Cunshan Wang

Topical tofacitinib for atopic dermatitis: a phase IIa randomized trial

Despite unmet need, 15 years have passed since a topical therapy with a new mechanism of action for atopic dermatitis (AD) has been approved. Janus kinase (JAK) inhibitor treatment effect via topical application in patients with AD is unknown.

Tofacitinib or Adalimumab versus Placebo for Psoriatic Arthritis.

Background Tofacitinib is an oral Janus kinase inhibitor that is under investigation for the treatment of psoriatic arthritis. We evaluated tofacitinib in patients with active psoriatic arthritis who previously had an inadequate response to conventional synthetic disease‐modifying antirheumatic drugs (DMARDs). Methods In this 12‐month, double‐blind, active‐controlled and placebo‐controlled, phase 3 trial, we randomly assigned patients in a 2:2:2:1:1 ratio to receive one of the following regimens: tofacitinib at a 5‐mg dose taken orally twice daily (107 patients), tofacitinib at a 10‐mg dose taken orally twice daily (104), adalimumab at a 40‐mg dose administered subcutaneously once every 2 weeks (106), placebo with a blinded switch to the 5‐mg tofacitinib dose at 3 months (52), or placebo with a blinded switch to the 10‐mg tofacitinib dose at 3 months (53). Placebo groups were pooled for analyses up to month 3. Primary end points were the proportion of patients who had an American College of Rheumatology 20 (ACR20) response (≥20% improvement from baseline in the number of tender and swollen joints and at least three of five other important domains) at month 3 and the change from baseline in the Health Assessment Questionnaire–Disability Index (HAQ‐DI) score (scores range from 0 to 3, with higher scores indicating greater disability) at month 3. Results ACR20 response rates at month 3 were 50% in the 5‐mg tofacitinib group and 61% in the 10‐mg tofacitinib group, as compared with 33% in the placebo group (P=0.01 for the comparison of the 5‐mg dose with placebo; P<0.001 for the comparison of the 10‐mg dose with placebo); the rate was 52% in the adalimumab group. The mean change in the HAQ‐DI score was ‐0.35 in the 5‐mg tofacitinib group and ‐0.40 in the 10‐mg tofacitinib group, as compared with ‐0.18 in the placebo group (P=0.006 for the comparison of the 5‐mg dose with placebo; P<0.001 for the comparison of the 10‐mg dose with placebo); the score change was ‐0.38 in the adalimumab group. The rate of adverse events through month 12 was 66% in the 5‐mg tofacitinib group, 71% in the 10‐mg tofacitinib group, 72% in the adalimumab group, 69% in the placebo group that switched to the 5‐mg tofacitinib dose, and 64% in the placebo group that switched to the 10‐mg tofacitinib dose. There were four cases of cancer, three serious infections, and four cases of herpes zoster in patients who received tofacitinib during the trial. Conclusions The efficacy of tofacitinib was superior to that of placebo at month 3 in patients with psoriatic arthritis who had previously had an inadequate response to conventional synthetic DMARDs. Adverse events were more frequent with tofacitinib than with placebo. (Funded by Pfizer; OPAL Broaden ClinicalTrials.gov number, NCT01877668.)

Tofacitinib for Psoriatic Arthritis in Patients with an Inadequate Response to TNF Inhibitors

