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International audience; BACKGROUND: Tezepelumab is a human monoclonal antibody that blocks thymic stromal lymphopoietin, an epithelial-cell–derived cytokine implicated in the pathogenesis of asthma. The efficacy and safety of tezepelumab in patients with severe, uncontrolled asthma require further assessment.METHODS: We conducted a phase 3, multicenter, randomized, double-blind, placebo-controlled trial. Patients (12 to 80 years of age) were randomly assigned to receive tezepelumab (210 mg) or placebo subcutaneously every 4 weeks for 52 weeks. The primary end point was the annualized rate of asthma exacerbations over a period of 52 weeks. This end point was also assessed in patients with baseline blood eosinophil counts of less than 300 cells per microliter. Secondary end points included the forced expiratory volume in 1 second (FEV1) and scores on the Asthma Control Questionnaire–6 (ACQ-6; range, 0 [no impairment] to 6 [maximum impairment]), Asthma Quality of Life Questionnaire (AQLQ; range, 1 [maximum impairment] to 7 [no impairment]), and Asthma Symptom Diary (ASD; range, 0 [no symptoms] to 4 [worst possible symptoms]).RESULTS: Overall, 1061 patients underwent randomization (529 were assigned to receive tezepelumab and 532 to receive placebo). The annualized rate of asthma exacerbations was 0.93 (95% confidence interval [CI], 0.80 to 1.07) with tezepelumab and 2.10 (95% CI, 1.84 to 2.39) with placebo (rate ratio, 0.44; 95% CI, 0.37 to 0.53; P

Tezepelumab is a human monoclonal antibody that blocks the activity of thymic stromal lymphopoietin. SOURCE evaluated the oral corticosteroid-sparing effect of tezepelumab in adults with oral corticosteroid-dependent asthma.We conducted this phase 3, multicentre, randomised, double-blind, placebo-controlled study across 60 sites in seven countries. Participants aged 18-80 years with physician-diagnosed asthma, who had been receiving medium-dose or high-dose inhaled corticosteroids and had at least one asthma exacerbation in the 12 months before screening were eligible. Patients who were receiving medium-dose inhaled corticosteroids must have had their dose increased to a high dose for at least 3 months before screening. After an oral corticosteroid optimisation phase of up to 8 weeks, participants were randomly assigned according to a computer-generated fixed block randomisation sequence to receive tezepelumab 210 mg or placebo subcutaneously every 4 weeks during a 48 week treatment period (4 week induction phase, 36 week oral corticosteroid reduction phase, and 8 week maintenance phase). Randomisation was stratified by region. Participants, investigators, and site staff were masked to treatment assignment. The primary endpoint was the categorised percentage reduction from baseline in daily oral corticosteroid dose at week 48 without the loss of asthma control. Efficacy and safety endpoints were assessed in all participants who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT03406078.Between March 5, 2018, and Sept 27, 2019, 150 participants were randomly assigned to receive tezepelumab 210 mg (n=74) or placebo (n=76). The cumulative odds of achieving a category of greater percentage reduction in an oral corticosteroid dose for daily maintenance at week 48 were similar with tezepelumab or placebo in the overall population (odds ratio [OR] 1·28 [95% CI 0·69-2·35], p=0·43; the primary endpoint was not met). The cumulative odds were higher with tezepelumab than with placebo in participants with baseline blood eosinophil counts of at least 150 cells per μL (2·58 [1·16-5·75]), but not in participants with counts below 150 cells per μL (0·40 [0·14-1·13]). Tezepelumab was well tolerated, with no safety concerns identified. 53 (72%) of 74 tezepelumab-assigned participants and 65 (86%) of 76 placebo-assigned participants reported an adverse event. Serious adverse events were reported in 12 (16%) participants in the tezepelumab group and 16 (21%) participants in the placebo group.We did not observe a significant improvement in oral corticosteroid dose reduction with tezepelumab versus placebo in the overall population of this oral corticosteroid-sparing study, although an improvement was observed in participants with baseline blood eosinophil counts of at least 150 cells per μL.AstraZeneca and Amgen.

