The Experts below are selected from a list of 8715 Experts worldwide ranked by ideXlab platform
G. Illei - One of the best experts on this subject based on the ideXlab platform.
-
OP0174 Alteration of mediators of vascular inflammation by anifrolumab in the phase iib muse study in sle
THURSDAY 14 JUNE 2018, 2018Co-Authors: Wendy I. White, L. Wang, Kerry A. Casey, Michael A Smith, G. Illei, Nickie L. Seto, Martin P. Playford, Philip M. Carlucci, Nehal N. MehtaAbstract:Background Cardiovascular disease remains one of the leading causes of death for patients with systemic lupus erythematosus (SLE), and the disease is widely known to feature premature atherosclerosis promoted by immune dysregulation. Neutrophil extracellular traps (NETs) can induce endothelial dysfunction and promote inflammatory events. Furthermore, sources of reactive oxygen species released during NET formation promote oxidised HDL, leading to deficient cholesterol efflux capacity (CEC). Type I interferons (IFNs) stimulate NET formation and inhibit vascular repair. Anifrolumab is a fully human, IgG1 κ monoclonal antibody that binds to IFNAR1 and blocks signalling of all type I IFNs. Thus, anifrolumab may decrease mechanisms of vascular damage in SLE. Objectives We evaluated the ability of anifrolumab to reduce in-vivo NET formation and improve CEC relative to standard of care (SOC) in the MUSE study.1 Methods Baseline IFN gene signature (IFNGS) test status (high or low) of MUSE patients was determined as described.1 Plasma samples from fasting patients (n=190) were obtained at days 1 and 365 of the MUSE study. Plasma MPO-, HNE- and CitH3-DNA NET complexes were quantified by ELISAs in the MUSE and healthy donor (HD) samples (n=20) as described.2 Wilcoxon rank-sum test was used to assess differences between groups. Post-treatment samples from the placebo (n=52) and 300 mg anifrolumab (n=73) groups were compared with baseline samples. Significance of change from baseline was determined using Wilcoxon signed-rank test. CEC was tested as described.3 Reproducibility of the CEC assay was assessed using percent coefficient of variation (CV) from the analysis of variance (ANOVA). SLE patients with defective baseline CEC were identified as those with CEC Results All three neutrophil NET complexes (NNCs) were elevated in SLE patients (p Conclusions Circulating NNCs were significantly elevated in patients with moderate to severe SLE as compared with HDs. Anifrolumab decreased circulating NNCs. Although changes in steroid dosages during MUSE did not affect CEC, anifrolumab significantly improved CEC over SOC. This work supports continued assessment of anifrolumab effects on vascular inflammation and endothelial damage in SLE. References [1] Furie R, et al. Arthritis Rheumatol2017;69:376–86. [2] Demoruelle MK, et al. Arthritis Rheumatol2017;69:1165–75. [3] Salahuddin T, et al. Eur Heart J2015;36:2662–5. Disclosure of Interest W. White Shareholder of: AstraZeneca, Employee of: MedImmune, N. Seto: None declared, M. Playford: None declared, K. Casey Shareholder of: AstraZeneca, Employee of: MedImmune, M. Smith Shareholder of: AstraZeneca, Employee of: MedImmune, P. Carlucci: None declared, B. Yu Shareholder of: AstraZeneca, Employee of: MedImmune, L. Wang Shareholder of: AstraZeneca, Employee of: MedImmune, G. Illei Shareholder of: AstraZeneca, Consultant for: MedImmune, N. Mehta Grant/research support from: Abbvie, Novartis, Janssen, Celgene, Employee of: NHLBI, M. Kaplan Grant/research support from: MedImmune
-
SAT0220 Effects of type I interferon inhibition on blood leukocyte subsets in patients treated in a phase IIB clinical study of anifrolumab in systemic lupus erythematosus (SLE)
Poster Presentations, 2017Co-Authors: Wendy I. White, L. Wang, Kerry A. Casey, Michael A Smith, Miguel A. Sanjuan, D Sinbaldi, G. IlleiAbstract:Background A Phase IIb randomized controlled study (NCT01753193) was conducted with anifrolumab, a fully human, anti-interferon (IFN)–α receptor (IFNAR) specific antibody in adults with moderate to severe SLE. Anifrolumab binds to subunit 1 of the IFNAR and inhibits the activity of all type I IFNs. A complete blood count analysis demonstrated that anifrolumab reversed leukopenia. However, the types of peripheral immune cells affected following treatment have not been reported. Objectives To better understand how changes in the immune cell repertoire may be associated with SLE severity, type I IFN test status (high vs. low), and treatment with anifrolumab, we performed flow cytometry to assess peripheral blood cell types: dendritic cells (myeloid and plasmacytoid), B cells (naive, memory, and plasma cells), neutrophils, and T cells (CD4, CD8, naive, memory, central memory, and effector). Methods Patients were randomized 1:1:1 to anifrolumab 300 mg, or 1,000 mg, or placebo (PBO) every 4 weeks for 48 weeks. Peripheral blood was collected from a subset of patients (91 total) on Days 1 (prior to first dose), 85, 141, 169, 253, 337, and 365. Patients were approximately evenly distributed between treatment arms. Baseline absolute immune cell numbers were compared over treatment course in the context of SLE Disease Activity Index (SLEDAI)–2K scores, type I IFN test, and therapy response. Statistics were calculated using the Student9s t-test; p-values ≤0.05 were considered statistically significant. Results At baseline, several blood cell types were lower for patients with SLEDAI ≥10, including naive B cells, and memory T and B cells. In IFN-high patients, neutrophils, memory T cells, and plasmacytoid dendritic cells (pDCs) were significantly decreased. Anifrolumab led to significant increases in absolute numbers of T-cell subsets in the blood of IFN-high patients. In contrast, no significant changes were observed for IFN-low patients. Observed increases were within normal reference ranges. The alterations did not appear to be secondary to tapering of oral corticosteroids, as these cell types were not significantly different in PBO groups, regardless of tapering. Patients with ≥6-point SLEDAI reductions following anifrolumab demonstrated significant increases in total CD4 and CD8 T cells, and nonsignificant decreases in memory B cells. Significant increases in pDCs were also evident. Anifrolumab did not cause significant differences in other cell types measured. Conclusions Memory T cell numbers, among other cell types, were significantly reduced in patients with SLEDAI ≥10 and those classified as IFN high at baseline. This suggests that, for patients with more severe disease, type I IFN may be involved in cell migration into the peripheral tissues from the blood. Consistent with this, we found that neutralization of type I IFN with anifrolumab promoted immigration and/or prevented emigration of potentially pathologic immune cells between the tissues and the blood. These data suggest that some effects observed following anifrolumab treatment might be a result of altering the migration patterns of T and other immune cells, which may partially explain its biological activity. Acknowledgements Funded by MedImmune. Medical writing support: R Plant, QXV Comms, an Ashfield company, funded by MedImmune. Disclosure of Interest W. White Shareholder of: AstraZeneca, Employee of: MedImmune LLC, K. Casey Shareholder of: AstraZeneca, Employee of: MedImmune LLC, M. Smith Shareholder of: AstraZeneca, Employee of: MedImmune LLC, L. Wang Employee of: MedImmune LLC, D. Sinbaldi Shareholder of: AstraZeneca, Employee of: MedImmune LLC, M. Sanjuan Employee of: MedImmune LLC, G. Illei Shareholder of: AstraZeneca, Employee of: MedImmune LLC
-
SAT0243 Exposure-response (E-R) analysis for selection of optimal dosage regimen of anifrolumab in patients (PTS) with systemic lupus erythematosus (SLE)
Poster Presentations, 2017Co-Authors: Lc Santiago, Philip Brohawn, L. Wang, G. Illei, Bing Wang, Lorin RoskosAbstract:Background Anifrolumab is a fully human IgG1 monoclonal antibody directed against subunit 1 of the type I interferon–α receptor (IFNAR1). It is in development for treatment of SLE. Objectives To support dosage selection for pivotal anifrolumab studies, using an E−R model. Methods In the Phase IIb MUSE study (NCT01438489),1 adult pts with moderate to severe SLE, who had inadequate responses to standard-of-care (SOC) medications, were randomized 1:1:1 to intravenous anifrolumab 300 or 1,000 mg or placebo every 4 weeks (Q4W), in addition to SOC medications, for 48 weeks. Pts were stratified by type I interferon gene signature (IFNGS) test status (high or low) using a validated 4-gene expression assay, oral corticosteroid dosage ( Results There was no PK difference between type I IFNGS test–high or –low pts (mean [standard deviation] Ctrough (Day 169): 17.0 [11.5] μg/mL and 23.3 [16.0] μg/mL, respectively). SRI (4) modeling demonstrated no anifrolumab treatment effect in type I IFNGS test–low pts compared with placebo; interpretation of this result may be limited by small sample size. In type I IFNGS test–high pts, a log-linear logistic model was used to describe the treatment effect of anifrolumab. Pt dropouts were more likely in nonresponders. Clinical simulations demonstrated dosages 300 mg, consistent with the Phase IIb MUSE study outcomes. Conclusions Based on E−R analyses and overall risk assessment, a 300 mg Q4W, intravenous dosage regimen is recommended for pivotal anifrolumab studies in pts with SLE. References Furie R, et al. Arthritis Rheumatol. 2017;69:376–86. Wang B, et al. Clin Pharmacol Ther. 2013;93:483−92. Acknowledgements Funded by MedImmune. Medical writing support: R. Plant, QXV Comms, an Ashfield company, funded by MedImmune. Disclosure of Interest L. Santiago Shareholder of: AstraZeneca, Employee of: MedImmune LLC, B. Wang Shareholder of: AstraZeneca, Employee of: MedImmune LLC, P. Brohawn Shareholder of: AstraZeneca, Employee of: MedImmune LLC, L. Wang Employee of: MedImmune LLC, G. Illei Shareholder of: AstraZeneca, Employee of: MedImmune LLC, L. Roskos Shareholder of: AstraZeneca, Employee of: AstraZeneca