Background Tofacitinib is an oral Janus kinase inhibitor that is under investigation for the treatment of psoriatic arthritis. We evaluated tofacitinib in patients with active psoriatic arthritis who had previously had an inadequate response to tumor necrosis factor (TNF) inhibitors. Methods In this 6‐month randomized, placebo‐controlled, double‐blind, phase 3 trial, we randomly assigned 395 patients, in a 2:2:1:1 ratio, to four regimens: 5 mg of tofacitinib administered orally twice daily (132 patients); 10 mg of tofacitinib twice daily (132 patients); placebo, with a switch to 5 mg of tofacitinib twice daily at 3 months (66 patients); or placebo, with a switch to 10 mg of tofacitinib twice daily at 3 months (65 patients). Data from the patients who received placebo during the first 3 months of the trial were pooled. The primary end points were the percentage of patients who had at least 20% improvement according to the criteria of the American College of Rheumatology (ACR20 response) and the change from baseline score on the Health Assessment Questionnaire–Disability Index (HAQ‐DI; scores range from 0 to 3, with higher scores indicating greater disability) at the month 3 analysis. Results At 3 months, the rates of ACR20 response were 50% with the 5‐mg dose of tofacitinib and 47% with the 10‐mg dose, as compared with 24% with placebo (P<0.001 for both comparisons); the corresponding mean changes from baseline in HAQ‐DI score were ‐0.39 and ‐0.35, as compared with ‐0.14 (P<0.001 for both comparisons). Serious adverse events occurred in 4% of the patients who received the 5‐mg dose of tofacitinib continuously and in 6% who received the 10‐mg dose continuously. Over the course of 6 months, there were four serious infections, three herpes zoster infections, one myocardial infarction, and one ischemic stroke among the patients who received tofacitinib continuously. Elevations of aspartate and alanine aminotransferase concentrations of three or more times the upper limit of the normal range occurred in more patients who received tofacitinib continuously than in patients who received placebo followed by tofacitinib. Conclusions In this trial involving patients with active psoriatic arthritis who had had an inadequate response to TNF inhibitors, tofacitinib was more effective than placebo over 3 months in reducing disease activity. Adverse events were more frequent with tofacitinib than with placebo. (Funded by Pfizer; OPAL Beyond ClinicalTrials.gov number, NCT01882439.)

Treatment of plaque psoriasis with an ointment formulation of the Janus kinase inhibitor, tofacitinib: a Phase 2b randomized clinical trial

BackgroundMost psoriasis patients have mild to moderate disease, commonly treated topically. Current topical agents have limited efficacy and undesirable side effects associated with long-term use. Tofacitinib is a small molecule Janus kinase inhibitor investigated for the topical treatment of psoriasis.MethodsThis was a 12-week, randomized, double-blind, parallel-group, vehicle-controlled Phase 2b study of tofacitinib ointment (2xa0% and 1xa0%) applied once (QD) or twice (BID) daily in adults with mild to moderate plaque psoriasis. Primary endpoint: proportion of patients with Calculated Physician’s Global Assessment (PGA-C) clear or almost clear and ≥2 grade improvement from baseline at Weeks 8 and 12. Secondary endpoints: proportion of patients with PGA-C clear or almost clear; proportion achieving Psoriasis Area and Severity Index 75 (PASI75) response; percent change from baseline in PASI and body surface area; change from baseline in Itch Severity Item (ISI). Adverse events (AEs) were monitored and clinical laboratory parameters measured.ResultsOverall, 435 patients were randomized and 430 patients received treatment. The proportion of patients with PGA-C clear or almost clear and ≥2 grade improvement from baseline at Week 8 was 18.6xa0% for 2xa0% tofacitinib QD (80xa0% confidence interval [CI] for difference from vehicle: 3.8, 18.2xa0%) and 22.5xa0% for 2xa0% tofacitinib BID (80xa0% CI: 3.1, 18.5xa0%); this was significantly higher vs vehicle for both dosage regimens. No significant difference vs vehicle was seen at Week 12. Significantly more patients achieved PGA-C clear or almost clear with 2xa0% tofacitinib QD and BID and 1xa0% tofacitinib QD (not BID) at Week 8, and with 2xa0% tofacitinib BID at Week 12. Pruritus was significantly reduced vs vehicle with 2xa0% and 1xa0% tofacitinib BID (starting Day 2), and 2xa0% tofacitinib QD (starting Day 3). Overall, 44.2xa0% of patients experienced AEs, 8.1xa0% experienced application site AEs, and 2.3xa0% experienced serious AEs. The highest incidence of AEs (including application site AEs) was in the vehicle QD group.ConclusionsIn adults with mild to moderate plaque psoriasis, 2xa0% tofacitinib ointment QD and BID showed greater efficacy than vehicle at Week 8, but not Week 12, with an acceptable safety and local tolerability profile.Trial registrationNCT01831466 registered March 28, 2013.