Background/Purpose Current SLE treatment options have limited efficacy and potential toxicities that impede an individual’s ability to remain on therapy. AMG 570 is a bispecific antibody inhibiting both ICOSL and BAFF that engages ICOSL on antigen-presenting cells (dendritic cells and B cells) and reduces circulating naive B cells in healthy subjects. This phase 2 study will employ SLE drug screening and response-adaptive randomization (RAR) to optimize dose selection of AMG 570 in subjects with active SLE and inadequate response to standard of care (SOC) therapy (NCT04058028). Methods In this adaptive, phase 2, placebo-controlled, dose-ranging study, subjects (N∼300, age 18–75 years) will be randomized to receive placebo or 1 of 3 doses of AMG 570 Q2W for 52 weeks, followed by 16 weeks of safety follow-up. The primary objective is to evaluate efficacy of AMG 570 compared with placebo at week 24 using the SLE Responder Index (SRI-4). Key secondary endpoints include SRI-4 at week 52 with oral corticosteroid (OCS) reduction (≥10 mg/day at baseline to ≤7.5 mg/day in weeks 44–52) and SRI-4 and Lupus Low Disease Activity State at week 52. Subjects will undergo 2 screening visits to fulfill criteria for active SLE and demonstrate adherence to prior SLE treatment including OCS, immunosuppressants, and/or immunomodulators. Blood screening tests will confirm detectable serum drug levels of baseline SOC medications. RAR aims to allocate more subjects to more efficacious doses while maintaining the placebo allocation constant; the randomization ratio could be adapted after interim analyses based on clinical efficacy. The trial includes interim analyses for futility using the Bayesian approach. Results Study ongoing. Conclusion This study will provide safety and efficacy data for AMG 570 compared with placebo, and its adaptive trial design aims to optimize development of a novel therapy for SLE patients with inadequate response to current SOC. Acknowledgments Amgen Inc. sponsored this study.

Biosimilars are highly similar versions of approved branded biologics. Unlike generics, they are not exact replicas of reference products. Minor differences between biosimilars and reference products in some aspects are expected; likewise, biosimilar products will differ from each other. The objective of this review is to discuss the challenges associated with the development and approval of biosimilar products that are unique because of their complex structure and specialized manufacturing processes, which can impact not only efficacy but also immunogenicity and safety. Regulatory guidelines recommend a totality-of-evidence approach focused on stepwise development that involves demonstration of structural similarity and functional equivalence. Structural and functional characteristics of the proposed biosimilar are compared with the reference product; similarity of these functions forms the foundation of the biosimilar development program, including potential animal studies, a human pharmacokinetics/pharmacodynamics equivalence study, and a clinical study to confirm similar efficacy, safety, and immunogenicity. The clinical study should be performed in a sensitive population using appropriate endpoints to allow detection of any clinically meaningful differences between the biosimilar and the reference product if such differences exist. In conclusion, development of biosimilars is focused on the minimization of potential differences between the proposed biosimilar and reference product and the establishment of a robust manufacturing process to consistently produce a high-quality biosimilar product.

Phase I studies have shown that AMG 151 activates glucokinase, a key enzyme in glucose homeostasis. The present randomized, placebo-controlled phase IIa study evaluated the dose-effect relationship of the glucokinase activator AMG 151 relative to placebo on fasting plasma glucose (FPG) in 236 patients (33-35 patients per arm) with type 2 diabetes treated with metformin. Patients received oral AMG 151 at 50, 100 or 200 mg twice daily, AMG 151 at 100, 200 or 400 mg once daily or matching placebo for 28 days. A significant linear dose-effect trend was observed with the twice-daily regimen (p = 0.004) for change in FPG to day 28. No trend was observed with the once-daily regimen. A higher incidence of hypoglycaemia and hypertriglyceridaemia was observed with AMG 151 administration. AMG 151 significantly reduced FPG when administered twice daily but not when administered once daily in patients with type 2 diabetes treated with metformin.

Biologics have brought a new dimension to the treatment of chronic diseases. As compared to small molecules, biologics are created in living cells and thus the manufacturing of biologics is a complex process. This chapter discusses the multistep approach used to manufacture biotechnology-derived biologics. The chapter also discusses biosimilars and the complexity of their development and manufacturing along with highlighting the differences between two often-confused terms—biosimilarity and comparability.

