177 results on '"Hernan, Valdez"'
Search Results
2. Adverse events of special interest in clinical trials of rheumatoid arthritis, psoriatic arthritis, ulcerative colitis and psoriasis with 37 066 patient-years of tofacitinib exposure
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Peter Nash, Hernan Valdez, Bruce E Sands, Thomas V Jones, Ann Madsen, Kim Papp, and Huaming Tan
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Medicine - Abstract
Objectives To analyse adverse events (AEs) of special interest across tofacitinib clinical programmes in rheumatoid arthritis (RA), psoriatic arthritis (PsA), ulcerative colitis (UC) and psoriasis (PsO), and to determine whether the incidence rates (IRs; unique patients with events per 100 patient-years) of these events are consistent across diseases.Methods The analysis included data from patients exposed to ≥1 dose of tofacitinib in phase 1, 2, 3 or 3b/4 clinical trials and long-term extension (LTE) studies (38 trials) in RA (23 trials), PsA (3 trials), UC (5 trials) and PsO (7 trials). All studies were completed by or before July 2019, except for one ongoing UC LTE study (data cut-off May 2019). IRs were obtained for AEs of special interest.Results 13 567 patients were included in the analysis (RA: n=7964; PsA: n=783; UC: n=1157; PsO: n=3663), representing 37 066 patient-years of exposure. Maximum duration of exposure was 10.5 years (RA). AEs within the ‘infections and infestations’ System Organ Class were the most common in all diseases. Among AEs of special interest, IRs were highest for herpes zoster (non-serious and serious; 3.6, 1.8, 3.5 and 2.4 for RA, PsA, UC and PsO, respectively) and serious infections (2.5, 1.2, 1.7 and 1.3 for RA, PsA, UC and PsO, respectively). Age-adjusted and sex-adjusted mortality ratios (weighted for country) were ≤0.2 across cohorts.Conclusions The tofacitinib safety profile in this analysis was generally consistent across diseases and with longer term follow-up compared with previous analyses.
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- 2021
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3. Phase 3 efficacy and safety of abrocitinib in adults with moderate-to-severe atopic dermatitis after switching from dupilumab (JADE EXTEND)
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Vivian Y, Shi, Tina, Bhutani, Luz, Fonacier, Mette, Deleuran, Stephen, Shumack, Hernan, Valdez, Fan, Zhang, Gary L, Chan, Michael C, Cameron, and Natalie C, Yin
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Adult ,safety ,Sulfonamides ,response ,atopic dermatitis ,abrocitinib ,Injections, Subcutaneous ,Pruritus ,efficacy ,Eczema ,Dermatology ,Antibodies, Monoclonal, Humanized ,Severity of Illness Index ,Dermatitis, Atopic ,Pyrimidines ,Treatment Outcome ,Double-Blind Method ,dupilumab ,Humans - Abstract
BACKGROUND: Abrocitinib efficacy by prior dupilumab response status in patients with moderate-to-severe atopic dermatitis (AD) has not previously been assessed in phase 3 studies.OBJECTIVE: Examine efficacy and safety of abrocitinib among patients who received prior dupilumab.METHODS: Patients with moderate-to-severe AD received abrocitinib 200 mg or 100 mg once-daily in JADE EXTEND (phase 3 extension) after dupilumab in double-blind, placebo-controlled phase 3 JADE COMPARE.RESULTS: Among prior dupilumab responders, ≥75% improvement in Eczema Area and Severity Index (EASI-75) was achieved in 93.5% and 90.2% of patients who received 12 weeks of abrocitinib 200 mg and 100 mg, respectively; ≥4-point improvement in Peak Pruritus Numerical Rating Scale (PP-NRS4) was achieved in 89.7% and 81.6%, respectively. Among prior dupilumab nonresponders, EASI-75 was achieved with abrocitinib 200 mg and 100 mg in 80.0% and 67.7% and PP-NRS4 in 77.3% and 37.8%, respectively. Most common adverse events among abrocitinib-treated patients were nasopharyngitis, nausea, acne, and headache. Conjunctivitis occurred less frequently with abrocitinib in comparison to prior dupilumab.LIMITATIONS: Short-term, 12-week analysis; no placebo arm.CONCLUSION: Efficacy and safety profile of abrocitinib in JADE EXTEND supports the role of abrocitinib as a treatment for patients with moderate-to-severe AD, regardless of prior dupilumab response status.
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- 2022
4. Efficacy and safety of abrocitinib versus dupilumab in adults with moderate-to-severe atopic dermatitis: a randomised, double-blind, multicentre phase 3 trial
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Kristian Reich, Jacob P Thyssen, Andrew Blauvelt, Kilian Eyerich, Weily Soong, Zakiya P Rice, H Chih-ho Hong, Norito Katoh, Fernando Valenzuela, Marco DiBonaventura, Tamara A Bratt, Fan Zhang, Claire Clibborn, Ricardo Rojo, Hernan Valdez, and Urs Kerkmann
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Adult ,Sulfonamides ,Pyrimidines ,Treatment Outcome ,Double-Blind Method ,Humans ,General Medicine ,Antibodies, Monoclonal, Humanized ,Severity of Illness Index ,Dermatitis, Atopic - Abstract
Phase 3 trials have assessed efficacy of abrocitinib versus placebo in moderate-to-severe atopic dermatitis, a common immunoinflammatory skin disease. This study assessed the efficacy and safety of abrocitinib versus dupilumab.This randomised, double-blind, double-dummy, active-controlled, parallel-treatment, phase 3 trial enrolled adults with moderate-to-severe atopic dermatitis who requir=ed systemic therapy or had inadequate response to topical medications. Participants were enrolled from 151 sites, located in Australia, Bulgaria, Canada, Chile, Finland, Germany, Hungary, Italy, Latvia, Poland, Slovakia, South Korea, Spain, Taiwan, and the USA. These participants were then randomly assigned (1:1) with block randomisation to receive oral abrocitinib (200 mg per day) or subcutaneous dupilumab (300 mg every 2 weeks) for 26 weeks. Participants were required to apply topical corticosteroids (medium or low potency), topical calcineurin inhibitors, or a topical phosphodiesterase 4 inhibitor to active lesion areas. Primary endpoints were response based on achieving a 4 point or higher improvement in Peak Pruritus Numerical Rating Scale (PP-NRS4) at week 2 and a 90% or better improvement in Eczema Area and Severity Index (EASI-90) at week 4. Family-wise type 1 error was controlled via a sequential multiple-testing procedure (two sided, α=0·05). Randomly assigned participants who received at least one dose of study intervention were included in the efficacy and safety analysis sets. This trial was completed on July 13, 2021 (NCT04345367).Between June 11, 2020, and Dec 16, 2020, 940 patients were screened and 727 were enrolled (362 in the abrocitinib group and 365 in the dupilumab group). Compared with dupilumab, a larger proportion of patients treated with abrocitinib reached the primary outcomes, PP-NRS4 at week 2 (172 [48%] of 357, 95% CI 43·0-53·4 vs 93 [26%] of 364, 21·1-30·0; difference 22·6%, 15·8-29·5; p0·0001), and EASI-90 at week 4 (101 [29%] of 354, 23·8-33·2 vs 53 [15%] of 364, 10·9-18·2; difference 14·1%, 8·2-20·0; p0·0001). Treatment-emergent adverse events were reported by 268 (74%) of 362 patients treated with abrocitinib and by 239 (65%) of 365 patients treated with dupilumab. Two non-treatment-related deaths occurred in the abrocitinib group.Abrocitinib 200 mg per day was more efficacious than dupilumab in adults with moderate-to-severe atopic dermatitis on background topical therapy in inducing early reductions of itch and atopic dermatitis disease signs. Both treatments were well tolerated over 26 weeks.Pfizer.
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- 2022
5. Comparing how well abrocitinib and dupilumab treat atopic dermatitis signs and symptoms: a plain language summary
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Kristian Reich, Jacob P. Thyssen, Andrew Blauvelt, Kilian Eyerich, Weily Soong, Zakiya P. Rice, H. Chih-ho Hong, Norito Katoh, Fernando Valenzuela, Marco DiBonaventura, Tamara A. Bratt, Fan Zhang, Claire Clibborn, Ricardo Rojo, Hernan Valdez, and Urs Kerkmann
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Oncology ,Immunology ,Immunology and Allergy - Abstract
What is this summary about? Atopic dermatitis (AD, also called atopic eczema) is a skin disease that that can affect a person for a long time and causes red or flaky skin that can be itchy and uncomfortable. Healthcare providers can prescribe medicated creams and ointments to reduce the visible signs and symptoms of AD, but these treatments are not always enough to keep it under control. A new medicine called abrocitinib is taken every day as a tablet. Abrocitinib works by slowing a part of the body's defense mechanism, called immune response, that is not functioning properly in AD. The clinical study described in this plain language summary, called JADE DARE, investigated how well and how safely 26 weeks of treatment with abrocitinib worked in adults with AD compared to an injected medicine, called dupilumab, that is also approved for AD. What were the results? The study showed that abrocitinib was more effective than dupilumab in providing itch relief after 2 weeks. In addition, people who were taking abrocitinib for 4 and 16 weeks experienced greater improvement in the visible skin signs of AD than people who were taking dupilumab. The number of people who had health complaints while taking abrocitinib was similar to the number of people who had health complaints while taking dupilumab. Most of these complaints were minor. What do the results mean? Abrocitinib was more effective than dupilumab in quickly improving the signs and symptoms of moderate or severe AD in people who did not show improvement with prescribed medications like creams or ointments. Clinical Trial Registration: NCT04345367 ( ClinicalTrials.gov )
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- 2023
6. Early clinical response to tofacitinib treatment as a predictor of subsequent efficacy: Results from two phase 3 studies of patients with moderate-to-severe plaque psoriasis
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Huaming Tan, Hernan Valdez, Chris E.M. Griffiths, Ulrich Mrowietz, Anna Tallman, Robert Wolk, and Kenneth Gordon
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pasi50 ,pasi75 ,auc ,early clinical improvement ,predictor of efficacy ,Dermatology ,RL1-803 - Abstract
Background: The ability to predict response to psoriasis treatments has important implications. Tofacitinib is an oral JAK inhibitor being investigated for psoriasis. Objective: The objective of this study is to identify and validate the clinical predictors of responses in psoriasis patients treated with tofacitinib. Methods: Selected baseline characteristics or early improvement in Psoriasis Area and Severity Index (PASI) in the phase 3 tofacitinib study OPT 1 (NCT01276639) were evaluated as predictors for a clinical response (75% improvement in PASI [PASI75]) at week 16. Predictive ability was assessed by the area-under-the-receiver operating characteristic curve (AUC-ROC). The predictive ability of the identified variables was validated with study OPT 2 (NCT01309737). Results: PASI improvement at weeks 8 and 12 demonstrated good discriminatory abilities to predict PASI75 response at week 16 (AUC-ROC ≥86% and 94%, respectively) in OPT 1. Validation with PASI50 response at week 8 in OPT 2 to predict PASI75 response at week 16 showed that the sensitivity, specificity, PPV, and NPV were 88%, 69%, 80%, and 81%, respectively, in tofacitinib-treated subjects. Conclusion: Achieving a PASI50 response after 8 weeks of treatment with tofacitinib in psoriasis patients appears to be a reliable predictor of achieving a PASI75 response at week 16. Trial registration: clinicaltrials.gov: NCT01276639 and NCT01309737
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- 2017
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7. Population pharmacokinetic‐pharmacodynamic modelling of platelet time‐courses following administration of abrocitinib
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Jessica, Wojciechowski, Bimal K, Malhotra, Xiaoxing, Wang, Luke, Fostvedt, Hernan, Valdez, and Timothy, Nicholas
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Adult ,Pharmacology ,Sulfonamides ,Pyrimidines ,Adolescent ,Humans ,Pharmacology (medical) ,Thrombocytopenia ,Dermatitis, Atopic - Abstract
Abrocitinib is a selective Janus kinase 1 inhibitor for the treatment of moderate-to-severe atopic dermatitis. Herein we describe the time-course of drug-induced platelet reduction following abrocitinib administration, identify covariates affecting platelet counts, and determine the probability of patients experiencing thrombocytopaenia while receiving abrocitinib.This analysis included data from two Phase 2 and three Phase 3 studies in psoriasis and atopic dermatitis patient populations administered abrocitinib 10-400 mg QD orally for up to 12 weeks, with platelet counts determined up to week 16. A semi-mechanistic model was developed to assess the impact of baseline platelet counts (170, 220 and 270 × 1000/μL), age and race on the platelet nadir and week 12 counts with once-daily abrocitinib 200 mg or 100 mg.Decreases in platelet counts were transient with the nadir occurring on average 24 days (95% prediction interval, 23-24) after continuous administration of abrocitinib 200 mg QD. Following administration of once-daily abrocitinib 200 mg, the probabilities of thrombocytopaenia (150 × 1000/μL) at the nadir were 8.6% and 95.5% for the typical patient with baseline platelet count of 270 × 1000/μL or 170 × 1000/μL, respectively. Adolescents had a lower probability of thrombocytopaenia compared with adults; platelet count distribution was similar in Asian and Western patients at the nadir and at week 12.This analysis supports the safety of once-daily abrocitinib 200 mg and 100 mg dosing regimens, with low probability of thrombocytopaenia during treatment, except for higher risk of low-grade thrombocytopaenia that diminished after 4 weeks in patients with low baseline platelet counts.