Integrated Efficacy Analysis of Tofacitinib, an Oral Janus Kinase Inhibitor, in Patients with Active Psoriatic Arthritis

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

OP0202 Efficacy and safety of tofacitinib, an oral janus kinase inhibitor, in patients with active psoriatic arthritis and an inadequate response to tumour necrosis factor inhibitors: opal beyond, a randomised, double-blind, placebo-controlled, phase 3 trial

Background Tofacitinib is an oral Janus kinase inhibitor under investigation for treatment of PsA. Objectives Evaluation of efficacy and safety of tofacitinib vs placebo (PBO) in adult patients (pts) with active PsA and an inadequate response (IR) to TNF inhibitors (TNFi). Methods Eligible pts in this 6-month, randomised, PBO-controlled, double-blind, multicentre, Phase 3 study had ≥6 months PsA diagnosis, met CASPAR criteria, had active arthritis (≥3 tender/painful and ≥3 swollen joints) at screening and baseline, active plaque psoriasis at screening and IR to ≥1 TNFi (discontinued due to inadequate efficacy or adverse event [AE]). Pts were randomised 2:2:1:1 to tofacitinib 5 mg twice daily (BID), tofacitinib 10 mg BID or PBO (advancing to tofacitinib 5 or 10 mg BID in a blinded manner at Month [M]3). Ongoing treatment with 1 conventional synthetic DMARD was required. Pts were followed through M6. Primary endpoints were ACR20 response rate and change (Δ) from baseline in Health Assessment Questionnaire-Disability Index (HAQ-DI) at M3. Results Pts were 92.1% white, 55.3% female and mean age was 50.0 years. At baseline, mean swollen and tender/painful joint counts were 22.0 and 11.8 respectively; mean HAQ-DI score was 1.3; 69.8% of pts had LEI >0; 49.2% had Dactylitis Severity Score (DSS) >0. Most patients (62.7%) had ≥3% BSA affected by psoriasis, for whom median PASI score was 7.9. Discontinuation rate at M3 was 7.6%, and 87.6% completed M6. ACR20 response and ΔHAQ-DI significantly improved with both tofacitinib doses vs PBO at M3 (Fig 1A,B) and were maintained to M6 (Fig 1C,D). Tofacitinib 5 mg and 10 mg BID demonstrated superior ACR20 response vs PBO as early as Week 2 (26.7% [p≤0.05] and 28.8% [p≤0.05] vs 13.0%). Secondary endpoints at M3 for tofacitinib 5 mg and 10 mg respectively were: ACR50 response, 29.8% (p≤0.05), 28.0% (p≤0.05); ACR70 response, 16.8% (not