-
OP0301 Type i ifn gene signature test–high and –low patients with moderate to severe sle disease activity have distinct gene expression signatures of immunologic pathways and cell types
Oral Presentations, 2017Co-Authors: Hao Liu, Brandon W Higgs, Chris Morehouse, Philip Brohawn, G. Illei, Katie Streicher, W Rees, Koustubh RanadeAbstract:Background Type I interferon (IFN) has been implicated in systemic lupus erythematosus (SLE) pathogenesis, and the majority of patients with SLE have elevated expression of type I IFN-inducible genes in their blood. Anifrolumab, a fully human, IgG 1 κ monoclonal antibody against the type I IFN receptor, is in Phase III development for the treatment of moderate to severe SLE (NCT02446912 and NCT02446899). Objectives We sought to understand other molecular pathways (either dependent on or independent of type I IFN signaling), to elucidate heterogeneous mechanisms in SLE, and to identify patient subsets for personalized disease management. Methods Baseline blood samples from adult patients with moderate to severe SLE from two Phase IIb clinical studies (NCT01438489, N=265; NCT01283139, N=416) were profiled with whole genome array analyses. Type I IFN gene signature (IFNGS) test status was determined by a central laboratory utilizing an analytically validated four gene ( IFI27, IFI44, IFI44L, RSAD2) quantitative polymerase chain reaction-based test from patients9 whole blood. A predetermined, delta Ct-based cut-off point, in the trough of the bimodal distribution, was utilized to segregate type I IFNGS test–high from –low patients at baseline. Blood from healthy controls was stimulated ex vivo with IFN-β, IFN-γ, IFN-λ, IFN-ω, or a pool of all IFN-α subtypes, with or without blocking antibodies for each IFN type, to develop IFN-type-specific signatures. Cell type- and cytokine pathway-specific gene signatures derived from the literature were also evaluated with the Phase IIb sample data. A Fisher9s exact test was used for enrichment calculations (signatures cut at median), and comparisons were adjusted for multiplicity through false discovery rate. Results A total of 79% of SLE patients in the combined study population had a type I IFNGS test–high status. From the type I IFNGS test–high patients, 29/95 signatures evaluated had significant enrichment, including those for B cells (q=1.17E-17, odds ratio [OR]=6.4), plasma cells (q=6.96E-11, OR=3.9), and CD40L signaling (q=1.07E-08, OR=3.3), relative to type I IFNGS test–low patients. In contrast, type I IFNGS test–low patients had enrichment for eosinophils (q=5.4E-6, OR=0.39) and type II IFN (IFN-γ) specifically inducible gene signatures (q=4.6E-3, OR=0.47). These findings were significant for the combined study population, as well as for the NCT01438489 study population, and were either significant or trending for the NCT01283139 population (q Conclusions SLE patients who are type I IFNGS test–high had elevated concentrations of B cells, plasma cells, and other inflammatory cytokine pathways. Type I IFNGS test–low patients, by contrast, were enriched for eosinophil and type II IFN pathways. These observations provide new insights into the molecular heterogeneity underlying SLE and suggest new therapeutic approaches, particularly for type I IFNGS test–low patients. Acknowledgements Funded by MedImmune. Medical writing support was provided by R. Plant, QXV Comms, an Ashfield business, UK. Disclosure of Interest H. Liu Employee of: MedImmune LLC, B. Higgs Shareholder of: AstraZeneca, Employee of: MedImmune LLC, W. Rees Employee of: MedImmune LLC, C. Morehouse Shareholder of: AstraZeneca, Employee of: MedImmune LLC, K. Streicher Employee of: MedImmune LLC, P. Brohawn Shareholder of: AstraZeneca, Employee of: MedImmune, G. Illei Shareholder of: AstraZeneca, Employee of: MedImmune LLC, K. Ranade Employee of: MedImmune LLC
-
THU0295 Anifrolumab Reduces Disease Activity in Multiple Organ Domains in Moderate To Severe Systemic Lupus Erythematosus (SLE)
Annals of the Rheumatic Diseases, 2016Co-Authors: Joan T Merrill, Jorn Drappa, Victoria P Werth, Munther Khamashta, Richard Furie, L. Wang, G. IlleiAbstract:Background As reported elsewhere, anifrolumab was evaluated in a Phase IIb study of SLE patients with moderate to severe disease activity, in which 305 patients received intravenous infusions of anifrolumab (300 mg, 1000 mg) or placebo every 4 weeks for 1 year. Both doses demonstrated increased rates of reduction in global disease activity, although a more favorable risk-benefit profile was observed with the 300-mg dose. Objectives To compare the impact of anifrolumab on individual organ domains in patients with moderate to severe SLE who participated in the Phase IIb study. Methods At Week 52, changes from baseline in organs domain activity were assessed using the British Isles Lupus Assessment Group (BILAG) and SLE Disease Activity Index 2000 (SLEDAI-2K). Improvement in a BILAG organ domain was defined as the transitioning from “A” or “B” to a lower score. Improvement in a SLEDAI domain required a lower score at Day 365 compared with baseline in at least one of its components. Results The majority of patients had baseline involvement of the mucocutaneous and/or musculoskeletal domains of SLEDAI-2K and BILAG. Compared with placebo, a greater percentage of patients in the anifrolumab-treated group improved in these frequently involved organs: [Mucocutaneous: SLEDAI-2K: placebo 38/100 (38.0%) vs. 300 mg 61/99 (61.6%; p Conclusions Anifrolumab treatment resulted in greater rates of improvement than placebo in multiple organs, with greatest impact seen with 300 mg anifrolumab. Acknowledgement Funded by MedImmune. Editorial assistance: K Alexander, QXV Comms, an Ashfield business, UK Disclosure of Interest J. Merrill Grant/research support from: MedImmune; Genentech/Roche, Consultant for: MedImmune, Genentech/Roche, Neovacs, R. Furie Consultant for: MedImmune, V. Werth Consultant for: MedImmune, M. Khamashta Grant/research support from: Bayer, Consultant for: INOVA diagnostics, MedImmune, GSK, UCB outside submitted work, J. Drappa Shareholder of: AstraZeneca, Employee of: MedImmune, L. Wang Employee of: MedImmune, G. Illei Shareholder of: AstraZeneca, Employee of: MedImmune
Darren Robertson - One of the best experts on this subject based on the ideXlab platform.
-
1017 p continuous glucose monitoring reveals comprehensive glucose control with medi0382 an oxyntomodulin like peptide with targeted glp 1 glucagon receptor activity
Diabetes, 2019Co-Authors: Victoria E. Parker, Darren Robertson, Maximilian G. Posch, Tim Heise, David C. Hornigold, Tao Wang, Leona Plummoerschel, Juris J Meier, Heike Schlichthaar, Beate M KlausAbstract:Background: MEDI0382 is an oxyntomodulin-like peptide with GLP-1/glucagon receptor activity under development for type 2 diabetes mellitus (T2DM). Continuous glucose monitoring (CGM) is valuable for evaluating glucose-lowering efficacy. Methods: As an exploratory part of a double-blind phase 2a study, CGM was performed for 52 days with a Freestyle Libre. Patients with T2DM received daily SC MEDI0382 (n = 26) or placebo (n = 13) for 49 days; doses were up-titrated weekly from 50 to 300 µg. CGM assessed percent time spent in target range (70-140 mg/dL) and hypoglycemia ( Results: Over 52 days, 95% patients had >70% complete CGM data. Time spent in target range was significantly greater with MEDI0382 vs. placebo (64.8-78.0% vs. 42.5-53.0%; min-max; all P ≤ 0.05). Time spent at Discussion: MEDI0382 rapidly stabilized glucose levels, improved glycemic variability, and delivered a consistent decrease in mean glucose. The benefits of more time spent in target range will need to be confirmed in larger trials. Disclosure V.E.R. Parker: Employee; Self; MedImmune. Stock/Shareholder; Self; AstraZeneca. D. Robertson: Employee; Self; AstraZeneca. Employee; Spouse/Partner; GlaxoSmithKline plc. Stock/Shareholder; Self; AstraZeneca. T. Wang: Employee; Self; MedImmune. D.C. Hornigold: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. M.G. Posch: None. T. Heise: Advisory Panel; Self; Mylan. Research Support; Self; ADOCIA, Boehringer Ingelheim International GmbH, Dance Biopharm Holdings Inc., Eli Lilly and Company, Gan & Lee Pharmaceuticals, Johnson & Johnson, MedImmune, Mylan, Nordic Bioscience, Novo Nordisk A/S, Pfizer Inc., Poxel, Saniona, Sanofi, Wockhardt, Zealand Pharma A/S. Speaker’s Bureau; Self; Eli Lilly and Company, Novo Nordisk A/S. L. Plum-Moerschel: None. J.J. Meier: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi. H. Schlichthaar: None. B.M. Klaus: None. P. Ambery: Employee; Self; AstraZeneca. B. Hirshberg: Employee; Self; AstraZeneca. Funding AstraZeneca
-
988 p medi0382 an oxyntomodulin like peptide with targeted glp 1 glucagon receptor activity promotes a dose dependent increase in gastric emptying time
