Anti-citrullinated protein autoantibodies promote inflammation and joint tissue injury and define a poor prognostic group of patients with rheumatoid arthritis (RA). Citrullinated autoantigens that drive this autoimmune response are generated by peptidylarginine deiminase (PAD) enzymes, which are predominately expressed and released by neutrophils and monocytes. Accordingly, blocking the enzymatic activity of PADs to curb the generation of citrullinated autoantigens that drive autoimmunity and tissue injury may provide therapeutic benefit. Herein, we developed a high affinity, bispecific, anti-PAD2/4, effector-null antibody, AZD1163, which potently inhibits recombinant PAD2 and PAD4 activity in both histone H3 and fibrinogen citrullination assays. AZD1163 inhibited all endogenous PAD activity in the serum of patients with RA irrespective of the presence of anti-PAD4 autoantibodies, and neutralized PAD activity in synovial fluid. AZD1163 also bound and internalized PADs expressed on cell membranes into low pH endosomes for degradation, reducing the surface expression and catalytic potential. Binding of AZD1163 to neutrophils and monocytes did not trigger complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, or the production of proinflammatory cytokines, or otherwise impact neutrophil phagocytosis, production of reactive oxygen species, or NETosis. In a non-human primate study of pharmacokinetics (PK) and pharmacodynamics, a single dose of AZD1163 exhibited PK consistent with a half-life extended antibody and a rapid and durable suppression of endogenous PAD activity. AZD1163 has a favorable preclinical safety profile. Collectively, these in vitro and in vivo pharmacology and safety data support the clinical development of AZD1163 as a novel therapeutic strategy for RA by reducing autoantigen load.

Aims Retinoic acid-related orphan receptor gamma (ROR gamma), a master regulator of T-helper 17 (Th17) cell function and differentiation, is an attractive target for treatment of Th17-driven diseases. This first-in-human study aimed to investigate the pharmacokinetics, pharmacodynamics, safety and tolerability of the inverse ROR gamma agonist AZD0284. Methods We conducted a phase I, randomized, single-blind, placebo-controlled, two-part, first-in-human study with healthy subjects receiving single (4-238 mg) or multiple (12-100 mg) oral doses of AZD0284 or placebo after overnight fasting. Subjects in the one single dose cohort additionally received a single dose of AZD0284 after a high-calorie meal. AZD0284 plasma concentrations, as well as inhibition of ex vivo-stimulated interleukin (IL)-17A release in whole blood, were frequently measured after both single and multiple dosing. Results Eighty-three men participated in the study. AZD0284 was absorbed rapidly into plasma after oral dosing and exhibited a terminal half-life of 13-16 hours. Both the area under the concentration-time curve (AUC) and maximum concentration (C-max) increased subproportionally with increasing dose (95% confidence intervals of slope parameter were 0.71-0.84 and 0.72-0.88 for AUC and C-max, respectively). Food intake delayed the absorption of AZD0284 but did not affect the overall exposure or half-life. AZD0284 showed dose-dependent reduction of ex vivo-stimulated IL-17A release after both single and multiple doses. No significant safety concerns were identified in the study. Conclusions AZD0284 was well tolerated, rapidly and dose-dependently absorbed, and reduced stimulated IL-17A release after single and multiple dosing. The results of this study support further clinical development of AZD0284.

Conclusions • Disease control is not achieved in approximately 5–10% of patients with asthma, despite the availability of standard-of-care therapies (inhaled corticosteroids in combination with long-acting β2 agonists).1 – This inability to achieve asthma control reduces patients’ quality of life and increases healthcare costs. • Type 2 cytokines, interleukin (IL)-4, IL-5 and IL-13, play crucial roles in asthma pathogenesis.2,3 • AZD1402/PRS-060 is an anti-IL-4 receptor α (IL-4Rα) tear lipocalin-derived Anticalin protein being developed for moderate-to-severe asthma (Figure 1). – AZD1402/PRS-060 has a high potency (KD 0.023 nM) and selectivity for human IL4-Rα and is being developed to target asthma locally via inhalation. • Dupilumab is a fully human IL-4Rα monoclonal antibody given by subcutaneous injection, which inhibits IL-4 and IL-13 signaling.4 – It has been shown to reduce exacerbations and improve lung function in patients with moderate-to-severe asthma. • Pitrakinra is an inhaled IL-4 mutein that antagonizes IL-4Rα and has been shown to have beneficial effects in a subset of patients with asthma.5 • Here, we describe the results of a phase 1, first-in-human study of AZD1402/PRS-060.

