POS0688 CHARACTERIZATION OF PK/PD OF ANIFROLUMAB IN PATIENTS WITH MODERATE TO SEVERE SLE

Background:In the TULIP-1 and TULIP-2 trials, anifrolumab, a type I interferon (IFN) receptor antibody, at a dosage of 300 mg once every 4 weeks (Q4W), demonstrated consistent median pharmacokinetic (PK) concentrations1 and sustained neutralization of the pharmacodynamic (PD) 21-gene type I IFN gene signature (IFNGS)2–4 in patients with moderate to severe systemic lupus erythematosus (SLE) despite standard therapy.Objectives:To characterize the PK/PD relationship of anifrolumab and to confirm anifrolumab 300 mg provides adequate PD neutralization in IFNGS test–high patients.Methods:This study included IFNGS test–high patients from the phase 3 randomized, placebo-controlled, 52-week TULIP-12 (NCT02446912) and TULIP-23 (NCT02446899) trials of intravenous anifrolumab 150 mg or 300 mg Q4W plus standard therapy. IFNGS test status (high or low) at screening was classified with an analytically validated 4-gene qPCR based test on whole blood.2 PD neutralization was measured with 21-gene type I IFNGS and expressed as a percentage change from baseline.3 For the graphic PK/PD analysis, patients with ≥1 quantifiable serum PK sample and ≥1 PD measurement before discontinuation were categorized depending on Cave (individual predicted average anifrolumab concentration over treatment duration) median and tertiles (T) for anifrolumab 150 mg and 300 mg, respectively. Median PD IFNGS neutralization and medium absolute deviations were compared across Cave subgroups. PK/PD modeling was assessed in patients with ≥1 quantifiable serum PK sample and a baseline and ≥1 postbaseline PD measurement before discontinuation, using a nonlinear mixed-effects model (NONMEM; version 7.3; ICON) to estimate parameters and characterize the PK/PD data. The PD/efficacy analysis included patients with ≥1 postbaseline PD measurement before discontinuation. BILAG-based Combined Lupus Assessment (BICLA) response rates at Week (W)52 were compared across median PD neutralization quartiles (Q) for pooled anifrolumab 300 mg and 150 mg groups.Results:The PK/PD graphic analysis included 654 IFNGS test–high patients (placebo [n=293]; anifrolumab 150 mg [n=72] or 300 mg [n=289]). Cave was generally higher with anifrolumab 300 mg (µg/mL, TULIP-1: T1 <32, T2 32–<44.3, T3 ≥44.3; TULIP-2: T1 <32.4, T2 32.4–<47.9, T3 ≥47.9) than with anifrolumab 150 mg (median 11.5 µg/mL); overlap between anifrolumab 300 mg and 150 mg Cave subgroups was small owing to nonlinearity. Anifrolumab 300 mg elicited rapid (by W44) and sustained median PD neutralization >80%, vs a lower and delayed PD neutralization (median >50% at W52) with anifrolumab 150 mg, and minimal PD neutralization with placebo. The median PD neutralization increased with higher Cave subgroups, plateauing at ~90% at W12–W52. All anifrolumab 300 mg Cave tertiles had a median PD neutralization ~80%; however, the variability was greater in the lowest Cave tertiles vs higher Cave tertiles across trials (Figure 1). The PK/PD modeling, which included 646 IFNGS test–high patients (placebo [n=289], anifrolumab 150 mg [n=70] or 300 mg [n=287]), gave an IC80 estimate of 3.88 μg/mL. The median W24 (study midpoint) Ctrough was higher with anifrolumab 300 mg vs 150 mg (15.6 vs 0.2 μg/mL); thus, the W24 Ctrough exceeded the IC80 in a higher proportion of patients treated with anifrolumab 300 mg vs 150 mg (~83% vs ~27%). The PD/efficacy analysis included 341 patients who received anifrolumab. Higher median percentage PD neutralization quartiles (Q1 <51.7%, Q2 51.7%–85.3%, Q3 85.3%–92.6%, Q4 >92.6%) were associated with higher W52 BICLA response rates (Q1 37.6%, Q2 49.4%, Q3 51.8%, Q4 58.1%).Conclusion:In TULIP-1 and TULIP-2, anifrolumab 300 mg yielded higher anifrolumab Cave vs 150 mg. High Cave was associated with rapid (W44–W12), substantial, and sustained PD neutralization of the 21-gene IFNGS in IFNGS test–high patients, which in turn was associated with higher efficacy.References:[1]Kuruvilla D. Poster 360, AAPS 2020.[2]Furie RA. Lancet Rheumatol. 2019;1:e208–19.[3]Morand EF. N Engl J Med. 2020;382:211–21.[4]Furie R. Arthritis Rheumatol. 2017;69:379–86.Acknowledgements:Writing assistance by Matilda Shackley, MPhil, of JK Associates Inc., part of Fishawack Health. This study was sponsored by AstraZeneca.Disclosure of Interests:Yen Lin Chia Employee of: AstraZeneca, Raj Tummala Employee of: AstraZeneca, Tu Mai Employee of: Genentech, Tomas Rouse Employee of: AstraZeneca, Wendy White Employee of: AstraZeneca, Eric F. Morand Speakers bureau: AstraZeneca, Consultant of: AstraZeneca, Grant/research support from: AstraZeneca, Richard Furie Consultant of: AstraZeneca, Grant/research support from: AstraZeneca

