Jorn Drappa

Anifrolumab, an Anti–Interferon‐α Receptor Monoclonal Antibody, in Moderate‐to‐Severe Systemic Lupus Erythematosus

To assess the efficacy and safety of anifrolumab, a type I interferon (IFN) receptor antagonist, in a phase IIb, randomized, double‐blind, placebo‐controlled study of adults with moderate‐to‐severe systemic lupus erythematosus (SLE).

Sifalimumab, an anti-interferon-α monoclonal antibody, in moderate to severe systemic lupus erythematosus: a randomised, double-blind, placebo-controlled study

Objectives The efficacy and safety of sifalimumab were assessed in a phase IIb, randomised, double-blind, placebo-controlled study (NCT01283139) of adults with moderate to severe active systemic lupus erythematosus (SLE). Methods 431 patients were randomised and received monthly intravenous sifalimumab (200 mg, 600 mg or 1200 mg) or placebo in addition to standard-of-care medications. Patients were stratified by disease activity, interferon gene-signature test (high vs low based on the expression of four genes) and geographical region. The primary efficacy end point was the percentage of patients achieving an SLE responder index response at week 52. Results Compared with placebo, a greater percentage of patients who received sifalimumab (all dosages) met the primary end point (placebo: 45.4%; 200 mg: 58.3%; 600 mg: 56.5%; 1200 mg 59.8%). Other improvements were seen in Cutaneous Lupus Erythematosus Disease Area and Severity Index score (200 mg and 1200 mg monthly), Physicians Global Assessment (600 mg and 1200 mg monthly), British Isles Lupus Assessment Group-based Composite Lupus Assessment (1200 mg monthly), 4-point reductions in the SLE Disease Activity Index−2000 score and reductions in counts of swollen joints and tender joints. Serious adverse events occurred in 17.6% of patients on placebo and 18.3% of patients on sifalimumab. Herpes zoster infections were more frequent with sifalimumab treatment. Conclusions Sifalimumab is a promising treatment for adults with SLE. Improvement was consistent across various clinical end points, including global and organ-specific measures of disease activity. Trial registration number NCT01283139; Results.

A phase 1b clinical trial evaluating sifalimumab, an anti-IFN-α monoclonal antibody, shows target neutralisation of a type I IFN signature in blood of dermatomyositis and polymyositis patients

Objective To assess the pharmacodynamic effects of sifalimumab, an investigational anti-IFN-α monoclonal antibody, in the blood and muscle of adult dermatomyositis and polymyositis patients by measuring neutralisation of a type I IFN gene signature (IFNGS) following drug exposure. Methods A phase 1b randomised, double-blinded, placebo controlled, dose-escalation, multicentre clinical trial was conducted to evaluate sifalimumab in dermatomyositis or polymyositis patients. Blood and muscle biopsies were procured before and after sifalimumab administration. Selected proteins were measured in patient serum with a multiplex assay, in the muscle using immunohistochemistry, and transcripts were profiled with microarray and quantitative reverse transcriptase PCR assays. A 13-gene IFNGS was used to measure the pharmacological effect of sifalimumab. Results The IFNGS was suppressed by a median of 53–66% across three time points (days 28, 56 and 98) in blood (p=0.019) and 47% at day 98 in muscle specimens post-sifalimumab administration. Both IFN-inducible transcripts and proteins were prevalently suppressed following sifalimumab administration. Patients with 15% or greater improvement from baseline manual muscle testing scores showed greater neutralisation of the IFNGS than patients with less than 15% improvement in both blood and muscle. Pathway/functional analysis of transcripts suppressed by sifalimumab showed that leucocyte infiltration, antigen presentation and immunoglobulin categories were most suppressed by sifalimumab and highly correlated with IFNGS neutralisation in muscle. Conclusions Sifalimumab suppressed the IFNGS in blood and muscle tissue in myositis patients, consistent with this molecules mechanism of action with a positive correlative trend between target neutralisation and clinical improvement. These observations will require confirmation in a larger trial powered to evaluate efficacy.