significant [NS]), 14.4% (NS); ≥75% improvement of PASI in pts with baseline BSA ≥3% and PASI >0, 21.3% (NS), 43.2% (p<0.0001); ΔLEI and ΔDSS in pts with baseline score >0: ΔLEI, -1.3 (p≤0.05) and -1.3 (p≤0.05) (least squares mean [LSM]); ΔDSS, -5.2 (p≤0.05) and -5.4 (p≤0.05) (LSM). Effects were maintained to M6. Frequency of serious AEs and discontinuations due to AEs was low and similar across treatment groups (Fig 1E). The most common AEs were upper respiratory tract infection (5.3–10.8%), nasopharyngitis (1.5–10.7%) and headache (4.5–9.1%). Conclusions In this study restricted to PsA pts with TNFi-IR, both tofacitinib doses appeared efficacious on musculoskeletal endpoints for treatment of PsA. No new safety risks were identified vs previous studies in other indications. Acknowledgements Previously presented at ACR 2016, to be presented at AAD 2017 and reproduced with permissions. This study was sponsored by Pfizer Inc. Editorial support was provided by AG McCluskey of CMC and was funded by Pfizer Inc. Disclosure of Interest D. Gladman Grant/research support from: Amgen, AbbVie, Bristol-Myers Squibb, Celgene, Janssen, Eli Lilly, Pfizer Inc, Novartis, UCB, Consultant for: Amgen, AbbVie, Bristol-Myers Squibb, Celgene, Janssen, Eli Lilly, Pfizer Inc, Novartis, UCB, Speakers bureau: Amgen, AbbVie, Bristol-Myers Squibb, Celgene, Janssen, Eli Lilly, Pfizer Inc, Novartis, UCB, W. F. Rigby Grant/research support from: Amgen, Pfizer Inc, Roche, Consultant for: Bristol-Meyers Squibb, Eli Lilly, Pfizer Inc, Roche, V. Azevedo Grant/research support from: Bristol-Myers Squibb, GSK, Pfizer Inc, UCB, Consultant for: AbbVie, Bristol-Myers Squibb, Janssen, Merck Novartis, Pfizer Inc, Serono, F. Behrens Grant/research support from: Abbvie, Pfizer Inc, Roche, Chugai, Prophylix, Bioline, Novartis, Consultant for: Abbvie, Pfizer Inc, Roche, Chugai, UCB, BMS, Celgene, MSD, Novartis, Biotest, Janssen, Genzyme, Lilly, R. Blanco: None declared, A. Kaszuba Consultant for: Janssen, Eli Lilly, Novartis, E. Kudlacz Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, C. Wang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, S. Menon Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, T. Hendrikx Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, K. Kanik Shareholder of: Pfizer Inc, Employee of: Pfizer Inc