Background ABP 501, an FDA- and EMA-approved biosimilar, is highly similar to adalimumab in structure, function, and pharmacokinetics. Objective Demonstrate similarity in efficacy, safety, and immunogenicity of ABP 501 versus adalimumab for moderate-to-severe plaque psoriasis. Methods Patients were randomised (1:1) to receive ABP 501 or adalimumab 40 mg every 2 weeks for 16 weeks. At Week 16, patients with ≥50% improvement from baseline in psoriasis area-and-severity index score (PASI) were eligible to continue to Week 52. Patients receiving ABP 501 continued; adalimumab patients were re-randomised (1:1) to continue adalimumab or undergo a single transition to ABP 501. Key efficacy assessments included % PASI improvement from baseline, PASI responders, and mean change in affected body surface area (BSA) from baseline to Weeks 16, 32, and 50. Safety was monitored via adverse events (AEs) and antidrug antibodies (ADAs) were assessed. Results 308 patients were re-randomised at Week 16 (ABP 501/ABP 501, n=152; adalimumab/adalimumab, n=79; adalimumab/ABP 501, n=77). PASI percent improvements from baseline were similar across groups for Weeks 16, 32, and 50 (range: 85.8%-88.2%), with no significant differences detected across groups in percentages of PASI 50, 75, 90, and 100 responders. Changes from baseline in %BSA affected were similar across groups and timepoints. No new safety signals were detected. AEs were balanced between groups. Percentages of patients with binding and neutralizing ADAs were similar across treatments. Conclusions ABP 501 and adalimumab have similar clinical efficacy, safety, and immunogenicity profiles over 52 weeks, including after single transition, in this patient population. This article is protected by copyright. All rights reserved.

Background ABP 710 is being developed as a biosimilar with the same amino acid sequence as infliximab, an anti-tumor necrosis factor therapy. Analytical and functional comparisons between ABP 710 and infliximab have been conducted and completed. Objectives This report describes the results of analyses comparing the pharmacokinetics (PK), safety, and immunogenicity of ABP 710 and infliximab sourced from the European Union (EU). Methods This was a single-blind, single-dose, parallel-group study among healthy adults, 18 to 45 years of age and with a body mass index of 18 to 30 kg/m2. Subjects were randomized to receive a 5 mg/kg intravenous infusion of either ABP 710 or infliximab. The primary objective of this analysis was demonstration of PK similarity of ABP 710 to infliximab based on area under the serum concentration-time curve from time 0 extrapolated to infinity (AUCinf; primary endpoint). PK equivalence was deemed achieved if the geometric mean (GM) ratio and its 90% confidence interval (CI) for AUCinf was within the range of 0.80 and 1.25. Secondary endpoints included maximum observed serum concentration (Cmax), area under the serum concentration-time curve from time 0 to last quantifiable concentration (AUClast), safety, and immunogenicity. Results Pharmacokinetics: A total of 49 subjects received ABP 710 and 49 subjects received infliximab. Following a single dose, the adjusted least square (LS) GM of AUCinf, AUClast, and Cmax for ABP 710 was 33559 μg·h/mL, 31789 μg·h/mL, and 123 μg/mL, respectively. The adjusted LS GM of AUCinf, AUClast, and Cmax for infliximab was 33706 μg·h/mL, 31847 μg·h/mL, and121 μg/mL, respectively. Ratios of adjusted LS GMs (90% CIs) between ABP 710 and infliximab for AUCinf, AUClast, and Cmax were 0.996 (0.904, 1.096), 0.998 (0.918, 1.086), and 1.021 (0.962, 1.083), respectively. Safety: There was one subject in the infliximab group who developed polyarthritis that resolved with treatment and the subject completed the study. There were no deaths, other serious adverse events, or treatment-emergent adverse events (TEAEs) leading to discontinuation from the study. The incidence of TEAEs was similar in the two treatment groups (ABP 710: 83.7%; infliximab: 83.7%); the majority of TEAEs were mild or moderate. The most frequently reported TEAEs were somnolence, headache, nasopharyngitis, upper respiratory tract infection, nausea, and lethargy. Immunogenicity: All subjects tested negative for antidrug antibodies (ADAs) prior to dosing. At the end of study (Day 57), 40% of subjects in the ABP 710 group and 27% in the infliximab group were positive for binding ADAs, and 13% of subjects in the ABP 710 group and 19% in the infliximab group were positive for neutralizing ADAs. Conclusions Results of this phase 1 study demonstrate PK similarity between ABP 710 and infliximab sourced from the EU among healthy subjects. The safety and immunogenicity profile were comparable between the treatment groups. Disclosure of Interest E. Krishnan Shareholder of: Amgen Inc., Employee of: Amgen Inc., V. Chow Shareholder of: Amgen Inc., Employee of: Amgen Inc., N. Zhang Shareholder of: Amgen Inc., Employee of: Amgen Inc., A. Kaliyaperumal Shareholder of: Amgen Inc., Employee of: Amgen Inc., P. Kaur Shareholder of: Amgen Inc., Employee of: Amgen Inc.