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- 2022
8. 330 Safety of abrocitinib in 3582 patients with moderate-to-severe atopic dermatitis with over 900 patients exposed for almost 2 years
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Eric L Simpson, Jonathan I Silverberg, Audrey Nosbaum, Kevin Winthrop, Emma Guttman-Yassky, Karin M Hoffmeister, Alexander Egeberg, Hernan Valdez, Haiyun Fan, Saleem A Farooqui, Gary Chan, Justine Alderfer, William Romero, and Susan Johnson
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Dermatology - Abstract
Abrocitinib is an oral Janus kinase 1 inhibitor with demonstrated efficacy in moderate-to-severe atopic dermatitis (AD). To evaluate the long-term safety profile of abrocitinib and provide relevant information for practitioners. Data from patients who received ≥1 dose of abrocitinib 200 mg or 100 mg in the JADE clinical program were pooled in two cohorts. The consistent-dose (CD) cohort comprised patients who received the same abrocitinib dose during the entire exposure time in parent phase 3 studies and/or the long-term extension study JADE EXTEND (NCT03422822). Parent studies were: JADE MONO-1 (NCT03349060), JADE MONO-2 (NCT03575871), JADE TEEN (NCT03796676), JADE COMPARE (NCT03720470), JADE DARE (NCT04345367; 200 mg only) and JADE REGIMEN (NCT03627767); in JADE REGIMEN only patients from the open-label run-in phase (200 mg only) who did not subsequently enter the randomized phase were included. Patients from the phase 2b study (NCT02780167) were also included in the CD cohort. The variable-dose (VD) cohort comprised patients who received different doses of abrocitinib (200 and 100 mg) throughout exposure time in the parent study JADE REGIMEN and in JADE EXTEND, if enrolled. Patients included in the VD cohort completed the open-label period of JADE REGIMEN (abrocitinib 200 mg only) and entered the randomized phase (abrocitinib 200 mg, abrocitinib 100 mg or placebo); some patients subsequently entered the JADE REGIMEN rescue phase (abrocitinib 200 mg) and/or JADE EXTEND (abrocitinib 200 or 100 mg). The data cutoff was 16 April 2021. A Cox regression analysis evaluated risk factors for specific events of interest. Data from 3582 patients (4313.4 patient-years) were analysed: 2784 patients in the CD cohort (abrocitinib 200 mg, n = 1761, abrocitinib 100 mg, n = 1023) and 798 patients in the VD cohort. Duration of exposure was ≥48 weeks in 43.6%, 66.9% and 86.1% and ≥96 weeks in 18.0%, 23.2% and 45.4% of patients in the CD 200 mg, 100 mg and VD cohorts, respectively. In the CD and VD cohorts, the median age was 30.0 and 29.0 years; 490 (17.6%) and 145 patients (18.2%) were adolescents, and 143 (5.1%) and 30 patients (3.8%) were aged ≥65 years at screening, respectively. Incidence rates (IRs; unique patients with events per 100 patient-years) of serious adverse events (SAEs), deaths, and treatment-emergent adverse events of special interest are shown in Table 1. IRs for SAEs were consistent across abrocitinib doses but were higher in patients aged ≥65 years vs. younger patients. Serious infections were the most frequent SAEs; frequency was not dose related. Herpes zoster (HZ), herpes simplex and pneumonia were the most frequent serious infections. From a Cox regression analysis, potential risk factors for treatment-emergent HZ included abrocitinib dose, baseline age, medical history of HZ, absolute lymphocyte count
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- 2023
9. Assessment of the Effects of Inhibition or Induction of CYP2C19 and CYP2C9 Enzymes, or Inhibition of OAT3, on the Pharmacokinetics of Abrocitinib and Its Metabolites in Healthy Individuals
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Xiaoxing, Wang, Martin E, Dowty, Ann, Wouters, Svitlana, Tatulych, Carol A, Connell, Vu H, Le, Sakambari, Tripathy, Melissa T, O'Gorman, Jennifer A, Winton, Natalie, Yin, Hernan, Valdez, and Bimal K, Malhotra
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Adult ,Pharmacology ,Sulfonamides ,Clinical Trials, Phase I as Topic ,Probenecid ,Cytochrome P-450 CYP2C19 ,Pyrimidines ,Cytochrome P-450 Enzyme System ,Fluvoxamine ,Area Under Curve ,Humans ,Drug Interactions ,Pharmacology (medical) ,Rifampin ,Fluconazole ,Cytochrome P-450 CYP2C9 - Abstract
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.
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- 2022
10. Population Pharmacokinetics of Abrocitinib in Healthy Individuals and Patients with Psoriasis or Atopic Dermatitis
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Jessica Wojciechowski, Bimal K. Malhotra, Xiaoxing Wang, Luke Fostvedt, Hernan Valdez, and Timothy Nicholas
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Adult ,Pharmacology ,Sulfonamides ,Pyrimidines ,Adolescent ,Body Weight ,Humans ,Psoriasis ,Pharmacology (medical) ,Dermatitis, Atopic - Abstract
Abrocitinib is a Janus kinase 1 inhibitor in development for the treatment of atopic dermatitis (AD). This work characterized orally administered abrocitinib population pharmacokinetics in healthy individuals, patients with psoriasis, and patients with AD and the effects of covariates on abrocitinib exposure.Abrocitinib concentration measurements (n = 6206) from 995 individuals from 11 clinical trials (seven phase I, two phase II, and two phase III) were analyzed, and a non-linear mixed-effects model was developed. Simulations of abrocitinib dose proportionality and steady-state accumulation of maximal plasma drug concentration (CA two-compartment model with parallel zero- and first-order absorption, time-dependent bioavailability, and time- and dose-dependent clearance best described abrocitinib pharmacokinetics. Abrocitinib coadministration with rifampin resulted in lower exposure, whereas Asian/other race coadministration with fluconazole and fluvoxamine, inflammatory skin conditions (psoriasis/AD), and hepatic impairment resulted in higher exposure. After differences in body weight are accounted for, Asian participants demonstrated a 1.43- and 1.48-fold increase in CA population pharmacokinetics model was developed for abrocitinib that can be used to predict abrocitinib steady-state exposure in the presence of drug-drug interaction effects or intrinsic patient factors. Key covariates in the study population accounting for variability in abrocitinib exposures are Asian race and adolescent age, although these factors are not clinically meaningful.NCT01835197, NCT02163161, NCT02201524, NCT02780167, NCT03349060, NCT03575871, NCT03634345, NCT03637790, NCT03626415, NCT03386279, NCT03937258.Abrocitinib is a drug approved in the UK and Japan for the treatment of atopic dermatitis. A population pharmacokinetic model for abrocitinib was developed based on data from 11 clinical trials that included 995 healthy individuals or patients with atopic dermatitis or psoriasis. Simulations of different patient factors, such as age, race, sex, body weight, liver function, and drug–drug interactions, were tested to examine differences in abrocitinib drug levels achieved in the body. The results of these simulations indicate that although there are some differences in abrocitinib exposure, no dose adjustments of abrocitinib are necessary based on these factors.
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- 2022
11. Patient‐reported outcomes from the JADE COMPARE randomized phase 3 study of abrocitinib in adults with moderate‐to‐severe atopic dermatitis
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Claire Feeney, Gil Yosipovitch, Daniela E. Myers, Chia-Yu Chu, Fan Zhang, Jacob P. Thyssen, Shawn G. Kwatra, Ricardo Rojo, Carle Paul, Hernan Valdez, and Marco DiBonaventura
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Adult ,Moderate to severe ,medicine.medical_specialty ,Eczema ,Phases of clinical research ,Dermatology ,Placebo ,Hospital Anxiety and Depression Scale ,Severity of Illness Index ,Dermatitis, Atopic ,Subcutaneous injection ,Double-Blind Method ,Internal medicine ,medicine ,Humans ,Patient Reported Outcome Measures ,Sulfonamides ,business.industry ,Atopic dermatitis ,Dermatology Life Quality Index ,medicine.disease ,Dupilumab ,Pyrimidines ,Treatment Outcome ,Infectious Diseases ,business - Abstract
Background: In JADE COMPARE, abrocitinib improved severity of atopic dermatitis (AD) and demonstrated rapid itch relief. Objectives: We examined clinically meaningful improvements in selected patient-reported outcomes (PROs). Methods: JADE COMPARE was a multicentre, phase 3 randomized, double-blind, placebo-controlled trial. Adults with moderate-to-severe AD were randomized 2:2:2:1 to receive 16 weeks of oral abrocitinib 200 or 100 mg once daily, dupilumab 300 mg subcutaneous injection every 2 weeks, or placebo, with background topical therapy. PROs included Dermatology Life Quality Index (DLQI), Patient-Oriented Eczema Measure (POEM), Night Time Itch Scale (NTIS), Pruritus and Symptoms Assessment for Atopic Dermatitis, Patient Global Assessment, SCORing Atopic Dermatitis, and Hospital Anxiety and Depression Scale. Results: At week 16, the proportion of patients achieving POEM scores
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- 2021
12. Rapid Improvement of Itch Associated With Atopic Dermatitis With Abrocitinib Is Partially Independent of Overall Disease Improvement: Results From Pooled Phase 2b and 3 Monotherapy Studies
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Urs Kerkmann, Marco DiBonaventura, Sonja Ständer, Michael C. Cameron, Eric L. Simpson, Saleem A. Farooqui, Brian S. Kim, Gil Yosipovitch, Jonathan I. Silverberg, Hernan Valdez, and Pinaki Biswas
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Adult ,Male ,Moderate to severe ,medicine.medical_specialty ,Dermatology ,Disease ,Placebo ,Severity of Illness Index ,Dermatitis, Atopic ,Clinical Trials, Phase II as Topic ,Double-Blind Method ,Internal medicine ,Studies ,otorhinolaryngologic diseases ,Humans ,Immunology and Allergy ,Medicine ,Pooled data ,skin and connective tissue diseases ,Protein Kinase Inhibitors ,Randomized Controlled Trials as Topic ,Sulfonamides ,business.industry ,Antipruritic Effect ,Atopic dermatitis ,Itch Relief ,medicine.disease ,Pyrimidines ,ComputingMethodologies_DOCUMENTANDTEXTPROCESSING ,Quality of Life ,business ,Body mass index - Abstract
Supplemental digital content is available in the text., Background Itch, the most bothersome symptom in atopic dermatitis, is largely mediated by pruritogenic cytokines via Janus kinase 1 signaling in cutaneous sensory neurons. Objectives The aims of the study were to assess the magnitude and rapidity of itch relief with the Janus kinase 1 selective inhibitor abrocitinib and to evaluate the extent to which the effect of abrocitinib on itch relief is independent of overall disease improvement. Methods Pooled data from 1 phase 2b (NCT02780167) and 2 phase 3 (NCT03349060, NCT03575871) double-blind, randomized, placebo-controlled monotherapy trials in moderate to severe atopic dermatitis (N = 942) were analyzed. Results Abrocitinib produced significant and clinically meaningful itch relief versus placebo from week 2 through week 12 (end of treatment) that was associated with marked sleep and quality-of-life improvements. Mean percentage reductions in itch scores 24 hours after the first dose were greater for both abrocitinib doses (200 and 100 mg) versus placebo. Itch improvement occurred regardless of baseline itch severity, sex, race, body mass index, or Investigator Global Assessment response, suggesting that abrocitinib-associated itch relief is at least partially independent of overall disease improvement. Conclusions Abrocitinib showed a rapid and profound antipruritic effect, partially independent of improvement in overall disease.