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POS0683 NOVEL STRINGENT OUTCOME MEASURES APPLIED TO THE PHASE 2 AND 3 ANIFROLUMAB TRIALS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.702 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 586.2-587

Author(s):

D. Isenberg ◽

I. N. Bruce ◽

R. Furie ◽

E. F. Morand ◽

Y. Tanaka ◽

...

Keyword(s):

Disease Activity ◽

Lupus Erythematosus ◽

Complete Resolution ◽

Response Rates ◽

Placebo Treatment ◽

Type I ◽

Phase 2 ◽

Research Support ◽

Treatment Difference ◽

Link Type

Background:Patients with systemic lupus erythematosus (SLE) who received anifrolumab, a type I interferon receptor antibody, had greater BILAG–based Composite Lupus Assessment (BICLA) response rates vs placebo at Week (W)52 in the phase 2 MUSE1 and the phase 3 TULIP-12 and TULIP-23 trials. Patients receiving anifrolumab also had fewer flares, and more patients were able to taper glucocorticoids (GC) vs placebo.1–3Objectives:To evaluate anifrolumab treatment response vs placebo in patients with SLE from MUSE, TULIP-1, and TULIP-2 using more stringent BICLA definitions, as well as a novel endpoint that requires dual BICLA and SLE Responder Index (SRI[4]) responses.Methods:MUSE (NCT01438489), TULIP-1 (NCT02446912), and TULIP-2 (NCT02446899) were randomized, placebo-controlled, 52-week trials of intravenous anifrolumab (every 4 weeks for 48 weeks) in patients with moderate to severe SLE despite standard therapy.1–3 Sustained GC taper was defined as taper to ≤7.5 mg/day in patients receiving GC ≥10 mg/day at baseline, or to less than or equal to baseline dose in patients receiving GC <10 mg/day at baseline, achieved by W40 and sustained through W52. Response rates were compared between anifrolumab 300 mg vs placebo groups for patients who 1) attained a W52 BICLA response with sustained GC taper; 2) attained a W52 BICLA response and no flares after W12 (flare defined as ≥1 new BILAG-2004 A or ≥2 new BILAG-2004 B scores vs the prior visit); 3) attained a W52 BICLA response with sustained GC taper and no flares after W12; 4) attained an enhanced BICLA (eBICLA) response at W52 that required complete resolution of all baseline BILAG-2004 activity (all baseline A/B scores to D; no worsening of C or D scores); and 5) met both BICLA and SRI(4) response criteria.Results:Evaluated patients received anifrolumab 300 mg (MUSE, n=99; TULIP-1 and TULIP-2, n=180) or placebo (MUSE, n=102; TULIP-1, n=184; TULIP-2, n=182). Response rate differences favoring anifrolumab 300 mg over placebo were observed for all 5 endpoints across MUSE, TULIP-1, and TULIP-2 (Figure 1). A greater proportion of patients had BICLA responses at W52 with sustained GC taper with anifrolumab vs placebo. More patients had BICLA responses at W52 with no flares after W12 with anifrolumab vs placebo. More patients had BICLA responses at W52 with both sustained GC taper and no flares after W12 with anifrolumab vs placebo (treatment difference, 15.3%–19.3%; nominal P≤0.006). More patients attained eBICLA responses (requiring complete resolution of baseline disease activity) at W52 with anifrolumab vs placebo (treatment difference, 11.1%–14.1%; nominal P≤0.017). In addition, more patients were dual BICLA and SRI(4) responders at W52 with anifrolumab vs placebo (treatment difference, 14.3%–28.6%; nominal P≤0.004).Conclusion:In phase 2 and 3 trials in patients with SLE, anifrolumab treatment was consistently associated with improved disease control vs placebo using stringent endpoint definitions, including BICLA response with sustained GC taper and no flares, an enhanced BICLA response requiring complete resolution of baseline disease activity, and dual BICLA and SRI(4) responses.References:[1]Furie R, et al. Arthritis Rheumatol. 2017;69:376–86.[2]Furie RA, et al. Lancet Rheumatol. 2019;1:e208–19.[3]Morand EF, et al. N Engl J Med. 2020;382:211–21.Acknowledgements:Writing assistance by Rosie Butler, PhD, of JK Associates Inc., part of Fishawack Health. This study was sponsored by AstraZeneca.Disclosure of Interests:David Isenberg Consultant of: AstraZeneca, Celgene, Merck Serono, UCB, and Servier, Ian N. Bruce Speakers bureau: AstraZeneca, GSK, and UCB, Consultant of: Eli Lilly, GSK, ILTOO, Merck Serono, and UCB, Grant/research support from: Genzyme/Sanofi, GSK, Roche, and UCB, Richard Furie Consultant of: AstraZeneca, Grant/research support from: AstraZeneca, Eric F. Morand Speakers bureau: AstraZeneca, Consultant of: AstraZeneca, Grant/research support from: AstraZeneca, Yoshiya Tanaka Speakers bureau: AbbVie, Asahi Kasei, Astellas, Bristol Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, GSK, Janssen, Mitsubishi-Tanabe, Novartis, Pfizer, Sanofi, and YL Biologics, Grant/research support from: AbbVie, Chugai, Daiichi-Sankyo, Eisai, Mitsubishi-Tanabe, Takeda, and UCB, Susan Manzi Consultant of: AstraZeneca, Grant/research support from: AstraZeneca, Kenneth Kalunian Consultant of: AstraZeneca, Konstantina Psachoulia Employee of: AstraZeneca, Emmanuelle Maho Employee of: AstraZeneca, Raj Tummala Employee of: AstraZeneca