AZD1402/PRS-060 is a novel inhaled Anticalin® molecule that antagonizes the IL-4 receptor alpha (IL-4Ra). A first-in-human study in healthy subjects was conducted to assess the safety, tolerability and pharmacokinetics (PK) of inhaled single ascending doses and intravenous infusion (IV) doses. In this study (NCT03384290), the drug was administered by nebulized oral inhalation at delivered doses between 0.1mg and 160mg (corresponding to device doses between 0.25mg and 400mg) or intravenous infusion (IV) at 1mg and 2mg. AZD1402/PRS-060 was found to be safe and well tolerated at all dose levels via both routes of administration and no serious adverse events were reported and no anti-drug antibodies were detected. Systemic, dose-dependent exposure was observed after inhaled delivered doses ≥8mg. Inhaled PK showed slow and prolonged absorption into the systemic circulation. Clearance and volume of distribution values after IV doses were indicative of clearance by renal filtration and a low tissue distribution. Target engagement, as assessed by inhibition of systemic STAT6 phosphorylation was dose-dependent and closely aligned with systemic exposure of the drug. Near complete and sustained inhibition of pSTAT6 was observed at higher inhaled doses. In the ongoing MAD study in mild asthmatics (NCT03574805), systemic target engagement (pSTAT6) will be compared with lung target engagement, assessed by measuring fractional nitric oxide in exhaled breath. This will help set inhaled doses for future studies of this first-in-class inhaled Anticalin molecule. The overall profile of the drug demonstrates its suitability for development as an inhaled drug for the treatment of asthma.

AZD1402/PRS-060 is a novel inhaled Anticalin® molecule antagonizing IL-4Ra. A multiple ascending dose clinical study (NCT03574805) was conducted in mild asthmatics (fractional exhaled nitric oxide (FeNO) levels ≥ 35ppb), to assess the safety, tolerability, pharmacokinetics and pulmonary and systemic IL-4Ra target engagement of AZD1402/PRS-060. The drug candidate was administered by nebulized oral inhalation at delivered doses between 2 and 20mg, twice daily for 9 days with one dose on day 10. All doses of AZD1402/PRS-060 were found to be safe and well tolerated; no serious adverse events were observed. Lung target engagement was determined by reduction of FeNO levels and systemic target engagement was determined ex vivo by inhibition of IL-4-stimulated signal transducer and activator of transcription 6 (STAT6) phosphorylation in whole blood. Significant and pronounced (≥25%) inhibition of FeNO was observed at all doses, including the 2mg delivered dose, where no systemic target engagement and minimal systemic exposure was observed. This suggests that local target engagement by the drug is sufficient to reduce airway inflammation, as measured by FeNO. The onset of FeNO reduction was rapid (after a single dose) and the maximum effect (day 4-5) vs placebo was sustained until dosing completion. Systemic target engagement was dose-dependent and closely aligned with systemic exposure of the drug. Pulmonary target engagement as shown by a substantial reduction in FeNO and the overall profile of the drug demonstrates its suitability for continued development as an inhaled therapy for asthma.

