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BackgroundPatients with cutaneous lupus erythematosus (CLE) experience disfiguring and painful lesions that can lead to psychological distress and significant impacts on quality of life.1 Treatment of patients with systemic lupus erythematosus (SLE) with anifrolumab, a type I interferon receptor antagonist, was associated with CLE Disease Area and Severity Index–Activity (CLASI-A) improvements compared with placebo through Week 52 in the phase 3 TULIP-1 and TULIP-2 SLE trials.2,3 CLASI assesses overall skin improvement and may be driven by erythema over the other components.4ObjectivesTo better understand the effect of anifrolumab on mucocutaneous SLE manifestations by analyzing the individual domains of CLASI-A using pooled data from the TULIP trials.MethodsTULIP-1 (NCT02446912) and TULIP-2 (NCT02446899) were randomized, double-blind, placebo-controlled, 52-week trials that evaluated efficacy and safety of intravenous anifrolumab administered every 4 weeks in patients with moderate to severe SLE despite standard therapy.2,3 In a post hoc analysis, individual CLASI-A domains (erythema, scale/hypertrophy, alopecia, and mucosal) were assessed at Week 24 (time point chosen to ensure adequate duration for improvement in slow-remitting manifestations [eg, scale, alopecia]) in 2 patient subgroups: 1) the “chronic” mucocutaneous subgroup (resembling chronic/discoid CLE), defined as patients with a baseline erythema score ≥4 and scale score ≥2, and alopecia score ≥1 or baseline mucosal lesions or ulceration score of 1; and 2) the “extended” mucocutaneous subgroup (resembling all CLE subtypes), defined as patients who met the “chronic” criteria or those who had a baseline erythema score ≥8.ResultsAcross the pooled TULIP trials, 360 patients received anifrolumab 300 mg and 366 patients received placebo. In patients with assessments at Week 24 in the “chronic” (anifrolumab n=58, placebo n=50) and “extended” (anifrolumab n=104, placebo n=96) subgroups, anifrolumab led to a greater mean percent reduction from baseline compared with placebo in erythema (chronic: −63.6% vs −39.9%; extended: −63.7% vs −41.2%) and scale/hypertrophy (chronic: −72.2% vs −42.6%; extended: −45.3% vs −7.3%). Anifrolumab-treated patients in both subgroups had no worsening in alopecia (chronic: 93.3% [56/60] vs 96.0% [48/50]; extended: 95.3% [102/107] vs 95.8% [92/96]) or mucous membrane (chronic: 95.0% [57/60] vs 96.0% [48/50]; extended: 96.3% [103/107] vs 94.8% [91/96]) from baseline vs placebo (Table 1).Table 1.Skin Responses at Week 24 Compared With BaselineCriteria, n (%)Chronic subgroupExtended subgroupAnifrolumab 300 mg (n=60)Placebo (n=50)Anifrolumab 300 mg (n=107)Placebo (n=96)Erythema score reduction≥25%53 (88.3)32 (64.0)93 (86.9)68 (70.8)≥50%42 (70.0)22 (44.0)71 (66.4)47 (49.0)≥60%34 (56.7)18 (36.0)61 (57.0)32 (33.3)Scale/hypertrophy score reduction≥10%49 (81.7)34 (68.0)55 (51.4)38 (39.6)≥25%47 (78.3)30 (60.0)53 (49.5)34 (35.4)≥50%46 (76.7)28 (56.0)51 (47.7)31 (32.3)No new/worsened lesions in any individual body area44 (73.3)26 (52.0)81 (75.7)56 (58.3)Alopecia≥1-point decreasea25 (41.7)19 (38.0)35 (32.7)27 (28.1)No worsening56 (93.3)48 (96.0)102 (95.3)92 (95.8)Mucosal lesion/ulceration1-point decreaseb25 (41.7)13 (26.0)39 (36.4)23 (24.0)No worsening57 (95.0)48 (96.0)103 (96.3)91 (94.8)aIf baseline score ≥1.bIf baseline score =1.ConclusionIn the phase 3 TULIP trials, SLE patients with mucocutaneous manifestations treated with anifrolumab experienced numerical improvements in erythema and scale/hypertrophy and no worsening in alopecia or mucous membrane CLASI-A domains compared with placebo, regardless of whether skin disease was classified by chronic or extended definitions. These encouraging data support further evaluation of anifrolumab in patients with CLE.References[1]Klein R. J Am Acad Dermatol. 