Diabetes, 2019Co-Authors: Darren Robertson, Victoria E. Parker, Marcella Petrone, Boaz Hirshberg, Lutz Jermutus, Philip Ambery, Tim Heise, Tao Wang, Leona Plummoerschel, Juris J MeierAbstract:Background: MEDI0382 is an oxyntomodulin-like peptide with targeted GLP-1/glucagon receptor activity under development for type 2 diabetes mellitus (T2DM). GLP-1 and glucagon promote delayed gastric emptying, and GLP-1 tolerance has been described. Methods: This exploratory part of a double-blind phase 2a study measured gastric emptying time (GET) in T2DM patients randomized to daily SC MEDI0382 (n = 20) or placebo (n = 6) for 49 days. Doses were up-titrated fortnightly from 50 to 300 µg. GET was measured after 13 C-octanoate ingestion via serial breath collection with plasma sampling for glucose, insulin, and MEDI0382 C trough levels. GET (t 1/2 = time for 13 C retention to decline 50%; t lag = time when percent excreted 13 C dose peaks) was measured at baseline; 15, 29, 43, 50 days; and 28 days post-dose. Results: GET t 1/2 was significantly prolonged from baseline, by 117.2 min (90% CI 56.2, 178.3) v placebo (-42.9 min; 90% CI -152.0, 66.2; P = 0.039), at 200 µg after 43 days of dosing. Also, at 43 days, t lag was significantly prolonged, by 46.5 min (90% CI, 16.9, 76) v placebo (-27.3 min; 90% CI, -80.0, 25.4; P = 0.048). Numerical increases in t 1/2 and t lag were seen at all dose levels; t lag increased with exposure, as exposure increased with dose up to 200 µg. Lesser delay occurred in GET on day 50 at 300 µg with similar exposure, but alongside significant reduction in glucose AUC of -25.3% (90% CI, -28.2, -22.4; P Discussion: MEDI0382 promoted dose-dependent increase in GET. Although tolerance to this effect may be evident from day 50, reduced postprandial glucose was observed concurrently and may indicate an insulinotropic effect. This unique profile displays characteristics of both short- and long-acting GLP-1 agonism, suggesting that these effects may be mediated by both glucagon and GLP-1 receptor agonism. Disclosure D. Robertson: Employee; Self; AstraZeneca. Employee; Spouse/Partner; GlaxoSmithKline plc. Stock/Shareholder; Self; AstraZeneca. V.E. Parker: Employee; Self; MedImmune. Stock/Shareholder; Self; AstraZeneca. P. Ambery: Employee; Self; AstraZeneca. M. Petrone: Employee; Self; MedImmune. T. Wang: Employee; Self; MedImmune. T. Heise: Advisory Panel; Self; Mylan. Research Support; Self; ADOCIA, Boehringer Ingelheim International GmbH, Dance Biopharm Holdings Inc., Eli Lilly and Company, Gan & Lee Pharmaceuticals, Johnson & Johnson, MedImmune, Mylan, Nordic Bioscience, Novo Nordisk A/S, Pfizer Inc., Poxel, Saniona, Sanofi, Wockhardt, Zealand Pharma A/S. Speaker9s Bureau; Self; Eli Lilly and Company, Novo Nordisk A/S. L. Plum-Moerschel: None. L. Jermutus: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. B. Hirshberg: Employee; Self; AstraZeneca. J.J. Meier: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Sanofi. Funding AstraZeneca
-
Effects of MEDI0382 on Pancreatic and Incretin Hormones
Diabetes, 2018Co-Authors: Victoria E. Parker, Lan-feng Tsai, Darren Robertson, Marcella Petrone, Cristina M. Rondinone, Boaz Hirshberg, Lutz Jermutus, Philip AmberyAbstract:MEDI0382, a GLP-1/glucagon dual receptor agonist, is being developed for the treatment of T2DM. GLP-1 receptor agonists promote glucose-dependent insulin release, suppress glucagon, and increase or have minimal effect on glucose-dependent insulinotropic polypeptide (GIP); knowledge of the effect on GLP-1 is limited. We characterized fasting and postprandial hormone profiles associated with MEDI0382 therapy. In a phase 2a study (NCT02548585), 51 subjects with T2DM and BMI 27-40 kg/m2 received MEDI0382 (uptitrated to 200 µg) or placebo (PBO) daily for 41 days. Glucose, insulin, glucagon, GIP, and GLP-1 were measured at baseline (day -1) and day 41 during a liquid mixed-meal tolerance test. MEDI0382 significantly reduced fasting glucose (-49.9 vs. -19.2 mg/dL for PBO; P Disclosure V.E.R. Parker: Employee; Self; MedImmune. Stock/Shareholder; Self; Accenture. Employee; Self; AstraZeneca. L. Tsai: Employee; Self; MedImmune. D. Robertson: Employee; Self; MedImmune. Employee; Spouse/Partner; GlaxoSmithKline plc. M. Petrone: Employee; Self; MedImmune. Stock/Shareholder; Self; MedImmune. C. Rondinone: Employee; Self; MedImmune. Stock/Shareholder; Self; AstraZeneca, F. Hoffmann-La Roche Ltd., Abbott, AbbVie Inc. B. Hirshberg: Employee; Self; AstraZeneca, MedImmune. L. Jermutus: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. P. Ambery: Employee; Self; MedImmune. Stock/Shareholder; Self; AstraZeneca.
-
Robust Glucose Control and Weight Loss after Six Weeks of Treatment with MEDI0382, a Balanced GLP-1/Glucagon Receptor Dual Agonist, in Patients with Type 2 Diabetes
Diabetes, 2018Co-Authors: Philip Ambery, Lan-feng Tsai, Darren Robertson, Marcella Petrone, Cristina M. Rondinone, Michael Stumvoll, Maximilian G. Posch, Tim Heise, Leona Plum-moerschel, Victoria E. ParkerAbstract:MEDI0382 is under development for the treatment of type 2 diabetes mellitus (T2DM). In a double-blind study (NCT02548585), 51 T2DM patients with BMI 27-40 kg/m 2 were randomized (1:1) to daily SC MEDI0382 200 μg or placebo (PBO). Based on ANCOVA with treatment and baseline (BL) values as covariates, MEDI0382 markedly reduced fasting glucose (change from BL at day 41, -49.9 vs. -19.2 mg/dL; P 0-4h , -32.8 vs. -10.2; P P = 0.0004). Weight loss was 3.8 kg vs. BL (1.7 kg vs. PBO; P = 0.0008); 92% of MEDI0382 patients lost >2 kg. Mean reduction in ambulatory systolic BP was -4.2 for MEDI0382 vs. -1.5 mmHg for PBO ( P = ns). As with marketed GLP-1 analogs, a mean pulse increase of 6.8 BPM for MEDI0382 vs. a fall of 2.0 BPM for PBO was seen ( P 3 severity, 3 led to study discontinuation for MEDI0382 vs. 1 for PBO, and 1 SAE in the PBO arm. Overall, MEDI0382 normalized fasting and postprandial blood glucose, significantly reduced body weight, and had an acceptable safety profile over 41 days of dosing in obese/overweight T2DM patients. Disclosure P. Ambery: Employee; Self; MedImmune. Stock/Shareholder; Self; AstraZeneca. M.W. Stumvoll: Speaker9s Bureau; Self; Novartis Pharmaceuticals Corporation. Advisory Panel; Self; AstraZeneca, Novo Nordisk A/S. Speaker9s Bureau; Self; Merck Foundation. M.G. Posch: None. T. Heise: Research Support; Self; ADOCIA, Boehringer Ingelheim GmbH, Dance Biopharm, Eli Lilly and Company, Janssen Research & Development, MedImmune, Merck Sharp & Dohme Corp., Mylan, Nordic Bioscience, Novo Nordisk A/S, Poxel SA, Roche Diagnostics Corporation, Saniona, Sanofi, Senseonics, Zealand Pharma A/S. Advisory Panel; Self; Novo Nordisk A/S, Mylan. Speaker9s Bureau; Self; Dexcom, Inc., Eli Lilly and Company, Novo Nordisk A/S, Sanofi. L. Plum-Moerschel: None. L. Tsai: Employee; Self; MedImmune. D. Robertson: Employee; Self; MedImmune. Employee; Spouse/Partner; GlaxoSmithKline plc. M. Petrone: Employee; Self; MedImmune. Stock/Shareholder; Self; MedImmune. C. Rondinone: Employee; Self; MedImmune. Stock/Shareholder; Self; AstraZeneca, F. Hoffmann-La Roche Ltd., Abbott, AbbVie Inc. V.E. Parker: Employee; Self; MedImmune. Stock/Shareholder; Self; Accenture. Employee; Self; AstraZeneca. B. Hirshberg: Employee; Self; AstraZeneca, MedImmune. L. Jermutus: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca.
-
MEDI0382, a GLP-1/Glucagon Receptor Dual Agonist, in Patients with Type 2 Diabetes—A Multiple-Ascending-Dose Study
Diabetes, 2018Co-Authors: Darren Robertson, Lan-feng Tsai, Marcella Petrone, Boaz Hirshberg, Michael Stumvoll, Maximilian G. Posch, Tim Heise, Leona Plum-moerschel, Gernot K. Klein, Cristina M. RondinoneAbstract:MEDI0382 is a GLP-1/glucagon receptor dual agonist under development for the treatment of type 2 diabetes mellitus (T2DM). This double-blind study (NCT02548585) evaluated MEDI0382 in T2DM patients with BMI 27-40 kg/m2. Subjects (n = 61) were randomized to once-daily subcutaneous MEDI0382 or placebo (PBO) at different dosing levels and uptitration schedules (100 μg [C1], 150 μg [C2], 200 μg [C3], and 300 μg (2 uptitration schedules, C4 and C5). Marked reduction in fasting and postprandial glucose was achieved with a ∼40% decrease in glucose AUC0-4h after mixed-meal testing across all cohorts (P ≤ 0.0102) (Figure 1A). Weight loss was observed at all dose levels and reached statistical significance (P = 0.024) at 300 μg (C4) (Figure 1B). Ambulatory systolic blood pressure decreased nonsignificantly from baseline in the 300-μg cohort (C4, -4.9 vs. -6.5 mmHg; C5, -9.1 vs. -5.0 mmHg). Similar to other marketed GLP-1 analogs, MEDI0382 increased pulse rate vs. PBO (C4, 8.4 vs. -2.4 BPM, P = 0.0039; C5, 5.8 vs. 0.2 BPM, P = 0.0796). Treatment-related adverse events occurred more often with MEDI0382 vs. PBO (86% [36/42] vs. 47% [9/19]); most events were mild or moderate in severity. In conclusion, MEDI0382 administered for up to 22 days showed a marked reduction in both fasting and postprandial glucose with weight reduction and an acceptable tolerability profile. Disclosure D. Robertson: Employee; Self; MedImmune. Employee; Spouse/Partner; GlaxoSmithKline plc. M.W. Stumvoll: Speaker9s Bureau; Self; Novartis Pharmaceuticals Corporation. Advisory Panel; Self; AstraZeneca, Novo Nordisk A/S. Speaker9s Bureau; Self; Merck Foundation. M.G. Posch: None. T. Heise: Research Support; Self; ADOCIA, Boehringer Ingelheim GmbH, Dance Biopharm, Eli Lilly and Company, Janssen Research & Development, MedImmune, Merck Sharp & Dohme Corp., Mylan, Nordic Bioscience, Novo Nordisk A/S, Poxel SA, Roche Diagnostics Corporation, Saniona, Sanofi, Senseonics, Zealand Pharma A/S. Advisory Panel; Self; Novo Nordisk A/S, Mylan. Speaker9s Bureau; Self; Dexcom, Inc., Eli Lilly and Company, Novo Nordisk A/S, Sanofi. L. Plum-Moerschel: None. G. Klein: None. L. Tsai: Employee; Self; MedImmune. M. Petrone: Employee; Self; MedImmune. Stock/Shareholder; Self; MedImmune. B. Hirshberg: Employee; Self; AstraZeneca, MedImmune. C. Rondinone: Employee; Self; MedImmune. Stock/Shareholder; Self; AstraZeneca, F. Hoffmann-La Roche Ltd., Abbott, AbbVie Inc. V.E. Parker: Employee; Self; MedImmune. Stock/Shareholder; Self; Accenture. Employee; Self; AstraZeneca. L. Jermutus: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. P. Ambery: Employee; Self; MedImmune. Stock/Shareholder; Self; AstraZeneca.