Objectives Targeting the granulocyte-macrophage colony-stimulating factor (GM-CSF) pathway holds great potential in the treatment of inflammatory diseases. Mavrilimumab, a human monoclonal GM-CSF receptor-α antibody, has demonstrated clinical efficacy in RA. Our current study aimed to elucidate mechanisms of action and identify peripheral biomarkers associated with therapeutic responses of GM-CSF antagonism in RA. Methods A 24-week placebo (PBO)-controlled trial was conducted in 305 RA patients who received mavrilimumab (30, 100 or 150 mg) or PBO once every 2 weeks. Serum biomarkers and whole blood gene expression profiles were measured by protein immunoassay and whole genome microarray. Results Mavrilimumab treatment induced significant down-regulation of type IV collagen formation marker (P4NP 7S), macrophage-derived chemokine (CCL22), IL-2 receptor α and IL-6 compared with PBO. Both early and sustained reduction of P4NP 7S was associated with clinical response to 150 mg mavrilimumab treatment. Gene expression analyses demonstrated reduced expression of transcripts enriched in macrophage and IL-22/IL-17 signalling pathways after GM-CSF blockade therapy. Myeloid and T cell-associated transcripts were suppressed in mavrilimumab-treated ACR20 responders but not non-responders. While CCL22 and IL-6 down-regulation may reflect a direct effect of GM-CSFR blockade on the production of pro-inflammatory mediators by myeloid cells, the suppression of IL-2 receptor α and IL-17/IL-22 associated transcripts suggests an indirect suppressive effect of mavrilimumab on T cell activation. Conclusion Our results demonstrated association of peripheral biomarker changes with therapeutic response to mavrilimumab in RA patients. The sustained efficacy of mavrilimumab in RA may result from both direct effects on myeloid cells and indirect effects on T cell activation after GM-CSFR blockade.

ObjectiveMavrilimumab, a human monoclonal antibody, targets granulocyte–macrophage colony‐stimulating factor receptor α. We undertook to determine the long‐term safety and efficacy of mavrilimumab in rheumatoid arthritis patients in 2 phase IIb studies (1071 and 1107) and in 1 open‐label extension study (ClinicalTrials.gov identifier: NCT01712399).MethodsIn study 1071, patients with an inadequate response to disease‐modifying antirheumatic drugs (DMARDs) received mavrilimumab (30, 100, or 150 mg) or placebo every other week plus methotrexate. In study 1107, patients with an inadequate response to anti–tumor necrosis factor agents and/or DMARDs received 100 mg mavrilimumab every other week or 50 mg golimumab every 4 weeks plus methotrexate. Patients entering the open‐label extension study received 100 mg mavrilimumab every other week plus methotrexate. Long‐term safety and efficacy of mavrilimumab were assessed.ResultsA total of 442 patients received mavrilimumab (14 of 245 patients from study 1071, 9 of 70 patients from study 1107, and 52 of 397 patients from the open‐label extension study discontinued mavrilimumab treatment throughout the studies). The cumulative safety exposure was 899 patient‐years; the median duration of mavrilimumab treatment was 2.5 years (range 0.1–3.3 years). The most common treatment‐emergent adverse events (AEs) were nasopharyngitis (n = 69; 7.68 per 100 patient‐years) and bronchitis (n = 51; 5.68 per 100 patient‐years). At weeks 74 and 104, 3.5% and 6.2% of patients, respectively, demonstrated reduction in forced expiratory volume in 1 second, while 2.9% and 3.4% of patients, respectively, demonstrated reduction in forced vital capacity (>20% reduction from baseline to <80% predicted). Most pulmonary changes were transient and only infrequently associated with AEs. Mavrilimumab at 100 mg every other week demonstrated sustained efficacy; at week 122, 65.0% of patients achieved a Disease Activity Score in 28 joints using the C‐reactive protein level (DAS28‐CRP) of <3.2, and 40.6% of patients achieved a DAS28‐CRP of <2.6.ConclusionLong‐term treatment with mavrilimumab maintained response and was well‐tolerated with no increased incidence of treatment‐emergent AEs. Safety data were comparable with those from both phase IIb qualifying studies.