SAT0439 Integrated safety summary of tofacitinib in psoriatic arthritis clinical studies

Background Tofacitinib is an oral Janus kinase inhibitor under investigation for psoriatic arthritis (PsA). Objectives To describe the safety profile of tofacitinib from integrated Phase (P)3 and long-term extension (LTE) studies. Methods Data were analysed for patients (pts) who received ≥1 dose of tofacitinib 5 or 10 mg BID or placebo (PBO), integrated across 2 P3 studies (OPAL Broaden [12 months; NCT01877668]; OPAL Beyond [6 months; NCT01882439]) and 1 LTE study (OPAL Balance [ongoing, database not locked; NCT01976364]). Common adverse events (AEs; occurring in ≥2% of tofacitinib pts in any group) were analysed in the PBO-controlled portion (Months 0–3) of the P3 studies (Cohort 1 [C1]). Serious AEs (SAEs) and discontinuations due to AEs were analysed over 12 months in pts randomised to tofacitinib 5 or 10 mg BID in P3 studies (Cohort 2a [C2a]); pts randomised to PBO were excluded from this analysis. Deaths and AEs of special interest (serious infections [SI], herpes zoster [HZ], opportunistic infections [OI] including HZ, major adverse cardiac events [MACE], malignancies, non-melanoma skin cancer [NMSC]) were evaluated in all tofacitinib-treated pts in the P3 and LTE studies (Cohort 3 [C3]). Incidence rates (IR; pts with events/100 pt-years [PY] and 95% confidence intervals) are reported. Laboratory results will be reported in future publications. Results C1 included 474 tofacitinib- and 236 PBO-treated pts; C2a included 474 tofacitinib-treated pts; and C3 included 783 tofacitinib-treated pts (exposure: 776 PY). Nasopharyngitis (5.9%) and headache (8.5%) were the most commonly reported AEs at Month 3 in pts receiving tofacitinib 5 and 10 mg BID, respectively (Table). In pts randomised to tofacitinib 5 or 10 mg BID, over 12 months (C2a), the IRs for SAEs were 7.92 (4.09, 13.84) and 8.11 (4.19, 14.17), respectively. Discontinuation due to AEs occurred in 11 (4.6%) and 11 (4.7%) pts randomised to tofacitinib 5 and 10 mg BID, respectively, with IRs of 7.16 (3.58, 12.82) and 7.31 (3.65, 13.08), respectively, over 12 months (C2a). Across all tofacitinib-treated pts in the P3 and LTE studies (C3), SIs occurred in 11 pts (1.4%; IR 1.40 [0.70, 2.50]). HZ was reported in 16 pts (2.0%; IR 2.05 [1.17, 3.33]) receiving tofacitinib. All 3 cases of multidermatomal HZ were adjudicated as OIs; these were the only OIs (0.4%; IR 0.38 [0.08, 1.11]). In C3, 2 deaths occurred (0.3%; IR 0.25 [0.03, 0.91]); all were considered unrelated to the study drug. MACE were reported in 3 pts (0.4%; IR 0.38 [0.08, 1.11]), malignancies (excluding NMSC) in 5 pts (0.6%; IR 0.63 [0.21, 1.48]) and NMSC in 4 pts (0.5%; IR 0.51 [0.14, 1.30]). Conclusions Tofacitinib was well tolerated in pts with PsA, with a safety profile consistent to that seen in RA; no new risks were identified. Longer-term follow-up and larger pt populations will provide further information on the safety profile of tofacitinib in pts with PsA. Acknowledgements These studies were sponsored by Pfizer Inc. Editorial support was provided by C Viegelmann of CMC and was funded by Pfizer Inc. Disclosure of Interest G. Burmester Grant/research support from: UCB, Consultant for: AbbVie, Bristol-Myers Squibb, Eli Lilly, Hexal, Janssen, MSD, MedImmune, Novartis, Pfizer Inc, Sanofi, Roche, Speakers bureau: AbbVie, Bristol-Myers Squibb, Hexal, MSD, Novartis, Pfizer Inc, Roche, O. FitzGerald Grant/research support from: AbbVie, Bristol-Myers Squibb, Consultant for: Bristol-Myers Squibb, Eli Lilly, Janssen, Pfizer Inc, Speakers bureau: Celgene, Janssen, Novartis, K. Winthrop Grant/research support from: Bristol-Myers Squibb, Pfizer Inc, Consultant for: AbbVie, Amgen, Bristol-Myers Squibb, Eli Lilly, Galapagos, Pfizer Inc, UCB, G. Williams Consultant for: Pfizer Inc, V. Azevedo Grant/research support from: Bristol-Myers Squibb, GSK, Pfizer Inc, UCB, Consultant for: AbbVie, Bristol-Myers Squibb, Janssen, Merck Novartis, Pfizer Inc, Serono, W. F. Rigby Grant/research support from: Amgen, Pfizer Inc, Roche, Consultant for: Bristol-Myers Squibb, Eli Lilly, Pfizer Inc, Roche, K. Kanik Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, C. Wang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, P. Biswas Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, T. Jones Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, S. Menon Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, N. Palmetto Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, R. Rojo Shareholder of: Pfizer Inc, Employee of: Pfizer Inc