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- 2021
13. Early Itch Response with Abrocitinib Is Associated with Later Efficacy Outcomes in Patients with Moderate-to-Severe Atopic Dermatitis: Subgroup Analysis of the Randomized Phase III JADE COMPARE Trial
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Sonja, Ständer, Shawn G, Kwatra, Jonathan I, Silverberg, Eric L, Simpson, Jacob P, Thyssen, Gil, Yosipovitch, Fan, Zhang, Michael C, Cameron, Ricardo Rojo, Cella, Hernan, Valdez, Marco, DiBonaventura, and Claire, Feeney
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Abrocitinib, an oral Janus kinase 1 inhibitor, provided significant itch relief by week 2 in patients with moderate-to-severe atopic dermatitis (AD) in the phase III JADE COMPARE trial.This post-hoc analysis of JADE COMPARE aimed to further characterize itch response and determined whether early itch relief could predict subsequent improvements in AD severity.JADE COMPARE was a randomized, double-blind, double-dummy, placebo-controlled trial. Adult patients (aged ≥ 18 years) with moderate-to-severe AD were randomly assigned to receive oral abrocitinib 200 mg or 100 mg once daily, subcutaneous dupilumab 300 mg every other week (after a 600-mg loading dose), or placebo, plus medicated topical therapy for 16 weeks. Assessments were ≥ 4-point improvement in Peak Pruritus Numerical Rating Scale (PP-NRS4) from days 2 to 15, Eczema Area and Severity Index (EASI), Investigator's Global Assessment (IGA) response, and Dermatology Life Quality Index (DLQI) scores at week 12. Association between week 2 PP-NRS4 and efficacy at week 12 was evaluated by chi-squared tests. The predictive value of early response for later efficacy was assessed by area under the receiver operating characteristic curve.As early as day 4 after treatment, a significantly greater proportion of patients achieved PP-NRS4 response with abrocitinib 200 mg (18.6%) versus dupilumab (5.6%; p 0.001) and placebo (6.0%; p 0.003). A similar trend was observed with abrocitinib at the 100-mg dose, with significantly greater PP-NRS4 response rates versus placebo as early as day 9. With both doses of abrocitinib, week 12 IGA 0/1, EASI-75, EASI-90, and DLQI 0/1 response rates were greater in week 2 PP-NRS4 responders than nonresponders; no differences were observed between week 2 PP-NRS4 responders and nonresponders in the dupilumab and placebo groups. Early improvement in PP-NRS at week 2 was associated with skin clearance at week 12 in abrocitinib-treated patients.Abrocitinib resulted in rapid relief from itch in patients with moderate-to-severe AD, with significant improvement in itch as early as day 4 after treatment with abrocitinib 200 mg compared with dupilumab and placebo. Abrocitinib-induced itch relief by week 2 was associated with subsequent improvements at week 12. [Video abstract available.] TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03720470. Early itch response with abrocitinib is associated with later efficacy outcomes in patients withmoderate-to-severe atopic dermatitis: subgroup analysis of the randomized phase III JADE COMPARE trial (MP4 335,375kb).Atopic dermatitis (AD), also called atopic eczema, is a skin disease that affects people throughout their lives. About 10% of adults worldwide have AD. Itch is the most bothersome symptom reported by people with AD and scratching this itch can damage the skin, resulting in painful sores. It is unknown if relief from itch can influence other symptoms of AD. We analyzed data from the JADE COMPARE study, which included 837 people who received treatment with abrocitinib, dupilumab or placebo. We studied how fast itch relief occurred after people received these treatments. We also wanted to study if rapid itch relief was associated with improvement in other signs of AD later on with continued treatment. We found that as early as 4 days after treatment, abrocitinib 200 mg provided significant relief from itch compared with dupilumab or placebo. People who had rapid itch relief within 2 weeks of treatment with abrocitinib were more likely to have clear or almost clear skin and improved quality of life after 12 weeks of continued treatment with abrocitinib. Rapid itch relief did not appear to increase the likelihood of clear skin at week 12 in people who received dupilumab. Larger studies are needed to confirm this result. This study provides important evidence for physicians as they analyze itch relief and determine treatment options for people with AD.
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- 2022
14. Contribution of a European‐Prevalent Variant near CD83 and an East Asian–Prevalent Variant near IL17RB to Herpes Zoster Risk in Tofacitinib Treatment: Results of Genome‐Wide Association Study Meta‐Analyses
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Tomohiro Hirose, Keishi Fujio, Baohong Zhang, Michael S. Vincent, David Martin, Shuji Sumitomo, Yuta Kochi, Nan Bing, Huanyu Zhou, James D. Clark, Xing Chen, Hernan Valdez, Kazuyoshi Ishigaki, and Yumi Tsuchida
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0301 basic medicine ,medicine.medical_specialty ,Full Length ,Immunology ,Immunoglobulins ,Rheumatoid Arthritis ,Genome-wide association study ,Herpes Zoster ,Polymorphism, Single Nucleotide ,Gastroenterology ,White People ,Arthritis, Rheumatoid ,03 medical and health sciences ,Psoriatic arthritis ,0302 clinical medicine ,Asian People ,Piperidines ,Rheumatology ,Antigens, CD ,Internal medicine ,medicine ,Humans ,Janus Kinase Inhibitors ,Psoriasis ,Immunology and Allergy ,Proportional Hazards Models ,Genetic association ,030203 arthritis & rheumatology ,Membrane Glycoproteins ,Receptors, Interleukin-17 ,Tofacitinib ,business.industry ,Proportional hazards model ,Incidence (epidemiology) ,Hazard ratio ,medicine.disease ,Logistic Models ,Pyrimidines ,030104 developmental biology ,Rheumatoid arthritis ,business ,Genome-Wide Association Study - Abstract
OBJECTIVE Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA), psoriatic arthritis, and ulcerative colitis, and has been previously investigated for psoriasis (PsO). This meta-analysis of genome-wide association studies (GWAS) was performed to identify genetic factors associated with increased risk/faster onset of herpes zoster (HZ) in subjects with RA or PsO receiving tofacitinib treatment, and to determine potential mechanisms that could be attributed to the varying rates of HZ across ethnicities. METHODS In an ethnicity/indication-specific, trans-ethnic, trans-population meta-analysis of GWAS in subjects with RA or PsO from phase II, phase III, and long-term extension studies of tofacitinib, 8 million genetic variants were evaluated for their potential association with time to an HZ event and incidence of an HZ event (case versus control) with tofacitinib treatment, using Cox proportional hazard and logistic regression analyses, respectively. RESULTS In total, 5,246 subjects were included (3,168 with RA and 2,078 with PsO). After adjustment for age, baseline absolute lymphocyte count, genetically defined ethnicity, and concomitant methotrexate use (in RA subjects only), 4 loci were significantly associated with faster onset of HZ in European subjects (P < 5 × 10-8 ), including a single-nucleotide polymorphism (SNP) near CD83 (frequency of risk allele ~2% in European subjects versus ~0.1% in East Asian subjects). In the trans-ethnic, trans-population meta-analysis, the CD83 SNP remained significant. Four additional significant loci were identified in the meta-analysis, among which a SNP near IL17RB was associated with faster onset of HZ (meta-analysis hazard ratio 3.6 [95% confidence interval 2.40-5.44], P = 7.6 × 10-10 ; frequency of risk allele ~12% in East Asian subjects versus
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- 2021
15. Impact of Oral Abrocitinib Monotherapy on Patient-Reported Symptoms and Quality of Life in Adolescents and Adults with Moderate-to-Severe Atopic Dermatitis: A Pooled Analysis of Patient-Reported Outcomes
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Eric L. Simpson, Ricardo Rojo, Daniela E. Myers, Pinaki Biswas, Hernan Valdez, Jacob P. Thyssen, Claire Feeney, Gil Yosipovitch, Marco DiBonaventura, Jonathan I. Silverberg, and Sonja Ständer
- Subjects
Sleep disorder ,medicine.medical_specialty ,business.industry ,Dermatology ,General Medicine ,Atopic dermatitis ,Placebo ,medicine.disease ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,Quality of life ,Internal medicine ,Severity of illness ,medicine ,Anxiety ,Original Research Article ,Young adult ,medicine.symptom ,business ,Depression (differential diagnoses) - Abstract
Background Atopic dermatitis imparts a substantial patient burden, including itch, sleep disturbance, and decreased health-related quality of life. Objective This analysis evaluated changes in patient-reported outcomes of disease-specific signs/symptoms and health-related quality of life in adult and adolescent patients with moderate-to-severe atopic dermatitis treated with once-daily oral abrocitinib 200-mg or 100-mg monotherapy. Methods Pooled data from one phase IIb (NCT02780167) and two phase III (NCT03349060, JADE MONO-1; NCT03575871, JADE MONO-2) monotherapy trials in adult and adolescent patients with moderate-to-severe atopic dermatitis were analyzed. Patient-reported outcome assessments included: global severity, itch, and multi-item measures that assess other signs and symptoms of atopic dermatitis. Additional patient-reported outcome assessments measured depression, anxiety, fatigue, disease-specific and general health-related quality of life, and work and general productivity among employed patients. Results Overall, 942 patients were included in this analysis. Improvements were observed from the first post-baseline assessment to week 12 across all patient-reported outcomes, including Patient Global Assessment (PtGA) score of 0/1 (35.5%, 19.8%, and 5.9% for 200 mg, 100 mg, and placebo, respectively), ≥ 4-point improvement in Night Time Itch Scale (NTIS; 57.0%, 42.7%, and 12.7%), change from baseline in Patient-Oriented Eczema Measure (POEM) score (− 11.4, − 8.2, and − 3.4), 1-point improvement in Pruritus and Symptoms Assessment for Atopic Dermatitis (PSAAD; 75.2%, 65.1%, and 33.5%), Hospital Anxiety and Depression Scales (HADS) anxiety (− 2.0, − 1.7, and − 1.0) and depression (− 1.7, − 1.3, and − 0.1). Conclusions Abrocitinib monotherapy improved disease-specific signs/symptoms and health-related quality of life across multiple domains as reported by adult and adolescent patients with moderate-to-severe atopic dermatitis, complementing clinician-reported efficacy and safety outcomes. Clinical Trial Registration NCT02780167 (registered 23 May, 2016), NCT03349060 (registered 21 November, 2017), NCT03575871 (registered 3 July, 2018). Supplementary Information The online version contains supplementary material available at 10.1007/s40257-021-00604-9.
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- 2021
16. Abrocitinib in the Treatment of Moderate-to-Severe Atopic Dermatitis Refractory to Dupilumab Treatment: An Analysis of JADE-EXTEND, a Phase 3 Long-Term Extension Study
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Vivian Shi, Tina Bhutani, Mette Deleuran, Luz Fonacier, Stephen Shumack, Fan Zhang, Michael C. Cameron, Gary L. Chan, Hernan Valdez, and Natalie Yin
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Dermatology - Published
- 2023
17. Safety of Abrocitinib in 3582 Patients With Moderate-to-Severe Atopic Dermatitis With Over 900 Patients Exposed for Almost 2 Years
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Eric L. Simpson, Johnathan Silverberg, Audrey Nosbaum, Kevin Winthrop, Emma Guttman-Yassky, Karin M. Hoffmeister, Alexander Egeberg, Hernan Valdez, Haiyun Fan, Saleem A. Farooqui, Gary L. Chan, Justine Alderfer, William Romero, and Susan Johnson
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Dermatology - Published
- 2023
18. Economic impact of abrocitinib monotherapy and combination therapy in patients with moderate-to-severe atopic dermatitis: Results from JADE MONO-2 and JADE COMPARE
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Pinaki Biswas, Melinda Gooderham, Daniela E. Myers, Chia-Yu Chu, Claire Feeney, Ricardo Rojo, Hernan Valdez, Marco DiBonaventura, Gerardo A. Encinas, Michael C. Cameron, Joseph C. Cappelleri, and Kathleen Peeples-Lamirande
- Subjects
Moderate to severe ,economic impact ,medicine.medical_specialty ,Letter ,Combination therapy ,atopic dermatitis ,business.industry ,abrocitinib ,Atopic dermatitis ,Dermatology ,medicine.disease ,JADE (particle detector) ,combination therapy ,monotherapy ,RL1-803 ,cost ,Medicine ,In patient ,business - Published
- 2021
19. Durability of Response to Abrocitinib in Patients with Moderate-to-Severe Atopic Dermatitis After Treatment Discontinuation in a Phase 2b Trial
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Melinda J, Gooderham, Giampiero, Girolomoni, Julian O, Moore, Jonathan I, Silverberg, Robert, Bissonnette, Seth, Forman, Elena, Peeva, Pinaki, Biswas, Hernan, Valdez, and Gary, Chan
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Pruritus ,Eczema ,Abrocitinib ,Atopic dermatitis ,Biomarker ,Discontinuation ,Dermatology - Abstract
Multiple clinical trials showed that 12 weeks of abrocitinib monotherapy was safe and effective for the treatment of moderate-to-severe atopic dermatitis (AD). The reversibility of pharmacologic activity after abrocitinib discontinuation was not described.This post hoc analysis used data from a phase 2b study to evaluate maintenance of disease control during a 4-week drug-free follow-up period in patients with moderate-to-severe AD treated with once-daily abrocitinib (200 mg/100 mg) or placebo for 12 weeks. Proportions of patients who achieved and maintained 50% or 75% improvement in Eczema Area and Severity Index (EASI-50/EASI-75), an Investigator's Global Assessment (IGA) score of 0/1, or at least a 4-point improvement in the pruritus numeric rating scale (pruritus NRS4) were determined. Biomarkers of Janus kinase inhibition and AD disease were measured in blood samples.Among week 12 responders to abrocitinib 200 mg, 77.4%, 42.3%, 21.1%, and 42.9% maintained their EASI-50, EASI-75, IGA, and pruritus NRS4 response at week 16; corresponding proportions of week 12 responders maintaining response to abrocitinib 100 mg were 51.9%, 35.0%, 33.3%, and 43.5%, respectively. Four weeks after abrocitinib discontinuation, all AD biomarkers reverted toward baseline levels, with high-sensitivity C-reactive protein and eosinophil percentage demonstrating the most complete recovery in patients treated with abrocitinib versus placebo.Abrocitinib discontinuation resulted in rapid reversal of disease control consistent with reversal of suppression of pharmacodynamic and AD-specific biomarkers during the drug-free follow-up period. Maintenance of response was inversely related to the threshold of improvement. Patients with moderate-to-severe AD using continuous abrocitinib therapy would likely have the best long-term outcomes.ClinicalTrials.gov identifier NCT02780167.
