Background:PF-06410293 (ADL-PF) is an adalimumab biosimilar approved for the treatment of several inflammatory and autoimmune indications.1The efficacy, safety and immunogenicity of ADL-PF and reference adalimumab sourced from the European Union (ADL-EU) in patients with rheumatoid arthritis (RA) have been demonstrated to be similar in a randomised controlled trial up to 26 weeks (wks; treatment period 1 [TP1]).2Objectives:To evaluate the efficacy, safety and immunogenicity of ADL-PF and ADL-EU in patients with moderate to severe RA on longer-term treatment, and following a treatment switch from ADL-EU to ADL-PF in a subset of patients.Methods:This multinational, randomised, double-blind, parallel-group study compared ADL-PF and ADL-EU in essentially biologic-naïve patients with active RA despite methotrexate (MTX) (NCT02480153). In TP1, patients were randomised (1:1) to ADL-PF or ADL-EU (40 mg subcutaneous injection every 2 wks) for 26 wks while continuing MTX (10–25 mg/wk). The primary endpoint was achievement of American College of Rheumatology response (ACR20) at Wk 12. At Wk 26, the start of treatment period 2 (TP2), patients receiving ADL-EU were blindly re-randomised (1:1) to remain on ADL-EU or switch to ADL-PF for 26 wks while patients receiving ADL-PF continued treatment in a blinded manner. Secondary efficacy endpoints at Wks 26, 30, 36, 44 and 52 (ACR20/50/70, European League Against Rheumatism [EULAR] response, Disease Activity Score [DAS] 28-4[CRP] <2.6 and ACR/EULAR defined remission), safety events and percentage of patients with anti-drug antibodies (ADA) were assessed.Results:In TP1, 597 patients were randomised to ADL-PF (n=297) or ADL-EU (n=300). At Wk 26, 552 patients were re-randomised for TP2 (continued ADL-PF, n=283; continued ADL-EU, n=135; switched from ADL-EU to ADL-PF, n=134). Patients who demonstrated at least minimal efficacy continued in TP2. Observed ACR20 rates were comparable between treatment groups at all visits during TP2 (Figure). Other measures of deep response (ACR70, EULAR good response, DAS28-4(CRP) <2.6 and ACR/EULAR defined remission) showed maintained efficacy during TP2 in all treatment groups. Incidences of treatment-emergent adverse events were comparable between treatment groups (Table). Overall, incidences of ADA through Wk 52 were comparable between treatment groups (47.3%, 54.1% and 45.9% for patients who continued ADL-PF, continued ADL-EU or switched from ADL-EU to ADL-PF, respectively). In patients who switched from ADL-EU to ADL-PF compared with patients who continued ADL-EU, the increase in ADA incidence over TP2 was 0.8% (from 45.1% to 45.9%) versus 6.7% (from 47.4% to 54.1%), respectively.Conclusion:TP2 results demonstrated comparable efficacy, safety and immunogenicity between ADL-PF and ADL-EU was maintained up to Wk 56 and was unaffected by a blinded switch from ADL-EU to ADL-PF at Wk 26.References:[1]Pfizer Inc, 2019.http://labeling.pfizer.com/ShowLabeling.aspx?id=12780[2]Fleischmann RM et al,Arthritis Res Ther2018;20:178.Table.All-causality TEAEs: Treatment Period 2 (Safety population)Continued ADL-PF(n=283)Continued ADL-EU(n=135)Switched from ADL-EU to ADL-PF(n=133)Number of AEs243112100Patients with events, n (%) AEs123 (43.5)60 (44.4)51 (38.3) Serious AEs4 (1.4)6 (4.4)3 (2.3) ≥ Grade 3 AEs7 (2.5)7 (5.2)4 (3.0)TEAEs leading to treatment discontinuation6 (2.1)8 (5.9)2 (1.5)Deaths000ADL-EU, adalimumab sourced from the European Union; ADL-PF, adalimumab biosimilar PF-06410293; AE, adverse event; TEAE, treatment-emergent AE.Acknowledgments:Medical writing support, provided by Jacqui Oliver of Engage Scientific Solutions. The study was funded by Pfizer.Disclosure of Interests:Roy Fleischmann Grant/research support from: AbbVie, Akros, Amgen, AstraZeneca, Bristol-Myers Squibb, Boehringer, IngelhCentrexion, Eli Lilly, EMD Serono, Genentech, Gilead, Janssen, Merck, Nektar, Novartis, Pfizer, Regeneron Pharmaceuticals, Inc., Roche, Samsung, Sandoz, Sanofi Genzyme, Selecta, Taiho, UCB, Consultant of: AbbVie, ACEA, Amgen, Bristol-Myers Squibb, Eli Lilly, Gilead, GlaxoSmithKline, Novartis, Pfizer, Sanofi Genzyme, UCB, Daniel Alvarez Shareholder of: Pfizer, Employee of: Pfizer, Amy Bock Shareholder of: Pfizer, Employee of: Pfizer, Carol Cronenberger Shareholder of: Pfizer, Employee of: Pfizer, Ivana Vranic Shareholder of: Pfizer, Employee of: Pfizer, Wuyan Zhang Shareholder of: Pfizer, Employee of: Pfizer, Rieke Alten Grant/research support from: Pfizer, Galapagos, Galapagos NV, Gilead, Gilead Sciences, Inc., Novartis, Consultant of: Pfizer, Speakers bureau: Pfizer

SummaryBackground. 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-a 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.