SAT0293 Safety and efficacy of tofacitinib, an oral janus kinase inhibitor, up to 36 months in patients with active psoriatic arthritis: data from the third interim analysis of opal balance, an open-label, long-term extension study

Background Tofacitinib is an oral Janus kinase inhibitor for the treatment of psoriatic arthritis (PsA). Objectives To report the safety, tolerability and efficacy of tofacitinib in patients (pts) with active PsA from an ongoing, open-label, long-term extension (LTE) study (OPAL Balance, NCT01976364; November 2017 data-cut; database not locked). Methods Eligible pts from 2 Phase (P)3 tofacitinib PsA studies (OPAL Broaden, NCT01877668; OPAL Beyond, NCT01882439) entered a 3u2009year LTE ≤3 months after completing the P3 study or discontinuing for reasons unrelated to study drug. Pts received tofacitinib 5u2009mg BID to Month (M)1, after which dose adjustments between 5 and 10u2009mg BID were permitted to improve efficacy, or for safety reasons. Pts receiving a csDMARD at P3 study entry continued the same csDMARD in the LTE. Primary endpoints were incidence and severity of adverse events (AEs) and changes from baseline (Δ) in laboratory values. Safety data are reported up to M36. Efficacy was evaluated up to M30 (when n>50) as a secondary endpoint. Results 686 pts were treated in OPAL Balance; 468 (68.2%) remained in the study at data cut-off. Mean (range) LTE tofacitinib exposure was 614 (1–1032) days. On Day 1, 675 pts (98.4%) received a csDMARD, which was discontinued in 86 pts (12.7%). To M36, 2189 AEs were reported in 546 pts (79.6%), 95 pts (13.8%) had serious AEs and 59 pts (8.6%) discontinued due to AEs. Serious infections occurred in 12 pts (1.7%), herpes zoster (HZ) in 20 pts (2.9%; 1 serious event), major adverse cardiovascular events in 5 pts (0.7%), malignancies in 24 pts (3.5%; including 12 pts with NMSC) and uveitis in 2 pts (0.3%). No AEs of gastrointestinal perforation or inflammatory bowel disease were reported. There were 5 deaths (not attributed to treatment, as assessed by the investigator) due to metastatic pancreatic carcinoma, acute cardiac failure/hypertensive heart disease, chronic obstructive pulmonary disease, pulmonary embolism and cardiovascular insufficiency. Four AEs of latent tuberculosis were reported in pts whose previously negative QuantiFERON response became positive. ALT was elevated ≥3u2009x ULN in 27 pts (4.0%), and AST≥3u2009x ULN in 15 pts (2.2%). Changes in laboratory values observed in P3 studies were generally stable in the LTE, except for a modest decrease in absolute lymphocyte count over time. Eight pts (1.2%) discontinued (protocol-mandated) due to laboratory value changes. ACR responses, ΔHAQ-DI, PASI75 response, ΔLeeds Enthesitis Index, ΔDactylitis Severity Score and ΔPain were maintained up to M30. Conclusions Over 36 months in the LTE, the safety profile of tofacitinib in active PsA pts was generally similar to that of the P3 studies. No new safety risks were identified. Efficacy across various PsA disease domains was maintained over time. Acknowledgements Study sponsored by Pfizer Inc. Medical writing support was provided by A MacLachlan of CMC and funded by Pfizer Inc. Disclosure of Interest P. Nash Grant/research support from: AbbVie, Bristol-Myers Squibb, Eli Lilly, Janssen, Novartis, Pfizer Inc, Roche, Sanofi, UCB, Consultant for: AbbVie, Bristol-Myers Squibb, Eli Lilly, Janssen, Novartis, Pfizer Inc, Roche, Sanofi, UCB, Speakers bureau: AbbVie, Bristol-Myers Squibb, Eli Lilly, Janssen, Novartis, Pfizer Inc, Roche, Sanofi, UCB, L. Coates Grant/research support from: AbbVie, Janssen, Consultant for: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Janssen, Eli Lilly, MSD, Novartis, Pfizer Inc, Sun Pharma, UCB, A. Kivitz Consultant for: AbbVie, Celgene, Genentech, Genzyme, Janssen, Merck, Novartis, Pfizer Inc, Sanofi, UCB, Speakers bureau: AbbVie, Celgene, Genentech, Genzyme, Janssen, Merck, Novartis, Pfizer Inc, Sanofi, UCB, P. Mease Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Janssen, Eli Lilly, Novartis, Pfizer Inc, Sun, UCB, Consultant for: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Janssen, Eli Lilly, Novartis, Pfizer Inc, Sun, UCB, Speakers bureau: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Genentech, Janssen, Novartis, Pfizer Inc, UCB, D. Gladman Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Novartis, Pfizer Inc, UCB, Consultant for: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Novartis, Pfizer Inc, UCB, J. Covarrubias-Cobos Grant/research support from: Bristol-Myers Squibb, Eli Lilly, Janssen, Pfizer Inc, D. Fleishaker Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, C. Wang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, E. Kudlacz Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, S. Menon Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, L. Fallon Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, T. Hendrikx Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, K. Kanik Shareholder of: Pfizer Inc, Employee of: Pfizer Inc

THU0299 An integrated analysis of changes in lipid levels and incidence of cardiovascular events following tofacitinib treatment in patients with psoriatic arthritis across phase 3 and long-term extension studies