2011;64:849–58.[2]Furie RA. Lancet Rheumatol. 2019;1:e208–19.[3]Morand EF. N Engl J Med. 2020;382:211–21.[4]Albrecht J. J Invest Dermatol. 2005;125:889–94.AcknowledgementsWriting assistance by Naomi Atkin (Fishawack Health). This study was sponsored by AstraZeneca.Disclosure of InterestsVictoria Werth Consultant of: Celgene, Medimmune, Resolve, Genentech, Idera, Janssen, Lilly, Pfizer, Biogen, BMS, Gilead, Amgen, Medscape, Nektar, Incyte, EMD Sorona, CSL Behring, Principia, Crisalis, Viela Bio, Argenx, Kwoya Kirin, Regeneron, AstraZeneca, Abbvie, Octapharma, GSK, Cugene, UCB, Corcept, Beacon Bioscience, Rome Pharmaceuticals, Horizon, Merck, Kezar, Sanofi, Bayer, Akari, Grant/research support from: Celgene, Janssen, Pfizer, Biogen, Gilead, Corbus Pharmaceuticals, Genentech, AstraZeneca, Viela, Syntimmune, Amgen, Regeneron, Argenx, CSL Behring, Ventus, q32 Bio, BMS, Jenny Wissmar Shareholder of: AstraZeneca, Employee of: AstraZeneca, Anna Strömbeck Employee of: AstraZeneca, Raj Tummala Shareholder of: AstraZeneca, Employee of: AstraZeneca, Christi Kleoudis Shareholder of: AstraZeneca, Employee of: AstraZeneca, Marius Albulescu Shareholder of: AstraZeneca Ltd, Consultant of: UCB, Kymab Ltd, Employee of: AstraZeneca Ltd

Background Mavrilimumab, a fully human monoclonal antibody, which targets granulocyte-macrophage colony-stimulating factor receptor-α, has demonstrated efficacy and an acceptable safety profile in prior 12- and 24-week studies.1,2 Objectives This analysis evaluated all long-term (LT) safety and efficacy, through 74 weeks of treatment, of mavrilimumab. Methods This open-label extension (OLE) study (NCT01712399) enrolled adult rheumatoid arthritis (RA) patients (pts) who had completed the EARTH EXPLORER 12 and 2 (NCT01715896) Phase IIb studies or were rescued as inadequate responders (from Week 12). Pts received subcutaneous mavrilimumab 100 mg every other week (eow), consistent with data from the Phase IIa study1. The primary objective was to assess the LT risk:benefit ratio of mavrilimumab via evaluation of i) Treatment emergent adverse events (TEAEs), TE serious AEs (TESAEs), and independently adjudicated pulmonary function tests (PFTs) ii) Exploratory LT efficacy endpoints (DAS28–CRP/ACR responses). AEs with onset date after start of mavrilimumab are presented. Change from baseline (BL) in modified Total Sharp Score (mTSS) was used to explore radiographic progression in EARTH EXPLORER 1 pts. Results At the 74 week (includes original study) cutoff, 391 pts had been enrolled in the OLE study. Of these, 329 (84.1%) continued on treatment, 62 (15.9%) discontinued (due to withdrawal of consent, 9 [2.3%]; adverse event, 7 [1.8%]; non study-related site closure, 20 [5.1%]; other, 24 [6.1%]; lost-to-follow-up, 1 [0.3%]; death [sudden cardiac arrest, preferred term cardiopulmonary failure], 1 [0.3%]), and 239 (61.1%) were assessed for efficacy at Week 74. Between the Phase IIb and OLE studies, 440 pts received mavrilimumab, with a safety exposure of 603 pt years (yr) and median duration of 1.6 yr. Most common TEAEs (n [/100 pt yr]) were nasopharyngitis (51 [8.45]), bronchitis (36 [5.97]) and hypertension (32 [5.30]); the serious infection rate was 1.82/100 pt yr. Pulmonary events/defined PFT changes occurred in a few pts and were generally transient with no signal identified (Table). Mavrilimumab demonstrated sustained efficacy (DAS28–CRP/ACR responses) (Table). After 74 weeks of treatment, 68% of pts showed no radiographic progression ( Conclusions Mavrilimumab continues to demonstrate a sustained efficacy and safety profile in pts with active RA, over the 74 week treatment duration reported. Although