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- 2022
20. Incidence of venous and arterial thromboembolic events reported in the tofacitinib rheumatoid arthritis, psoriasis and psoriatic arthritis development programmes and from real-world data
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Manfred Hauben, Keith S. Kanik, Joel M. Kremer, Jeffrey R. Curtis, Christina Charles-Schoeman, Alina Onofrei, Eric Hung, Stanley Cohen, Cunshan Wang, Hernan Valdez, Thomas V. Jones, Carol A. Connell, Philip J. Mease, Ann Madsen, Jeff Greenberg, Wendi Malley, Daniela Graham, Lara Fallon, John Woolcott, and Huifeng Yun
- Subjects
Adult ,Male ,rheumatoid arthritis ,medicine.medical_specialty ,Immunology ,030204 cardiovascular system & hematology ,General Biochemistry, Genetics and Molecular Biology ,Arthritis, Rheumatoid ,03 medical and health sciences ,Psoriatic arthritis ,0302 clinical medicine ,Rheumatology ,Piperidines ,Rheumatic Diseases ,Thromboembolism ,Internal medicine ,Psoriasis ,medicine ,Immunology and Allergy ,Humans ,Pyrroles ,Risk factor ,Protein Kinase Inhibitors ,Aged ,Janus kinase inhibitor ,030203 arthritis & rheumatology ,psoriatic arthritis ,Clinical Trials as Topic ,Tofacitinib ,business.industry ,Incidence (epidemiology) ,Incidence ,Arthritis, Psoriatic ,Middle Aged ,medicine.disease ,Ulcerative colitis ,Treatment ,Observational Studies as Topic ,Pyrimidines ,Antirheumatic Agents ,Rheumatoid arthritis ,Female ,business ,DMARDs (synthetic) ,Pulmonary Embolism - Abstract
ObjectivesTofacitinib is a Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ulcerative colitis, and has been investigated in psoriasis (PsO). Routine pharmacovigilance of an ongoing, open-label, blinded-endpoint, tofacitinib RA trial (Study A3921133; NCT02092467) in patients aged ≥50 years and with ≥1 cardiovascular risk factor identified a higher frequency of pulmonary embolism (PE) and all-cause mortality for patients receiving tofacitinib 10 mg twice daily versus those receiving tumour necrosis factor inhibitors and resulted in identification of a safety signal for tofacitinib. Here, we report the incidence of deep vein thrombosis (DVT), PE, venous thromboembolism (VTE; DVT or PE) and arterial thromboembolism (ATE) from the tofacitinib RA (excluding Study A3921133), PsA and PsO development programmes and observational studies. Data from an ad hoc safety analysis of Study A3921133 are reported separately within.MethodsThis post-hoc analysis used data from separate tofacitinib RA, PsO and PsA programmes. Incidence rates (IRs; patients with events per 100 patient-years’ exposure) were calculated for DVT, PE, VTE and ATE, including for populations stratified by defined baseline cardiovascular or VTE risk factors. Observational data from the US Corrona registries (including cardiovascular risk factor stratification), IBM MarketScan research database and the US FDA Adverse Event Reporting System (FAERS) database were analysed.Results12 410 tofacitinib-treated patients from the development programmes (RA: n=7964; PsO: n=3663; PsA: n=783) were included. IRs (95% CI) of thromboembolic events among the all tofacitinib cohorts’ average tofacitinib 5 mg and 10 mg twice daily treated patients for RA, respectively, were: DVT (0.17 (0.09–0.27) and 0.15 (0.09–0.22)); PE (0.12 (0.06–0.22) and 0.13 (0.08–0.21)); ATE (0.32 (0.22–0.46) and 0.38 (0.28–0.49)). Among PsO patients, IRs were: DVT (0.06 (0.00–0.36) and 0.06 (0.02–0.15)); PE (0.13 (0.02–0.47) and 0.09 (0.04–0.19)); ATE (0.52 (0.22–1.02) and 0.22 (0.13–0.35)). Among PsA patients, IRs were: DVT (0.00 (0.00–0.28) and 0.13 (0.00–0.70)); PE (0.08 (0.00–0.43) and 0.00 (0.00–0.46)); ATE (0.31 (0.08–0.79) and 0.38 (0.08–1.11)). IRs were similar between tofacitinib doses and generally higher in patients with baseline cardiovascular or VTE risk factors. IRs from the overall Corrona populations and in Corrona RA patients (including tofacitinib-naïve/biologic disease-modifying antirheumatic drug-treated and tofacitinib-treated) with baseline cardiovascular risk factors were similar to IRs observed among the corresponding patients in the tofacitinib development programme. No signals of disproportionate reporting of DVT, PE or ATE with tofacitinib were identified in the FAERS database.ConclusionsDVT, PE and ATE IRs in the tofacitinib RA, PsO and PsA programmes were similar across tofacitinib doses, and generally consistent with observational data and published IRs of other treatments. As expected, IRs of thromboembolic events were elevated in patients with versus without baseline cardiovascular or VTE risk factors, and were broadly consistent with those observed in the Study A3921133 ad hoc safety analysis data, although the IR (95% CI) for PE was greater in patients treated with tofacitinib 10 mg twice daily in Study A3921133 (0.54 (0.32–0.87)), versus patients with baseline cardiovascular risk factors treated with tofacitinib 10 mg twice daily in the RA programme (0.24 (0.13–0.41)).
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- 2020
21. Early Quantification of Systemic Inflammatory Proteins Predicts Long-Term Treatment Response to Tofacitinib and Etanercept
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Julie Lee, Lewis Tomalin, Hernan Valdez, James G. Krueger, Mayte Suárez-Fariñas, Gabriel Berstein, Robert Wolk, Jae Hwan Kim, Lori Fitz, and Joel Correa da Rosa
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Adult ,Male ,0301 basic medicine ,Oncology ,medicine.medical_specialty ,Time Factors ,Anti-Inflammatory Agents ,Dermatology ,Disease ,Biochemistry ,Biomarkers, Pharmacological ,Etanercept ,Cohort Studies ,Machine Learning ,Placebos ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Double-Blind Method ,Piperidines ,Predictive Value of Tests ,Internal medicine ,Psoriasis ,medicine ,Clinical endpoint ,Humans ,Computer Simulation ,Molecular Biology ,Aged ,Tofacitinib ,Receiver operating characteristic ,business.industry ,Interleukin-17 ,Cell Biology ,Middle Aged ,Prognosis ,medicine.disease ,Blood proteins ,Pyrimidines ,Treatment Outcome ,030104 developmental biology ,030220 oncology & carcinogenesis ,Female ,Tumor necrosis factor alpha ,Inflammation Mediators ,business ,medicine.drug - Abstract
The application of machine learning to longitudinal gene-expression profiles has demonstrated potential to decrease the assessment gap, between biochemical determination and clinical manifestation, of a patient’s response to treatment. Although psoriasis is a proven testing ground for treatment-response prediction using transcriptomic data from clinically accessible skin biopsies, these biopsies are expensive, invasive, and challenging to obtain from certain body areas. Response prediction from blood biochemical measurements could be a cheaper, less invasive predictive platform. Longitudinal profiles for 92 inflammatory and 65 cardiovascular disease proteins were measured from the blood of psoriasis patients at baseline, and 4-weeks, following tofacitinib (janus kinase-signal transducer and activator of transcription-inhibitor) or etanercept (tumor necrosis factor-inhibitor) treatment, and predictive models were developed by applying machine-learning techniques such as bagging and ensembles. This data driven approach developed predictive models able to accurately predict the 12-week clinical endpoint for psoriasis following tofacitinib (area under the receiver operating characteristic curve [auROC] = 78%), or etanercept (auROC = 71%) treatment in a validation dataset, revealing a robust predictive protein signature including well-established psoriasis markers such as IL-17A and IL-17C, highlighting potential for biologically meaningful and clinically useful response predictions using blood protein data. Although most blood classifiers were outperformed by simple models trained using Psoriasis Area Severity Index scores, performance might be enhanced in future studies by measuring a wider variety of proteins.
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- 2020
22. Rapidity of Improvement in Signs/Symptoms of Moderate-to-Severe Atopic Dermatitis by Body Region with Abrocitinib in the Phase 3 JADE COMPARE Study
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Andrew Alexis, Marjolein de Bruin-Weller, Stephan Weidinger, Weily Soong, Sebastien Barbarot, Ileana Ionita, Fan Zhang, Hernan Valdez, Claire Clibborn, and Natalie Yin
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Dermatology - Abstract
Atopic dermatitis (AD) can affect multiple body regions and is especially burdensome when involving exposed skin areas. Rapid, effective treatment of AD across body regions remains an unmet need, particularly for difficult-to-treat areas such as the head and neck area. We investigated the temporal and regional patterns of clinical improvement in AD with the use of abrocitinib, an orally available Janus kinase 1 selective inhibitor under development for the treatment of moderate-to-severe AD.We performed a post hoc analysis of data from JADE COMPARE, a phase 3, multicenter, randomized, double-blind, double-dummy trial that evaluated the efficacy and safety of abrocitinib 200 mg once daily, abrocitinib 100 mg once daily, dupilumab 300 mg subcutaneous injection every 2 weeks, and placebo in adult patients with moderate-to-severe AD who were concomitantly receiving medicated topical therapy. Assessments included the Eczema Area and Severity Index (EASI) and SCORing Atopic Dermatitis (SCORAD) index.With abrocitinib 200 mg, time to ≥ 75% improvement in EASI (EASI-75) occurred at a median of 29 days across body regions, including the head and neck region. With abrocitinib 100 mg, EASI-75 response was achieved at a median of 30-32 days for the trunk and lower limbs, and at 56-57 days for the head and neck region and upper limbs. With dupilumab, EASI-75 response was achieved at a median of 43 days for the trunk and 57 days for other regions. EASI body region scores significantly improved with abrocitinib 200 mg and 100 mg versus placebo at week 2 (p 0.0001 for all comparisons). Improvements with abrocitinib were maintained up to week 16.Rapid and persistent improvement in AD across all body regions was observed with abrocitinib treatment. Abrocitinib may be useful in patients with AD that affects difficult-to-treat anatomical areas or who require a rapid response.Clinicaltrials.gov identifier: NCT03720470.Atopic dermatitis (AD) is the most common form of eczema. It is a long-lasting skin disease that often affects multiple body regions. AD may decrease a person’s quality of life, especially when it involves skin areas that are visible to others. Quick, effective treatment for AD across multiple body regions is needed, especially in areas that are difficult to treat and/or cosmetically important, such as the head and neck area. Abrocitinib is a medicine taken orally that is being developed to treat moderate-to-severe AD. Researchers analyzed data from a clinical study called JADE COMPARE (Clinicaltrials.gov identifier: NCT03720470). It evaluated the effectiveness and safety of abrocitinib 200 mg taken once daily, abrocitinib 100 mg taken once daily, and placebo (no study medication) plus medicated skin cream in adults with moderate-to-severe AD. Abrocitinib 200 mg and 100 mg significantly improved the extent and severity of AD as assessed by a measure called the Eczema Area and Severity Index (EASI) compared to placebo at week 2. Improvements were maintained for up to 16 weeks. With abrocitinib 200 mg, the time to ≥ 75% improvement in EASI (EASI-75) was approximately 29 days across body regions, including the head and neck region. With abrocitinib 100 mg, this EASI-75 response occurred at approximately 30 to 32 days for the trunk and legs and at 56 to 57 days for the head and neck region and arms. Abrocitinib may be effective in people with AD that affects difficult-to-treat parts of the body or in those who need a fast response.
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- 2021
23. Comparing abrocitinib and dupilumab in the treatment of atopic dermatitis: a plain language summary
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Eric L. Simpson, Carle Paul, Jeremias Antinew, Hernan Valdez, Ricardo Rojo, Bimal Malhotra, Thomas Bieber, Jacek Zdybski, Jonathan I. Silverberg, Andrew Pink, Marco DiBonaventura, Pinaki Biswas, Chia-Yu Chu, Seth Forman, Ileana A. Ionita, Rodney Sinclair, Diamant Thaçi, Yoko Kataoka, and Fan Zhang
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Adult ,medicine.medical_specialty ,Immunology ,Signs and symptoms ,Disease ,Placebo ,Antibodies, Monoclonal, Humanized ,Severity of Illness Index ,Dermatitis, Atopic ,Clinical study ,Double-Blind Method ,Immunology and Allergy ,Medicine ,Humans ,Language ,Sulfonamides ,business.industry ,Atopic dermatitis ,medicine.disease ,Dupilumab ,Dermatology ,Pyrimidines ,Treatment Outcome ,Oncology ,business ,Healthcare providers - Abstract
Atopic dermatitis (AD, also called atopic eczema) is a long-term skin disease that causes intensely itchy, red skin. Healthcare providers can prescribe medicated creams and ointments to reduce the signs and symptoms of AD. However, these treatments are not always enough to provide relief. A new medicine called abrocitinib, which is taken every day as a tablet, reduces part of the body’s immune response that happens in AD. The clinical study described in this plain language summary, called JADE COMPARE, investigated how well and how safely 16 weeks of treatment with abrocitinib worked in adults with AD compared to placebo (‘dummy treatment’) and a medicine that is already approved for AD, called dupilumab. The study showed that abrocitinib was better than placebo in improving the signs and symptoms of AD after 16 weeks. In addition, patients who were taking abrocitinib 200 mg for 2 weeks experienced greater relief from itch than patients who were taking abrocitinib 100 mg, placebo, or dupilumab. More people who took abrocitinib 200 mg reported side effects than those taking abrocitinib 100 mg, placebo, or dupilumab, but most of these side effects were mild or moderate. ClinicalTrials.gov NCT number: NCT03720470 .