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OP0131 ANIFROLUMAB EFFECTS ON RASH AND ARTHRITIS IN PATIENTS WITH SLE AND IMPACT OF INTERFERON SIGNAL IN POOLED DATA FROM PHASE 3 TRIALS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.1471 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 75-76

Author(s):

J. T. Merrill ◽

V. Werth ◽

R. Furie ◽

E. F. Morand ◽

J. M. Kahlenberg ◽

...

Keyword(s):

Disease Activity ◽

Lupus Erythematosus ◽

Cutaneous Lupus Erythematosus ◽

Small Sample ◽

Type I ◽

Research Support ◽

Phase 3 ◽

Pooled Data ◽

Link Type ◽

The Impact

Background:Treatment with the type I interferon (IFN) receptor antibody anifrolumab was associated with clinical improvements in mucocutaneous and musculoskeletal disease activity in patients with systemic lupus erythematosus (SLE) in the phase 2 MUSE trial (NCT01438489) and phase 3 TULIP trials.1–4 Because rash and arthritis are the most common manifestations of SLE, the effect of anifrolumab on these symptoms can be examined in biomarker-defined subsets, as previously reported for the MUSE trial.2Objectives:To evaluate the effect of anifrolumab on rash and arthritis in patients with SLE, and the impact of IFN gene signature (IFNGS) on treatment response, using disease measures of different stringency in pooled data from the phase 3 TULIP trials.Methods:TULIP-1 (NCT02446912) and TULIP-2 (NCT02446899) were placebo-controlled, 52-week trials of intravenous anifrolumab administered every 4 weeks in patients with moderate to severe SLE.3,4 In this post hoc analysis, outcomes of rash and arthritis were evaluated using mucocutaneous and musculoskeletal domains of the SLE Disease Activity Index 2000 (SLEDAI-2K) and the British Isles Lupus Assessment Group (BILAG) index. In addition, the modified Cutaneous Lupus Erythematosus Disease Area and Severity Index (mCLASI) score was used to evaluate rash, and tender and swollen joint counts were used to assess arthritis.Results:360 patients received anifrolumab 300 mg (IFNGS test–high, n=298; IFNGS test–low, n=62) and 366 patients were given placebo (IFNGS test–high, n=302; IFNGS test–low, n=64). Change from baseline to Week 52 compared with placebo was measured by outcomes, ordered by their stringency. More anifrolumab-treated patients achieved rash improvement using SLEDAI-2K (complete resolution: difference 13.5%, nominal P<0.001), BILAG (at least 1 severity grade lowering: difference 15.5%, nominal P<0.001), and mCLASI (≥50% improvement, if baseline score >0: difference 15.6%, nominal P<0.001). Results were comparable in the IFNGS test–high subset (SLEDAI-2K: difference 17.0%, nominal P<0.001, BILAG: difference 16.1%, nominal P<0.001; mCLASI: difference 18.1%, nominal P<0.001). There was a trend toward anifrolumab-associated rash improvement in IFNGS test–low patients using BILAG (Figure). More patients receiving anifrolumab had SLEDAI-2K–defined resolution in arthritis (difference 8.2%, nominal P=0.029), BILAG