AIM:The aim of our study was to identify pharmacodynamic biomarkers and assess differential effects of tumor necrosis factor (TNF)- and non-TNF-targeting agents on rheumatoid arthritis (RA) patients with an inadequate response to anti-TNF agents (anti-TNF-IR) in comparison with biologic-naïve patients.METHODS:EARTH EXPLORER 2, a phase IIb trial, evaluated golimumab, an anti-TNF antibody, and mavrilimumab, an granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor antibody, in disease-modifying antirheumatic drug (DMARD)-IR and anti-TNF-IR patients. Our current study assessed peripheral protein markers and gene expression levels in association with clinical response post-treatment in two disease strata.RESULTS:Serum proteomics results indicated the existence of specific pharmacodynamic markers for golimumab and mavrilimumab, regardless of prior anti-TNF treatment. In contrast, both antibodies induced early and sustained suppression of RA disease markers, including interleukin (IL)-6, C-reactive protein, IL2RA, and matrix metalloproteinase 1, in DMARD-IR patients. Golimumab-induced early changes rapidly returned toward baseline concentrations in anti-TNF-IR patients, whereas mavrilimumab-induced changes were maintained through to day 169. RNA sequencing demonstrated gene expression changes at day 169 after administration of mavrilimumab but not golimumab in anti-TNF-IR patients. Additionally, receiver operating characteristic curve and regression analysis showed the association of early IL-6 change and subsequent clinical responses to golimumab in anti-TNF-IR patients.CONCLUSION:Our results revealed golimumab- and mavrilimumab-specific pharmacodynamic biomarkers, and demonstrated differential biomarker-treatment relationships in anti-TNF-IR and DMARD-IR patients, respectively. Early IL-6 change after anti-TNF antibody treatment may be a potential predictive biomarker for selection of different treatment regimens in anti-TNF-IR patients.

ObjectiveThis 24‐week, phase IIb, double‐blind study was undertaken to evaluate the efficacy and safety of mavrilimumab (a monoclonal antibody to granulocyte–macrophage colony‐stimulating factor receptor α) and golimumab (a monoclonal antibody to tumor necrosis factor [anti‐TNF]) in patients with rheumatoid arthritis (RA) who have had an inadequate response to disease‐modifying antirheumatic drugs (DMARDs) (referred to as DMARD‐IR) and/or inadequate response to other anti‐TNF agents (referred to as anti‐TNF–IR).MethodsPatients with active RA and a history of DMARD‐IR (≥1 failed regimen) or DMARD‐IR (≥1 failed regimen) and anti‐TNF–IR (1–2 failed regimens) were randomized 1:1 to receive either mavrilimumab 100 mg subcutaneously every other week or golimumab 50 mg subcutaneously every 4 weeks alternating with placebo every 4 weeks, administered concomitantly with methotrexate. The primary end points were the American College of Rheumatology 20% improvement (ACR20), 50% improvement, and 70% improvement response rates at week 24, percentage of patients achieving a Disease Activity Score in 28 joints using C‐reactive protein level (DAS28‐CRP) of <2.6 at week 24, percentage of patients with a score improvement of >0.22 on the Health Assessment Questionnaire (HAQ) disability index (DI) at week 24, and safety/tolerability measures. This study was not powered to formally compare the 2 treatments.ResultsAt week 24, differences in the ACR20, ACR50, and ACR70 response rates between the mavrilimumab treatment group (n = 70) and golimumab treatment group (n = 68) were as follows: in all patients, −3.5% (90% confidence interval [90% CI] −16.8, 9.8), −8.6% (90% CI −22.0, 4.8), and −9.8% (90% CI −21.1, 1.4), respectively; in the anti‐TNF–IR group, 11.1% (90% CI −7.8, 29.9), −8.7% (90% CI −28.1, 10.7), and −0.7% (90% CI −18.0, 16.7), respectively. Differences in the percentage of patients achieving a DAS28‐CRP of <2.6 at week 24 between the mavrilimumab and golimumab groups were −11.6% (90% CI −23.2, 0.0) in all patients, and −4.0% (90% CI −20.9, 12.9) in the anti‐TNF–IR group. The percentage of patients achieving a >0.22 improvement in the HAQ DI score at week 24 was similar between the treatment groups. Treatment‐emergent adverse events were reported in 51.4% of mavrilimumab‐treated patients and 42.6% of golimumab‐treated patients. No deaths were reported, and no specific safety signals were identified.ConclusionThe findings of this study demonstrate the clinical efficacy of both treatments, mavrilimumab at a dosage of 100 mg every other week and golimumab at a dosage of 50 mg every 4 weeks, in patients with RA. Both regimens were well‐tolerated in patients who had shown an inadequate response to DMARDs and/or other anti‐TNF agents.