Aims: To determine the cost-effectiveness of treatment sequences of biologic disease-modifying anti-rheumatic drugs or Janus kinase/STAT pathway inhibitors (collectively referred to as bDMARDs) vs conventional DMARDs (cDMARDs) from the US societal perspective for treatment of patients with moderately to severely active rheumatoid arthritis (RA) with inadequate responses to cDMARDs. Materials and methods: An individual patient simulation model was developed that assesses the impact of treatments on disease based on clinical trial data and real-world evidence. Treatment strategies included sequences starting with etanercept, adalimumab, certolizumab, or abatacept. Each of these treatment strategies was compared with cDMARDs. Incremental cost, incremental quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs) were calculated for each treatment sequence relative to cDMARDs. The cost-effectiveness of each strategy was determined using a US willingness-to-pay (WTP) threshold of $150,000/QALY. Results: For the base-case scenario, bDMARD treatment sequences were associated with greater treatment benefit (i.e. more QALYs), lower lost productivity costs, and greater treatment-related costs than cDMARDs. The expected ICERs for bDMARD sequences ranged from ∼$126,000 to $140,000 per QALY gained, which is below the US-specific WTP. Alternative scenarios examining the effects of homogeneous patients, dose increases, increased costs of hospitalization for severely physically impaired patients, and a lower baseline Health Assessment Questionnaire (HAQ) Disability Index score resulted in similar ICERs. Conclusions: bDMARD treatment sequences are cost-effective from a US societal perspective.

Background ABP 501 is a biosimilar of adalimumab. Objective We sought to compare the efficacy and safety of ABP 501 with adalimumab. Methods This 52-week, double-blind study randomized patients with moderate to severe psoriasis to ABP 501 or adalimumab. At week 16, those with 50% or more improvement in Psoriasis Area and Severity Index score from baseline on ABP 501 continued the same treatment, whereas adalimumab-treated patients were rerandomized to adalimumab or ABP 501. Clinical similarity in Psoriasis Area and Severity Index percent improvement from baseline to week 16 (primary end point) was established if the point estimate of treatment difference and its 2-sided 95% confidence interval between groups was within equivalence margin of ±15. Patients, including those undergoing a single transition at week 16, were evaluated for safety and immunogenicity. Results Psoriasis Area and Severity Index percent improvement at week 16 was 80.9 for ABP 501 and 83.1 for adalimumab (least-square mean difference −2.18 [95% confidence interval −7.39 to 3.02]). Adverse events (67.2% [117/174] vs 63.6% [110/173]) and antidrug antibody incidence (55.2% [96/174] vs 63.6% [110/173]) for ABP 501 vs adalimumab were similar. Safety, including immunogenicity, was similar among groups after single transition (week 20). Limitations The 52-week data are not reported here. Conclusions ABP 501 was shown to be clinically similar to adalimumab. Safety and immunogenicity were not impacted immediately after single transition (adalimumab to ABP 501).