Brandon W Higgs - One of the best experts on this subject based on the ideXlab platform.
-
AB1212 Analytical validation of an interferon-inducible gene expression kit as a potential diagnostic test for anifrolumab
Diagnostics and imaging procedures, 2018Co-Authors: Philip Brohawn, Brandon W Higgs, S. Patel, A. Moody, P. Cooper, Koustubh RanadeAbstract:Background Anifrolumab, a fully human monoclonal antibody that binds to the type I interferon receptor, is in Phase III development for moderate to severe systemic lupus erythematosus (SLE). Patients with greater interferon-inducible gene signatures (IFNGS) have enhanced response to anifrolumab treatment.1 AstraZeneca and QIAGEN developed an in-vitro diagnostic test for interferon-inducible gene expression (IFIGx). Efficacy of anifrolumab will be evaluated in patients with high and low IFNGS. Objectives We aimed to analytically validate the IFIGx kit for use in a pivotal clinical study and potentially to support future regulatory submission. Methods The IFIGx kit measures expression of four interferon-inducible genes (IF127, IF114, IF114L and RSAD2) compared with three housekeeping genes. Measurements were performed on mRNA extracted from whole blood from adults with SLE. A score was generated that identified patients as “IFNGS test–high” or “IFNGS test–low.” Analytical validation involved six studies measuring lot interchangeability, linearity, repeatability, reproducibility, cross contamination, and system verification. Results Repeatability was 100%. Reproducibility was >96%. No cross contamination was observed. Results of all studies validated the IFIGx kit (table 1). Conclusions The IFIGx kit was shown to be a robust, reproducible diagnostic test for IFNGS. The IFIGx kit has demonstrated value in prior anifrolumab studies,1 and will be used both for patient stratification in Phase III studies and to support anifrolumab regulatory filings. Reference [1] Furie, et al. Arthritis Rheumatol. 2017;69:376–86. Disclosure of Interest P. Brohawn Employee of: MedImmune LLC, B. Higgs Employee of: MedImmune LLC, S. Patel Employee of: AstraZeneca, A. Moody Employee of: QIAGEN Manchester Ltd, P. Cooper Employee of: QIAGEN Manchester Ltd, K. Ranade Employee of: MedImmune LLC
-
OP0301 Type i ifn gene signature test–high and –low patients with moderate to severe sle disease activity have distinct gene expression signatures of immunologic pathways and cell types
Oral Presentations, 2017Co-Authors: Hao Liu, Brandon W Higgs, Chris Morehouse, Philip Brohawn, G. Illei, Katie Streicher, W Rees, Koustubh RanadeAbstract:Background Type I interferon (IFN) has been implicated in systemic lupus erythematosus (SLE) pathogenesis, and the majority of patients with SLE have elevated expression of type I IFN-inducible genes in their blood. Anifrolumab, a fully human, IgG 1 κ monoclonal antibody against the type I IFN receptor, is in Phase III development for the treatment of moderate to severe SLE (NCT02446912 and NCT02446899). Objectives We sought to understand other molecular pathways (either dependent on or independent of type I IFN signaling), to elucidate heterogeneous mechanisms in SLE, and to identify patient subsets for personalized disease management. Methods Baseline blood samples from adult patients with moderate to severe SLE from two Phase IIb clinical studies (NCT01438489, N=265; NCT01283139, N=416) were profiled with whole genome array analyses. Type I IFN gene signature (IFNGS) test status was determined by a central laboratory utilizing an analytically validated four gene ( IFI27, IFI44, IFI44L, RSAD2) quantitative polymerase chain reaction-based test from patients9 whole blood. A predetermined, delta Ct-based cut-off point, in the trough of the bimodal distribution, was utilized to segregate type I IFNGS test–high from –low patients at baseline. Blood from healthy controls was stimulated ex vivo with IFN-β, IFN-γ, IFN-λ, IFN-ω, or a pool of all IFN-α subtypes, with or without blocking antibodies for each IFN type, to develop IFN-type-specific signatures. Cell type- and cytokine pathway-specific gene signatures derived from the literature were also evaluated with the Phase IIb sample data. A Fisher9s exact test was used for enrichment calculations (signatures cut at median), and comparisons were adjusted for multiplicity through false discovery rate. Results A total of 79% of SLE patients in the combined study population had a type I IFNGS test–high status. From the type I IFNGS test–high patients, 29/95 signatures evaluated had significant enrichment, including those for B cells (q=1.17E-17, odds ratio [OR]=6.4), plasma cells (q=6.96E-11, OR=3.9), and CD40L signaling (q=1.07E-08, OR=3.3), relative to type I IFNGS test–low patients. In contrast, type I IFNGS test–low patients had enrichment for eosinophils (q=5.4E-6, OR=0.39) and type II IFN (IFN-γ) specifically inducible gene signatures (q=4.6E-3, OR=0.47). These findings were significant for the combined study population, as well as for the NCT01438489 study population, and were either significant or trending for the NCT01283139 population (q Conclusions SLE patients who are type I IFNGS test–high had elevated concentrations of B cells, plasma cells, and other inflammatory cytokine pathways. Type I IFNGS test–low patients, by contrast, were enriched for eosinophil and type II IFN pathways. These observations provide new insights into the molecular heterogeneity underlying SLE and suggest new therapeutic approaches, particularly for type I IFNGS test–low patients. Acknowledgements Funded by MedImmune. Medical writing support was provided by R. Plant, QXV Comms, an Ashfield business, UK. Disclosure of Interest H. Liu Employee of: MedImmune LLC, B. Higgs Shareholder of: AstraZeneca, Employee of: MedImmune LLC, W. Rees Employee of: MedImmune LLC, C. Morehouse Shareholder of: AstraZeneca, Employee of: MedImmune LLC, K. Streicher Employee of: MedImmune LLC, P. Brohawn Shareholder of: AstraZeneca, Employee of: MedImmune, G. Illei Shareholder of: AstraZeneca, Employee of: MedImmune LLC, K. Ranade Employee of: MedImmune LLC
-
op0165 beneficial effects of an anti ifnar1 monoclonal antibody on immune cell dysregulation and complement system abnormalities of systemic lupus erythematosus an exploratory analysis of phase iib clinical trial of anifrolumab
Annals of the Rheumatic Diseases, 2016Co-Authors: Xiang Guo, Brandon W Higgs, Philip Brohawn, L. Wang, G. Illei, Wendy I. WhiteAbstract:Background Anifrolumab is a fully human IgG 1 κ monoclonal antibody directed against subunit 1 of the type I interferon alpha receptor (IFNAR1). A Phase IIb randomized clinical trial of adult patients with systemic lupus erythematosus (SLE) has been conducted for anifrolumab. Objectives To assess downstream effects of anifrolumab on peripheral biomarkers and pathophysiologic pathways in patients with SLE. Methods In the MUSE study, 305 patients with moderate to severe SLE were randomized in a 1:1:1 ratio to receive a fixed intravenous dosage of placebo or anifrolumab (300 or 1,000 mg), in addition to standard of care medications, every 28 days for 1 year. Patients were stratified by IFN gene signature status (high vs. low) based on a 4-gene expression assay. Selected proteins were measured in sera of SLE patients procured at baseline, 85, 169, and 365 days post-administration along with 30 healthy controls (HCs) using a multiplex luminex immunoassay. Results Serum concentrations of 134 proteins were measured for 30 HCs and 304 SLE patients at baseline (missing sample for one patient), of which 229 had a high IFN signature (IFN-high) and 75 did not (IFN-low). Mann-Whitney U test identified 55 proteins with higher levels and 12 proteins with lower levels in IFN-high patients than IFN-low patients and/or HCs ( p p Conclusions Our results demonstrate a distinct proteome profile of IFN-high patients compared with IFN-low patients and HCs. Anifrolumab administration elicits a widespread impact on peripheral biomarkers of patients with SLE. Beneficial effects on both immune cell dysregulation and complement system abnormalities may be key contributors to the mechanism of action of anifrolumab in SLE. Disclosure of Interest X. Guo Shareholder of: MedImmune/AstraZeneca, Employee of: MedImmune/AstraZeneca, L. Wang Shareholder of: MedImmune/AstraZeneca, Employee of: MedImmune/AstraZeneca, G. Illei Shareholder of: MedImmune/AstraZeneca, Employee of: MedImmune/AstraZeneca, P. Brohawn Shareholder of: MedImmune/AstraZeneca, Employee of: MedImmune/AstraZeneca, B. Higgs Shareholder of: MedImmune/AstraZeneca, Employee of: MedImmune/AstraZeneca, W. White Shareholder of: MedImmune/AstraZeneca, Employee of: MedImmune/AstraZeneca