mavrilimumab 100 mg eow is suboptimal compared with 150 mg eow in DMARD-IR pts,2 efficacy results are comparable with those of previous studies.1,2 References Burmester G, et al. Ann Rheum Dis 2013;72:1445–1452 Burmester G, et al. Arthritis Rheum 2014;66:S1231 Acknowledgement Funded by MedImmune. Editorial assistance: K Alexander, QXV Comms, an Ashfield business, UK Joint senior authors: D. Close and M. Weinblatt Disclosure of Interest G. Burmester Consultant for: MedImmune, I. McInnes Grant/research support from: Research award to University of Glasgow, Consultant for: MedImmune, AstraZeneca, 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, M. Weinblatt, Grant/research support from: BMS, UCB, Crescendo Bioscience, Consultant for: MedImmune, AstraZeneca, Amgen, Abbvie, BMS, Crescendo Bioscience, Lilly, Pfizer, UCB, Roche

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 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 Of patients with RA, ∼40% of do not achieve a minimal acceptable improvement (ACR20) despite modern biologic therapy.1,2,3 Granulocyte-macrophage colony-stimulating factor (GM–CSF) is implicated in RA pathogenesis via myeloid and granulocyte cell lineage activation. In a 12-week Phase IIa study, mavrilimumab, a first-in-class inhibitor of the GM–CSF receptor-α demonstrated a sustained effect via this novel therapeutic pathway in RA.4 Objectives To evaluate the efficacy and safety of mavrilimumab in patients with moderate to severe, adult-onset RA in a 24-week, Phase IIb study. Methods Patients (18–80 yrs; inadequate response to ≥1 DMARDs; DAS28–CRP ≥3.2; ≥4 SJC) receiving MTX were randomized to receive 1 of 3 SC mavrilimumab dosages (150, 100, 30 mg every other week [eow]) or placebo (PBO) plus MTX (7.5–25.0 mg/week). Co-primary endpoints were change in DAS28–CRP (Day 1 to Week 12) and ACR20 response rate (Week 24). Safety and tolerability were measured through assessment of AEs and pulmonary parameters. Results were analyzed using the modified ITT population. Results 326 patients from Europe, South America, and South Africa (mean [SD] age, 51.8 [11.1] yrs; female, 86.5%; mean [SD] DAS28–CRP, 5.8 [0.9]; RF+/anti-CCP+, 81.9%) received mavrilimumab 150, 100 or 30 mg eow or PBO (N=79, 85, 81 and 81, respectively). At Week 12, a statistically significant difference in DAS28–CRP change from baseline (p 90% of patients entered a long-term, open-label extension study. Conclusions This Phase IIb study demonstrated the potential benefit of inhibiting macrophage activity via the GM–CSF receptor-α pathway on RA disease activity. The study met both co-primary endpoints with a clear dosage response. Mavrilimumb was well-tolerated over the 24-week study period. References Weinblatt ME, et al. N Engl J Med 1999;340:253–9. Lipsky PE, et al. N Engl J Med 2000;343:1594–602. Weinblatt ME, et al. Arthritis Rheum 2003;48:35–45, Burmester GR, et al. Ann Rheum Dis 2013;72:1445–52. Acknowledgements Funded: MedImmune. Editorial assistance: N Panagiotaki, QXV Communications, UK †Joint senior authors. Disclosure of Interest G. Burmester Grant/research support from: AbbVie, Pfizer, UCB, Roche, Consultant for: AbbVie, BMS, Novartis, MedImmune, MSD, Pfizer, UCB, Roche, Speakers bureau: AbbVie, BMS, Novartis, MSD, Pfizer, UCB, Roche, I. McInnes Grant/research support from: MedImmune (Research award to University of Glasgow), Consultant for: MedImmune, AstraZeneca, J. Kremer Shareholder of: Corrona, Grant/research support from: AbbVie, Amgen, Genentech, Lilly, Pfizer, Consultant for: AbbVie, Amgen, Genentech, Lilly, Pfizer, BMS, Employee of: Corrona, P. Miranda Grant/research support from: MedImmune (to support protocol), M. Korkosz: None declared, J. Vencovsky: None declared, A. Rubbert-Roth Grant/research support