severity lessening (difference 11.8%, nominal P=0.002), and ≥50% decrease in tender/swollen joint counts, when ≥6 at baseline (difference 12.6%, nominal P=0.016). Results were comparable in the IFNGS test–high subset (SLEDAI-2K: difference 11.7%, nominal P=0.005; BILAG: difference 12.9%, nominal P=0.003; joint counts: difference 11.3%, nominal P=0.054). In IFNGS test–low patients, there was a trend toward anifrolumab-associated arthritis improvement when measured using BILAG, and the effect of anifrolumab on the number of swollen/tender joint counts was similar to the IFNGS test–high group, although the IFNGS test–low sample size in this analysis was very small (Figure).Conclusion:In pooled data from the TULIP trials, anifrolumab treatment was associated with improvements in rash and arthritis using measures of different stringency. The SLEDAI-2K findings were largely driven by the subset of patients who were IFNGS test–high. However, using measures that were more sensitive to change, despite small sample sizes, IFNGS test–low patients may also have benefit.References:[1]Furie R, et al. Arthritis Rheumatol. 2017;69:376–86.[2]Merrill JT, et al. Lupus Sci Med. 2018;5:e000284.[3]Furie RA, et al. Lancet Rheumatol. 2019;1:e208–19.[4]Morand EF, et al. N Engl J Med. 2020;382:211–21.Acknowledgements:Writing assistance by Victoria Alikhan, PhD, of JK Associates Inc., part of Fishawack Health. This study was sponsored by AstraZeneca.Disclosure of Interests:Joan T Merrill Consultant of: AstraZeneca, AbbVie, Amgen, Aurinia, BMS, EMD Serono, GSK, Remegen, Janssen, Provention, and UCB, Grant/research support from: BMS and GSK, Victoria Werth Speakers bureau: University of Pennsylvania, who own the copyright for the CLASI and SDASI, Consultant of: AbbVie, Amgen, Argenx, AstraZeneca, Biogen, BMS, Celgene, Chrysalis, CSL Behring, Cugene, Eli Lilly, EMD Serono, Genentech, GSK, Incyte, Idera, Janssen, Kirin, Medimmune, Medscape, Nektar, Octapharma, Pfizer, Principa, Regeneron, Resolve, and Viela Bio, Grant/research support from: AstraZeneca, Biogen, Celgene, Corbus Pharmaceuticals, Genentech, Gilead, Janssen, Pfizer, Syntimmune, and Viela Bio, Richard Furie Consultant of: AstraZeneca, Grant/research support from: AstraZeneca, Eric F. Morand Speakers bureau: AstraZeneca, Consultant of: AstraZeneca, Grant/research support from: AstraZeneca, J Michelle Kahlenberg Consultant of: Admirex Pharmaceuticals, AstraZeneca, Aurinia Pharmaceuticals, BMS, Boehringer Ingelheim, Eli Lilly, and Ventus Therapeutics, Grant/research support from: BMS/Celgene and Q32 Bio, Gabriel Abreu Employee of: AstraZeneca, Raj Tummala Employee of: AstraZeneca

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OP0049 EFFICACY OF ANIFROLUMAB IN ACTIVE SYSTEMIC LUPUS ERYTHEMATOSUS: PATIENT SUBGROUP ANALYSIS OF BICLA RESPONSE IN 2 PHASE 3 TRIALS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.3557 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 32-32

Author(s):