-
ab0167 pharmacokinetics of sifalimumab and target modulation of a type i interferon gene signature in patients with moderate to severe systemic lupus erythematosus
Annals of the Rheumatic Diseases, 2015Co-Authors: Chris Morehouse, Brandon W Higgs, Philip Brohawn, Lorin Roskos, B Zheng, Gabriel RobbieAbstract:Background Sifalimumab is a fully human, IgG 1 κ monoclonal antibody in Phase IIb clinical development for systemic lupus erythematosus (SLE). Sifalimumab binds to and neutralizes the majority of IFN-α subtypes. Objectives We assessed the pharmacokinetic and pharmacodynamic effects of sifalimumab through analysis of the blood of adult patients with moderate to severe SLE enrolled in a Phase IIb study. Methods Adult patients who satisfied ACR classification criteria for SLE were enrolled in a Phase IIb randomized controlled trial 1 and received sifalimumab 200, 600, or 1,200 mg intravenously every 4 weeks, or placebo (following starting doses at Days 1, 15, and 29). Blood specimens were collected for PK and PD assessments at several time points from pre-dosage to 516 days after initial administration. Sifalimumab drug concentrations were measured via a validated electrochemiluminescence assay, and PK parameters were determined by noncompartmental analysis. Transcript profiling was conducted through real-time quantitative reverse transcription–polymerase chain reaction (qRT–PCR) on a type I IFN-inducible gene signature (IFNGS). Results Sifalimumab serum concentrations exhibited linear and dose-proportional PK over the 200 to 1,200 mg every 4 weeks dosage range. Mean maximum concentration (C max ) and trough concentrations (C trough ), respectively, ranged from 117 to 562 ug/mL and 19.9 to 150 ug/mL, respectively, at steady state. Mean clearance and half-life ranged from 0.11 to 0.14 L/day and 24 to 26 days. A total of 349 of 431 patients (81%) were positive for the IFNGS in whole blood at baseline. Expression of IFNGS in whole blood decreased following sifalimumab administration for all dosages in patients positive for the IFNGS at baseline. Neutralization scores were calculated for each available time point (Days 15 to 365), based on patients9 Day-1 baseline expression IFNGS values. Percentage neutralization scores for each dosage arm were summarized (mean ± SE) for all available time points. In the 200-mg every 4 week dosage arm, a moderate mean signature neutralization (6.1–21.8%) was observed at Day 15 and maintained through Day 365. Maximum mean neutralization (21.8%) was observed at Day 15. In the 600-mg every 4 week dosage arm, moderate mean signature neutralization (8.3–27%) was observed at Day 15 and maintained through Day 365. Maximum mean neutralization (27%) was observed at Day 15. Finally, in the 1,200 mg every 4 week dosage arm, slightly more substantial mean signature neutralization (17.7–25.3%) was observed at Day 15 and maintained through Day 365. Maximum mean neutralization (25.3%) was observed at Day 15. IFNGS induction was noted for the placebo at each time point assessed. For all patients who received sifalimumab, maximum mean signature neutralization was observed at the first time point assessed (Day 15), while near-equivalent to sub-maximal neutralization magnitudes were noted at subsequent time points. Conclusions Sifalimumab PK was linear and dose-proportional. Sifalimumab demonstrated expected mechanism of action in SLE. Target engagement of sifalimumab was confirmed with inhibition of the IFNGS. As expected, inhibition of IFN signature was less than complete over the dosage range tested. References Khamashta M, et al. Arthritis Rheumatol. 2014;66:3530–31 (Abs L4). Acknowledgements Funded by MedImmune. Disclosure of Interest C. Morehouse Shareholder of: AstraZeneca, Employee of: MedImmune, P. Brohawn Shareholder of: AstraZeneca, Employee of: MedImmune, B. Higgs Shareholder of: AstraZeneca, Employee of: MedImmune, B. Zheng Employee of: MedImmune, Y. Yao Shareholder of: AstraZeneca, Employee of: MedImmune, L. Roskos Shareholder of: AstraZeneca, Employee of: MedImmune, G. Robbie Shareholder of: AstraZeneca, Employee of: MedImmune
-
THU0459 RNA Sequencing Reveals Over-Expression of IGG4 and IGE MRNAS and Activated TH2-Related, Treg-Related, and Other Cytokine Pathways in the Blood of IGG4-Related and Mikulicz's Disease Patients
Annals of the Rheumatic Diseases, 2014Co-Authors: Brandon W Higgs, Laura Richman, Wei Zhu, Christopher Morehouse, Yanying Liu, Jianping Guo, Yinong Sebastian, Yihong YaoAbstract:Background IgG4-related disease (IgG4RD) is a spectrum of systemic indications characterized by fibrosclerosis in various organs, tissue infiltrating IgG4+ plasma cells, and sometimes elevation of IgG4 in the serum. Mikulicz9s disease (MD) is one of multiple IgG4RDs with single organ involvement including lachrymal, parotid, and submandibular glands. The pathogenesis of these diseases has been linked to infection and autoimmunity with a predominance of Th2- and Treg-cell cytokines driving increased levels of eosinophils, IgG4, and IgE, ultimately leading to cell infiltration and organ damage. To date, less is known about the molecular differences between IgG4RD and MD, as well as transcriptome-wide mediators of disease. Objectives We evaluated most altered molecular pathways in the blood of IgG4RD and MD patients. Methods Blood was procured from 13 MD (ages 32-65; 7 Male), 9 IgG4RD (ages 48-80; 9 Male), and 10 healthy control (ages 30-57; 7 Male) Chinese subjects and RNA was sequenced with Illumina HiSeq. Seven MD and 5 IgG4RD patients were treated with ≤20mg prednisone with one other glucocorticoid-sparing agent. In IgG4RD, 342 and 683 genes were over- and under-expressed, respectively and 35 and 33 genes were over- and under-expressed in MD (q 2). Gene signatures were identified from ex vivo stimulation experiments with whole blood. All comparisons were relative to controls unless stated. Results IgG4 was the most over-expressed mRNA in both MD and IgG4RD (fold>32; q IgG4RD =0.001, q MD =0.002), with IgE mRNA among the top 10 most over-expressed (fold>8; q IgG4RD =0.0003, q MD =0.01) and both correlated with each other (r=0.85) and IL-5R mRNA (r IgG4 =0.80; r IgE =0.64), which was suppressed in patients treated with prednisone compared to those not (p IgG4RD =0.008; p MD =0.0001). The same mRNA suppression of IgG4 and IgE was seen in MD patients on prednisone compared to those not (p IgG4 =0.002 and p IgG4RD =0.004; p IgG4RD =0.03; p MD =0.03). Conclusions Our study shows the increase of IgG4 and IgE mRNAs, the activation of Th2, Treg, and other inflammatory cytokine pathways in both diseases compared to controls. A reduced B cell signature in the blood of IgG4RD and MD patients suggests infiltration to disease sites. Prednisone treatment suppresses IgG4 and IgE mRNAs in MD, IL-5R mRNA in both diseases, and activates IL-10 pathways in both diseases compared to treatment naive patients. Further studies need to be conducted to confirm these observations and correlate them with clinical activity. Disclosure of Interest : B. Higgs Shareholder of: Astra Zeneca, Employee of: MedImmune, Y. Liu: None declared, J. Guo: None declared, C. Morehouse Shareholder of: Astra Zeneca, Employee of: MedImmune, Y. Sebastian Shareholder of: Astra Zeneca, Employee of: MedImmune, W. Zhu Shareholder of: Astra Zeneca, Employee of: MedImmune, L. Richman Shareholder of: Astra Zeneca, Employee of: MedImmune, Y. Yao Shareholder of: Astra Zeneca, Employee of: MedImmune, Z. Li: None declared DOI 10.1136/annrheumdis-2014-eular.2255
