinib in patients (pts) with RA based on their baseline (BL) body mass index (BMI). Methods Data were analysed from six Phase 3 studies for pts who were methotrexate-naive (NCT01039688) or had an inadequate response to DMARDs (NCT00960440, NCT00847613, NCT00814307, NCT00856544, NCT00853385) and received ≥1 dose of tofacitinib 5 or 10 mg twice daily (BID) or placebo (PBO). Pts were stratified by BL BMI ( Results Overall, 1589, 1611 and 681 pts received tofacitinib 5 and 10 mg BID and PBO, respectively, with 1690, 1173 and 1017 pts in the BMI Conclusions Results of this post hoc analysis suggest that tofacitinib is associated with improvements in RA outcomes compared with PBO regardless of BL BMI category. In both tofacitinib and PBO groups, similar trends in improvements were seen in most endpoints regardless of BMI category, implying that the effect of BL BMI is not specific to tofacitinib. Further investigation is needed to assess the degree of impactof BMI on tofacitinib efficacy. Acknowledgements: Study sponsored by Pfizer Inc. Medical writing support was provided by C Viegelmann of CMC and funded by Pfizer Inc. Disclosure of Interest: A. DikranianGrant/research support from: AbbVie, Mallinckrodt, Pfizer Inc, Speakers bureau:AbbVie, Amgen, Celgene, Mallinckrodt, Pfizer Inc, M. Gonzalez-Gay Consultant for: Pfizer Inc, F. Wellborne Grant/research support from: AbbVie, BMS, EliLilly, Novartis, Pfizer Inc, Sanofi/Genzyme/Regeneron, Consultant for: AbbVie,BMS, Novartis, Pfizer Inc, Sanofi/Genzyme/Regeneron, Speakers bureau: AbbVie,BMS, Eli Lilly, Novartis, Pfizer Inc, Sanofi/Genzyme/Regeneron, J.Alvaro-Gracia Consultant for: Abbvie, BMS, Eli Lilly, MSD, Novartis, PfizerInc, Roche, Sanofi/Genzyme/Regeneron, Speakers bureau: Abbvie, BMS, Eli Lilly,MSD, Novartis, Pfizer Inc, Roche, Sanofi/Genzyme/Regeneron, L. Takiya Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, L. Stockert Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, D. Chapman Shareholder of: Pfizer Inc,Employee of: Pfizer Inc, S. Tatulych Shareholder of: Pfizer Inc, Employee of:Pfizer Inc, P. Dahl Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, J.Curtis Grant/research support from: Amgen, Corrona, Crescendo Bio, Pfizer Inc, Consultant for: AbbVie, Amgen, BMS, Corrona, Eli Lilly, Janssen, Myriad, Roche/Genentech,UCB

Background Tofacitinib is an oral JAK inhibitor for the treatment of RA. There is no direct comparison of tofacitinib monotherapy vs tofacitinib +MTX in MTX inadequate responders (IR) and limited data comparing tofacitinib (±MTX) vs adalimumab (ADA) +MTX in patients (pts) with RA. Objectives To compare efficacy and safety of tofacitinib monotherapy, tofacitinib+MTX, and ADA+MTX in a head-to-head, non-inferiority trial in MTX-IR pts. Methods In this randomised, triple-dummy, active-controlled, 1-year, Phase 3b/4 trial (ORAL Strategy; NCT02187055), pts had active RA (≥4 tender/painful joints on motion and ≥4 swollen joints [28-joint count] at baseline [BL]) inadequately controlled with MTX. Pts were randomised 1:1:1 to receive tofacitinib 5 mg twice daily (5 mg mono BID), tofacitinib 5 mg BID +MTX (5 mg BID+MTX) or subcutaneous ADA 40 mg every other week +MTX (ADA+MTX); MTX dose: 15–25 mg/wk. The primary endpoint was ACR50 at Month (Mo) 6. Non-inferiority