This study aims to evaluate patient perceptions of subcutaneous denosumab or oral alendronate in postmenopausal women with or at risk for osteoporosis and how these perceptions influence adherence.Postmenopausal women with low bone mass were randomized to denosumab 60 mg every 6 months for 1 year (treatment period 1 [TP1]) followed by alendronate 70 mg once weekly for 1 year (treatment period 2 [TP2]), or vice versa. Beliefs about Medicines Questionnaire data were collected at baseline and at 6, 12, 18, and 24 months; a necessity-concerns differential (NCD) was calculated for each time point. Logistic regression analyses were performed to evaluate the influences of baseline characteristics on nonadherence.Participants included 250 women (alendronate/denosumab, n = 124; denosumab/alendronate, n = 126). During TP1, the NCD at month 6 was higher with denosumab than with alendronate (P = 0.0076). In TP2, the NCD was higher for women switched to denosumab than for women switched to alendronate at 6 months (P = 0.0126) and 12 months (P = 0.4605). Denosumab was preferred to alendronate regardless of treatment sequence (P0.0001). Covariate analysis revealed that higher TP2 baseline necessity scores were associated with lower odds of nonadherence (P = 0.0055), whereas higher concerns about medication scores were associated with higher odds of nonadherence (P = 0.0247). Higher NCD scores were also associated with lower odds of nonadherence (P = 0.0015).Participants preferred denosumab to alendronate while on treatment and had more positive perceptions of denosumab than alendronate. These perceptions were associated with better adherence.

Objectives ABP 501 is a Food and Drug Administration-approved biosimilar to adalimumab; structural, functional and pharmacokinetic evaluations have shown that the two are highly similar. We report results from a phase III study comparing efficacy, safety and immunogenicity between ABP 501 and adalimumab. Methods In this randomised, double-blind, active comparator-controlled, 26-week equivalence study, patients with moderate to severe active rheumatoid arthritis (RA) despite methotrexate were randomised (1:1) to ABP 501 or adalimumab (40 mg) every 2 weeks. Primary endpoint was risk ratio (RR) of ACR20 between groups at week 24. Primary hypothesis that the treatments were equivalent would be confirmed if the 90% CI for RR of ACR20 at week 24 fell between 0.738 and 1.355, demonstrating that ABP 501 is similar to adalimumab. Secondary endpoints included Disease Activity Score 28-joint count-C reactive protein (DAS28-CRP). Safety was assessed via adverse events (AEs) and laboratory evaluations. Antidrug antibodies were assessed to determine immunogenicity. Results A total of 526 patients were randomised (n=264, ABP 501; n=262 adalimumab) and 494 completed the study. ACR20 response at week 24 was 74.6% (ABP 501) and 72.4% (adalimumab). At week 24, the RR of ACR20 (90% CI) between groups was 1.039 (0.954, 1.133), confirming the primary hypothesis. Changes from baseline in DAS28-CRP, ACR50 and ACR70 were similar. There were no clinically meaningful differences in AEs and laboratory abnormalities. A total of 38.3% (ABP 501) and 38.2% (adalimumab) of patients tested positive for binding antidrug antibodies. Conclusions Results from this study demonstrate that ABP 501 is similar to adalimumab in clinical efficacy, safety and immunogenicity in patients with moderate to severe RA. Trial registration number NCT01970475; Results.

ObjectiveTo demonstrate pharmacokinetic (PK) similarity of biosimilar candidate ABP 501 relative to adalimumab reference product from the USA and European Union (EU) and evaluate safety, tolerability and immunogenicity of ABP 501.MethodsRandomised, single-blind, single-dose, three-arm, parallel-group study; healthy subjects were randomised to receive ABP 501 (n=67), adalimumab (USA) (n=69) or adalimumab (EU) (n=67) 40 mg subcutaneously. Primary end points were area under the serum concentration-time curve from time 0 extrapolated to infinity (AUCinf) and the maximum observed concentration (Cmax). Secondary end points included safety and immunogenicity.ResultsAUCinf and Cmax were similar across the three groups. Geometrical mean ratio (GMR) of AUCinf was 1.11 between ABP 501 and adalimumab (USA), and 1.04 between ABP 501 and adalimumab (EU). GMR of Cmax was 1.04 between ABP 501 and adalimumab (USA) and 0.96 between ABP 501 and adalimumab (EU). The 90% CIs for the GMRs of AUCinf and Cmax were within the prespecified standard PK equivalence criteria of 0.80 to 1.25. Treatment-related adverse events were mild to moderate and were reported for 35.8%, 24.6% and 41.8% of subjects in the ABP 501, adalimumab (USA) and adalimumab (EU) groups; incidence of antidrug antibodies (ADAbs) was similar among the study groups.ConclusionsResults of this study demonstrated PK similarity of ABP 501 with adalimumab (USA) and adalimumab (EU) after a single 40-mg subcutaneous injection. No new safety signals with ABP 501 were identified. The safety and tolerability of ABP 501 was similar to the reference products, and similar ADAb rates were observed across the three groups.Trial registration numberEudraCT number 2012-000785-37; Results.