Background Cardiovascular (CV) disease and cardiometabolic syndrome are common comorbidities/causes of mortality in patients (pts) with psoriatic arthritis (PsA). Tofacitinib is an oral JAK inhibitor for the treatment of PsA. Objectives To investigate changes in lipid levels and incidence of CV events in pts with PsA treated with tofacitinib in Phase (P) 3 and long-term extension (LTE) studies. Methods Data were analysed for pts who received ≥1u2009dose of tofacitinib 5 or 10u2009mg BID or placebo (PBO), integrated across 2u2009P3 studies (OPAL Broaden [12 months (m); NCT01877668, including adalimumab control]; OPAL Beyond [6u2009m; NCT01882439]) and 1 LTE study (OPAL Balance [data cut-off May 2016; ongoing, database not locked; NCT01976364]). Lipid levels were assessed throughout P3 and LTE studies; this analysis included data from the PBO-controlled period (M0–3) of P3 studies. Blood pressure, hypertension events (standardised MedDRA query [narrow]) and adjudicated (independent/blinded to treatment) major adverse cardiovascular events (MACE) are reported for all pts who received ≥1u2009dose of tofacitinib (pooled across doses for hypertension and MACE). Incidence rates (IR; pts with events/100 pt-years [PY]) and 95%u2009CI are reported. Results Overall, 783 pts (776 PY of tofacitinib exposure) were included in P3 and LTE studies; treatment duration was 1–927 days. After 3u2009m of tofacitinib treatment in P3 studies, dose-dependent increases in lipid levels were observed with tofacitinib; minimal changes were observed with PBO, except for triglycerides (figure 1). Concurrent increases in high-density and low-density lipoprotein (HDL/LDL) and no change in the total cholesterol/HDL ratio were shown. Across P3 and LTE studies, no clinically significant changes in mean systolic or diastolic blood pressure were seen to 24u2009m. Hypertension events were reported in 38 (4.9%) pts: IR 4.93 [95% CI 3.49, 6.77]. Of these events, 4 led to pt discontinuation and 2 were serious adverse events. MACE were reported for 3 (0.4%) pts receiving tofacitinib (IR 0.38 [95% CI 0.08, 1.11]) and included sudden cardiac death (57 days of exposure at time of event), myocardial infarction (197 days) and ischaemic stroke (80 days). This is within the range reported in tofacitinib studies in pts with psoriasis (IR 0.24 [0.15, 0.37]; 8,759 PY of exposure) and rheumatoid arthritis (RA) (IR 0.38 [0.30, 0.47]; 21,286 PY of exposure). No dose-dependent effects on blood pressure were apparent.Abstract THU0299 – Figure 1 Mean% change from baseline in lipid levels to Month 3 integrated across Phase 3 studies. BID, twice daily; SE, standard error Conclusions In pts with PsA, the magnitude and dose dependency of increases in lipid levels to M3 were consistent with findings in tofacitinib studies in pts with psoriasis and RA. In P3 and LTE studies, no clinically significant changes were seen in blood pressure or incidence of hypertension. Incidence of MACE was within the range reported in prior tofacitinib studies in psoriasis and RA; however, the long latency of MACE requires longer-term observation. Acknowledgements Study sponsored by Pfizer Inc. Medical writing support was provided by A MacLachlan of CMC and funded by Pfizer Inc. Disclosure of Interest D. Gladman Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Novartis, Pfizer Inc, UCB, Consultant for: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Novartis, Pfizer Inc, UCB, C. Charles-Schoeman Grant/research support from: AbbVie, Bristol-Myers Squibb, Pfizer Inc, Consultant for: Amgen, Gilead, Pfizer Inc, Regeneron-Sanofi, I. McInnes Grant/research support from: Celgene, Janssen, Novartis, Pfizer Inc, Roche, UCB, Consultant for: AbbVie, Celgene, Janssen, Novartis, Pfizer Inc, Roche, UCB, D. Veale Grant/research support from: AbbVie, Actelion, Bristol-Myers Squibb, Janssen, MSD, Novartis, Pfizer Inc, Roche, UCB, Speakers bureau: AbbVie, Actelion, Bristol-Myers Squibb, Janssen, MSD, Novartis, Pfizer Inc, Roche, UCB, B. Thiers Consultant for: Pfizer Inc, Valeant Pharmaceuticals, D. Graham Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, C. Wang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, T. Jones Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, R. Wolk Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, R. DeMasi Shareholder of: Pfizer Inc, Employee of: Pfizer Inc

OP0216 Efficacy and safety of tofacitinib, an oral janus kinase inhibitor, or adalimumab in patients with active psoriatic arthritis and an inadequate response to conventional synthetic disease-modifying antirheumatic drugs (CSDMARDS): a randomised, placebo-controlled, phase 3 trial