between treatments was declared if the lower bound of 98.34% two-sided confidence intervals of the difference of ACR50 response at Mo 6 was larger than -13% (based on meta analysis of ADA trials 1 ), and superiority if it was larger than 0%. Other endpoints included: ACR20/50/70 and least-squares mean changes from BL in SDAI, DAS28-4(ESR) and HAQ-DI at Mos 6 and 12. Safety was assessed throughout the trial. Results 1146 pts were randomised and treated (5 mg mono BID: n=384; 5 mg BID+MTX: n=376; ADA+MTX: n=386). Demographics and BL disease characteristics were similar across groups. Most pts were female (82.7–83.1%), white (75.9–77.1%), with a mean age of 49.7–50.7 years, median disease duration of 5.4–6.1 years and mean HAQ-DI score of 1.6. Across groups, 80.2–81.6% of pts completed the study. ACR50 response rate at Mo 6 was 38.3% for 5 mg mono BID, 46.0% for 5 mg BID+MTX and 43.8% for ADA+MTX. Non-inferiority was demonstrated for 5 mg BID+MTX vs ADA+MTX (P Conclusions Tofacitinib 5 mg BID+MTX was as effective as ADA+MTX in MTX-IR pts with RA. However, clinical outcomes of all 3 regimens, including tofacitinib 5 mg BID monotherapy, were comparable. There were no new or unexpected safety issues. References Machado et al. Rev Bras Reumatol 2013;53:419–430. Acknowledgements This study was funded by Pfizer Inc. Editorial support provided by D Binks of CMC. Disclosure of Interest R. Fleischmann Grant/research support from: Abbott, Amgen, Astellas, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Genentech, Eli Lilly, Janssen, Novartis, Pfizer Inc, Regeneron Pharmaceuticals Inc., Sanofi Aventis, Roche, UCB, Consultant for: Abbott, Akros, Amgen, Bristol-Myers Squibb, Celgene, Genentech, Eli Lilly, Janssen, Novartis, Pfizer Inc, Sanofi Aventis, UCB, E. Mysler Grant/research support from: AbbVie, Bristol-Myers Squibb, Eli Lilly, Janssen, Medimmune, Pfizer Inc and Roche, Consultant for: AbbVie, Bristol-Myers Squibb, Eli Lilly, Janssen, Medimmune, Pfizer Inc and Roche, Speakers bureau: AbbVie, Bristol-Myers Squibb, Eli Lilly, Janssen, Medimmune, Pfizer Inc and Roche, S. Hall Consultant for: Pfizer Inc, Celgene, Roche, AbbVie, Eli Lilly, Janssen, A. Kivitz Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Genentech and Pfizer Inc, Consultant for: AbbVie, Amgen, Bristol-Myers Squibb, Genentech and Pfizer Inc, Speakers bureau: AbbVie, Amgen, Bristol-Myers Squibb, Genentech, and Pfizer Inc, R. Moots Grant/research support from: Biogen, Bristol-Myers Squibb, Chugai, Novartis, Pfizer, Roche, Sandoz, UCB Pharma, Consultant for: Biogen, Bristol-Myers Squibb, Chugai, Novartis, Pfizer, Roche, Sandoz, UCB Pharma, Speakers bureau: Biogen, Bristol-Myers Squibb, Chugai, Novartis, Pfizer, Roche, Sandoz, UCB Pharma, Z. Luo Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, S. Tatulych Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, R. DeMasi Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, K. Soma Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, R. Zhang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, L. Takiya Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, C. Mojcik Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, S. Krishnaswami Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, S. Menon Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, J. Smolen Grant/research support from: AbbVie, Janssen, Lilly, MSD, Pfizer Inc, and Roche, Consultant for: AbbVie, Amgen, AstraZeneca, Astro, Celgene, Celtrion, Glaxo, ILTOO, Janssen, Lilly, MedImmune, MSD, Novartis-Sandoz, Pfizer Inc, Roche, Samsung, Sanofi, and UCB, Speakers bureau: AbbVie, Amgen, AstraZeneca, Astro, Celgene, Celtrion, Glaxo, ILTOO, Janssen, Lilly, MedImmune, MSD, Novartis-Sandoz, Pfizer Inc, Roche, Samsung, Sanofi, and UCB