Background ABP 501 is being developed as a biosimilar candidate to adalimumab, a fully human recombinant monoclonal antibody. Evidence from analytical and pharmacokinetic comparisons indicates that ABP 501 is highly similar to adalimumab. Results of efficacy and safety from a phase 3 study comparing ABP 501 with adalimumab in subjects with rheumatoid arthritis (RA) have been previously presented. 1,2 Objectives To report descriptive results from additional efficacy analysis based on clinical disease activity index (CDAI) and simplified disease activity index (SDAI) composite indices as well as results for the ACR individual components. These analyses provide information on alternate methods for disease management. Methods This was a randomized, double-blind, active-controlled study in adult subjects with moderate to severe RA who had an inadequate response to methotrexate. Subjects were randomized in a 1:1 ratio (ABP 501: n=264; adalimumab: n=262) to receive either ABP 501 or adalimumab 40 mg subcutaneously every 2 weeks. Details of the study design have been previously reported. 1 For these analyses descriptive summaries of CDAI, SDAI and individual American College of Rheumatology response criteria (ACR) components were generated. Results Baseline characteristics were well balanced between groups. At week 24, the mean (SD) CDAI improvement from baseline was 25.94 (12.62) for ABP 501 and 25.06 (12.02) for adalimumab. At week 24, the mean (SD) SDAI improvement from baseline was 26.57 (12.97) for ABP 501 and 25.64 (12.31) for adalimumab. Results for CDAI, SDAI and individual ACR components at baseline and week 24 are shown in the Table. The overall safety and immunogenicity profile of ABP 501 was comparable to that of adalimumab and has been previously reported. 1,2 Conclusions These additional analyses confirm that the of efficacy ABP 501 is comparable to adalimumab in multiple clinical characterisitics providing further evidence that ABP 501 is similar to adalimumab. References Cohen et al. Presented at: American College of Rheumatology Annual Meeting; November 2015; San Francisco, CA. Abstract 2054. Matsumoto et al. Presented at: American College of Rheumatology Annual Meeting; November 2015; San Francisco, CA. Abstract 2757. Acknowledgement Monica Ramchandani, PhD for medical writing. Disclosure of Interest S. Cohen Consultant for: Amgen, N. Zhang Shareholder of: Amgen, Employee of: Amgen, P. Kaur Shareholder of: Amgen, Employee of: Amgen