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- 2021
24. Magnitude and Time Course of Response to Abrocitinib for Moderate-to-Severe Atopic Dermatitis
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Kristian Reich, Peter A. Lio, Robert Bissonnette, Andrew F. Alexis, Mark G. Lebwohl, Andrew E. Pink, Kenji Kabashima, Mark Boguniewicz, Roman J. Nowicki, Hernan Valdez, Fan Zhang, Marco DiBonaventura, Michael C. Cameron, and Claire Clibborn
- Subjects
Immunology and Allergy - Abstract
Emerging treatments for moderate-to-severe atopic dermatitis (AD) may provide greater and faster improvement in AD signs and symptoms than current therapies.To examine JADE COMPARE (NCT03720470) data using stringent efficacy end points.Adults with moderate-to-severe AD were randomly assigned 2:2:2:1 to receive oral abrocitinib 200 or 100 mg once daily, subcutaneous dupilumab 300 mg every 2 weeks (600-mg loading dose), or placebo, with medicated topical therapy for 16 weeks. Stringent response thresholds were applied for Eczema Area and Severity Index (EASI), Investigator's Global Assessment, Dermatology Life Quality Index, Peak Pruritus Numerical Rating Scale, and Night Time Itch Scale severity.At week 16, 48.9%, 38.0%, and 38.8% of the abrocitinib 200-mg, 100-mg, and dupilumab groups, respectively, achieved greater than or equal to 90% improvement from baseline in EASI versus 11.3% placebo; 14.9%, 12.6%, and 6.5% achieved Investigator's Global Assessment 0 (clear) versus 4.8% placebo; 29.7%, 21.6%, and 24.0% achieved Dermatology Life Quality Index 0/1 (no/minimal impact on quality of life) versus 10.6% placebo; and 57.1%, 44.5%, and 46.1% achieved Night Time Itch Scale severity 0/1 (no/minimal night-time itch) versus 31.9% placebo. Kaplan-Meier median time to greater than or equal to 90% improvement from baseline in EASI was 59, 113, and 114 days in the abrocitinib 200-mg, 100-mg, and dupilumab groups, respectively, and was not evaluable for placebo; median time to Peak Pruritus Numerical Rating Scale 0/1 (no/very minimal itch) was 86 and 116 days for abrocitinib 200-mg and dupilumab groups, respectively, and was not evaluable for abrocitinib 100-mg and placebo groups.A greater proportion of patients treated with abrocitinib than placebo had almost complete control of AD signs and symptoms.
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- 2022
25. Integrated Safety Analysis of Abrocitinib for the Treatment of Moderate-to-Severe Atopic Dermatitis From the Phase II and Phase III Clinical Trial Program
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Kevin L. Winthrop, Eric L. Simpson, Emma Guttman-Yassky, Ricardo Rojo, Jonathan I. Silverberg, Andrew John Thorpe, Hernan Valdez, Susan Johnson, William Romero, Min Zhang, Alexander Egeberg, Audrey Nosbaum, Saleem A. Farooqui, and Karin M. Hoffmeister
- Subjects
Adult ,Male ,medicine.medical_specialty ,Skin Neoplasms ,Time Factors ,Adolescent ,Nausea ,Dermatology ,Placebo ,Infections ,Sudden death ,Gastroenterology ,Herpes Zoster ,Dermatitis, Atopic ,Young Adult ,Risk Factors ,Internal medicine ,Acne Vulgaris ,Medicine ,Humans ,Original Research Article ,Lymphocyte Count ,Adverse effect ,Protein Kinase Inhibitors ,Aged ,Sulfonamides ,business.industry ,Platelet Count ,Incidence ,Cholesterol, HDL ,Headache ,Correction ,Herpes Simplex ,General Medicine ,Atopic dermatitis ,Cholesterol, LDL ,Venous Thromboembolism ,Middle Aged ,medicine.disease ,Clinical trial ,Pyrimidines ,Tolerability ,Cardiovascular Diseases ,Cohort ,Female ,medicine.symptom ,business - Abstract
Background Pivotal phase III studies demonstrated that abrocitinib, an oral, once-daily, JAK1-selective inhibitor, is effective treatment for moderate-to-severe atopic dermatitis (AD) as monotherapy and in combination with topical therapy. Objective The aim of this study was to evaluate the long-term safety of abrocitinib 200 mg and 100 mg in an integrated analysis of a phase IIb study, four phase III studies, and one long-term extension study. Methods Two cohorts were analyzed: a placebo-controlled cohort from 12- to 16-week studies and an all-abrocitinib cohort including patients who received one or more abrocitinib doses. Adverse events (AEs) of interest and laboratory data are reported. Results Total exposure in the all-abrocitinib cohort (n = 2856) was 1614 patient-years (PY); exposure was ≥ 24 weeks in 1248 patients and ≥ 48 weeks in 606 (maximum 108 weeks). In the placebo-controlled cohort (n = 1540), dose-related AEs (200 mg, 100 mg, placebo) were nausea (14.6%, 6.1%, 2.0%), headache (7.8%, 5.9%, 3.5%), and acne (4.7%, 1.6%, 0%). Platelet count was reduced transiently in a dose-dependent manner; 2/2718 patients (200-mg group) had confirmed platelet counts of < 50 × 103/mm3 at week 4. Incidence rates (IRs) were 2.33/100PY and 2.65/100 PY for serious infection, 4.34/100PY and 2.04/100PY for herpes zoster, and 11.83/100PY and 8.73/100PY for herpes simplex in the 200-mg and 100-mg groups, respectively. IRs for nonmelanoma skin cancer, other malignancies, and major adverse cardiovascular events were < 0.5/100PY for both doses. Five venous thromboembolism events occurred (IR 0.30/100PY), all in the 200-mg group. There were three deaths due to gastric carcinoma (diagnosed at day 43), sudden death, and COVID-19. Conclusion Abrocitinib, with proper patient and dose selection, has a manageable tolerability and longer-term safety profile appropriate for long-term use in patients with moderate-to-severe AD. Trial Registries ClinicalTrials.gov: NCT02780167, NCT03349060, NCT03575871, NCT03720470, NCT03627767, NCT03422822. Supplementary Information The online version contains supplementary material available at 10.1007/s40257-021-00618-3.
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- 2021
26. Long-term effectiveness of live herpes zoster vaccine in patients with rheumatoid arthritis subsequently treated with tofacitinib
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Connie Chen, Lisy Wang, Ernest Choy, Koshika Soma, Pinaki Biswas, Ann Wouters, Hernan Valdez, William F. C. Rigby, Elie Needle, and Kevin L. Winthrop
- Subjects
0301 basic medicine ,rheumatoid arthritis ,Male ,Letter ,Time Factors ,medicine.disease_cause ,Severity of Illness Index ,Arthritis, Rheumatoid ,0302 clinical medicine ,Piperidines ,Immunology and Allergy ,Herpes Zoster Vaccine ,Janus kinase inhibitor ,education.field_of_study ,treatment ,Middle Aged ,Combined Modality Therapy ,Treatment Outcome ,Rheumatoid arthritis ,Zoster vaccine ,Female ,medicine.drug ,medicine.medical_specialty ,Vaccines, Live, Unattenuated ,Immunology ,Population ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,Rheumatology ,Internal medicine ,medicine ,Humans ,Pyrroles ,education ,Protein Kinase Inhibitors ,Aged ,030203 arthritis & rheumatology ,Tofacitinib ,business.industry ,Varicella zoster virus ,medicine.disease ,vaccination ,030104 developmental biology ,Pyrimidines ,business ,Follow-Up Studies - Abstract
Herpes zoster (HZ) incidence is higher in patients with rheumatoid arthritis (RA) compared with the general population,1 and it may be further increased with disease-modifying antirheumatic drugs (DMARDs).2 Tofacitinib is an oral Janus kinase inhibitor for the treatment of RA. Real-world data indicate that HZ incidence is approximately twofold higher with tofacitinib versus biologic DMARDs (bDMARDs).3 Current American College of Rheumatology guidelines conditionally recommend that patients with RA aged ≥50 years receive HZ vaccine prior to tofacitinib or bDMARDs.4 We previously evaluated the immunogenicity of a live attenuated zoster vaccine (LZV), administered 2–3 weeks prior to tofacitinib or placebo with background conventional synthetic DMARDs. Both groups had similar varicella zoster virus (VZV)-specific immune responses, and overall immune responses were comparable with those of healthy volunteers in previous studies.5 We have now followed this patient cohort in an open-label, long-term extension (LTE) study of tofacitinib. Patients enrolled in the index study (A3921237; NCT02147587)5 could join ORAL Sequel (LTE study; A3921024; NCT00413699) 14 weeks post-vaccination, where they received open-label tofacitinib 5 or 10 mg two times per day (online supplementary figure S1); background RA therapy was also allowed. Patients were followed for 27 months. Post-vaccination, adverse events (AEs), including discontinuations due to AEs, were recorded during the study within 28 days of …
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- 2020
27. Impact de l’abrocitinib sur la réponse vaccinale chez les adolescents présentant une dermatite atopique modérée à sévère recevant les vaccins courants contre la diphtérie, la coqueluche et le tétanos dans l’étude de phase III JADE TEEN
- Author
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Michael J. Cork, Gary L. Chan, Carsten Flohr, Lawrence F. Eichenfield, Claire Feeney, Fan Zhang, Ricardo Rojo, Hernan Valdez, Sébastien Barbarot, and Christine Bangert
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Ocean Engineering ,Safety, Risk, Reliability and Quality - Abstract
Introduction L’abrocitinib, un inhibiteur de JAK-1 par voie orale, ameliore de maniere significative les signes et symptomes de la dermatite atopique chez les adolescents et les adultes presentant une DA moderee a severe. L’impact de l’abrocitinib sur l’immunogenicite des vaccins courants chez les adolescents n’est pas connu. Cette etude a evalue son effet sur l’induction de reponses immunitaires au vaccin de rappel diphterie, coqueluche acellulaire et tetanos (DCaT) chez les adolescents de l’essai JADE TEEN. Materiel et methodes Les adolescents âges de 12–17 ans presentant une DA moderee a severe ont ete randomises (1/1/1) pour recevoir 200 mg ou 100 mg d’abrocitinib ou un placebo par voie orale une fois par jour pendant 12 semaines avec un traitement topique; un groupe de patients (n = 25) a recu le vaccin DCaT a la semaine S8. La proportion de patients ayant obtenu une augmentation ≥ 4 fois des concentrations d’IgG dirigees contre les antigenes vaccinaux entre l’inclusion (S8) et 4 semaines apres (S12), consideree comme une reponse satisfaisante, a ete evaluee pour chaque bras de traitement. Resultats Six patients recevant l’abrocitinib 200 mg, 9 l’abrocitinib 100 mg et 10 le placebo ont recu un vaccin DCaT (calendrier vaccinal). Des echantillons seriques etaient disponibles avant la vaccination pour respectivement 5, 8 et 10 patients et a S4 apres la vaccination pour respectivement 4, 8 et 10 patients. Une augmentation ≥ 4 fois des taux d’anticorps anti-toxine tetanique a ete obtenue chez 100 % (4/4), 75 % (6/8) et 50 % (5/10) des patients des groupes respectivement abrocitinib 200 mg, 100 mg et placebo ; des taux d’anticorps anti-toxine diphterique chez 100 % (4/4), 62,5 % (5/8) et 80 % (8/10) des patients ; et des taux d’anticorps diriges contre les antigenes coquelucheux acellulaires chez 100 % (4/4), 75 % (6/8) et 70 % (7/10) des patients pour la toxine pertussique ; chez 100 % (4/4), 62,5 % (5/8) et 70 % (7/10) des patients pour l’hemagglutinine filamenteuse ; chez 0 % (0/4), 0 % (0/8) et 10 % (1/10) des patients pour les fimbriae types 2/3 ; et chez 100 % (4/4), 87,5 % (7/8) et 80 % (8/10) des patients pour la pertactine. Parmi les patients vaccines avec le DCaT, des evenements indesirables (EI) apparus sous traitement ayant debute a la S8 ou apres (date de la vaccination avec le DCaT) ont ete rapportes chez 16,7 % (1/6), 33,3 % (3/9) et 10,0 % (1/10) des patients des groupes respectivement abrocitinib 200 mg, 100 mg et placebo ; aucun de ces EI n’etait severe, grave ou n’a entraine l’arret du traitement. Discussion Il n’y a pas eu de differences notables dans les reponses immunitaires au vaccin DCaT chez les adolescents recevant l’abrocitinib vs placebo. Malgre la taille limitee de l’echantillon, les resultats suggerent des reponses adequates au vaccin DCaT.
