BackgroundThis double-blind, randomized, 78-week study evaluated the efficacy, safety, immunogenicity, pharmacokinetics, and pharmacodynamics of PF-06410293, a candidate adalimumab biosimilar, versus adalimumab reference product (Humira®) sourced from the EU (adalimumab-EU) in biologic-naïve patients with active rheumatoid arthritis (RA) despite methotrexate (MTX) (10–25 mg/week). We report results for the first 26 weeks of treatment.MethodsPatients with active RA (N = 597) were randomly assigned (1:1) to PF-06410293 or adalimumab-EU, while continuing with MTX treatment. The primary endpoint was American College of Rheumatology 20% improvement (ACR20) at week 12. Therapeutic equivalence was concluded if the two-sided 95% confidence interval (CI) for the ACR20 difference between the two arms was entirely contained within the symmetric equivalence margin (±14%). Additionally, a two-sided 90% CI was calculated by using an asymmetric equivalence margin (−12%, 15%). Secondary efficacy endpoints to week 26 included ACR20/50/70, change from baseline Disease Activity Score based on high-sensitivity C-reactive protein [DAS28–4(CRP)], European League Against Rheumatism (EULAR) response, DAS28–4(CRP) of less than 2.6, and ACR/EULAR remission. QuantiFERON-TB testing was performed at screening and week 26.ResultsPatients (78.7% of whom were female and whose mean age was 52.5 years) had a mean baseline RA duration of 6.8 years. The mean baseline DAS28–4(CRP) values were 5.9 (PF-06410293) and 6.1 (adalimumab-EU). The observed week-12 ACR20 values were 68.7% (PF-06410293) and 72.7% (adalimumab-EU) in the intention-to-treat population. With non-responder imputation, the treatment difference in week-12 ACR20 was −2.98% and corresponding CIs—95% CI (−10.38%, 4.44%) and 90% CI (−9.25%, 3.28%)—were entirely contained within the equivalence margins (symmetric and asymmetric, respectively). The secondary efficacy endpoints were similar between arms. Over 26 weeks, injection-site reactions occurred in 1.7% versus 2.0%, hypersensitivity events in 4.4% versus 8.4%, pneumonia in 0.7% versus 2.0%, and opportunistic infections in 2.4% versus 1.7% in the PF-06410293 and adalimumab-EU arms, respectively. One death due to myocardial infarction occurred (adalimumab-EU arm). Rates of anti-drug antibody incidence were 44.4% (PF-06410293) and 50.5% (adalimumab-EU).ConclusionsThe study results demonstrate that efficacy, safety, and immunogenicity of PF-06410293 and adalimumab-EU were similar during the first 26 weeks of treatment in patients with active RA on background MTX.Trial registrationClinicalTrials.gov Identifier: NCT02480153. First posted on June 24, 2015; EU Clinical Trials Register EudraCT number: 2014-000352-29. Start date: October 27, 2014.Electronic supplementary materialThe online version of this article (10.1186/s13075-018-1676-y) contains supplementary material, which is available to authorized users.

ObjectiveTo investigate the efficacy, safety, immunogenicity and pharmacokinetics of biosimilar adalimumab (ADL) PF-06410293 (ADL-PF; adalimumab-afzb) versus EU-sourced reference ADL (ADL-EU) in patients with active rheumatoid arthritis (RA) on longer-term treatment and after being switched from ADL-EU to ADL-PF.MethodsIn this multinational, double-blind study, patients with active RA were initially randomised to ADL-PF or ADL-EU for 26 weeks (treatment period (TP) 1). At the start of TP2 (weeks 26–52), patients in the ADL-EU arm were blindly re-randomised 1:1 to remain on ADL-EU (ADL-EU/ADL-EU; n=135) or switched to ADL-PF (ADL-EU/ADL-PF; n=134); patients receiving ADL-PF continued blinded treatment (ADL-PF/ADL-PF; n=283).ResultsThe American College of Rheumatology 20% improvement (ACR20) response rates were comparable between treatment groups at all visits during TP2. At week 52, ACR20 response rates were 82.7% (ADL-PF/ADL-PF), 79.3% (ADL-EU/ADL-EU) and 84.3% (ADL-EU/ADL-PF). Other measures of deep response (ACR50/70, ACR/EULAR-defined remission, EULAR good response, and Disease Activity Score in 28 Joints Based on High-Sensitivity C-Reactive Protein <2.6) and Health Assessment Questionnaire−Disability Index were maintained over TP2 and comparable between groups. Treatment-emergent adverse events were reported in 43.5% (ADL-PF/ADL-PF), 44.4% (ADL-EU/ADL-EU) and 38.3% (ADL-EU/ADL-PF) of patients; there were no clinically meaningful differences in the safety profiles between groups. The percentage of patients who were antidrug antibody positive was comparable overall among ADL-PF/ADL-PF (47.3%), ADL-EU/ADL-EU (54.1%) and ADL-EU/ADL-PF (45.9%).ConclusionsThe similar efficacy, safety, immunogenicity and pharmacokinetics of ADL-PF and ADL-EU, maintained up to week 52, were unaffected by blinded treatment switch from ADL-EU to ADL-PF at week 26.Trial registration numberClinicalTrials.gov identifier: NCT02480153; EudraCT number: 2014-000352-29.