L. Wang - One of the best experts on this subject based on the ideXlab platform.
-
OP0174 Alteration of mediators of vascular inflammation by anifrolumab in the phase iib muse study in sle
THURSDAY 14 JUNE 2018, 2018Co-Authors: Wendy I. White, L. Wang, Kerry A. Casey, Michael A Smith, G. Illei, Nickie L. Seto, Martin P. Playford, Philip M. Carlucci, Nehal N. MehtaAbstract:Background Cardiovascular disease remains one of the leading causes of death for patients with systemic lupus erythematosus (SLE), and the disease is widely known to feature premature atherosclerosis promoted by immune dysregulation. Neutrophil extracellular traps (NETs) can induce endothelial dysfunction and promote inflammatory events. Furthermore, sources of reactive oxygen species released during NET formation promote oxidised HDL, leading to deficient cholesterol efflux capacity (CEC). Type I interferons (IFNs) stimulate NET formation and inhibit vascular repair. Anifrolumab is a fully human, IgG1 κ monoclonal antibody that binds to IFNAR1 and blocks signalling of all type I IFNs. Thus, anifrolumab may decrease mechanisms of vascular damage in SLE. Objectives We evaluated the ability of anifrolumab to reduce in-vivo NET formation and improve CEC relative to standard of care (SOC) in the MUSE study.1 Methods Baseline IFN gene signature (IFNGS) test status (high or low) of MUSE patients was determined as described.1 Plasma samples from fasting patients (n=190) were obtained at days 1 and 365 of the MUSE study. Plasma MPO-, HNE- and CitH3-DNA NET complexes were quantified by ELISAs in the MUSE and healthy donor (HD) samples (n=20) as described.2 Wilcoxon rank-sum test was used to assess differences between groups. Post-treatment samples from the placebo (n=52) and 300 mg anifrolumab (n=73) groups were compared with baseline samples. Significance of change from baseline was determined using Wilcoxon signed-rank test. CEC was tested as described.3 Reproducibility of the CEC assay was assessed using percent coefficient of variation (CV) from the analysis of variance (ANOVA). SLE patients with defective baseline CEC were identified as those with CEC Results All three neutrophil NET complexes (NNCs) were elevated in SLE patients (p Conclusions Circulating NNCs were significantly elevated in patients with moderate to severe SLE as compared with HDs. Anifrolumab decreased circulating NNCs. Although changes in steroid dosages during MUSE did not affect CEC, anifrolumab significantly improved CEC over SOC. This work supports continued assessment of anifrolumab effects on vascular inflammation and endothelial damage in SLE. References [1] Furie R, et al. Arthritis Rheumatol2017;69:376–86. [2] Demoruelle MK, et al. Arthritis Rheumatol2017;69:1165–75. [3] Salahuddin T, et al. Eur Heart J2015;36:2662–5. Disclosure of Interest W. White Shareholder of: AstraZeneca, Employee of: MedImmune, N. Seto: None declared, M. Playford: None declared, K. Casey Shareholder of: AstraZeneca, Employee of: MedImmune, M. Smith Shareholder of: AstraZeneca, Employee of: MedImmune, P. Carlucci: None declared, B. Yu Shareholder of: AstraZeneca, Employee of: MedImmune, L. Wang Shareholder of: AstraZeneca, Employee of: MedImmune, G. Illei Shareholder of: AstraZeneca, Consultant for: MedImmune, N. Mehta Grant/research support from: Abbvie, Novartis, Janssen, Celgene, Employee of: NHLBI, M. Kaplan Grant/research support from: MedImmune
-
SAT0220 Effects of type I interferon inhibition on blood leukocyte subsets in patients treated in a phase IIB clinical study of anifrolumab in systemic lupus erythematosus (SLE)
Poster Presentations, 2017Co-Authors: Wendy I. White, L. Wang, Kerry A. Casey, Michael A Smith, Miguel A. Sanjuan, D Sinbaldi, G. IlleiAbstract:Background A Phase IIb randomized controlled study (NCT01753193) was conducted with anifrolumab, a fully human, anti-interferon (IFN)–α receptor (IFNAR) specific antibody in adults with moderate to severe SLE. Anifrolumab binds to subunit 1 of the IFNAR and inhibits the activity of all type I IFNs. A complete blood count analysis demonstrated that anifrolumab reversed leukopenia. However, the types of peripheral immune cells affected following treatment have not been reported. Objectives To better understand how changes in the immune cell repertoire may be associated with SLE severity, type I IFN test status (high vs. low), and treatment with anifrolumab, we performed flow cytometry to assess peripheral blood cell types: dendritic cells (myeloid and plasmacytoid), B cells (naive, memory, and plasma cells), neutrophils, and T cells (CD4, CD8, naive, memory, central memory, and effector). Methods Patients were randomized 1:1:1 to anifrolumab 300 mg, or 1,000 mg, or placebo (PBO) every 4 weeks for 48 weeks. Peripheral blood was collected from a subset of patients (91 total) on Days 1 (prior to first dose), 85, 141, 169, 253, 337, and 365. Patients were approximately evenly distributed between treatment arms. Baseline absolute immune cell numbers were compared over treatment course in the context of SLE Disease Activity Index (SLEDAI)–2K scores, type I IFN test, and therapy response. Statistics were calculated using the Student9s t-test; p-values ≤0.05 were considered statistically significant. Results At baseline, several blood cell types were lower for patients with SLEDAI ≥10, including naive B cells, and memory T and B cells. In IFN-high patients, neutrophils, memory T cells, and plasmacytoid dendritic cells (pDCs) were significantly decreased. Anifrolumab led to significant increases in absolute numbers of T-cell subsets in the blood of IFN-high patients. In contrast, no significant changes were observed for IFN-low patients. Observed increases were within normal reference ranges. The alterations did not appear to be secondary to tapering of oral corticosteroids, as these cell types were not significantly different in PBO groups, regardless of tapering. Patients with ≥6-point SLEDAI reductions following anifrolumab demonstrated significant increases in total CD4 and CD8 T cells, and nonsignificant decreases in memory B cells. Significant increases in pDCs were also evident. Anifrolumab did not cause significant differences in other cell types measured. Conclusions Memory T cell numbers, among other cell types, were significantly reduced in patients with SLEDAI ≥10 and those classified as IFN high at baseline. This suggests that, for patients with more severe disease, type I IFN may be involved in cell migration into the peripheral tissues from the blood. Consistent with this, we found that neutralization of type I IFN with anifrolumab promoted immigration and/or prevented emigration of potentially pathologic immune cells between the tissues and the blood. These data suggest that some effects observed following anifrolumab treatment might be a result of altering the migration patterns of T and other immune cells, which may partially explain its biological activity. Acknowledgements Funded by MedImmune. Medical writing support: R Plant, QXV Comms, an Ashfield company, funded by MedImmune. Disclosure of Interest W. White Shareholder of: AstraZeneca, Employee of: MedImmune LLC, K. Casey Shareholder of: AstraZeneca, Employee of: MedImmune LLC, M. Smith Shareholder of: AstraZeneca, Employee of: MedImmune LLC, L. Wang Employee of: MedImmune LLC, D. Sinbaldi Shareholder of: AstraZeneca, Employee of: MedImmune LLC, M. Sanjuan Employee of: MedImmune LLC, G. Illei Shareholder of: AstraZeneca, Employee of: MedImmune LLC
-
SAT0243 Exposure-response (E-R) analysis for selection of optimal dosage regimen of anifrolumab in patients (PTS) with systemic lupus erythematosus (SLE)
Poster Presentations, 2017Co-Authors: Lc Santiago, Philip Brohawn, L. Wang, G. Illei, Bing Wang, Lorin RoskosAbstract:Background Anifrolumab is a fully human IgG1 monoclonal antibody directed against subunit 1 of the type I interferon–α receptor (IFNAR1). It is in development for treatment of SLE. Objectives To support dosage selection for pivotal anifrolumab studies, using an E−R model. Methods In the Phase IIb MUSE study (NCT01438489),1 adult pts with moderate to severe SLE, who had inadequate responses to standard-of-care (SOC) medications, were randomized 1:1:1 to intravenous anifrolumab 300 or 1,000 mg or placebo every 4 weeks (Q4W), in addition to SOC medications, for 48 weeks. Pts were stratified by type I interferon gene signature (IFNGS) test status (high or low) using a validated 4-gene expression assay, oral corticosteroid dosage ( Results There was no PK difference between type I IFNGS test–high or –low pts (mean [standard deviation] Ctrough (Day 169): 17.0 [11.5] μg/mL and 23.3 [16.0] μg/mL, respectively). SRI (4) modeling demonstrated no anifrolumab treatment effect in type I IFNGS test–low pts compared with placebo; interpretation of this result may be limited by small sample size. In type I IFNGS test–high pts, a log-linear logistic model was used to describe the treatment effect of anifrolumab. Pt dropouts were more likely in nonresponders. Clinical simulations demonstrated dosages 300 mg, consistent with the Phase IIb MUSE study outcomes. Conclusions Based on E−R analyses and overall risk assessment, a 300 mg Q4W, intravenous dosage regimen is recommended for pivotal anifrolumab studies in pts with SLE. References Furie R, et al. Arthritis Rheumatol. 2017;69:376–86. Wang B, et al. Clin Pharmacol Ther. 2013;93:483−92. Acknowledgements Funded by MedImmune. Medical writing support: R. Plant, QXV Comms, an Ashfield company, funded by MedImmune. Disclosure of Interest L. Santiago Shareholder of: AstraZeneca, Employee of: MedImmune LLC, B. Wang Shareholder of: AstraZeneca, Employee of: MedImmune LLC, P. Brohawn Shareholder of: AstraZeneca, Employee of: MedImmune LLC, L. Wang Employee of: MedImmune LLC, G. Illei Shareholder of: AstraZeneca, Employee of: MedImmune LLC, L. Roskos Shareholder of: AstraZeneca, Employee of: AstraZeneca
-
THU0295 Anifrolumab Reduces Disease Activity in Multiple Organ Domains in Moderate To Severe Systemic Lupus Erythematosus (SLE)
