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B-cell depletion in SLE: clinical and trial experience with rituximab and ocrelizumab and implications for study design

B cells are believed to be central to the disease process in systemic lupuserythematosus (SLE), making them a target for new therapeutic intervention. In recentyears there have been many publications regarding the experience in SLE of B-celldepletion utilising rituximab, an anti-CD20 mAb that temporarily depletes B cells,reporting promising results in uncontrolled open studies and in routine clinical use.However, the two large randomised controlled trials in extra-renal lupus (EXPLORERstudy) and lupus nephritis (LUNAR study) failed to achieve their primary endpoints.Based on the clinical experience with rituximab this failure was somewhat unexpectedand raised a number of questions and concerns, not only into the true level ofbenefit of B-cell depletion in a broad population but also how to test the true levelof effectiveness of an investigational agent as we seek to improve the design oftherapeutic trials in SLE. A better understanding of what went wrong in these trialsis essential to elucidate the underlying reasons for the disparate observations notedin open studies and controlled trials. In this review, we focus on various factorsthat may affect the ability to accurately and confidently establish the level oftreatment effect of the investigational agent, in this case rituximab, in the twostudies and explore hurdles faced in the randomised controlled trials investigatingthe efficacy of ocrelizumab, the humanised anti-CD20 mAb, in SLE. Further, based onthe lessons learned from the clinical trials, we make suggestions that could beimplemented in future clinical trial design to overcome the hurdles faced.

A randomised phase IIb study of mavrilimumab, a novel GM–CSF receptor alpha monoclonal antibody, in the treatment of rheumatoid arthritis

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.

Efficacy and safety of mavrilimumab in Japanese subjects with rheumatoid arthritis: Findings from a Phase IIa study

Abstract Objective. A phase IIa study investigated efficacy and safety/tolerability of ascending doses of mavrilimumab (anti-granulocyte-macrophage colony-stimulating factor receptor [GM-CSFR]α monoclonal antibody) in adult subjects with moderate to severe rheumatoid arthritis from Japan and Europe. Findings from the Japanese population are presented. Methods. Fifty-one subjects received mavrilimumab (10–100 mg) or placebo subcutaneously every other week for 12 weeks, followed by a 12-week follow-up period. The primary endpoint was the proportion of subjects achieving a Disease Activity Score using 28 joints (DAS28)-C-reactive protein (CRP) response (decrease > 1.2 from baseline). Secondary endpoints included DAS28-CRP remission, Health Assessment Questionnaire Disability Index (HAQ-DI) and American College of Rheumatology (ACR) response. Results. By Week 12, more mavrilimumab- versus placebo-treated subjects achieved a DAS28-CRP response (50.0% vs. 23.5%, p = 0.081); a significant response was seen in the 30 mg and 100 mg dose groups (both 75.0% vs. 23.5%, p = 0.028). The 100 mg group also demonstrated statistically significant HAQ-DI and ACR20 responses at Week 12. Results were generally consistent between Japanese and European populations. Overall, adverse events (AEs) were mild to moderate in intensity with one serious AE of pneumonia, considered possibly treatment-related. Conclusions. A rapid and clinically meaningful response was seen in subjects treated with GM-CSFRα blockade with mavrilimumab, supporting further investigation of mavrilimumab for the treatment of RA in Japanese subjects.

A Randomized Phase IIb Study of Mavrilimumab and Golimumab in Rheumatoid Arthritis

This 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).

Mavrilimumab, a Fully Human Granulocyte-Macrophage Colony-Stimulating Factor Receptor α Monoclonal Antibody: Long-Term Safety and Efficacy in Patients With Rheumatoid Arthritis

Mavrilimumab, 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).