Objectives Despite the therapeutic value of current rheumatoid arthritis (RA) treatments, agents with alternative modes of action are required. Mavrilimumab, a fully human monoclonal antibody targeting the granulocyte–macrophage colony-stimulating factor receptor-α, was evaluated in patients with moderate-to-severe RA. Methods In a phase IIb study (NCT01706926), patients with inadequate response to ≥1 synthetic disease-modifying antirheumatic drug(s), Disease Activity Score 28 (DAS28)−C reactive protein (CRP)/erythrocyte sedimentation rate ≥3.2, ≥4 swollen joints despite methotrexate (MTX) were randomised 1:1:1:1 to subcutaneous mavrilimumab (150, 100, 30 mg), or placebo every other week (eow), plus MTX for 24 weeks. Coprimary outcomes were DAS28−CRP change from baseline to week 12 and American College of Rheumatology (ACR) 20 response rate (week 24). Results 326 patients were randomised (150 mg, n=79; 100 mg, n=85; 30 mg, n=81; placebo, n=81); 305 completed the study (September 2012–June 2013). Mavrilimumab treatment significantly reduced DAS28−CRP scores from baseline compared with placebo (change from baseline (SE); 150 mg: −1.90 (0.14), 100 mg: −1.64 (0.13), 30 mg: −1.37 (0.14), placebo: −0.68 (0.14); p<0.001; all dosages compared with placebo). Significantly more mavrilimumab-treated patients achieved ACR20 compared with placebo (week 24: 73.4%, 61.2%, 50.6% vs 24.7%, respectively (p<0.001)). Adverse events were reported in 43 (54.4%), 36 (42.4%), 41 (50.6%) and 38 (46.9%) patients in the mavrilimumab 150, 100, 30 mg eow and placebo groups, respectively. No treatment-related safety signals were identified. Conclusions Mavrilimumab significantly decreased RA disease activity, with clinically meaningful responses observed 1 week after treatment initiation, representing a novel mechanism of action with persuasive therapeutic potential. Trial registration number NCT01706926; results.

Background Collectively, the cell surface Fc region of IgG receptors (FcγRs) engage soluble IgG and IgG containing immune complexes and trigger activation or inhibtory signals that play a critical role in the regulation of immune responses. The low affinity FcγRIIA (CD32A) is the most widely expressed activating FcγR in humans and appears to drive autoantibody and immune complex mediated autoimmune disorders. So far a therapeutic targeting this receptor has not been developed. Objectives To generate and characterize a novel humanized effector-deficient FcγRIIA antibody (MEDI9600) for clinical development. Methods The mode of action of MEDI9600 was assessed by confocal microscopy, whole blood internalization, and binding competition assays. Multiple cell based assays were used to measure autoantibody and immune complex mediated responses. The safety of MEDI9600 was assessed in in vitro by neutrophil migration, activation and opsonophagocytic killing assays. Safety and pharmacokinetics were examined in vivo in a single-dose PK/PD study in cynomolgus monkey. Results We generated a humanized effector-deficient FcγRIIA antibody (MEDI9600) that potently blocks both autoantibody and immuno complex-mediated proinflammatory responses from a variety of cell types. This includes the inhibition of Toll-like receptor stimulatory immune complexes that induce type I Interferons from pDC, and the inhibition of anti-neutrophil cytoplasmic antibody (ANCA) induced production of reactive oxygen species from neutrophils, which are associated with the pathogenesis of systemic lupus and ANCA vasculitis respectively. MEDI9600 specifically binds FcγRIIA and its suppressive activity is attributed to its capacity to block ligand engagement and to internalize the receptor from the cell surface. Moreover, in vivo studies indicate that MEDI9600 has a favorable pharmacokinetic and safety profile. Conclusions We have generated MEDI9600, a specific humanized antibody antagonist of FcγRIIA with null effector function that may provide a novel therapeutic approach in the treatment of immune complex mediated diseases. Disclosure of Interest None declared