Annals of the Rheumatic Diseases, 2016Co-Authors: Joan T Merrill, Jorn Drappa, Victoria P Werth, Munther Khamashta, Richard Furie, L. Wang, G. IlleiAbstract:Background As reported elsewhere, anifrolumab was evaluated in a Phase IIb study of SLE patients with moderate to severe disease activity, in which 305 patients received intravenous infusions of anifrolumab (300 mg, 1000 mg) or placebo every 4 weeks for 1 year. Both doses demonstrated increased rates of reduction in global disease activity, although a more favorable risk-benefit profile was observed with the 300-mg dose. Objectives To compare the impact of anifrolumab on individual organ domains in patients with moderate to severe SLE who participated in the Phase IIb study. Methods At Week 52, changes from baseline in organs domain activity were assessed using the British Isles Lupus Assessment Group (BILAG) and SLE Disease Activity Index 2000 (SLEDAI-2K). Improvement in a BILAG organ domain was defined as the transitioning from “A” or “B” to a lower score. Improvement in a SLEDAI domain required a lower score at Day 365 compared with baseline in at least one of its components. Results The majority of patients had baseline involvement of the mucocutaneous and/or musculoskeletal domains of SLEDAI-2K and BILAG. Compared with placebo, a greater percentage of patients in the anifrolumab-treated group improved in these frequently involved organs: [Mucocutaneous: SLEDAI-2K: placebo 38/100 (38.0%) vs. 300 mg 61/99 (61.6%; p Conclusions Anifrolumab treatment resulted in greater rates of improvement than placebo in multiple organs, with greatest impact seen with 300 mg anifrolumab. Acknowledgement Funded by MedImmune. Editorial assistance: K Alexander, QXV Comms, an Ashfield business, UK Disclosure of Interest J. Merrill Grant/research support from: MedImmune; Genentech/Roche, Consultant for: MedImmune, Genentech/Roche, Neovacs, R. Furie Consultant for: MedImmune, V. Werth Consultant for: MedImmune, M. Khamashta Grant/research support from: Bayer, Consultant for: INOVA diagnostics, MedImmune, GSK, UCB outside submitted work, J. Drappa Shareholder of: AstraZeneca, Employee of: MedImmune, L. Wang Employee of: MedImmune, G. Illei Shareholder of: AstraZeneca, Employee of: MedImmune
-
OP0291 Anifrolumab, An Anti-Interferon-Alpha Receptor Monoclonal Antibody, in Moderate To Severe Systemic Lupus Erythematosus (SLE)
Annals of the Rheumatic Diseases, 2016Co-Authors: Richard Furie, Kenneth Kalunian, Jorn Drappa, Joan T Merrill, Philip Brohawn, Victoria P Werth, Munther Khamashta, L. Wang, G. Illei, Stephen YooAbstract:Background Increased activity of the type I interferon (IFN) pathway is central to the pathogenesis of SLE. Blocking the type I receptor may reduce SLE activity more effectively than inhibiting IFN-α alone. Objectives Efficacy and safety of anifrolumab were assessed in a Phase IIb, randomized, double-blind, placebo-controlled study of adults with moderate to severe SLE (the MUSE study). Methods 305 patients were treated for 48 weeks with intravenous anifrolumab (300 mg or 1000 mg) or placebo, in addition to standard-of-care medications. Randomization was stratified by SLE Disease Activity Index 2000 (SLEDAI-2K) score ( Results The primary endpoint was met by more anifrolumab-treated patients [placebo vs. 300 mg vs. 1000 mg: 17.6%, 34.3% ( p =0.014), 28.8% ( p =0.063)] with greater effect sizes observed in the 75% of patients who had a high baseline IFN signature [13.2%, 36.0% ( p =0.004), 28.2% ( p =0.029)]. At Day 365 more anifrolumab-treated patients achieved SRI(4) responses [40.2%, 62.6%, ( p p =0.043)], BILAG-based Composite Lupus Assessment (BICLA) [25.7%, 53.5% ( p p =0.018)], modified SRI(6) [28.4%, 49.5% ( p =0.002), 44.7% ( p =0.015)], and SLEDAI-2K ≤2 [17.6%, 35.4% ( p =0.004), 32.7% ( p =0.012)]. Major clinical response (BILAG “C” or better in all domains at Day 169 maintained to Day 365) was achieved by 6.9%, 19.2% ( p =0.012), and 17.3% ( p =0.025) of patients. BILAG “A” flares were reported in more placebo- vs. anifrolumab-treated patients (16.7%, 9.1%, 10.6%). In patients with baseline Cutaneous Lupus Erythematosus Disease Area and Severity Index activity score ≥10, more anifrolumab-treated patients attained a ≥50% reduction by Day 365 [30.8%, 63.0% ( p =0.013), 58.3% ( p =0.077)]. In patients with ≥8 swollen and ≥8 tender joints at baseline more anifrolumab-treated patients achieved ≥50% decrease in joint count [48.6%, 69.6% ( p =0.038), 64.6% ( p =0.156)]. Although steroid tapering was not mandated, OCS reduction to ≤7.5 mg/d at Day 365 was achieved by 26.6%, 56.4%, and 31.7% of patients. The observed benefits were driven by results in the IFN-high subpopulation (figure). Median suppression of 21 IFN-regulated genes was ∼90% for both doses of anifrolumab. Patients in the placebo group had the lowest incidence of Herpes zoster (2.0%, 5.1%, 9.5%) and cases reported as influenza (2.0%, 6.1%, 7.6%); there were no differences in the incidence of serious adverse events (18.8%, 16.2%, 17.1%). The incidence of infusion-related reactions was similar (5.9%, 2.0%, 3.8%). Conclusions Anifrolumab significantly reduced disease activity across all clinical endpoints. Enhanced effects in IFN-high patients support the pathobiology of this treatment strategy. Acknowledgement Funded by MedImmune. Editorial assistance: K Alexander, QXV Comms, an Ashfield business, UK Disclosure of Interest R. Furie Consultant for: MedImmune, J. Merrill Grant/research support from: MedImmune; Genentech/Roche, Consultant for: MedImmune, Genentech/Roche, Neovacs, V. Werth Consultant for: MedImmune, M. Khamashta: None declared, K. Kalunian Grant/research support from: MedImmune, Consultant for: AstraZeneca, P. Brohawn Shareholder of: AstraZeneca, Employee of: MedImmune, G. Illei Shareholder of: AstraZeneca, Employee of: MedImmune, J. Drappa Shareholder of: AstraZeneca, Employee of: MedImmune, L. Wang Employee of: MedImmune, S. Yoo Shareholder of: AstraZeneca; Regenx Bio, Consultant for: Regenx Bio
Philip Brohawn - One of the best experts on this subject based on the ideXlab platform.
-
AB1212 Analytical validation of an interferon-inducible gene expression kit as a potential diagnostic test for anifrolumab
Diagnostics and imaging procedures, 2018Co-Authors: Philip Brohawn, Brandon W Higgs, S. Patel, A. Moody, P. Cooper, Koustubh RanadeAbstract:Background Anifrolumab, a fully human monoclonal antibody that binds to the type I interferon receptor, is in Phase III development for moderate to severe systemic lupus erythematosus (SLE). Patients with greater interferon-inducible gene signatures (IFNGS) have enhanced response to anifrolumab treatment.1 AstraZeneca and QIAGEN developed an in-vitro diagnostic test for interferon-inducible gene expression (IFIGx). Efficacy of anifrolumab will be evaluated in patients with high and low IFNGS. Objectives We aimed to analytically validate the IFIGx kit for use in a pivotal clinical study and potentially to support future regulatory submission. Methods The IFIGx kit measures expression of four interferon-inducible genes (IF127, IF114, IF114L and RSAD2) compared with three housekeeping genes. Measurements were performed on mRNA extracted from whole blood from adults with SLE. A score was generated that identified patients as “IFNGS test–high” or “IFNGS test–low.” Analytical validation involved six studies measuring lot interchangeability, linearity, repeatability, reproducibility, cross contamination, and system verification. Results Repeatability was 100%. Reproducibility was >96%. No cross contamination was observed. Results of all studies validated the IFIGx kit (table 1). Conclusions The IFIGx kit was shown to be a robust, reproducible diagnostic test for IFNGS. The IFIGx kit has demonstrated value in prior anifrolumab studies,1 and will be used both for patient stratification in Phase III studies and to support anifrolumab regulatory filings. Reference [1] Furie, et al. Arthritis Rheumatol. 2017;69:376–86. Disclosure of Interest P. Brohawn Employee of: MedImmune LLC, B. Higgs Employee of: MedImmune LLC, S. Patel Employee of: AstraZeneca, A. Moody Employee of: QIAGEN Manchester Ltd, P. Cooper Employee of: QIAGEN Manchester Ltd, K. Ranade Employee of: MedImmune LLC
-
SAT0243 Exposure-response (E-R) analysis for selection of optimal dosage regimen of anifrolumab in patients (PTS) with systemic lupus erythematosus (SLE)
Poster Presentations, 2017Co-Authors: Lc Santiago, Philip Brohawn, L. Wang, G. Illei, Bing Wang, Lorin RoskosAbstract:Background Anifrolumab is a fully human IgG1 monoclonal antibody directed against subunit 1 of the type I interferon–α receptor (IFNAR1). It is in development for treatment of SLE. Objectives To support dosage selection for pivotal anifrolumab studies, using an E−R model. Methods In the Phase IIb MUSE study (NCT01438489),1 adult pts with moderate to severe SLE, who had inadequate responses to standard-of-care (SOC) medications, were randomized 1:1:1 to intravenous anifrolumab 300 or 1,000 mg or placebo every 4 weeks (Q4W), in addition to SOC medications, for 48 weeks. Pts were stratified by type I interferon gene signature (IFNGS) test status (high or low) using a validated 4-gene expression assay, oral corticosteroid dosage ( Results There was no PK difference between type I IFNGS test–high or –low pts (mean [standard deviation] Ctrough (Day 169): 17.0 [11.5] μg/mL and 23.3 [16.0] μg/mL, respectively). SRI (4) modeling demonstrated no anifrolumab treatment effect in type I IFNGS test–low pts compared with placebo; interpretation of this result may be limited by small sample size. In type I IFNGS test–high pts, a log-linear logistic model was used to describe the treatment effect of anifrolumab. Pt dropouts were more likely in nonresponders. Clinical simulations demonstrated dosages 300 mg, consistent with the Phase IIb MUSE study outcomes. Conclusions Based on E−R analyses and overall risk assessment, a 300 mg Q4W, intravenous dosage regimen is recommended for pivotal anifrolumab studies in pts with SLE. References Furie R, et al. Arthritis Rheumatol. 2017;69:376–86. Wang B, et al. Clin Pharmacol Ther. 2013;93:483−92. Acknowledgements Funded by MedImmune. Medical writing support: R. Plant, QXV Comms, an Ashfield company, funded by MedImmune. Disclosure of Interest L. Santiago Shareholder of: AstraZeneca, Employee of: MedImmune LLC, B. Wang Shareholder of: AstraZeneca, Employee of: MedImmune LLC, P. Brohawn Shareholder of: AstraZeneca, Employee of: MedImmune LLC, L. Wang Employee of: MedImmune LLC, G. Illei Shareholder of: AstraZeneca, Employee of: MedImmune LLC, L. Roskos Shareholder of: AstraZeneca, Employee of: AstraZeneca