Background Tofacitinib is an oral Janus kinase inhibitor under investigation for treatment of psoriatic arthritis (PsA). Objectives To assess the efficacy and safety of tofacitinib vs placebo (PBO) in patients (pts) with active PsA. Methods Eligible pts in this randomised, PBO- and active-controlled, 12-month Phase 3 trial had ≥6-months PsA diagnosis, fulfilled CASPAR criteria, had active arthritis (≥3 tender/painful and ≥3 swollen joints) and active plaque psoriasis at screening, inadequate response to ≥1 csDMARD, and were tumour necrosis factor-inhibitor (TNFi)-naïve. 422 pts were randomised 2:2:2:1:1 to tofacitinib 5 or 10 mg twice daily (BID), adalimumab 40 mg subcutaneous injection every 2 weeks, or PBO (advancing to tofacitinib 5 or 10 mg BID at Month [M]3). Stable treatment with 1 csDMARD was required. Primary endpoints comparing tofacitinib vs PBO were ACR20 response rate and change from baseline in Health Assessment Questionnaire Disability Index (ΔHAQ-DI) at M3. Secondary endpoints included: ACR20 response rates and ΔHAQ-DI through M12; pts achieving ACR50, ACR70, ≥75% improvement of PASI and PsARC at all time points; and changes from baseline in LEI, Dactylitis Severity Score and SPARCC Enthesitis Index. Radiographic progression was assessed by van der Heijde-modified Total Sharp Score (mTSS). Results 96.9% of pts were white and 53.3% were female; mean age was 47.9 years. 96.2% and 88.4% of pts completed M3 and M12, respectively. At M3, tofacitinib 5 and 10 mg BID significantly improved ACR20 response rates (50.5% [p≤0.05] and 60.6% [p<0.0001] vs 33.3%; Fig 1A) and ΔHAQ-DI (-0.35 [p≤0.05] and -0.40 [p<0.001] vs -0.18; Fig 1B) vs PBO, with responses maintained to M12 (Fig 1C&D). Greater efficacy was also seen for adalimumab vs PBO. Tofacitinib 5 and 10 mg BID were superior to PBO for ACR20 response rates at Week 2 (22.4% [p<0.001] and 31.7% [p<0.0001] vs 5.7%; Fig 1C). Secondary endpoints supported primary findings (data not shown). >91% of pts were radiographic non-progressors at M12 (defined as an increase from baseline in mTSS ≤0.5). M12 safety findings were similar between groups (Fig 1E). The most common adverse events were upper respiratory tract infection (7.5–10.6%), nasopharyngitis (7.5–11.5%) and headache (3.8–10.6%). Conclusions In TNFi-naïve pts with active PsA, tofacitinib was superior to PBO in ACR20 response rates and ΔHAQ-DI at M3, with superiority vs PBO as early as Week 2 for ACR20, which was maintained to M12. No new safety risks were identified vs previous studies in other indications. Acknowledgements Previously presented at ACR 2016, to be presented at AAD 2017 and reproduced with permissions. This study was sponsored by Pfizer Inc. Editorial support was provided by AG McCluskey of CMC and was funded by Pfizer Inc. Disclosure of Interest P. Mease Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, Novartis, Pfizer Inc, Sun, UCB, Consultant for: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Crescendo, CORRONA, Dermira, Janssen, Eli Lilly, Merck, Novartis, Pfizer Inc, Sun, UCB, Zynerba, Speakers bureau: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Crescendo, Genentech, Janssen, Novartis, Pfizer Inc, UCB, S. Hall Consultant for: AbbVie, Celgene, Eli Lilly, Janssen, Pfizer Inc, Roche, O. FitzGerald Grant/research support from: AbbVie, Bristol-Myers Squibb, Consultant for: Bristol-Myers Squibb, Eli Lilly, Janssen, Pfizer Inc, Speakers bureau: Celgene, Janssen, Novartis, D. van der Heijde Consultant for: AbbVie, Amgen, Astellas, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi, Eli Lilly, Galapagos, Janssen, Merck, Novartis, Pfizer Inc, Roche, Sanofi-Aventis, UCB, Employee of: Imaging Rheumatology BV, J. Merola Grant/research support from: Biogen Idec, Consultant for: AbbVie, Amgen, Biogen Idec, Eli Lilly, Janssen, Momenta, Mallinckrodt, Novartis, Pfizer Inc, Speakers bureau: AbbVie, Eli Lilly, F. Avila-Zapata: None declared, D. Cieślak: None declared, D. Graham Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, C. Wang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, S. Menon Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, T. Hendrikx Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, K. Kanik Shareholder of: Pfizer Inc, Employee of: Pfizer Inc