Background RA is associated with pulmonary comorbidity and lung function decline over time, but longitudinal assessment of pulmonary abnormalities in the context of RA treatment needs further characterisation. Mavrilimumab, an investigational human monoclonal antibody, inhibits GM-CSF by binding to the GM-CSF receptor α subunit. Objectives To investigate the pulmonary safety of mavrilimumab because of the theoretical risk of inhibiting alveolar macrophage function and causing pulmonary alveolar proteinosis (PAP). Methods Pulmonary monitoring included standardised serial pulmonary function testing (spirometry and diffusing capacity of lung carbon monoxide [DLCO]), chest X-rays, assessments of dyspnoea and pulmonary adverse events (AEs) in two randomised, double-blind studies (NCT01706926; NCT01715896) where patients (pts) with moderate to severe RA received mavrilimumab 30, 100 or 150 mg every other week (eow), or placebo and mavrilimumab 100 mg eow or golimumab 50 mg every 4 weeks, respectively. Eligible pts transferred to the open-label extension study (NCT01712399) and received mavrilimumab 100 mg eow. All studies excluded pts with clinically significant uncontrolled pulmonary disease. An Independent Pulmonary Evaluation Committee (IPEC), blinded to treatment, adjudicated pulmonary AEs and lung function abnormalities. Results Mavrilimumab was received by 442 pts with cumulative safety data exposure of approximately 900 pt-yrs and a median (range) exposure time of 2.5 (0.1–3.3) yrs. Baseline (BL) characteristics are shown (Table). Mean dyspnoea (Table), forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC) and DLCO were mostly maintained within 5% of BL values for pts treated with mavrilimumab during the clinical programme. Clinically relevant decreases in predicted FEV1 and FVC (>20% from BL and <80% predicted) were demonstrated by ≤6.2% of pts at any visit (Table); decreases were mostly transient with no apparent trends. Overall, 83 pts (9.24/100 pt-yrs) reported ≥1 pulmonary AE; bronchitis was reported most frequently (34 pts [3.78/100 pt-yrs]); one AE was considered serious and treatment-related (acute bronchitis). The reported pulmonary AE rate was generally stable over time. No suspected or confirmed PAP cases were found by IPEC and no pulmonary-related deaths were reported. Conclusions We believe this is the most comprehensive longitudinal study of pulmonary function in a clinical RA programme. The BL pulmonary function profile indicates that this is not a normal population from a pulmonary health perspective. Mavrilimumab was not associated with substantial decline in pulmonary function or PAP in pts treated up to 3.3 years; its acceptable safety profile advocates initiation of Phase III studies with mavrilimumab. Further studies are now required to fully characterise pulmonary function over time in RA. Acknowledgements Funded by MedImmune. Medical writing support: R Plant, QXV Comms, an Ashfield company, funded by MedImmune. ^Senior author. Disclosure of Interest G. Burmester Consultant for: MedImmune, M. Michaels Employee of: MedImmune, D. Close Employee of: MedImmune, A. Godwood Shareholder of: AstraZeneca, Employee of: MedImmune, K. Middleton Employee of: MedImmune (contracted employment at time of study), P. Miranda Grant/research support from: Amgen, Medimmune, Janssen, Pfizer, Celltrion, Abbott, Sanofi, Actelion, Merck & Co, Boehringer, BMS, Consultant for: Pfizer [Etanecept: Fee less than USD5000], J. Vencovský Consultant for: Pfizer, Elli Lilly, MSD, Novartis, Speakers bureau: Biogen, Pfizer, MSD, Abbvie, Novartis, Boehringer, UCB, BMS, J. Kremer Shareholder of: Corrona, Grant/research support from: Abbvie, Amgen, Genentech, Lilly, Pfizer, Consultant for: Abbvie, Amgen, BMS, Genentech, Lilly, Pfizer, Employee of: Corrona, I. McInnes Grant/research support from: MedImmune [The University of Glasgow is a charity registered in Scotland, charity number SC004401 Grant/research support: Research award to University of Glasgow], Consultant for: MedImmune, M. Albulescu Shareholder of: MedImmune, Employee of: MedImmune, M. Weinblatt Grant/research support from: BMS, UCB, Crescendo Bioscience. Amgen, dxterity, Consultant for: MedImmune, Astra Zeneca, Amgen, Abbvie, BMS, Crescendo bioscience, Lilly, Pfizer, UCB, Roche, novartis