-
OP0301 Type i ifn gene signature test–high and –low patients with moderate to severe sle disease activity have distinct gene expression signatures of immunologic pathways and cell types
Oral Presentations, 2017Co-Authors: Hao Liu, Brandon W Higgs, Chris Morehouse, Philip Brohawn, G. Illei, Katie Streicher, W Rees, Koustubh RanadeAbstract:Background Type I interferon (IFN) has been implicated in systemic lupus erythematosus (SLE) pathogenesis, and the majority of patients with SLE have elevated expression of type I IFN-inducible genes in their blood. Anifrolumab, a fully human, IgG 1 κ monoclonal antibody against the type I IFN receptor, is in Phase III development for the treatment of moderate to severe SLE (NCT02446912 and NCT02446899). Objectives We sought to understand other molecular pathways (either dependent on or independent of type I IFN signaling), to elucidate heterogeneous mechanisms in SLE, and to identify patient subsets for personalized disease management. Methods Baseline blood samples from adult patients with moderate to severe SLE from two Phase IIb clinical studies (NCT01438489, N=265; NCT01283139, N=416) were profiled with whole genome array analyses. Type I IFN gene signature (IFNGS) test status was determined by a central laboratory utilizing an analytically validated four gene ( IFI27, IFI44, IFI44L, RSAD2) quantitative polymerase chain reaction-based test from patients9 whole blood. A predetermined, delta Ct-based cut-off point, in the trough of the bimodal distribution, was utilized to segregate type I IFNGS test–high from –low patients at baseline. Blood from healthy controls was stimulated ex vivo with IFN-β, IFN-γ, IFN-λ, IFN-ω, or a pool of all IFN-α subtypes, with or without blocking antibodies for each IFN type, to develop IFN-type-specific signatures. Cell type- and cytokine pathway-specific gene signatures derived from the literature were also evaluated with the Phase IIb sample data. A Fisher9s exact test was used for enrichment calculations (signatures cut at median), and comparisons were adjusted for multiplicity through false discovery rate. Results A total of 79% of SLE patients in the combined study population had a type I IFNGS test–high status. From the type I IFNGS test–high patients, 29/95 signatures evaluated had significant enrichment, including those for B cells (q=1.17E-17, odds ratio [OR]=6.4), plasma cells (q=6.96E-11, OR=3.9), and CD40L signaling (q=1.07E-08, OR=3.3), relative to type I IFNGS test–low patients. In contrast, type I IFNGS test–low patients had enrichment for eosinophils (q=5.4E-6, OR=0.39) and type II IFN (IFN-γ) specifically inducible gene signatures (q=4.6E-3, OR=0.47). These findings were significant for the combined study population, as well as for the NCT01438489 study population, and were either significant or trending for the NCT01283139 population (q Conclusions SLE patients who are type I IFNGS test–high had elevated concentrations of B cells, plasma cells, and other inflammatory cytokine pathways. Type I IFNGS test–low patients, by contrast, were enriched for eosinophil and type II IFN pathways. These observations provide new insights into the molecular heterogeneity underlying SLE and suggest new therapeutic approaches, particularly for type I IFNGS test–low patients. Acknowledgements Funded by MedImmune. Medical writing support was provided by R. Plant, QXV Comms, an Ashfield business, UK. Disclosure of Interest H. Liu Employee of: MedImmune LLC, B. Higgs Shareholder of: AstraZeneca, Employee of: MedImmune LLC, W. Rees Employee of: MedImmune LLC, C. Morehouse Shareholder of: AstraZeneca, Employee of: MedImmune LLC, K. Streicher Employee of: MedImmune LLC, P. Brohawn Shareholder of: AstraZeneca, Employee of: MedImmune, G. Illei Shareholder of: AstraZeneca, Employee of: MedImmune LLC, K. Ranade Employee of: MedImmune LLC
-
OP0291 Anifrolumab, An Anti-Interferon-Alpha Receptor Monoclonal Antibody, in Moderate To Severe Systemic Lupus Erythematosus (SLE)
Annals of the Rheumatic Diseases, 2016Co-Authors: Richard Furie, Kenneth Kalunian, Jorn Drappa, Joan T Merrill, Philip Brohawn, Victoria P Werth, Munther Khamashta, L. Wang, G. Illei, Stephen YooAbstract:Background Increased activity of the type I interferon (IFN) pathway is central to the pathogenesis of SLE. Blocking the type I receptor may reduce SLE activity more effectively than inhibiting IFN-α alone. Objectives Efficacy and safety of anifrolumab were assessed in a Phase IIb, randomized, double-blind, placebo-controlled study of adults with moderate to severe SLE (the MUSE study). Methods 305 patients were treated for 48 weeks with intravenous anifrolumab (300 mg or 1000 mg) or placebo, in addition to standard-of-care medications. Randomization was stratified by SLE Disease Activity Index 2000 (SLEDAI-2K) score ( Results The primary endpoint was met by more anifrolumab-treated patients [placebo vs. 300 mg vs. 1000 mg: 17.6%, 34.3% ( p =0.014), 28.8% ( p =0.063)] with greater effect sizes observed in the 75% of patients who had a high baseline IFN signature [13.2%, 36.0% ( p =0.004), 28.2% ( p =0.029)]. At Day 365 more anifrolumab-treated patients achieved SRI(4) responses [40.2%, 62.6%, ( p p =0.043)], BILAG-based Composite Lupus Assessment (BICLA) [25.7%, 53.5% ( p p =0.018)], modified SRI(6) [28.4%, 49.5% ( p =0.002), 44.7% ( p =0.015)], and SLEDAI-2K ≤2 [17.6%, 35.4% ( p =0.004), 32.7% ( p =0.012)]. Major clinical response (BILAG “C” or better in all domains at Day 169 maintained to Day 365) was achieved by 6.9%, 19.2% ( p =0.012), and 17.3% ( p =0.025) of patients. BILAG “A” flares were reported in more placebo- vs. anifrolumab-treated patients (16.7%, 9.1%, 10.6%). In patients with baseline Cutaneous Lupus Erythematosus Disease Area and Severity Index activity score ≥10, more anifrolumab-treated patients attained a ≥50% reduction by Day 365 [30.8%, 63.0% ( p =0.013), 58.3% ( p =0.077)]. In patients with ≥8 swollen and ≥8 tender joints at baseline more anifrolumab-treated patients achieved ≥50% decrease in joint count [48.6%, 69.6% ( p =0.038), 64.6% ( p =0.156)]. Although steroid tapering was not mandated, OCS reduction to ≤7.5 mg/d at Day 365 was achieved by 26.6%, 56.4%, and 31.7% of patients. The observed benefits were driven by results in the IFN-high subpopulation (figure). Median suppression of 21 IFN-regulated genes was ∼90% for both doses of anifrolumab. Patients in the placebo group had the lowest incidence of Herpes zoster (2.0%, 5.1%, 9.5%) and cases reported as influenza (2.0%, 6.1%, 7.6%); there were no differences in the incidence of serious adverse events (18.8%, 16.2%, 17.1%). The incidence of infusion-related reactions was similar (5.9%, 2.0%, 3.8%). Conclusions Anifrolumab significantly reduced disease activity across all clinical endpoints. Enhanced effects in IFN-high patients support the pathobiology of this treatment strategy. Acknowledgement Funded by MedImmune. Editorial assistance: K Alexander, QXV Comms, an Ashfield business, UK Disclosure of Interest R. Furie Consultant for: MedImmune, J. Merrill Grant/research support from: MedImmune; Genentech/Roche, Consultant for: MedImmune, Genentech/Roche, Neovacs, V. Werth Consultant for: MedImmune, M. Khamashta: None declared, K. Kalunian Grant/research support from: MedImmune, Consultant for: AstraZeneca, P. Brohawn Shareholder of: AstraZeneca, Employee of: MedImmune, G. Illei Shareholder of: AstraZeneca, Employee of: MedImmune, J. Drappa Shareholder of: AstraZeneca, Employee of: MedImmune, L. Wang Employee of: MedImmune, S. Yoo Shareholder of: AstraZeneca; Regenx Bio, Consultant for: Regenx Bio
-
op0165 beneficial effects of an anti ifnar1 monoclonal antibody on immune cell dysregulation and complement system abnormalities of systemic lupus erythematosus an exploratory analysis of phase iib clinical trial of anifrolumab
Annals of the Rheumatic Diseases, 2016Co-Authors: Xiang Guo, Brandon W Higgs, Philip Brohawn, L. Wang, G. Illei, Wendy I. WhiteAbstract:Background Anifrolumab is a fully human IgG 1 κ monoclonal antibody directed against subunit 1 of the type I interferon alpha receptor (IFNAR1). A Phase IIb randomized clinical trial of adult patients with systemic lupus erythematosus (SLE) has been conducted for anifrolumab. Objectives To assess downstream effects of anifrolumab on peripheral biomarkers and pathophysiologic pathways in patients with SLE. Methods In the MUSE study, 305 patients with moderate to severe SLE were randomized in a 1:1:1 ratio to receive a fixed intravenous dosage of placebo or anifrolumab (300 or 1,000 mg), in addition to standard of care medications, every 28 days for 1 year. Patients were stratified by IFN gene signature status (high vs. low) based on a 4-gene expression assay. Selected proteins were measured in sera of SLE patients procured at baseline, 85, 169, and 365 days post-administration along with 30 healthy controls (HCs) using a multiplex luminex immunoassay. Results Serum concentrations of 134 proteins were measured for 30 HCs and 304 SLE patients at baseline (missing sample for one patient), of which 229 had a high IFN signature (IFN-high) and 75 did not (IFN-low). Mann-Whitney U test identified 55 proteins with higher levels and 12 proteins with lower levels in IFN-high patients than IFN-low patients and/or HCs ( p p Conclusions Our results demonstrate a distinct proteome profile of IFN-high patients compared with IFN-low patients and HCs. Anifrolumab administration elicits a widespread impact on peripheral biomarkers of patients with SLE. Beneficial effects on both immune cell dysregulation and complement system abnormalities may be key contributors to the mechanism of action of anifrolumab in SLE. Disclosure of Interest X. Guo Shareholder of: MedImmune/AstraZeneca, Employee of: MedImmune/AstraZeneca, L. Wang Shareholder of: MedImmune/AstraZeneca, Employee of: MedImmune/AstraZeneca, G. Illei Shareholder of: MedImmune/AstraZeneca, Employee of: MedImmune/AstraZeneca, P. Brohawn Shareholder of: MedImmune/AstraZeneca, Employee of: MedImmune/AstraZeneca, B. Higgs Shareholder of: MedImmune/AstraZeneca, Employee of: MedImmune/AstraZeneca, W. White Shareholder of: MedImmune/AstraZeneca, Employee of: MedImmune/AstraZeneca