Summary Background Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis. The Oral Rheumatoid Arthritis triaL (ORAL) Strategy aimed to assess the comparative efficacy of tofacitinib monotherapy, tofacitinib plus methotrexate, and adalimumab plus methotrexate for the treatment of rheumatoid arthritis in patients with a previous inadequate response to methotrexate. Methods ORAL Strategy was a 1 year, double-blind, phase 3b/4, head-to-head, non-inferiority, randomised controlled trial in patients aged 18 years or older with active rheumatoid arthritis despite methotrexate therapy. Patients were randomly assigned (1:1:1) to receive oral tofacitinib (5 mg twice daily) monotherapy, oral tofacitinib (5 mg twice daily) plus methotrexate, or subcutaneous adalimumab (40 mg every other week) plus methotrexate at 194 centres in 25 countries. Eligible patients received live zoster vaccine at investigators' discretion. The primary endpoint was the proportion of patients who attained an American College of Rheumatology response of at least 50% (ACR50) at month 6 in the full analysis set (patients who were randomly assigned to a group and received at least one dose of the study treatment). Non-inferiority between groups was shown if the lower bound of the 98·34% CI of the difference between comparators was larger than −13·0%. This trial is registered with ClinicalTrials.gov, number NCT02187055. Findings 1146 patients received treatment (384 had tofacitinib monotherapy; 376 had tofacitinib and methotrexate; and 386 had adalimumab and methotrexate). At 6 months, ACR50 response was attained in 147 (38%) of 384 patients with tofacitinib monotherapy, 173 (46%) of 376 patients with tofacitinib and methotrexate, and 169 (44%) of 386 patients with adalimumab and methotrexate. Non-inferiority was declared for tofacitinib and methotrexate versus adalimumab and methotrexate (difference 2% [98·34% CI −6 to 11]) but not for tofacitinib monotherapy versus either adalimumab and methotrexate (−6 [−14 to 3]) or tofacitinib and methotrexate (−8 [−16 to 1]). In total, 23 (6%) of 384 patients receiving tofacitinib monotherapy, 26 (7%) of 376 patients receiving tofacitinib plus methotrexate, and 36 (9%) of 386 patients receiving adalimumab plus methotrexate discontinued due to adverse events. Two (1%) of the 384 patients receiving tofacitinib monotherapy died. No new or unexpected safety issues were reported for either treatment in this study for up to 1 year. Interpretation Tofacitinib and methotrexate combination therapy was non-inferior to adalimumab and methotrexate combination therapy in the treatment of rheumatoid arthritis in patients with an inadequate response to methotrexate in this trial. Tofacitinib monotherapy was not shown to be non-inferior to either combination. Funding Pfizer Inc.