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- 2021
28. Abrocitinib versus Placebo or Dupilumab for Atopic Dermatitis
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Thomas, Bieber, Eric L, Simpson, Jonathan I, Silverberg, Diamant, Thaçi, Carle, Paul, Andrew E, Pink, Yoko, Kataoka, Chia-Yu, Chu, Marco, DiBonaventura, Ricardo, Rojo, Jeremias, Antinew, Ileana, Ionita, Rodney, Sinclair, Seth, Forman, Jacek, Zdybski, Pinaki, Biswas, Bimal, Malhotra, Fan, Zhang, Hernan, Valdez, and J'Cinda, Bitters
- Subjects
Adult ,Male ,medicine.medical_specialty ,Injections, Subcutaneous ,Administration, Oral ,030204 cardiovascular system & hematology ,Placebo ,Antibodies, Monoclonal, Humanized ,Severity of Illness Index ,law.invention ,Dermatitis, Atopic ,Placebos ,03 medical and health sciences ,0302 clinical medicine ,Randomized controlled trial ,Double-Blind Method ,law ,Severity of illness ,medicine ,Humans ,030212 general & internal medicine ,Protein Kinase Inhibitors ,Sulfonamides ,Janus kinase 1 ,Dose-Response Relationship, Drug ,business.industry ,Pruritus ,Interleukin-4 Receptor alpha Subunit ,General Medicine ,Atopic dermatitis ,Janus Kinase 1 ,medicine.disease ,Dermatology ,Dupilumab ,Immunoglobulin A ,body regions ,Clinical trial ,Pyrimidines ,Monoclonal ,Female ,business - Abstract
The oral Janus kinase 1 (JAK1) inhibitor abrocitinib, which reduces interleukin-4 and interleukin-13 signaling, is being investigated for the treatment of atopic dermatitis. Data from trials comparing JAK1 inhibitors with monoclonal antibodies, such as dupilumab, that block interleukin-4 receptors are limited.In a phase 3, double-blind trial, we randomly assigned patients with atopic dermatitis that was unresponsive to topical agents or that warranted systemic therapy (in a 2:2:2:1 ratio) to receive 200 mg or 100 mg of abrocitinib orally once daily, 300 mg of dupilumab subcutaneously every other week (after a loading dose of 600 mg), or placebo; all the patients received topical therapy. The primary end points were an Investigator's Global Assessment (IGA) response (defined as a score of 0 [clear] or 1 [almost clear] on the IGA [scores range from 0 to 4], with an improvement of ≥2 points from baseline) and an Eczema Area and Severity Index-75 (EASI-75) response (defined as ≥75% improvement from baseline in the score on the EASI [scores range from 0 to 72]) at week 12. The key secondary end points were itch response (defined as an improvement of ≥4 points in the score on the Peak Pruritus Numerical Rating Scale [scores range from 0 to 10]) at week 2 and IGA and EASI-75 responses at week 16.A total of 838 patients underwent randomization; 226 patients were assigned to the 200-mg abrocitinib group, 238 to the 100-mg abrocitinib group, 243 to the dupilumab group, and 131 to the placebo group. An IGA response at week 12 was observed in 48.4% of patients in the 200-mg abrocitinib group, 36.6% in the 100-mg abrocitinib group, 36.5% in the dupilumab group, and 14.0% in the placebo group (P0.001 for both abrocitinib doses vs. placebo); an EASI-75 response at week 12 was observed in 70.3%, 58.7%, 58.1%, and 27.1%, respectively (P0.001 for both abrocitinib doses vs. placebo). The 200-mg dose, but not the 100-mg dose, of abrocitinib was superior to dupilumab with respect to itch response at week 2. Neither abrocitinib dose differed significantly from dupilumab with respect to most other key secondary end-point comparisons at week 16. Nausea occurred in 11.1% of the patients in the 200-mg abrocitinib group and 4.2% of those in the 100-mg abrocitinib group, and acne occurred in 6.6% and 2.9%, respectively.In this trial, abrocitinib at a dose of either 200 mg or 100 mg once daily resulted in significantly greater reductions in signs and symptoms of moderate-to-severe atopic dermatitis than placebo at weeks 12 and 16. The 200-mg dose, but not the 100-mg dose, of abrocitinib was superior to dupilumab with respect to itch response at week 2. Neither abrocitinib dose differed significantly from dupilumab with respect to most other key secondary end-point comparisons at week 16. (Funded by Pfizer; JADE COMPARE ClinicalTrials.gov number, NCT03720470.).
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- 2021
29. Correction to: Impact of Oral Abrocitinib Monotherapy on Patient-Reported Symptoms and Quality of Life in Adolescents and Adults with Moderate-to-Severe Atopic Dermatitis: A Pooled Analysis of Patient-Reported Outcomes
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Pinaki Biswas, Gil Yosipovitch, Eric L. Simpson, Jonathan I. Silverberg, Ricardo Rojo, Jacob P. Thyssen, Daniela E. Myers, Sonja Ständer, Claire Feeney, Marco DiBonaventura, and Hernan Valdez
- Subjects
Moderate to severe ,Adult ,Male ,medicine.medical_specialty ,Adolescent ,Administration, Oral ,Dermatology ,Efficiency ,Anxiety ,Severity of Illness Index ,Dermatitis, Atopic ,Young Adult ,Quality of life (healthcare) ,medicine ,Humans ,Janus Kinase Inhibitors ,Patient Reported Outcome Measures ,Fatigue ,Aged ,Sulfonamides ,business.industry ,Depression ,Pruritus ,Correction ,General Medicine ,Atopic dermatitis ,Middle Aged ,medicine.disease ,Pooled analysis ,Pyrimidines ,Treatment Outcome ,Quality of Life ,Female ,business - Abstract
Atopic dermatitis imparts a substantial patient burden, including itch, sleep disturbance, and decreased health-related quality of life.This analysis evaluated changes in patient-reported outcomes of disease-specific signs/symptoms and health-related quality of life in adult and adolescent patients with moderate-to-severe atopic dermatitis treated with once-daily oral abrocitinib 200-mg or 100-mg monotherapy.Pooled data from one phase IIb (NCT02780167) and two phase III (NCT03349060, JADE MONO-1; NCT03575871, JADE MONO-2) monotherapy trials in adult and adolescent patients with moderate-to-severe atopic dermatitis were analyzed. Patient-reported outcome assessments included: global severity, itch, and multi-item measures that assess other signs and symptoms of atopic dermatitis. Additional patient-reported outcome assessments measured depression, anxiety, fatigue, disease-specific and general health-related quality of life, and work and general productivity among employed patients.Overall, 942 patients were included in this analysis. Improvements were observed from the first post-baseline assessment to week 12 across all patient-reported outcomes, including Patient Global Assessment (PtGA) score of 0/1 (35.5%, 19.8%, and 5.9% for 200 mg, 100 mg, and placebo, respectively), ≥ 4-point improvement in Night Time Itch Scale (NTIS; 57.0%, 42.7%, and 12.7%), change from baseline in Patient-Oriented Eczema Measure (POEM) score (- 11.4, - 8.2, and - 3.4), 1-point improvement in Pruritus and Symptoms Assessment for Atopic Dermatitis (PSAAD; 75.2%, 65.1%, and 33.5%), Hospital Anxiety and Depression Scales (HADS) anxiety (- 2.0, - 1.7, and - 1.0) and depression (- 1.7, - 1.3, and - 0.1).Abrocitinib monotherapy improved disease-specific signs/symptoms and health-related quality of life across multiple domains as reported by adult and adolescent patients with moderate-to-severe atopic dermatitis, complementing clinician-reported efficacy and safety outcomes.NCT02780167 (registered 23 May, 2016), NCT03349060 (registered 21 November, 2017), NCT03575871 (registered 3 July, 2018).
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- 2021
30. Host-Directed and Immune-Based Therapies for Human Immunodeficiency Virus Infection
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Hernan Valdez, Michael M. Lederman, Bharat Ramratnam, and Timothy P. Flanigan
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- 2020
31. Correction to: Population Pharmacokinetics of Abrocitinib in Healthy Individuals and Patients with Psoriasis or Atopic Dermatitis
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Jessica Wojciechowski, Bimal K. Malhotra, Xiaoxing Wang, Luke Fostvedt, Hernan Valdez, and Timothy Nicholas
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Pharmacology ,Pharmacology (medical) - Published
- 2022
32. Efficacy and safety of abrocitinib in adults and adolescents with moderate-to-severe atopic dermatitis (JADE MONO-1): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial
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Svitlana Tatulych, Thomas Bieber, Claire Feeney, Catherine Maari, Rodney Sinclair, Andreas Wollenberg, Michael J. Cork, Pinaki Biswas, Eric L. Simpson, Roland Aschoff, Carsten Flohr, Seth Forman, Hernan Valdez, Ricardo Rojo, Jacob P. Thyssen, Nina Magnolo, and Gil Yosipovitch
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Adult ,Male ,Canada ,medicine.medical_specialty ,Adolescent ,Eczema ,Administration, Oral ,030204 cardiovascular system & hematology ,Placebo ,Severity of Illness Index ,Eczema Area and Severity Index ,Dermatitis, Atopic ,law.invention ,Placebos ,03 medical and health sciences ,0302 clinical medicine ,Double-Blind Method ,Randomized controlled trial ,law ,Internal medicine ,Severity of illness ,Ethnicity ,medicine ,Humans ,030212 general & internal medicine ,Child ,Protein Kinase Inhibitors ,Aged ,Asthma ,Body surface area ,Sulfonamides ,business.industry ,Australia ,Janus Kinase 1 ,General Medicine ,Atopic dermatitis ,Middle Aged ,medicine.disease ,United States ,Europe ,Clinical trial ,Pyrimidines ,Treatment Outcome ,Case-Control Studies ,Female ,Safety ,business - Abstract
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
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- 2020
33. Modified- versus immediate-release tofacitinib in Japanese rheumatoid arthritis patients: a randomized, phase III, non-inferiority study
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Connie Chen, Richard Zhang, Thomas C. Stock, Chenhui Deng, Hernan Valdez, Shigeyuki Toyoizumi, Christopher F. Mojcik, Yoshiya Tanaka, Naonobu Sugiyama, Haiyun Fan, Tatjana Lukic, Manisha Lamba, and Hirotoshi Yuasa
- Subjects
Adult ,Male ,medicine.medical_specialty ,Arthritis ,Gastroenterology ,law.invention ,Arthritis, Rheumatoid ,03 medical and health sciences ,0302 clinical medicine ,Double-Blind Method ,Japan ,Piperidines ,Rheumatology ,Randomized controlled trial ,law ,Internal medicine ,Humans ,Janus Kinase Inhibitors ,Medicine ,Pyrroles ,Pharmacology (medical) ,030212 general & internal medicine ,Immediate release ,Adverse effect ,Janus kinase inhibitor ,030203 arthritis & rheumatology ,tofacitinib ,Tofacitinib ,non-inferiority ,business.industry ,Middle Aged ,Clinical Science ,medicine.disease ,once daily ,Clinical trial ,Pyrimidines ,Treatment Outcome ,Antirheumatic Agents ,Delayed-Action Preparations ,Rheumatoid arthritis ,twice daily ,Female ,business ,RA - Abstract
Objective Tofacitinib is an oral Janus kinase inhibitor for treatment of RA. We compared tofacitinib modified-release (MR) 11 mg once daily (QD) with tofacitinib immediate-release (IR) 5 mg twice daily (BID) in Japanese patients with RA and inadequate response to MTX. Methods Phase III, randomized, double-blind, double-dummy, 12-week study. Patients were randomized to tofacitinib MR 11 mg QD (n = 104) or IR 5 mg BID (n = 105), with stable MTX. Compliance was based on returned pill counts. The primary objective was to demonstrate non-inferiority of MR 11 mg QD to IR 5 mg BID. Non-inferiority was declared if the upper bound of the two-sided 95% CI for the difference in change from baseline in DAS28-4(CRP) at week 12 was
- Published
- 2018
34. Tofacitinib in patients with moderate-to-severe chronic plaque psoriasis: long-term safety and efficacy in an open-label extension study
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Anna M. Tallman, Tsen-Fang Tsai, N. Bakos, F. Valenzuela, Hernan Valdez, M.K. Harper, Huaming Tan, Annie Gardner, Robert Bissonnette, Neil J. Korman, and William C. Ports
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Adult ,Male ,medicine.medical_specialty ,Time Factors ,Drug-Related Side Effects and Adverse Reactions ,Administration, Oral ,Dermatology ,Severity of Illness Index ,Drug Administration Schedule ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,Piperidines ,Psoriasis Area and Severity Index ,Psoriasis ,Internal medicine ,Severity of illness ,medicine ,Humans ,Pyrroles ,030212 general & internal medicine ,Adverse effect ,Protein Kinase Inhibitors ,Janus kinase inhibitor ,Tofacitinib ,business.industry ,Extension study ,Janus Kinase 3 ,Middle Aged ,medicine.disease ,Clinical trial ,Pyrimidines ,Treatment Outcome ,Female ,business ,Follow-Up Studies - Abstract
Background Tofacitinib is an oral Janus kinase inhibitor. Final safety and efficacy data from an open-label extension study of tofacitinib in psoriasis are reported. Objectives To evaluate the long-term safety and durability of efficacy of tofacitinib in adults with moderate-to-severe chronic plaque psoriasis. Methods Eligible patients who completed qualifying phase II/III tofacitinib studies received tofacitinib 10 mg twice daily (q12h) until month 3; subsequently, the dose could be adjusted by investigators to either 5 or 10 mg q12h. Adverse events (AEs) are reported up to month 66 and laboratory data up to month 54. Efficacy end points up to month 54 included Physician's Global Assessment of 'clear' or 'almost clear' (PGA response) and 75% improvement in Psoriasis Area and Severity Index (PASI 75). Results Overall, 2867 patients received tofacitinib, with a median treatment duration of 35·6 months. Adverse events (AEs) and serious AEs were reported in 82·5% and 13·7% of patients, respectively; 13·9% of patients discontinued owing to AEs; and 29 patients died. Incidence rates (patients with event/100 patient-years) were 1·16 for serious infections, 0·67 for malignancies and 0·26 for major adverse cardiovascular events. After initial changes in qualifying studies, most laboratory parameters were generally stable over 54 months. PGA response was achieved by 52-62% of patients and PASI 75 by 56-74% of patients at each study visit through month 54. Conclusions In patients with psoriasis, the safety profile of tofacitinib over 66 months was similar to previous reports in phase III studies and efficacy was sustained through 54 months (NCT01163253).