Oral JAK3 (PF-06651600) and TYK2/JAK1 (PF-06700841) inhibitors were shown to be efficacious and well tolerated in patients with moderate to severe (50% scalp hair loss) alopecia areata (AA). A substudy of this Phase 2 trial (PF-06651600, n¼18; PF-06700841, n¼16; placebo, n¼12) evaluated changes in lesional scalp biomarkers after 12 and 24 weeks of treatment using microarrays, qPCR, and immunohistochemistry. A total of 2264 genes were significantly up-or downregulated after 12 or 24 weeks of treatment across all patients and treatment groups (fold change >1.5; p<0.05). Significant gene-level changes from baseline in lesional transcriptomic profiles of 62% and 115% (12 weeks) and 162% and 104% (24 weeks) were obtained in the PF-06651600 and PF-06700841 groups, respectively, which differed significantly from those in the placebo group (week 12, 18%; week 24, 6%). With both treatments, patient-level T-cell activation, Th1, Th2, and IL12/23 pathways were significantly downregulated (p<0.05 at weeks 12 and/or 24) and hair keratins (KRT35, 40, 75, 83, 85, 86, KRTAP1) were significantly upregulated (p<0.05 at weeks 12 and/or 24). Most of these changes were significantly correlated (p<0.05) with clinical (Severity of Alopecia Tool score) improvements from baseline. No significant changes were seen with placebo. Greater improvements in clinical and transcriptomic parameters correlated with a shorter AA duration (<3.5 years). Overall, clinical improvements in patients with AA treated with PF-06651600 and PF-06700841 were associated with downregulation of Th1, Th2, and IL-12/23 immune responses and upregulation of hair keratins, with greater responses in patients with shorter disease duration.

Psoriasis (PsO) generates systemic inflammation which may be related to cardiovascular disease (CVD) events. Red cell distribution width (RDW) and mean platelet volume (MPV) appear to be systemic sensors that reflect disordered bone marrow response, and are markers for major adverse cardiac events. We asked whether elevated RDW and/or MPV were related to the risk of CVD events in PsO patients. We performed a retrospective study of psoriasis patients obtained from the Explorys electronic health record database. Psoriasis patients aged 18-65 with available RDW or MPV measurements were included. Patients with diabetes mellitus, Crohns disease, rheumatoid arthritis and generalized atherosclerosis were excluded. Chi-squared test was used for comparisons. Patients with psoriatic arthritis (PsA) were examined independently of PsO patients. A total of 39,510 patients had PsO; 1,920 patients exhibited elevated RDW plus MPV (5%), 7,060 had elevated RDW and normal MPV (18%), and 3,710 had normal RDW and elevated MPV (9%). The incidence of myocardial infarction (MI) was highest among patients with elevated RDW and MPV (OR 3.4, 95% CI 2.7-4.2, p<0.001), followed by patients with high RDW and normal MPV (OR 2.4, 95% CI 2.1-2.8, p<0.001), as compared to normal/low MPV and RDW patients. Atrial fibrillation, coronary artery disease, heart failure and peripheral vascular disease also had elevated OR ranging from 2-8.3, (p<0.001 each) in psoriasis patients with elevated RDW or elevated RDW plus MPV. Among patients with PSA, elevated RDW also increased the risk of an MI with an OR¼1.8, p<0.001. In a cohort of 23 PsO patients followed longitudinally for 1 year, 4 patients had elevated RDW at baseline; among these, 3 patients had a PASI75 response, and RDW was normalized for these responders. Bone marrow sensing of psoriatic inflammation likely alters RDW and MPV responses that are also associated with increased CVD risk.

The International Dermatology Outcome Measures initiative defined a set of domains to be measured in all psoriasis clinical trials. Psoriatic arthritis (PsA) Symptoms is part of this set. This work seeks to define PsA screening in psoriasis clinical trials and to identify appropriate measures for PsA symptoms. The performance of 4 screening tools and the psychometric properties of 3 PsA symptoms measures (Patient Global (PG)-arthritis, Routine Assessment of Patient Index Data-3 (RAPID3) and Psoriatic Arthritis Impact of Disease (PsAID)) were presented to stakeholders in a pre-Delphi, face-to-face meeting. Participants voted on the role of PsA screening in psoriasis trials, and on the clinimetric properties of PG-arthritis, RAPID3 and PsAID. Of the 47 stakeholders who participated in the voting, 93% agreed that all psoriasis trial participants should be screened for PsA. Our tesults showed that 48% of the participants voted that PGarthritis matched the domain, 62% agreed that it was feasible, and 29% believed that it was sensitive to change. With regards to RAPID3, 61% felt that it was a good reflection of the domain, 65% claimed that it was feasible, and 54% voted that it was responsive. Finally, 58% of participants agreed PsAID was a good measure for PsA symptoms, 73% voted it was feasible, and 50% claimed it was responsive. This pre-Delphi study showed all psoriasis trial participants should be screened for PsA. RAPID3 and PsAID slightly outperformed PG-arthritis in measuring PsA symptoms. This will be followed by a Delphi-survey involving a larger stakeholder group.