Background ABP 501 is being developed as a biosimilar candidate to adalimumab (Humira®), a fully human recombinant monoclonal antibody (mAb). ABP 501 has the same amino acid sequence and similar post-translational modifications as adalimumab. It is well known that serum antibodies to adalimumab are associated with lower serum adalimumab concentration. 1 Objectives To evaluate the pharmacokinetics (PK) and anti-drug antibody (ADA) relationship of ABP 501 and adalimumab sourced from the US and EU. Methods This was a single-blind, single-dose, three-arm, parallel-group study. Healthy men and women were randomized to receive 40-mg subcutaneous (SC) injection of ABP 501, adalimumab (US), or adalimumab (EU); PK, safety, and immunogenicity were evaluated. For PK evaluation, serum samples were collected predose; 1, 4, 8, 12, and 24 hours postdose; at each return visit (days 3, 4, 5, 6, 7, 8, 9, 11, 14, 16, 22, 29, 36, 43, 50, and 57); and at the end of study (day 63). Serum concentrations of each mAb were determined using a validated electrochemiluminescent (ECL) assay. Individual concentration-time data for all three molecules were analyzed by noncompartmental PK analysis methods. For ADA analysis, serum samples were collected on days 1 (predose), 16, 29, and 63. A screening immunoassay was used to detect and a confirmatory immunoassay was used to confirm the specificity of binding antibodies. All samples were tested against all three test molecules. The assay sensitivity for ADAs in presence of 25 μg/mL drug was approximately 0.02 μg/mL. Results Results demonstrating the equivalence of PK, safety, and immunogenicity of ABP 501 compared with adalimumab (US) and adalimumab (EU) have been previously presented. 2,3 No preexisting ADAs were detected at baseline. Subjects who developed binding antibodies in each group were as follows: ABP 501, 36 (54%); adalimumab (US), 38 (55%); and adalimumab (EU), 45 (67%). Median time to maximum concentration (t max ) and geometric means of maximum observed serum concentration (C max ) were similar following the single-dose SC injection of all three molecules independent of ADA status. Overall exposure (area under serum concentration-time curve, AUC) was approximately 20%–30% lower in ADA-positive compared with ADA-negative subjects for all three molecules. Consistent with lower exposure were the shorter elimination half-lives (t 1/2 ) in ADA-positive subjects. On average, t 1/2 was 6–7 days in ADA-positive subjects compared with 12–15 days in ADA-negative subjects. Conclusions Results of this analysis demonstrated that ADA status influences the pharmacokinetics of ABP 501, adalimumab (US), and adalimumab (EU). This is in line with the previously published literature. It is important to continue to monitor this relationship in subsequent pivotal studies when comparing the biosimilar candidate to the reference product to understand if there is an associated change in efficacy. References Bartelds GM, et al. Ann Rheum Dis. 2007;66(7):921-926. Kaur P, et al. Presented at: European League Against Rheumatism Annual Meeting; June 2014; Paris, France. Abstract FRI0264. Kaur P, et al. Presented at: American College of Rheumatology Annual Meeting; November 2014; Boston, MA. Abstract 1504. Acknowledgements Michael Moxness, PhD for clinical immunology work, Amy Rasmussen for study management and Monica Ramchandani, PhD for medical writing. Disclosure of Interest P. Kaur Shareholder of: Amgen stock, Employee of: Amgen, V. Chow Shareholder of: Amgen stock, Employee of: Amgen, N. Zhang Shareholder of: Amgen stock, Employee of: Amgen, R. Markus Shareholder of: Amgen stock, Employee of: Amgen

e14659 Background: ABP 215 is a biosimilar candidate to bevacizumab (BEV), a monoclonal antibody (mAb) that binds and inhibits vascular endothelial growth factor (VEGF). Biosimilar mAbs are likely ...

711 Background: ABP 215 is a biosimilar candidate to bevacizumab (BEV), a monoclonal antibody (mAb) that binds and inhibits vascular endothelial growth factor (VEGF). Biosimilar mAbs are likely to have differences in product quality attributes due to different expression systems, bioprocess and purification, so demonstration of functional similarity and pharmacokinetic (PK) equivalence is the foundation for biosimilarity. Objectives: To assess functional similarity and PK equivalence of ABP 215 and BEV sourced from EU and US. Methods: Functional similarity testing included binding to VEGF and VEGF isoforms by surface plasmon resonance and to FcRn and FcγRIIIa. Inhibition of proliferation and VEGFR2 autophosphorylation was compared in endothelial cells. PK equivalence was evaluated in a randomized, single-dose, 3-arm study in healthy adult male subjects. Primary endpoints were area under the serum concentration-time curve from time 0 to infinity (AUCinf) and maximum observed serum concentration (Cmax). Secondary endpoints were safety, tolerability, and immunogenicity. Results: ABP 215 and BEV (EU) are functionally similar as previously presented. Binding affinity to VEGF was similar between ABP 215 (117 pM) and BEV (US) (126 pM) as was binding to VEGF165 and VEGF121. Binding to FcRn was similar between ABP 215 (95-102%) and BEV (96-111%). Binding to FcγRIIIa was also similar; ABP 215 (108-115%) and BEV (85-93%). Potency in proliferation inhibition was similar between ABP 215 (91-97%) and BEV (91-96%), as was inhibition of autophosphorylation. After a single dose, geometric mean (GM) of Cmax and AUCinf for ABP 215 were 87.2 µg/mL and 29,400 µg.h/mL, for BEV (US) were 89.1 µg/mL and 29,600 µg.h/mL, for BEV (EU) were 84.7 µg/mL and 30,600 µg.h/mL. The 90% CIs of GM ratio for Cmax and AUCinf were within pre-specified equivalence criterion of 0.80 to 1.25 confirming PK equivalence. There were no adverse events (AEs) or serious AEs leading to study discontinuation. Treatment-related AEs were reported for 22.1% in ABP 215, 16.4% in BEV (US) and 22.4% in BEV (EU) groups; no subjects developed anti-drug antibodies. Conclusions: ABP 215 is similar to BEV in sensitive functional tests and equivalent to BEV based on results of the phase 1 PK study.