from: Pfizer, Chugai, Consultant for: MSD, USB, Abbott, Pfizer, Roche, BMS, Chugai, Speakers bureau: Roche, Pfizer, UCB, E. Mysler Grant/research support from: Medimmune, Roche, BMS, Pfizer, M. Sleeman Shareholder of: AstraZeneca, Employee of: MedImmune, A. Godwood Shareholder of: AstraZeneca, Employee of: MedImmune, M. Albulescu Employee of: MedImmune, D. Close Shareholder of: AstraZeneca, Employee of: MedImmune, M. Weinblatt Grant/research support from: BMS, UCB, Crescendo Bioscience, Consultant for: MedImmune, AstraZeneca, Amgen, Abbvie, BMS, Crescendo Bioscience, Lilly, Pfizer, UCB, Roche

Background Macrophages are pivotal to the pathogenesis of rheumatoid arthritis (RA), and their inflammatory products drive many of the signs and symptoms of disease. Mavrilimumab inhibits macrophage activation and survival via blockade of granulocyte-macrophage colony-stimulating factor receptor-α (GM–CSFR-α) and has demonstrated sustained clinical benefit in patients with RA. 1 Objectives To examine time to onset of clinical response to mavrilimumab in the EARTH EXPLORER 1 study. Methods In a 24-week, Phase IIb study (NCT01706926), patients with adult-onset RA (18–80 years; Disease Activity Score 28 C-reactive protein [DAS28–CRP] >3.2; ≥4 swollen joints; inadequate response to ≥1 disease-modifying antirheumatic drugs [DMARDs]) receiving concomitant methotrexate were enrolled. Patients received mavrilimumab (150, 100, or 30 mg every other week [eow]) or placebo, administered subcutaneously with methotrexate (7.5–25.0 mg/week). Efficacy assessments included DAS28–CRP, American College of Rheumatology (ACR)20/50/70 responses, CRP, erythrocyte sedimentation rate (ESR), swollen joint count (SJC), tender joint count (TJC), and pain assessments. Results 326 patients with mean (SD) DAS28–CRP 5.8 (0.9) were randomized to mavrilimumab (150, 100, or 30 mg eow) or placebo (N=79, 85, 81, and 81, respectively). At Week 1 (first assessment), all mavrilimumab dosages demonstrated significant reductions from baseline in DAS28–CRP ( p p =0.003 to p Conclusions By targeting activated macrophages via inhibition of GM–CSFR-α, mavrilimumab substantially reduced patients9 RA disease activity early in their treatment, from first dose (Week 1) to final assessment for many patients, as evaluated by several clinical outcomes. References Burmester GR, et al. Ann Rheum Dis. 2013;72:1445–52. Acknowledgements Funded: MedImmune Ltd. Editorial assistance: N Panagiotaki, QXV Communications, UK Disclosure of Interest I. McInnes Grant/research support from: MedImmune (Research award to University of Glasgow), Consultant for: MedImmune, AstraZeneca, G. Burmester Grant/research support from: AbbVie, Pfizer, UCB, Roche, Consultant for: AbbVie, BMS, Novartis, MedImmune, MSD, Pfizer, UCB, Roche, Speakers bureau: AbbVie, BMS, Novartis, MSD, Pfizer, UCB, Roche, J. Kremer Shareholder of: Corrona, Grant/research support from: AbbVie, Amgen, Genentech, Lilly, Pfizer, Consultant for: AbbVie, Amgen, Genentech, Lilly, Pfizer, BMS, Employee of: Corrona, P. Miranda Grant/research support from: MedImmune (to support protocol), M. Korkosz: None declared, J. Vencovsky: None declared, A. Rubbert-Roth Grant/research support from: Pfizer, Chugai, Consultant for: MSD, UCB, Abbott, Pfizer, Roche, BMS, Chugai, Speakers bureau: Roche, Pfizer, UCB, E. Mysler Grant/research support from: MedImmune, Roche, BMS, Pfizer, D. Close Shareholder of: AstraZeneca, Employee of: MedImmune, M. Sleeman Shareholder of: AstraZeneca, Employee of: MedImmune, A. Godwood Shareholder of: AstraZeneca, Employee of: MedImmune, M. Albulescu Employee of: MedImmune, M. Weinblatt Grant/research support from: BMS, UCB, Crescendo Bioscience, Consultant for: MedImmune, AstraZeneca, Amgen, Abbvie, BMS, Crescendo bioscience, Lilly, Pfizer, UCB, Roche