OP0291 Anifrolumab, An Anti-Interferon-Alpha Receptor Monoclonal Antibody, in Moderate To Severe Systemic Lupus Erythematosus (SLE)

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 (<10 or ≥10), oral corticosteroid (OCS) dose (<10 or ≥10 mg/day), and IFN gene signature status (high vs. low) based on a 4-gene expression assay. The primary endpoint was the percentage of patients achieving an SLE Responder Index [SRI(4)] response at Day 169 with sustained reduction of OCS (<10 mg/day and ≤Day 1 dose from Day 85 to 169). 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<0.001), 53.8%, (p=0.043)], BILAG-based Composite Lupus Assessment (BICLA) [25.7%, 53.5% (p<0.001), 41.2% (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

THU0295 Anifrolumab Reduces Disease Activity in Multiple Organ Domains in Moderate To Severe Systemic Lupus Erythematosus (SLE)

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<0.001) vs. 1000 mg 51/102 (50.0%; p=0.082); BILAG: 24/87 (27.6%) vs. 49/84 (58.3%; p<0.001) vs. 33/82 (40.2%; p=0.069); Musculoskeletal: SLEDAI-2K: 42/99 (42.4%) vs. 55/97 (56.7%; p=0.032) vs. 50/98 (51.0%; p=0.197); BILAG: 47/95 (49.5%) vs. 64/94 (68.1%; p=0.005) vs. 54/91 (59.3%; p=0.149)]. Trends suggesting potential benefits were observed in most of the other less frequently active domains including SLEDAI-2K cardiorespiratory, vascular, hematological, and constitutional, and BILAG cardiorespiratory and constitutional domains. Of those patients who had involvement in the SLEDAI-2K immunological domain at baseline [positive anti-double-stranded-DNA (anti-dsDNA) and/or low complement level], a greater number of patients in the anifrolumab groups [placebo: 4/53 (7.5%); 300 mg: 9/43 (20.9%; p=0.068); 1000 mg: 18/59 (30.5%; p=0.004)] had lower scores at Day 365, representing a normalization of anti-dsDNA and/or hypocomplementemia. However, among patients who had a normal anti-dsDNA and/or normal complements at baseline a slightly greater number of patients treated with 300 mg anifrolumab had an increase in the score representing the development of a new anti-dsDNA or hypocomplementemia compared with baseline [placebo: 7/79 (8.9%); 300 mg: 11/82 (13.4%), 1000 mg: 6/79 (7.6%)]. 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

Systemic Lupus Erythematosus (SLE) Responder Index response is associated with global benefit for patients with SLE

A post-hoc analysis of pooled data from two Phase IIb trials (sifalimumab; NCT01283139, anifrolumab; NCT01438489) assessed the clinical significance of a Systemic Lupus Erythematosus (SLE) Responder Index (SRI(4)) response (Week 52) for 736 patients with moderate to severe SLE disease activity (study entry). SRI(4) responders achieved significantly greater improvements in clinical outcome measures (including percentages of patients with a ≥ 7-point reduction in SLE Disease Activity Index (SLEDAI)–2000 (2K), British Isles Lupus Assessment Group “A” or “2B” flare rate, and oral corticosteroid reduction to ≤7.5 mg/day; change from baseline in Physician’s Global Assessment; and numbers of SLEDAI–2K organ domains with improvement), as well as in patient-reported outcomes (Patient’s Global Assessment, Functional Assessment of Chronic Illness Therapy−Fatigue; Short-Form 36 Health Survey Physical Component Summary, Mental Component Summary, Vitality domain scores) vs. nonresponders. Of patients with abnormal serologies, SRI(4) responders had numerically greater improvements (baseline to Week 52) in anti-double-stranded DNA concentrations vs. nonresponders (p = 0.051), but there were no differences in C3/C4 concentration changes between the two groups. These results confirm previous findings in a different cohort, indicating that an SRI(4) response is associated with global clinical benefit.

CT-03 Anifrolumab reduces disease activity in multiple organ domains in patients with moderate to severe systemic lupus erythematosus