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- 2018
35. Association between serum interleukin-17A and clinical response to tofacitinib and etanercept in moderate to severe psoriasis
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Catherine Soderstrom, Julie Lee, A. Quazi, C. A. Mebus, Lori Fitz, Stephanie Fraser, Robert Wolk, Weidong Zhang, Gabriel Berstein, and Hernan Valdez
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Male ,medicine.medical_specialty ,Dermatology ,Placebo ,Severity of Illness Index ,Gastroenterology ,Etanercept ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,Double-Blind Method ,Piperidines ,Psoriasis Area and Severity Index ,Psoriasis ,Internal medicine ,Severity of illness ,medicine ,Humans ,Pyrroles ,Protein Kinase Inhibitors ,Janus kinase inhibitor ,030203 arthritis & rheumatology ,Tofacitinib ,Tumor Necrosis Factor-alpha ,business.industry ,Interleukin-17 ,Remission Induction ,medicine.disease ,Pyrimidines ,Linear Models ,Female ,Interleukin 17 ,business ,Immunosuppressive Agents ,medicine.drug - Abstract
Background Psoriasis is a systemic inflammatory disease with a pathophysiology involving interleukin (IL)-17. Tofacitinib is an oral Janus kinase inhibitor. Etanercept is a tumour necrosis factor-α inhibitor used in the treatment of psoriasis. Neither agent inhibits IL-17 directly. Aim To evaluate correlations between circulating IL-17A and clinical efficacy in patients with psoriasis treated with tofacitinib or etanercept. Methods Serum concentrations of IL-17A homodimer and IL-17A/F heterodimer were determined by immunoassays at weeks 0, 4 and 12 in patients with moderate to severe psoriasis treated with placebo (n = 60), tofacitinib 5 mg twice daily (n = 184), tofacitinib 10 mg twice daily (n = 190), or etanercept 50 mg subcutaneously twice weekly (n = 190). Disease severity was assessed using the Psoriasis Area and Severity Index (PASI) and clinical response was defined as patients achieving ≥ 75% improvement from baseline PASI (PASI75). Results Serum levels of IL-17A homodimer at week 0 showed moderate correlation with PASI, with a Spearman correlation coefficient of 0.43. Furthermore, serum levels of IL-17A homodimer showed a clear correlation with clinical response, with a decrease of 57.1% in patients achieving PASI75 at week 12, but only 15.9% decrease in nonresponders. PASI75 responders had lower median concentrations of IL-17A (range across treatments: 0.24-0.27 pg/mL) at week 12 vs. nonresponders (0.37-0.62 pg/mL), regardless of the treatment. Serum IL-17A/F heterodimer showed similar decreases at week 12 in responders and nonresponders. Conclusions Baseline serum IL-17A correlates moderately with psoriasis severity. Reduction in circulating IL-17A is required for disease remission regardless of therapeutic agent.
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- 2018
36. Correction to: Integrated Safety Analysis of Abrocitinib for the Treatment of Moderate-to-Severe Atopic Dermatitis From the Phase II and Phase III Clinical Trial Program
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Eric L. Simpson, Karin M. Hoffmeister, Susan Johnson, Kevin L. Winthrop, Alexander Egeberg, Saleem A. Farooqui, Jonathan I. Silverberg, Ricardo Rojo, Hernan Valdez, Audrey Nosbaum, Andrew John Thorpe, Emma Guttman-Yassky, William Romero, and Min Zhang
- Subjects
Clinical trial ,Moderate to severe ,medicine.medical_specialty ,business.industry ,medicine ,Dermatology ,General Medicine ,Atopic dermatitis ,medicine.disease ,business - Published
- 2021
37. 077 Effect of Cytochrome P450 Inhibition and Induction and Organic Anion Transporter 3 Inhibition on the Pharmacokinetics of Abrocitinib Active Moiety in Healthy Individuals
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A. Wouters, M.E. Dowty, Hernan Valdez, Bimal Malhotra, Vu Le, C. Connell, S. Tatulych, and X. Wang
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Biochemistry ,Organic anion transporter 1 ,biology ,Pharmacokinetics ,Chemistry ,Healthy individuals ,biology.protein ,Moiety ,Cytochrome P450 ,Cell Biology ,Dermatology ,Molecular Biology - Published
- 2021
38. Efficacy and Safety of Abrocitinib in Combination With Topical Therapy in Adolescents With Moderate-to-Severe Atopic Dermatitis
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Gary Chan, Sébastien Barbarot, Marco DiBonaventura, Claire Feeney, Zsuzsanna Szalai, Carsten Flohr, Fan Zhang, Hernan Valdez, Lawrence F. Eichenfield, Zhirong Yao, Hidetoshi Takahashi, Elaine C. Siegfried, Robert Sidbury, Ricardo Rojo, and Ryszard Galus
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Male ,medicine.medical_specialty ,Adolescent ,Eczema ,Dermatology ,Placebo ,Severity of Illness Index ,Eczema Area and Severity Index ,Dermatitis, Atopic ,law.invention ,Double-Blind Method ,Randomized controlled trial ,law ,Interquartile range ,Internal medicine ,medicine ,Humans ,Child ,Adverse effect ,Sulfonamides ,business.industry ,Correction ,Atopic dermatitis ,medicine.disease ,Dupilumab ,Topical medication ,Pyrimidines ,Treatment Outcome ,Female ,business - Abstract
Dupilumab subcutaneous injection is approved for treating moderate-to-severe atopic dermatitis (AD) in adolescents, but there has been too little research on an efficacious systemic oral treatment with a favorable benefit-risk profile for adolescents with moderate-to-severe AD.To investigate the efficacy and safety of oral abrocitinib plus topical therapy in adolescents with moderate-to-severe AD.The phase 3, randomized, double-blind, placebo-controlled study JADE TEEN was conducted in countries of the Asia-Pacific region, Europe, and North America in patients aged 12 to 17 years with moderate-to-severe AD and an inadequate response to 4 consecutive weeks or longer of topical medication or a need for systemic therapy for AD. The study was conducted between February 18, 2019, and April 8, 2020. The data were analyzed after study completion.Patients were randomly assigned 1:1:1 to receive once-daily oral abrocitinib, 200 mg or 100 mg, or placebo for 12 weeks in combination with topical therapy.Coprimary end points were achievement of an Investigator's Global Assessment (IGA) response of clear (0) or almost clear (1) with improvement of 2 or more grades from baseline (IGA 0/1) and 75% or greater improvement from baseline in Eczema Area and Severity Index (EASI-75) response at week 12. Key secondary end points included 4-point or greater improvement in Peak Pruritus Numerical Rating Scale (PP-NRS4) at week 12. Adverse events (AEs) were monitored.This study included 285 adolescents with moderate-to-severe AD (145 boys [50.9%] and 140 girls [49.1%]), of whom 160 (56.1%) were White and 94 (33.0%) were Asian; the median age was 15 years (interquartile range 13-17 years). Substantially more patients treated with abrocitinib (200 mg or 100 mg) vs placebo achieved an IGA response of 0/1 (46.2%; 41.6% vs 24.5%; P .05 for both), EASI-75 (72.0%; 68.5% vs 41.5%; P .05 for both), and PP-NRS4 (55.4%; 52.6% vs 29.8%; P .01 for 200 mg vs placebo) at week 12. Adverse events were reported for 59 (62.8%), 54 (56.8%), and 50 (52.1%) patients in the 200 mg, 100 mg, and placebo groups, respectively; nausea was more common with abrocitinib, 200 mg (17 [18.1%]) and 100 mg (7 [7.4%]). Herpes-related AEs were infrequent; 1 (1.1%), 0, and 2 (2.1%) patients had serious AEs.This randomized clinical trial found that oral abrocitinib combined with topical therapy was significantly more effective than placebo with topical therapy in adolescents with moderate-to-severe AD, with an acceptable safety profile.ClinicalTrials.gov identifier: NCT03796676.
- Published
- 2021
39. Effects of maraviroc and efavirenz on markers of immune activation and inflammation and associations with CD4+ cell rises in HIV-infected patients.
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Nicholas Funderburg, Magdalena Kalinowska, James Eason, James Goodrich, Jayvant Heera, Howard Mayer, Natasa Rajicic, Hernan Valdez, and Michael M Lederman
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Medicine ,Science - Abstract
Maraviroc treatment for HIV-1 infected patients results in larger CD4(+) T cell rises than are attributable to its antiviral activity alone. We investigated whether this is due to modulation of T cell activation and inflammation.Thirty maraviroc-treated patients from the Maraviroc versus Efavirenz Regimens as Initial Therapy (MERIT) study were randomly selected from among those who had CCR5-tropic (R5) HIV on screening and achieved undetectable HIV RNA (2 µg/mL increased from 45% to 66% in the efavirenz arm, but remained constant in the maraviroc arm (P = 0.033). Decreases in CD38 expression on CD8(+) T cells were correlated with CD4(+) T cell rises for maraviroc treatment (r = -0.4, P = 0.048), but not for treatment with efavirenz.Maraviroc-treated patients had earlier, modest decreases in certain markers of immune activation and inflammation, although in this small study, many of the differences were not statistically significant. Levels of high-sensitivity C-reactive protein remained constant in the maraviroc arm and increased in the efavirenz arm. Decreases in immune activation correlated with increased CD4(+) T cell gains.ClinicalTrials.gov NCT00098293.
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- 2010
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40. Metabolic and immune activation effects of treatment interruption in chronic HIV-1 infection: implications for cardiovascular risk.