Background Active RA significantly impairs patients9 health-related quality of life (HRQOL) and physical function. Granulocyte-macrophage colony-stimulating factor (GM–CSF) plays a key role in macrophage activation and RA pathogenesis, including inflammatory and arthritic pain development. A Phase IIa study in active RA demonstrated that mavrilimumab produced clinically meaningful improvements across a variety of PROs. 1 Objectives To assess mavrilimumab9s effects on HRQOL and physical function in RA patients in a 24-week Phase IIb study. Methods In an RCT (NCT01706926), we evaluated the efficacy and safety of 3 subcutaneous mavrilimumab dosages (150 mg, 100 mg, and, 30 mg every other week [eow]) vs. placebo over 24 weeks. Patients with adult-onset RA (18–80 years; DAS28–CRP ≥3.2; ≥4 swollen joints; inadequate response to ≥1 DMARDs) receiving concomitant methotrexate were enrolled. Co-primary endpoints were changes in DAS28–CRP score (Day 1 to Week 12) and ACR20 response (Week 24). PRO endpoints included changes from baseline and percentage responders in patient assessments of pain, HRQOL (SF-36 Mental Component Summary [MCS] and Physical Component Summary [PCS] scores), physical function (HAQ DI), and fatigue (FACIT-F). Patients could enter a long-term, open-label extension study at Week 12 (not reported). Results 326 patients (mean [SD] age, 51.8 [11.1] years; female, 86.5%) with a mean (SD) DAS28–CRP of 5.8 (0.9) were randomized to mavrilimumab 150, 100, or 30 mg eow, or placebo (N=79, 85, 81, and 81, respectively). Both co-primary endpoints (DAS28–CRP at Week 12; ACR20 at Week 24) were met at all mavrilimumab dosages. At Weeks 12 and 24, all mavrilimumab treatment groups exhibited improvements in pain, SF-36 PCS, SF-36 MCS, HAQ DI and FACIT-F vs. placebo, with >50% of patients receiving mavrilimumab 150 mg eow achieving a clinically meaningful response. At this dosage, significant improvements were demonstrated across all PRO endpoints ( p =0.019 to p p =0.007, Week 24; p =0.187). Statistically significant improvements in pain were demonstrated for mavrilimumab beginning at Week 1. Of patients receiving mavrilimumab 150, 100, and 30 mg eow with a pain response at Week 12, 66.7% (28/42), 69.2% (27/39), and 72.2% (26/36) maintained responses at Week 24. HAQ DI responses at Week 12 were maintained at Week 24 in 78.8% (41/52), 84.0% (42/50), and 75.0% (33/44) of patients (mavrilimumab 150, 100, and 30 mg eow, respectively). Conclusions Targeting activated macrophages through inhibition of the GM–CSFR-α pathway with mavrilimumab, especially at a dosage of 150 mg eow, substantially and rapidly reduced RA disease activity. In turn, patients receiving mavrilimumab achieved significant, clinically meaningful, and sustained improvements in PROs that reflected the patients9 pain, HRQOL, physical function, and fatigue. The majority of mavrilimumab patients with improvement in pain and physical function at Week 12 sustained these improvements through Week 24 References Burmester GR, et al. Ann Rheum Dis. 2013;72:1445–52. Acknowledgements Funded: MedImmune Ltd. Editorial assistance: N Panagiotaki, QXV Communications, UK Disclosure of Interest J. Kremer Shareholder of: Corrona, Grant/research support from: AbbVie, Amgen, Genentech, Lilly, Pfizer, Consultant for: AbbVie, Amgen, Genentech, Lilly, Pfizer, BMS, Employee of: Corrona, G. Burmester Grant/research support from: AbbVie, Pfizer, UCB, Roche, Consultant for: AbbVie, BMS, Novartis, MedImmune, MSD, Pfizer, UCB, Roche, Speakers bureau: AbbVie, BMS, Novartis, MSD, Pfizer, UCB, Roche, M. Weinblatt Grant/research support from: BMS, UCB, Crescendo Bioscience, Consultant for: MedImmune, AstraZeneca, Amgen, Abbvie, BMS, Crescendo bioscience, Lilly, Pfizer, UCB, Roche, A. Williams Shareholder of: AstraZeneca, Employee of: MedImmune, N. Karlsson Shareholder of: AstraZeneca, Employee of: AstraZeneca, A. Godwood Shareholder of: AstraZeneca, Employee of: MedImmune, M. Albulescu Employee of: MedImmune, D. Close Shareholder of: AstraZeneca, Employee of: MedImmune