Background Adalimumab (Humir®) is a recombinant IgG1 monoclonal antibody that binds to TNFα blocking its interaction with p55 and p75 cell surface receptors. ABP 501 is being developed as a biosimilar candidate to adalimumab, contains a fully human recombinant monoclonal antibody with same amino acid sequence and similar post-translational modifications. Evidence from analytical comparisons indicates that ABP 501 is highly similar to adalimumab. We describe the pharmacokinetic results of ABP 501 compared with adalimumab (EU). Objectives To demonstrate pharmacokinetic equivalence of ABP 501 to adalimumab Methods This was a single-blind, single-dose, 3-arm, parallel-group study. Subjects were randomized to receive 40-mg subcutaneous (SC) injection of ABP 501, adalimumab (US) or adalimumab (EU). Subjects included healthy male and female subjects, 18 to 45 years of age with a body mass index of 18 to 30 kg/m 2 . Primary endpoint was demonstration of pharmacokinetic equivalence of ABP 501 relative to adalimumab, based on area under the serum concentration-time curve (AUC) from time 0 extrapolated to infinity (AUC inf ) and the maximum observed serum concentration (C max ). Pre-specified equivalence criterion for all parameters was 90% confidence interval (CI) for geometric means (GM) ratio within 0.80 to 1.25. Secondary endpoints included the safety, tolerability, and immunogenicity. Results A total of 67 subjects received ABP 501 and 67 subjects received adalimumab (EU). Following single dose, the GM of C max , AUC last and AUC inf for ABP 501 were 3.22ng/ml, 2002.27 ng.h/ml and 2136.95ng.h/ml and a median t max of 190.82 hr. The GM of C max , AUC last and AUC inf for adalimumab (EU) were 3.37 ng/ml, 2022.62 ng.h/ml and 2046.82 ng.h/ml and a median t max of 168.00 hr. Ratio of adjusted least square geometric means (90% CIs) between ABP 501 and adalimumab (EU) for C max was 0.96 (0.89, 1.03); AUC inf was 1.04 (0.93, 1.17) and AUC last was 0.99 (0.89, 1.10). The 90% CIs of GM ratio for C max AUC inf , and AUC last were fully contained within 0.80 to 1.25, confirming the bioequivalence between ABP 501 and adalimumab (EU). There were no treatment related serious adverse events, or treatment related adverse events leading to discontinuation from the study. The most frequently reported treatment-related AEs included headache, nausea, nasopharyngitis, and oropharyngeal pain. No pre-existing anti-drug antibodies (ADA) were detected at baseline. In the ABP 501 treatment group, 36 (54%) subjects developed binding antibodies and 12 (18%) developed neutralizing antibodies. In the adalimumab (EU) treatment group, 45 (67%) subjects developed binding antibodies and 14 (21%) developed neutralizing antibodies. Conclusions Results of this phase 1 study demonstrated bioequivalence of ABP 501 following a single 40-mg SC injection relative to that from a 40-mg SC injection of adalimumab (EU). No new safety signals with ABP 501 treatment were identified. Disclosure of Interest P. Kaur Shareholder of: Amgen, Employee of: Amgen, V. Chow Shareholder of: Amgen, Employee of: Amgen, N. Zhang Shareholder of: Amgen, Employee of: Amgen, M. Moxness Shareholder of: Amgen, Employee of: Amgen, R. Markus Shareholder of: Amgen, Employee of: Amgen DOI 10.1136/annrheumdis-2014-eular.2166