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

Background/objective REFLECTIONS B538–02 is a randomized, double-blind comparative study of the adalimumab (ADL) biosimilar PF-06410293, (ADL-PF), and reference ADL sourced from the European Union (ADL-EU) in patients with active RA. Therapeutic equivalence was demonstrated based on ACR20 responses at week 12 (primary endpoint). We report long-term safety, immunogenicity, and efficacy of ADL-PF in patients who continued ADL-PF treatment throughout 78 weeks or who switched from ADL-EU to ADL-PF at week 26 or week 52. Methods Eligible patients (2010 ACR/EULAR RA diagnosis criteria for ≥ 4 months; inadequate response to MTX, ≤ 2 doses non-ADL biologic), stratified by geographic regions were initially randomized (1:1) in treatment period 1 (TP1) to ADL-PF or ADL-EU (40 mg subcutaneously, biweekly), both with MTX (10–25 mg/week). At week 26 (start of TP2), patients receiving ADL-EU were re-randomized to remain on ADL-EU or transition to ADL-PF for 26 weeks. At week 52 (start of TP3), all patients received open-label treatment with ADL-PF for 26 weeks and were followed after last treatment dose to week 92. To evaluate maintenance of response after switching or remaining on ADL-PF, ACR20, DAS28-4(CRP), and other measures of clinical response/remission were assessed through week 78 as secondary endpoints. Three groups were evaluated: biosimilar, week 26 switch, and week 52 switch. Results Overall, 507 patients participated in TP3. ACR20 response rates at week 52 were 88.4%, 88.2%, and 87.6% for the biosimilar, week 26, and week 52 switch groups, respectively. ACR20 response rates and DAS28-4(CRP) scores were sustained and comparable across groups in TP3. Incidence of treatment-emergent adverse events (AEs) during TP3 and follow-up was 42.6% (biosimilar), 37.0% (week 26 switch), and 50.8% (week 52 switch); 3 (0.6%) patients (all week 52 switch) reported treatment-related serious AEs. ADL-PF was generally well tolerated, with a comparable safety profile across groups. Overall, incidences of patients with anti-drug antibodies in TP3 and follow-up were comparable among groups (46.1%, 46.5%, and 54.2%, respectively). Conclusions There were no clinically meaningful differences in safety, immunogenicity, and efficacy for patients who were maintained on ADL-PF for 78 weeks and those who had switched from ADL-EU at week 26 or week 52. Trial registration ClinicalTrials.gov, NCT02480153. First posted on June 24, 2015; EU Clinical Trials Register; EudraCT number: 2014-000352-29. Start date, October 27, 2014

Introduction The aim of this sub-study was to evaluate injection success of patients with rheumatoid arthritis (RA) and their caregivers administering the adalimumab (ADL) biosimilar, PF-06410293 (ADL-PF: adalimumab-afzb; Abrilada ® /Amsparity ® /Xilbrilada ® ) by prefilled pen (PFP) during the open-label treatment period in year two (weeks 52–78) of a phase 3 multinational, double-blind, clinical study (NCT02480153) comparing ADL-PF and reference ADL (Humira ® ) sourced from the EU. Methods This sub-study included adult patients with active RA not adequately controlled by methotrexate. Patients received subcutaneous ADL-PF 40 mg by prefilled syringe (PFS) at weeks 52 and 54, then six biweekly doses (weeks 56–66) of ADL-PF 40 mg each via a single-use PFP device. Training was given on first injection at week 56; all injections were given by patients/caregivers. The primary endpoint was delivery system success rate (DSSR): the percentage of participants (i.e., actual PFP user) achieving delivery success for each of the six attempted PFP injections. Injection success was recorded by the observer (Observer Assessment Tool) and participant (Participant Assessment Tool). Results In total, 50 patients with no experience self-injecting with an autoinjector/injection pen were included (74.0% female; mean age at screening, 54.9 years; mean RA duration, 8.0 years). Of these, 49 (98.0%) completed the sub-study and 46 (92.0%) received all six PFP injections. Overall DSSR ( n = 294 injections) across visits was 100% (95% CI 92.0–100.0%). Complete injection was confirmed following inspection of 292 used and returned PFPs. A total of 47/49 (95.9%) participants who completed the sub-study elected to continue study treatment using PFP injections, rather than switching back to the PFS. Conclusions All actual PFP users could safely and effectively administer ADL-PF by PFP at each visit, and nearly all participants who completed the sub-study elected to continue study treatment using PFP injections. Trial registration ClinicalTrials.gov identifier: NCT02480153; EudraCT number: 2014-000352-29. Supplementary Information The online version contains supplementary material available at 10.1007/s40744-022-00439-8.