Background The CD40-CD40L pathway may play a major role in autoimmune disorders like rheumatoid arthritis (RA). Blocking this pathway may be a promising new treatment for RA-patients. BI 655064 is a novel humanized antagonistic anti-CD40 monoclonal antibody, free of agonistic activity and without antibody-dependent cellular- or complement-dependent cytotoxicity. BI 655064 binds human CD40 on B cells in whole blood with an EC 90 of 6.85±0.74 nM. Objectives BI 655064 was investigated in healthy volunteers to assess safety, tolerability, PK and PD after single and multiple dosing. Methods In a single-blinded randomized, placebo-controlled trial in healthy subjects, BI 655064 was administered to 72 male subjects in increasing single doses of 0.2-120 mg i.v. and 40-120 mg s.c. A double-blinded multiple rising dose study was conducted in 40 male and female subjects at doses of 80-240 mg q1w s.c. for 4 weeks. Blood samples were analyzed for PK, CD40-receptor occupancy (RO) and inhibition of CD40L-induced CD54-upregulation throughout the entire trial duration. Results All doses of BI 655064 were well tolerated in both studies. There was no-drug related serious adverse event (AE) or significant AE reported. Reported AEs were mainly of mild intensity and did not show a dose-relationship. There was no significant difference in the total number of subjects with AE [BI 655064: 47/86 (54%) vs. placebo: 16/26 (61%)] or category of reported AEs between subjects treated with BI 655064 or placebo (combined data from both studies). The most frequently reported AEs were headache (BI 655064 23% vs. placebo 19%) and upper respiratory tract infection (BI 655064 13% vs placebo 12%) in both studies (combined data). There was no evidence of thromboembolism or bleeding, no hypersensitivity reaction, no cytokine release and no relevant change in safety laboratory tests including coagulation parameters. BI 655064 plasma exposure increased in a supra-proportional manner indicating target mediated drug clearance with a terminal half-life ranging between 6 and 13 days. At single i.v. doses of 20 mg and higher, there was >90% RO and >90% inhibition of CD40L-induced CD54 upregulation for 24 hours after dosing. Single doses of 120 mg i.v. or s.c resulted in >90% RO and >90% inhibition of CD54 upregulation for at least one week. After multiple dosing, persistent >90% RO and >90% inhibition of CD40L-induced CD54 upregulation was maintained for the entire treatment period and for 3 weeks after the last dose for all doses of 120 mg q1w and above. Conclusions Early trials with BI 655064 show a favorable clinical safety profile and high potential to block the CD40-CD40L pathway supporting clinical trials with BI 655064 in RA-patients. Disclosure of Interest C. Schwabe Employee of: Auckland Clinical Studies, F. Wagner Employee of: Charite Research Institute, I. Filler Employee of: Charite Research Institute, M. Albulescu Employee of: Boehringer-Ingelheim, P. Rose Employee of: Boehringer-Ingelheim, B. Emerson Employee of: Boehringer-Ingelheim, T. Doan Employee of: Boehringer-Ingelheim, B. Rosenstock Employee of: Boehringer-Ingelheim, D. Joseph Employee of: Boehringer-Ingelheim, J. Hilbert Employee of: Boehringer-Ingelheim, C. Scholch Employee of: Boehringer-Ingelheim, J. Habeck Employee of: Boehringer-Ingelheim, R. Thiedmann Employee of: Boehringer-Ingelheim, S. Padula Employee of: Boehringer-Ingelheim, J. Steffgen Employee of: Boehringer-Ingelheim