Background Anifrolumab was evaluated in a Phase IIb study of adults with moderate to severe systemic lupus erythematosus (SLE), in which 305 patients received intravenous infusions of anifrolumab (300 mg, 1000 mg) or placebo for 48 weeks. Global disease activity was reduced in both dose groups compared with placebo, although a more favourable risk-benefit profile was observed with the 300-mg dose. This analysis of the Phase IIb study compared the impact of anifrolumab on individual organ domains in patients. Materials and methods Changes from baseline in organ domain activity were assessed at Week 52 using the SLE Disease Activity Index 2000 (SLEDAI-2K) and British Isles Lupus Assessment Group (BILAG). SLEDAI domain improvement required a lower score compared with baseline in at least one of its components. BILAG organ domain improvement was defined as the transitioning from “A” or “B” to a lower score. Results The majority of patients had baseline involvement of the mucocutaneous and/or musculoskeletal domains of SLEDAI-2K and BILAG. A greater percentage of anifrolumab-treated patients demonstrated improvement in these frequently involved domains compared with placebo (Table 1). Potential benefits were observed in most of the other less frequently active domains, including SLEDAI-2K cardiorespiratory, vascular, haematological, and constitutional; and BILAG cardiorespiratory and constitutional domains. In patients with baseline involvement in the SLEDAI-2K immunological domain (positive anti–double-stranded DNA [anti-dsDNA] and/or low complement level), normalisation of anti-dsDNA and/or hypocomplementemia were seen more frequently at Day 365 in patients receiving anifrolumab compared with placebo (Table 1). However, among patients who had a normal anti-dsDNA and/or normal complements at baseline, a slightly greater number of patients in the 300-mg anifrolumab group had an increase in the score representing the development of a new anti-dsDNA or hypocomplementemia compared with baseline (Table 1). Conclusions Treatment with anifrolumab resulted in greater rates of improvement in multiple organ domains compared with placebo. The greatest impact was seen with 300-mg anifrolumab. Abstract CT-03 Table 1 Changes from baseline in organ domain activity at Day 365 Placebo Anifrolumab 300 mg* P-Value Anifrolumab 1000 mg* P-Value Organ domain improvement at Day 365 BILAG, n (%) Mucocutaneous 24/87 (27.6) 49/84 (58.3) <0.001 33/82 (40.2) 0.069 Musculoskeletal 47/95 (49.5) 64/94 (68.1) 0.005 54/91 (59.3) 0.149 SLEDAI-2K, n (%) Mucocutaneous 38/100 (38.0) 61/99 (61.6) <0.001 51/102 (50.0) 0.082 Musculoskeletal 42/99 (42.4) 55/97 (56.7) 0.032 50/98 (51.0) 0.197 Immunological 4/53 (7.5) 9/43 (20.9) 0.068 18/59 (30.5) 0.004 Organ domain worsening at Day 365 SLEDAI-2K, n (%) Immunological 7/79 (8.9) 11/82 (13.4) – 6/79 (7.6) – *Every 28 days from Day 1 to Day 337. BILAG, British Isles Lupus Assessment Group; SLEDAI-2K, SLE Disease Activity Index 2000 Acknowledgements Funded by MedImmune. Editorial assistance was provided by K Alexander, PhD (QXV Comms, an Ashfield business, part of UDG Healthcare plc, Macclesfield, UK), which was funded by MedImmune. Trial Registration ClinicalTrials.gov number, NCT01438489

AB0183 The Effect of Geography on the Efficacy of Sifalimumab, an Anti-Interferon-Alpha Monoclonal Antibody, in Moderate to Severe Systemic Lupus Erythematosus

Background The efficacy and safety of sifalimumab were assessed in a Phase IIb, randomized, double-blind, placebo-controlled study of adults with moderate to severe systemic lupus erythematosus (SLE). Sifalimumab is 1 of 2 compounds targeting the type I interferon pathway that is currently under assessment for evaluation in Phase III studies. Objectives To assess geographic differences as potential confounders of efficacy in a worldwide sifalimumab Phase IIb study. Methods 431 patients were randomized and received monthly intravenous sifalimumab (200 mg, 600 mg, or 1200 mg) or placebo. The primary efficacy endpoint was the percentage of patients achieving an SLE responder index [SRI] at Week 52. Overall results from this study were presented at the 2014 American College of Rheumatology (ACR) annual meeting.1 Here we present results from a pre-specified randomization stratification factor based on geographic region: Region 1: high expected response to standard of care (SOC) - Central America, South America, Eastern Europe, Asia; Region 2: low expected SOC response - North America, Western Europe, South Africa. Results Of the 431 patients, 296 (68.7%) were from Region 1 and 135 (31.3%) from Region 2. Compared with placebo, more patients who received sifalimumab met the primary endpoint (placebo, 45.4%; 200 mg, 58.3%; 600 mg, 56.5%; 1200 mg, 59.8%) with greater response rates observed in Region 1 than in Region 2. There was a larger distinction (Δ) between sifalimumab plus SOC and placebo plus SOC responses in Region 2 compared with Region 1. (Figure). This distinction was not attributable to differences in baseline SLE Disease Activity Index 2000 (SLEDAI-2K), physician global assessment, or British Isles Lupus Assessment Group (BILAG)-2004 scores which were similar for patients in both regions. Differences in several demographic and clinical characteristics were seen between patients in Region 1 vs Region 2: mean weight (64.7 kg vs 72.8 kg), mean age (38.0 years vs 42.5 years), median time from diagnosis to randomization (80.1 months vs 138.4 months), mean Systemic Lupus International Collaborating Clinics (SLICC)/ACR Damage Index (0.5 vs 1.1), and SOC (use of antimalarials [70.9% vs 78.5%], azathioprine [30.4% vs 15.6%], methotrexate [11.8% vs 21.5%], mycophenolate [3.7% vs 22.2%], and corticosteroids [92.9% vs 68.9%], as well as average corticosteroid dosage [11.7 mg/day vs 9.3 mg/day]). Conclusions Response to treatment with sifalimumab in adult patients with moderate to severe SLE showed a greater distinction in the SRI endpoint in patients who received sifalimumab vs placebo in Region 2 compared with Region 1. This may, in part, be reflective of regional populations with different baseline characteristics or differences in SOC. References Khamashta M et al. Arthritis Rheumatol. 2014;66:S10 (Abstract L4) Acknowledgements Funded: MedImmune. Editorial Assistance: Mark Hughes, PhD, QXV Communications, UK Disclosure of Interest M. Khamashta Grant/research support from: Bayer, Consultant for: INOVA diagnostics, Medimmune, GSK, UCB, G. Illei Shareholder of: AstraZeneca, Employee of: MedImmune, J. Drappa Employee of: MedImmune, L. Wang Employee of: MedImmune, W. Greth Shareholder of: AstraZeneca, Employee of: MedImmune/AstraZeneca