OP0034 Efficacy and Safety of Mavrilimumab, A Fully Human Gm–CSFR-Alpha Monoclonal Antibody in Patients with Rheumatoid Arthritis: Primary Results from the Earth Explorer 1 Study

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<0.001) was observed for all dosages of mavrilimumab vs. PBO. At Week 24, a significantly greater percentage of all mavrilimumab-treated patients also met the ACR20 co-primary endpoint vs. PBO (table). A dosage response was observed across several secondary endpoints, with separation from PBO evident as early as Week 1 and first dose. The most common treatment-emergent AEs were headache (7.6%, 4.7%, 6.2%, 2.5%), nasopharyngitis (7.6%, 3.5%, 4.9%, 7.4%) and bronchitis (5.1%, 1.2%, 3.7%, 7.4%) for mavrilimumab 150, 100, 30 mg eow or PBO, respectively. There was no increase in pulmonary AEs for mavrilimumab vs. PBO (6.3%, 3.5%, 6.2% vs. 9.9%). No serious infections were observed in the 100 and 150 mg eow groups. Two cases of pneumonia were observed (one each in mavrilimumab 30 mg eow and PBO groups). There were no deaths or anaphylaxis, and no apparent dosage relationship for AEs. >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

SAT0146 Earth Explorer 2, A Phase IIB Exploratory Study Evaluating Efficacy and Safety of Mavrilimumab, A Fully Human Granulocyte-Macrophage Colony-Stimulating Factor Receptor-Alpha Monoclonal Antibody, and The Tumor Necrosis Factor Antagonist Golimumab in Rheumatoid Arthritis

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

Blockade of GM-CSF pathway induced sustained suppression of myeloid and T cell activities in rheumatoid arthritis

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.

AB0445 Exposure–Efficacy Analysis of Mavrilimumab in Rheumatoid Arthritis: Modeling and Simulation of Phase II Clinical Data

Background Mavrilimumab, a fully human monoclonal antibody targeting the granulocyte-macrophage colony-stimulating factor receptor (GM–CSFR) α, is in Phase IIb investigation for the treatment of rheumatoid arthritis (RA). Objectives We characterized the exposure–efficacy relationship of mavrilimumab with data from two Phase II randomized controlled trials of patients with moderate to severe RA, via population modeling and clinical simulations. Methods In a Phase IIa study, adult patients with active RA received 7 subcutaneous administrations of mavrilimumab (10, 30, 50 or 100 mg every other week [eow]). Mavrilimumab pharmacokinetics and efficacy (DAS28–CRP, ACR20/50) were modeled using a population approach. Clinical simulations were performed to facilitate the design of a Phase IIb trial, in which RA patients received placebo or mavrilimumab (30, 100, or 150 mg eow) for 24 weeks. We developed a joint probability model to describe the risk of voluntary dropouts at each scheduled visit of the Phase IIb study. The exposure–response relationship for mavrilimumab was characterized by clinical simulations via the PK-efficacy dropout model. Results Mavrilimumab and placebo treatment effects observed in the Phase IIa study were adequately described by mechanistic PK-efficacy model. Although mavrilimumab 150 mg eow was not evaluated in the Phase IIa study, improved efficacy was observed at this dosage in Phase IIb, as predicted by a priori clinical simulations. The hazard rate of patient dropout prior to next scheduled visits was significantly greater for non-responders, and substantially greater for lower dosage groups at Week 12, when patient rollover to an open-label extension study was permitted. Clinical simulations indicated that the maximum efficacy was reached at the 150-mg eow dosage. Conclusions Efficacy outcomes of the Phase IIb study confirmed the rational selection of mavrilimumab 150 mg eow as the best dosage, through modeling of Phase IIa data. Joint modeling of placebo effect, treatment response, and informative dropout greatly facilitates interpretation of Phase IIb results, and will assist in the design of late-stage clinical trials for mavrilimumab. Disclosure of Interest D. Jin Shareholder of: AstraZeneca, Employee of: MedImmune, C.-Y. Wu Shareholder of: AstraZeneca, Employee of: MedImmune, L. Roskos Shareholder of: AstraZeneca, Employee of: MedImmune, A. Godwood Shareholder of: AstraZeneca, Employee of: MedImmune, D. Close Shareholder of: AstraZeneca, Employee of: MedImmune, B. Wang Shareholder of: AstraZeneca, Employee of: MedImmune

OP0331 A novel humanized effector-deficient fcyriia antibody inhibits immune complex mediated proinflammatory responses

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