Background Mavrilimumab, a fully human monoclonal antibody targeting the granulocyte-macrophage colony-stimulating factor receptor-α, has demonstrated efficacy and safety in disease-modifying antirheumatic drug (DMARD)-inadequate responder (IR) patients (pts) with rheumatoid arthritis (RA).1 Objectives Few head-to-head studies in tumor necrosis factor antagonist (aTNF)-IR assess alternative aTNFs vs. other agents; this Phase IIb exploratory study (NCT01715896) evaluates the efficacy and safety of mavrilimumab and golimumab in aTNF-IR and DMARD-IR pts. Methods This 24-week study enrolled pts with active RA (28-joint Disease Activity Score [DAS28]–C-reactive protein [CRP]/erythrocyte sedimentation rate ≥3.2); ≥4 swollen joints; inadequate response to ≥1 DMARDs and/or 1–2 aTNFs receiving concomitant methotrexate (MTX; 7.5–25.0 mg/week). Pts received subcutaneous mavrilimumab 100 mg every other week (eow), based on data from the Phase IIa study,2 or golimumab 50 mg alternating with placebo eow. Key endpoints were ACR20/50/70 responses, DAS28–CRP <3.2 and <2.6, Health Assessment Questionnaire Disability Index improvement >0.22 at Week 24 and safety/tolerability. Treatment estimates for mavrilimumab and golimumab are presented with standard errors. Results Pts were randomized to mavrilimumab or golimumab (1:1) (Table). Data for pts receiving mavrilimumab 100 mg eow and golimumab 50 mg at Week 24 are shown for the aTNF-IR, DMARD-IR and overall strata (Table). The most common treatment-emergent adverse events (TEAEs) for mavrilimumab 100 mg and golimumab 50 mg were nasopharyngitis (5.7%, 1.5%), headache (4.3%, 2.9%), upper respiratory tract infection (4.3%, 2.9%), viral upper respiratory tract infection (4.3%, 2.9%), and hepatic enzyme increase (4.3%, 2.9%), respectively. Related serious TEAEs were pneumocystis pneumonia (n=1) and lung disorder (n=1) [both in golimumab-treated pts]. No deaths were reported and no significant pulmonary safety signals were identified. Conclusions In this exploratory study, mavrilimumab 100 mg eow and golimumab 50 mg demonstrated efficacy and an acceptable safety profile in DMARD-IR and aTNF-IR pts. The study was not powered to demonstrate statistical significance between mavrilimumab and golimumab. As mavrilimumab 100 mg eow has previously been shown to be suboptimal compared with 150 mg eow in DMARD-IR pts (EARTH EXPLORER 1),1 additional studies are needed to establish the benefit of a higher dose in pts with moderate to severe RA and inadequate response to aTNF agents. References Burmester G, et al. Arthritis Rheum. 2014;66:S1231 Burmester G, et al. Ann Rheum Dis. 2013;72:1445–1452 Acknowledgement Funded by MedImmune. Editorial assistance: K Alexander, QXV Comms, an Ashfield business, UK Joint senior authors: D. Close and G. Burmester Disclosure of Interest M. Weinblatt Grant/research support from: BMS, UCB, Crescendo Bioscience, Consultant for: MedImmune, Astra Zeneca, Amgen, Abbvie, BMS, Crescendo Bioscience, Lilly, Pfizer, UCB, Roche, I. McInnes Grant/research support from: Research award to University of Glasgow, Consultant for: MedImmune, Astra Zeneca, J. Kremer Shareholder of: Corrona, Grant/research support from: Abbvie, Amgen, Genentech, Lilly, Pfizer, Consultant for: Abbvie, Amgen, BMS, Genentech, Lilly, Pfizer, Employee of: Corrona, P. Miranda Grant/research support from: Clinical trials: Amgen, Medimmune, Janssen, Pfizer, Celltrion, Abbott, Sanofi, Actelion, Merck & Co, Boehringer, BMS, Consultant for: Pfizer for Etanecept (fee less than USD5000), J. Vencovský Consultant for: Pfizer, Servier, Samsumg, Eli lilley, BMS, Novartis, A. Godwood Shareholder of: AstraZeneca, Employee of: MedImmune, M. Albulescu Employee of: MedImmune, D. Close, Employee of: MedImmune, G. Burmester, Consultant for: MedImmune