AB0189 Geographic Differences in Demographics, Clinical Characteristics, and Standard of Care in Multinational Studies of Patients with Moderate to Severe Sle

Background Most randomized controlled clinical trials (RCTs) in systemic lupus erythematosus (SLE) include stratification factors to assure a balanced allocation of subgroups that might respond differently to therapeutic interventions. Strata could include baseline disease activity, baseline corticosteroid dosage, or race. Despite such stratification, geographic differences appear to impact responses in some studies. Sifalimumab and anifrolumab are fully human, IgG1 κ monoclonal antibodies in Phase IIb clinical development for SLE. Sifalimumab binds to and neutralizes the majority of IFN-α subtypes (Phase II study completed1). Anifrolumab binds to and neutralizes the type I IFN receptor and thus prevents signaling by any of the type I IFNs (Phase II study ongoing). Objectives To assess geographic differences as potential confounders of efficacy analysis, we compared demographic data, baseline clinical characteristics, and standard of care (SOC) across geographic regions of 2 worldwide sifalimumab and anifrolumab Phase IIb SLE RCTs. Methods This post-hoc analysis compared combined baseline data from the 2 RCTs between pre-specified geographic regions with an expected high placebo plus SOC response (Region 1 [R1]: Central America, South America, Eastern Europe, Asia) and low placebo plus SOC response (Region 2 [R2]: North America, Western Europe, South Africa). Eligibility criteria, similar for the 2 studies, resulted in enrollment of patients with moderate to severe SLE. Patients with active lupus nephritis or severe neuropsychiatric SLE were excluded. Results Of the 736 randomized patients, 507 (68.9%) were from R1, and 229 (31.1%) were from R2. There were no clinically meaningful differences between regions in mean scores of global measures of disease activity (SLEDAI-2K: 11.3 vs 10.8; BILAG-2004 composite: 19.3 vs 19.2; physician global assessment: 1.79 vs 1.83). However, differences were seen in mean values of several demographic characteristics: patients from R1 were younger (38.0 vs 43.0 years), had a lower BMI (25.2 vs 28.1 kg.m2), a shorter duration of SLE (81.8 vs 131.2 months), and a lower SLICC/ACR damage index score (0.5 vs 1.1). In addition, higher percentages of R1 patients had elevated double-stranded DNA antibodies (85.0% vs 67.3%) and hypocomplementemia (C3: 44.8% vs 33.6%; C4: 29.0% vs 18.3%). Antimalarial use during the study was similar, but more R1 patients were treated with azathioprine (28.2%.vs 12.2%) and corticosteroids (94.1% vs 65.1%) and at higher corticosteroid dosages (≥10 mg/day: 66.9% vs 36.7%). In contrast, fewer patients received mycophenolate in R1 (5.1% vs 21.0%). Conclusions SLE patients enrolled in RCTs from different geographic regions had notable differences in some demographic and baseline clinical characteristics as well as prescribed SOC medications. These differences may impact the analysis of the treatment response with SOC and/or investigational drug. Therefore, an imbalance in patients from regions with expected high or low SOC response should be considered in the feasibility and statistical considerations in SLE RCTs. References Khamashta M et al. Arthritis Rheumatol. 2014;66:S10 (Abstract L4) Acknowledgements Funded: MedImmune. Editorial Assistance: Mark Hughes, PhD, QXV Communications, UK Disclosure of Interest R. Furie Consultant for: Medimmune, M. Khamashta Grant/research support from: Bayer, Consultant for: INOVA diagnostics, Medimmune, GSK, UCB, L. Wang Employee of: MedImmune, J. Drappa Employee of: MedImmune, W. Greth Shareholder of: AstraZeneca, Employee of: MedImmune/AstraZeneca, G. Illei Shareholder of: AstraZeneca, Employee of: MedImmune