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Pablo Tebas, William Keith Henry, Roy Matining, Deborah Weng-Cherng, John Schmitz, Hernan Valdez, Nasreen Jahed, Laurie Myers, William G Powderly, and David Katzenstein
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Medicine ,Science - Abstract
Concern about costs and antiretroviral therapy (ART)-associated toxicities led to the consideration of CD4 driven strategies for the management of HIV. That approach was evaluated in the SMART trial that reported an unexpected increase of cardiovascular events after treatment interruption (TI). Our goal was to evaluate fasting metabolic changes associated with interruption of antiretroviral therapy and relate them to changes of immune activation markers and cardiovascular risk.ACTG 5102 enrolled 47 HIV-1-infected subjects on stable ART, with or=500 cells/microL. Subjects were randomly assigned to continue ART for 18 weeks with or without 3 cycles of interleukin-2 (IL-2) (cycle = 4.5 million IU sc BID x 5 days every 8 weeks). After 18 weeks ART was discontinued in all subjects until the CD4 cell count dropped below 350 cells/microL. Glucose and lipid parameters were evaluated every 8 weeks initially and at weeks 2, 4, 8 and every 8 weeks after TI. Immune activation was evaluated by flow-cytometry and soluble TNFR2 levels.By week 8 of TI, levels of total cholesterol (TC) (median (Q1, Q3) (-0.73 (-1.19, -0.18) mmol/L, p
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- 2008
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41. 27590 Abrocitinib in the treatment of moderate-to-severe atopic dermatitis refractory to dupilumab treatment: An analysis of JADE-EXTEND, a phase 3 long-term extension study
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Hernan Valdez, Mette Deleuran, Vivian Y. Shi, Fan Zhang, Michael C. Cameron, Stephen Shumack, Luz Fonacier, Tina Bhutani, Gary Chan, and Natalie Yin
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Moderate to severe ,medicine.medical_specialty ,Refractory ,business.industry ,Extension study ,medicine ,Dermatology ,Atopic dermatitis ,medicine.disease ,business ,Dupilumab ,JADE (particle detector) - Published
- 2021
42. 27550 Durability of response to abrocitinib in patients with moderate-to-severe atopic dermatitis (AD) after treatment discontinuation in a phase 2b trial
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Melinda Gooderham, Jonathan I. Silverberg, Julian O’Neil Moore, Hernan Valdez, Giampiero Girolomoni, Robert Bissonnette, Gary Chan, Pinaki Biswas, Elena Peeva, and Seth Forman
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Moderate to severe ,medicine.medical_specialty ,business.industry ,medicine ,In patient ,Dermatology ,Atopic dermatitis ,business ,medicine.disease ,After treatment ,Discontinuation - Published
- 2021
43. 27582 Abrocitinib improves work productivity through improvement in pruritus and sleep: Results from the JADE MONO-2 study in patients with moderate-to-severe atopic dermatitis (AD)
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Ricardo Rojo, Mette Deleuran, Claire Feeney, Gil Yosipovitch, Daniela E. Myers, Hernan Valdez, John C Su, Andrew John Thorpe, Andrew G. Bushmakin, Luz Fonacier, and Joseph C. Cappelleri
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Moderate to severe ,medicine.medical_specialty ,Work productivity ,business.industry ,Internal medicine ,medicine ,In patient ,Dermatology ,Atopic dermatitis ,medicine.disease ,business ,Sleep in non-human animals ,JADE (particle detector) - Published
- 2021
44. 27237 Effect of abrocitinib vs dupilumab and placebo on patient-reported outcomes (PROs) in moderate-to-severe atopic dermatitis (AD) in JADE COMPARE
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Fan Zhang, Ricardo Rojo, Daniela E. Myers, Gil Yosipovitch, Jacob P. Thyssen, Shawn G. Kwatra, Chia-Yu Chu, Claire Feeney, Carle Paul, Hernan Valdez, and Marco DiBonaventura
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Moderate to severe ,medicine.medical_specialty ,business.industry ,medicine ,Dermatology ,Atopic dermatitis ,medicine.disease ,Placebo ,business ,JADE (particle detector) ,Dupilumab - Published
- 2021
45. 27603 Rapid itch relief with abrocitinib predicts later skin clearance: A post hoc analysis vs dupilumab and placebo in JADE COMPARE
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Eric L. Simpson, Ricardo Rojo, Claire Feeney, Jacob P. Thyssen, Fan Zhang, Sonja Ständer, Shawn G. Kwatra, Marco DiBonaventura, Hernan Valdez, Gil Yosipovitch, and Michael C. Cameron
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business.industry ,Anesthesia ,Post-hoc analysis ,Medicine ,Dermatology ,Itch Relief ,business ,Placebo ,JADE (particle detector) ,Dupilumab - Published
- 2021
46. Adverse events of special interest in clinical trials of rheumatoid arthritis, psoriatic arthritis, ulcerative colitis and psoriasis with 37 066 patient-years of tofacitinib exposure
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Ann Madsen, Thomas V. Jones, Stanley Cohen, Huaming Tan, Kim A. Papp, Hernan Valdez, Bruce E. Sands, Lori Stockert, Gerd R Burmester, and Peter Nash
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medicine.medical_specialty ,rheumatoid ,Immunology ,Arthritis ,Arthritis, Rheumatoid ,Psoriatic arthritis ,Piperidines ,Rheumatology ,Internal medicine ,Psoriasis ,therapeutics ,medicine ,Humans ,Immunology and Allergy ,autoimmune diseases ,Adverse effect ,Tofacitinib ,business.industry ,Arthritis, Psoriatic ,Treatments ,medicine.disease ,Ulcerative colitis ,Clinical trial ,Pyrimidines ,Treatment Outcome ,arthritis ,Rheumatoid arthritis ,Medicine ,Colitis, Ulcerative ,psoriatic ,business - Abstract
ObjectivesTo analyse adverse events (AEs) of special interest across tofacitinib clinical programmes in rheumatoid arthritis (RA), psoriatic arthritis (PsA), ulcerative colitis (UC) and psoriasis (PsO), and to determine whether the incidence rates (IRs; unique patients with events per 100 patient-years) of these events are consistent across diseases.MethodsThe analysis included data from patients exposed to ≥1 dose of tofacitinib in phase 1, 2, 3 or 3b/4 clinical trials and long-term extension (LTE) studies (38 trials) in RA (23 trials), PsA (3 trials), UC (5 trials) and PsO (7 trials). All studies were completed by or before July 2019, except for one ongoing UC LTE study (data cut-off May 2019). IRs were obtained for AEs of special interest.Results13 567 patients were included in the analysis (RA: n=7964; PsA: n=783; UC: n=1157; PsO: n=3663), representing 37 066 patient-years of exposure. Maximum duration of exposure was 10.5 years (RA). AEs within the ‘infections and infestations’ System Organ Class were the most common in all diseases. Among AEs of special interest, IRs were highest for herpes zoster (non-serious and serious; 3.6, 1.8, 3.5 and 2.4 for RA, PsA, UC and PsO, respectively) and serious infections (2.5, 1.2, 1.7 and 1.3 for RA, PsA, UC and PsO, respectively). Age-adjusted and sex-adjusted mortality ratios (weighted for country) were ≤0.2 across cohorts.ConclusionsThe tofacitinib safety profile in this analysis was generally consistent across diseases and with longer term follow-up compared with previous analyses.
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- 2021
47. Herpes Zoster and Tofacitinib: Clinical Outcomes and the Risk of Concomitant Therapy
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Stephen Lindsey, Haiyun Fan, Connie Chen, Chudy I. Nduaka, Lisy Wang, Tomohiro Hirose, Kunihiro Yamaoka, Eustratios Bananis, Jeffrey R. Curtis, Hernan Valdez, Yoshiya Tanaka, Kevin L. Winthrop, and Alan M. Mendelsohn
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medicine.medical_specialty ,Immunology ,Rheumatoid Arthritis ,Herpes Zoster ,Gastroenterology ,Arthritis, Rheumatoid ,03 medical and health sciences ,0302 clinical medicine ,Piperidines ,Rheumatology ,Internal medicine ,Concomitant Therapy ,medicine ,Humans ,Immunology and Allergy ,Pyrroles ,030212 general & internal medicine ,Leflunomide ,030203 arthritis & rheumatology ,Tofacitinib ,Proportional hazards model ,business.industry ,Incidence (epidemiology) ,Vaccination ,medicine.disease ,Confidence interval ,Surgery ,Pyrimidines ,Concomitant ,Rheumatoid arthritis ,business ,medicine.drug - Abstract
Objective Patients with rheumatoid arthritis (RA) are at increased risk of herpes zoster (HZ), and the risk appears to be increased in patients treated with tofacitinib. The aim of this study was to evaluate whether concomitant treatment with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) or glucocorticoids (GCs) contributes to the increased risk of HZ in RA patients treated with tofacitinib. Methods HZ cases were identified from the databases of 2 phase I, 9 phase II, 6 phase III, and 2 long-term extension studies of tofacitinib in RA patients. Crude incidence rates (IRs) of all HZ events (serious and nonserious) per 100 patient-years (with 95% confidence intervals [95% CIs]) were calculated for unique patients. Within phase III studies, we described HZ rates according to concomitant csDMARD treatment and baseline GC use. A multivariable Cox proportional hazards regression model was used to evaluate HZ risk factors across studies. Results Across all studies (6,192 patients; 16,839 patient-years), HZ was reported in 636 tofacitinib-treated patients (IR 4.0, 95% CI 3.7–4.4). In most cases (93%), HZ was classified as nonserious, and the majority of patients (94%) had involvement of only 1 dermatome. HZ IRs varied across regions, from 2.4 (95% CI 2.0–2.9) in Eastern Europe to 8.0 (95% CI 6.6–9.6) in Japan and 8.4 (95% CI 6.4–10.9) in Korea. Within phase III studies, HZ IRs varied according to tofacitinib dose, background csDMARD treatment, and baseline use of GCs. The IRs were numerically lowest for monotherapy with tofacitinib 5 mg twice daily without GCs (IR 0.56 [95% CI 0.07–2.01]) and highest for tofacitinib 10 mg twice daily with csDMARDs and GCs (IR 5.44 [95% CI 3.72–7.68]). Age, GC use, tofacitinib dose, and enrollment within Asia were independent risk factors for HZ. Conclusion Patients receiving treatment with tofacitinib and GCs appear to have a greater risk of developing HZ compared with patients receiving tofacitinib monotherapy without GCs.
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- 2017
48. Comparative Assessment of PASI and Variations of PGA×BSA as Measures of Psoriasis Severity
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Huaming Tan, Kristina Callis Duffin, Hernan Valdez, and Jessica A. Walsh
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Body surface area ,medicine.medical_specialty ,Tofacitinib ,business.industry ,Dermatology ,medicine.disease ,Etanercept ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,Rheumatology ,Psoriasis Area and Severity Index ,030220 oncology & carcinogenesis ,Psoriasis ,Medicine ,business ,medicine.drug - Abstract
Background Commonly used instruments for measuring psoriasis, such as Psoriasis Area and Severity Index (PASI), have limitations, including high complexity. Objective Determine if PGA×BSA or PGA×√BSA are practical alternatives to PASI for measuring severity and treatment response. Methods Data from a Phase 3 study in 1,101 patients treated for moderate to severe psoriasis were used. PASI was the reference standard. Correlations (Pearson coefficients), test-retest reliability (intraclass correlation coefficients), responsiveness to treatment (percentage change and effect size), and correspondence (sensitivity and specificity) were assessed. Results Correlation coefficients of change (baseline at Week 12) were 0.90 between PASI and either PGA×BSA and PGA×√BSA. ICCs were 0.90. Both instruments demonstrated similar percentage change from baseline and effect sizes. Sensitivities of PGA×BSA and PGA×√BSA were 99% and 95%, and specificities were 76% and 87%, respectively. Conclusions PGA×BSA and PGA×√BSA had similar measurement properties as PASI. PGA×BSA is a practical alternative to PASI.
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- 2017
49. Herpes zoster in psoriasis patients treated with tofacitinib
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Alexander Egeberg, Scott T. Rottinghaus, Mark Lebwohl, Kaori Ito, Huaming Tan, Jeffrey M Weinberg, Arnon D. Cohen, Pankaj Gupta, Hernan Valdez, Mandeep Kaur, Kevin L. Winthrop, Lotus Mallbris, and Stephen K. Tyring
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Adult ,Male ,medicine.medical_specialty ,Adolescent ,Dermatology ,Placebo ,Herpes Zoster ,Etanercept ,Young Adult ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,Asian People ,Piperidines ,Risk Factors ,Psoriasis Area and Severity Index ,Psoriasis ,Internal medicine ,medicine ,Humans ,Pyrroles ,030212 general & internal medicine ,Adverse effect ,Aged ,Proportional Hazards Models ,Aged, 80 and over ,Biological Products ,Tofacitinib ,business.industry ,Incidence ,Hazard ratio ,Age Factors ,Middle Aged ,medicine.disease ,Surgery ,Hospitalization ,Pyrimidines ,Rheumatoid arthritis ,Female ,business ,Immunosuppressive Agents ,medicine.drug - Abstract
Background Tofacitinib is an oral Janus kinase (JAK) inhibitor. Immunomodulatory therapies can increase the risk for herpes zoster (HZ) in patients with psoriasis. Objective To evaluate the relationship between tofacitinib use and HZ risk. Methods We used phases 2 and 3 and long-term extension (LTE) data from the tofacitinib development program in psoriasis to calculate HZ incidence rates (IR; events per 100 patient-years); potential HZ risk factors were evaluated using Cox-proportional hazard models. Results One hundred thirty (3.6%) patients on tofacitinib (IR 2.55), no patients on placebo, and 2 using etanercept (IR 2.68) developed HZ. Nine patients (7%) were hospitalized, and 8 (6%) had multidermatomal HZ; no encephalitis, visceral involvement, or deaths occurred. In total, 121 (93%) patients on tofacitinib continued or resumed use after HZ. HZ risk factors included Asian descent (hazard ratio [HR] 2.92), using tofacitinib 10 mg twice daily (vs 5 mg twice daily; HR 1.72), prior use of biologics (HR 1.72), and older age (HR 1.30). Limitations Generalizability to other psoriasis populations might be limited. The effect of HZ vaccination was not studied. Conclusion Tofacitinib is associated with increased HZ risk relative to placebo. Asian race, increasing age, higher dose, and prior biologic exposure are associated with heightened risk.
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- 2017
50. Evaluating Dosage Optimality for Tofacitinib, an Oral Janus Kinase Inhibitor, in Plaque Psoriasis, and the Influence of Body Weight
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MM Hutmacher, Charles A Mebus, Kim A. Papp, Sriram Krishnaswami, Huaming Tan, Priya Gupta, Kaori Ito, Scott T. Rottinghaus, Robert Wolk, and Hernan Valdez
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medicine.medical_specialty ,Tofacitinib ,business.industry ,Body weight ,030226 pharmacology & pharmacy ,Dermatology ,Gastroenterology ,law.invention ,Clinical trial ,030207 dermatology & venereal diseases ,03 medical and health sciences ,Dose–response relationship ,0302 clinical medicine ,Randomized controlled trial ,law ,Psoriasis Area and Severity Index ,Modeling and Simulation ,Internal medicine ,medicine ,Potency ,Pharmacology (medical) ,business ,Janus kinase inhibitor - 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.
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- 2017
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