Background Psoriasis is a systemic inflammatory disease associated with increased cardiovascular (CV) risk and altered lipid metabolism. Tofacitinib is an oral Janus kinase inhibitor. Objective The aim of the study was to investigate the effects of tofacitinib on traditional and nontraditional lipid parameters and CV risk markers in patients with psoriasis from a phase III study, OPT Pivotal 1. Methods Patients with psoriasis were randomized to tofacitinib 5 or 10 mg twice daily (BID) or placebo BID. Serum samples were collected at baseline, week 4, and week 16. Analyses included serum cholesterol levels, triglycerides, lipoproteins, lipid particles, lipid-related parameters/CV risk markers, and high-density lipoprotein (HDL) function analyses. Results At week 16, small concurrent increases in mean low-density lipoprotein cholesterol (LDL-C) and HDL cholesterol (HDL-C) levels were observed with tofacitinib; total cholesterol/HDL-C ratio did not change. There was no significant change in the number of small dense LDL particles, which are considered to be more atherogenic than large particles, and oxidized LDL did not increase. Paraoxonase 1 activity, linked to HDL antioxidant capacity, increased, and HDL-associated serum amyloid A, which reduces the anti-atherogenic potential of HDL, decreased. HDL capacity to promote cholesterol efflux from macrophages did not change. Lecithin–cholesterol acyltransferase activity, which is associated with reverse cholesterol transport, increased. Markers of systemic inflammation, serum amyloid A and C-reactive protein, decreased with tofacitinib. Conclusion While small increases in lipid levels are observed with tofacitinib treatment in patients with psoriasis, effects on selected lipid-related parameters and other circulating CV risk biomarkers are not suggestive of an increased CV risk [NCT01276639].

Tofacitinib is an oral Janus kinase inhibitor. Efficacy and safety of tofacitinib in patients with moderate-to-severe plaque psoriasis have been demonstrated.We sought to assess the efficacy of tofacitinib for the treatment of nail psoriasis over a period of 52 weeks.In 2 identical phase 3 studies (OPT Pivotal 1 and 2), patients were randomized 2:2:1 to receive tofacitinib 5 mg, tofacitinib 10 mg, or placebo, twice daily. At week 16, placebo-treated patients were re-randomized to tofacitinib. This post hoc analysis of patients with existing nail psoriasis assessed the Nail Psoriasis Severity Index (NAPSI) score and proportions of patients achieving ≥50% reduction in NAPSI from baseline (NAPSI50), NAPSI75, or NAPSI100.Baseline mean NAPSI scores for patients treated with tofacitinib 5 mg (N = 487), tofacitinib 10 mg (N = 476), and placebo (N = 233) twice daily were 27.0, 27.3, and 26.9, respectively. At week 16, significantly (all P .05) more patients receiving tofacitinib 5 mg and tofacitinib 10 mg versus placebo twice daily achieved NAPSI50 (32.8%, 44.2% vs 12.0%), NAPSI75 (16.9%, 28.1% vs 6.8%), and NAPSI100 (10.3%, 18.2% vs 5.1%), respectively. Improvements were sustained to week 52.Limitations include discontinuation of clinical nonresponders at week 28.Tofacitinib treatment resulted in improvements in nail psoriasis versus placebo at week 16; improvements were maintained over 52 weeks [NCT01276639; NCT01309737].

Tofacitinib is a Janus kinase inhibitor being investigated for the treatment of moderate-to-severe plaque psoriasis. We report efficacy of tofacitinib in patient subgroups based on pooled data from two Phase 3 trials (spanNCT/span01276639,spanNCT/span01309737).br /To assess consistency of treatment effects of tofacitinib versus placebo in subgroups defined by baseline characteristics, and to ascertain whether baseline characteristics are of value in optimizing tofacitinib use.br /Pooled data from the two trials were used to evaluatege;75% reduction in PASI from baseline (PASI75 response) in subgroups defined by age, age at psoriasis onset, gender, race, geographical region, weight, body mass index, diabetes, metabolic syndrome, tobacco/alcohol use, psoriatic arthritis, disease activity, and prior therapy.br /Week 16 PASI75 response rates (N=1843) were 43%, 59% and 9% with tofacitinib 5 and 10mg twice daily (BID) and placebo, respectively (each Plt;0.0001 versus placebo). Tofacitinib 5 and 10mg BID were effective regardless of baseline characteristics. Across subgroups, tofacitinib generally produced greater response rates with the 10 versus 5mg BID dosage. Lower absolute response rates were seen in heavier patients and patients with prior biologic experience.br /Both tofacitinib dosages demonstrated consistent efficacy versus placebo across subgroups. Lower response rates were seen in heavier patients and those with prior biologic experience. Tofacitinib 10mg BID resulted in a substantial proportion of responders regardless of baseline characteristics.br /br /emJ Drugs Dermatol./em2016;15(5):568-580.