Background Treatment of rheumatoid arthritis (RA) patients by anti-tumour necrosis factors (anti-TNFs), such as golimumab, has substantially improved patient outcomes. However, unmet therapeutic needs exist for the significant proportion of patients who do not respond to current biologics treatment. Mavrilimumab is a fully human monoclonal antibody which inhibits the granulocyte-macrophage colony-stimulating factor receptor α (GM–CSFR-α). Recently, a Phase IIb study has been completed to evaluate the efficacy and safety of mavrilimumab and golimumab in both disease-modifying antirheumatic drug (DMARD)-inadequate responder (IR) and anti-tumor necrosis factor-inadequate responders (anti-TNF-IR) patients (EARTH EXPLORER 2, NCT01715896). Objectives To assess peripheral biomarkers and pathophysiological pathways modulated by mavrilimumab in comparison with golimumab in both DMARD-IR and anti-TNF-IR RA patients. Methods In total, 75 DMARD-IR and 63 anti-TNF-IR patients were randomized in a 1:1 ratio to receive subcutaneous 100 mg mavrilimumab (n=70) every other week (Q2W) or 50 mg golimumab (n=68) Q2W alternating with placebo, in combination with methotrexate (7.5–25.0 mg/week) for 24 weeks. Serum levels of 18 RA-associated proteins as well as 3 protease-derived protein fragments were measured in 71 DMARD-IR and 61 anti-TNF-IR RA patients at baseline and 4 time points post-administration. Transcriptome sequencing was used to measure gene expression changes in whole blood of RA patients at baseline and day 169 post-administration. Results Serum levels of CCL22 and CCL17 were suppressed by mavrilimumab but not golimumab, while CXCL13 and ICAM1 levels were suppressed by golimumab but not mavrilimumab. Those four proteins may be specific pharmacodynamic markers for the two biologics respectively. More interestingly, both mavrilimumab and golimumab demonstrated early and sustained suppression of multiple inflammatory markers in DMARD-IR patients, including CRP, SAA, MMP1, MMP3, IL6, VEGF, IL2R, and CD163. However, golimumab-induced early changes rapidly returned towards baseline levels in anti-TNF-IR patients, while serum protein suppression by mavrilimumab was maintained through day 169 in anti-TNF-IR patients. Similarly, mavrilimumab administration was associated with durable suppression of extracellular matrix markers, C1M, C3M, and P4NP7S, while golimumab only induced a transient change of the three markers in anti-TNF-IR patients. Furthermore, RNA sequencing results demonstrated significant regulation of 1547 transcripts at day 169 after mavrilimumab administration while golimumab had no impact on whole blood gene expression in anti-TNF-IR patients. In contrast, significant changes of 1042 and 2058 transcripts were observed in DMARD-IR patients at day 169 after mavrilimumab and golimumab administration respectively. Conclusions Our study demonstrated sustained suppression of RA disease markers by mavrilimumab but not golimumab in anti-TNF-IR patients, suggesting the potential of greater long-term disease control by mavrilimumab than golimumab in this population of RA patients. Disclosure of Interest X. Guo Shareholder of: MedImmune/AstraZeneca, Employee of: MedImmune/AstraZeneca, S. Wang Shareholder of: MedImmune/AstraZeneca, Employee of: MedImmune/AstraZeneca, A. Bay-Jensen Employee of: Nordic Bioscience, M. Karsdal Employee of: Nordic Bioscience, A. Godwood Shareholder of: MedImmune/AstraZeneca, Employee of: MedImmune/AstraZeneca, D. Close Shareholder of: MedImmune/AstraZeneca, Employee of: MedImmune/AstraZeneca, P. Ryan Shareholder of: MedImmune/AstraZeneca, Employee of: MedImmune/AstraZeneca, L. Roskos Shareholder of: MedImmune/AstraZeneca, Employee of: MedImmune/AstraZeneca, W. White Shareholder of: MedImmune/AstraZeneca, Employee of: MedImmune/AstraZeneca