Tofacitinib is an oral Janus kinase inhibitor that improves clinical measures of psoriasis.We sought to assess patient-reported outcomes in tofacitinib-treated patients with moderate to severe plaque psoriasis over 52 weeks.In 2 identical, phase III studies (Oral treatment for Psoriasis Trial Pivotal 1 [NCT01276639], n = 901, and Pivotal 2 [NCT01309737], n = 960), patients were randomized 2:2:1 to receive 5 or 10 mg of tofacitinib or placebo, twice daily. At week 16, placebo-treated patients were re-randomized to tofacitinib. Dermatology Life Quality Index score, Itch Severity Item score, Patient Global Assessment score, and patient satisfaction were assessed.Baseline Dermatology Life Quality Index score indicated substantial health-related quality of life impairment. At week 16, a greater proportion of patients achieved Dermatology Life Quality Index score of 1 or less (no effect of psoriasis on health-related quality of life) with tofacitinib 5 and 10 mg twice daily versus placebo (Oral treatment for Psoriasis Trial Pivotal 1/2: 26.7%/28.6% and 40.2%/48.2% vs 4.6%/6.0%, respectively; P .0001); improvements were maintained through week 52. Similar patterns were observed with Patient Global Assessment. Improvements in itch were particularly rapid, observed 1 day after treatment initiation for both tofacitinib doses versus placebo (P .05). At week 16, more patients were satisfied with tofacitinib versus placebo (P .0001).Clinical nonresponders discontinued at week 28.Tofacitinib demonstrated improvement in health-related quality of life and patient-reported symptoms that persisted over 52 weeks.

Background Tofacitinib is an oral Janus kinase inhibitor being investigated for psoriasis. Objective We sought to elucidate the molecular mechanisms underlying the clinical efficacy of tofacitinib in patients with psoriasis. Methods Twelve patients with plaque psoriasis were randomized (3:1) to receive 10 mg of tofacitinib or placebo twice daily for 12 weeks. Biopsy specimens were taken from nonlesional (baseline) and lesional (baseline, days 1 and 3, and weeks 1, 2, 4, and 12) skin. Biopsy specimens were examined for psoriatic epidermal features (thickness, Ki67 + keratinocytes and keratin 16 [KRT16] mRNA expression, and phosphorylated signal transducer and activator of transcription [pSTAT] + nuclei) and T-cell and dendritic cell (DC) subsets by using immunohistochemistry, and mRNA transcripts were quantified by using a microarray. Results In lesional skin keratinocyte pSTAT1 and pSTAT3 staining was increased at baseline but reduced after 1 day of tofacitinib (baseline, median of 1290 pSTAT1 + cells/μm 2 ; day 1, median of 332 pSTAT1 + cells/μm 2 ; and nonlesional, median of 155 pSTAT1 + cells/μm 2 ). Epidermal thickness and KRT16 mRNA expression were significantly and progressively reduced after days 1 and 3 of tofacitinib administration, respectively (eg, KRT16 decreased 2.74-fold, day 3 vs baseline, P = .016). Decreases in DC and T-cell numbers were observed after weeks 1 and 2, respectively. At week 4, significant decreases in IL-23/T H 17 pathways were observed that persisted through week 12. Improvements in clinical and histologic features were strongly associated with changes in expression of psoriasis-related genes and reduction in IL-17 gene expression. Conclusions Tofacitinib has a multitiered response in patients with psoriasis: (1) rapid attenuation of keratinocyte Janus kinase/STAT signaling; (2) removal of keratinocyte-induced cytokine signaling, leading to reductions in pathologic DC and T-cell numbers to nonlesional levels; and (3) inhibition of the IL-23/T H 17 pathway.

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.