E. F. Morand ◽

R. Furie ◽

Y. Tanaka ◽

R. Kalyani ◽

G. Abreu ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Lupus Erythematosus ◽

Age At Onset ◽

Standard Of Care ◽

Response Rates ◽

Type I ◽

Systemic Lupus ◽

Research Support ◽

Phase 3 ◽

Organ Systems

Background:Treatment of patients with systemic lupus erythematosus (SLE) with the type I interferon (IFN) receptor inhibitor anifrolumab resulted in higher British Isles Lupus Assessment Group (BILAG)–based Composite Lupus Assessment (BICLA) response rates vs placebo at Week 52 in the phase 3 randomized trials, TULIP-2 (primary endpoint; 16.3% difference)1and TULIP-1 (secondary endpoint; 16.4% difference).2BICLA is a validated composite global disease measure that registers both partial and complete improvement within organ systems.Objectives:TULIP-2 and TULIP-1 data were analyzed to evaluate BICLA responses to anifrolumab vs placebo at Week 52 in protocol-defined subgroups of patients with active SLE.Methods:TULIP-2 and TULIP-1 were randomized, double-blind, placebo-controlled trials that evaluated efficacy and safety of intravenous anifrolumab vs placebo administered every 4 weeks, with the primary endpoints assessed at Week 52, in patients with moderate to severe SLE despite standard-of-care treatment.1,2BICLA responses are defined by all of the following: reduction of baseline BILAG-2004 A and B domain scores to B/C/D and C/D, respectively, and no worsening in any organ system; no worsening of the SLE Disease Activity Index 2000 (SLEDAI-2K) score; no worsening of ≥0.3 points in the Physician’s Global Assessment (range 0–3); no trial treatment discontinuation; and no use of medications restricted by the protocol.3BICLA responses were compared between anifrolumab 300 mg and placebo groups, and robustness of BICLA responses was assessed across protocol-defined subgroups. TULIP-1 data were analyzed incorporating the amended restricted medication rules, as described.2Results:In TULIP-2 and TULIP-1, 180 patients in each trial received anifrolumab 300 mg (182 and 184 patients received placebo, respectively). Baseline demographics, disease characteristics, and standard-of-care medications were balanced between anifrolumab and placebo groups within both TULIP trials. Patients in TULIP-2 and TULIP-1 had comparable BICLA responses (Figure). Across multiple subgroups, higher percentages of patients achieved BICLA responses at Week 52 in the anifrolumab vs placebo arms (Figure). There was concordance of BICLA responses favoring anifrolumab across the protocol-defined subgroups of baseline disease severity (SLEDAI-2K <10 points [difference 15.3%, TULIP-2; 16.9%, TULIP-1] vs ≥10 points [difference 16.7%, TULIP-2; 17.1%, TULIP-1]) and baseline oral corticosteroid use (prednisone or equivalent <10 mg/d [difference 20.1%, TULIP-2; 16.2%, TULIP-1] vs ≥10 mg/d [difference 12.0%, TULIP-2; 17.7%, TULIP-1]). Numerically different BICLA effect sizes between the anifrolumab vs placebo arms were observed in both studies in relation to baseline IFN gene signature status (high [difference 17.3%, TULIP-2; 19.1%, TULIP-1] vs low [difference 11.2%, TULIP-2; 7.5%, TULIP-1]). Other subgroups including age, sex, age at onset, race, and anti-drug antibody status showed similar uniformity of response.Conclusion:The uniformity of robust BICLA response rates across prespecified subgroups in both phase 3 trials shows consistent clinical benefit of anifrolumab irrespective of patient baseline characteristics. However, given the small patient numbers in some subgroups, these results should be interpreted with caution.References:[1]Morand EF, et al.N Engl J Med.2020;382:211–221.[2]Furie RA, et al.Lancet Rheumatol. 2019;1:e208–e219.[3]Wallace DJ, et al.Ann Rheum Dis.2014;73:183–190.Disclosure of Interests:Eric F. Morand Grant/research support from: AstraZeneca, Consultant of: AstraZeneca, Speakers bureau: AstraZeneca, Richard Furie Grant/research support from: AstraZeneca, Biogen, Consultant of: AstraZeneca, Biogen, Yoshiya Tanaka Grant/research support from: Asahi-kasei, Astellas, Mitsubishi-Tanabe, Chugai, Takeda, Sanofi, Bristol-Myers, UCB, Daiichi-Sankyo, Eisai, Pfizer, and Ono, Consultant of: Abbvie, Astellas, Bristol-Myers Squibb, Eli Lilly, Pfizer, Speakers bureau: Daiichi-Sankyo, Astellas, Chugai, Eli Lilly, Pfizer, AbbVie, YL Biologics, Bristol-Myers, Takeda, Mitsubishi-Tanabe, Novartis, Eisai, Janssen, Sanofi, UCB, and Teijin, Rubana Kalyani Employee of: AstraZeneca, Gabriel Abreu Employee of: AstraZeneca, Lilia Pineda Employee of: AstraZeneca, Raj Tummala Employee of: AstraZeneca

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POS0698 BIIB059 DEMONSTRATED A CONSISTENT THERAPEUTIC EFFECT ON SRI-4 RESPONSE ACROSS SUBGROUPS OF PARTICIPANTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS IN THE LILAC PHASE 2 STUDY

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2021-eular.2570 ◽

2021 ◽

Vol 80 (Suppl 1) ◽

pp. 597-598

Author(s):

R. Van Vollenhoven ◽

R. Furie ◽

K. Kalunian ◽

S. Navarra ◽

J. Romero-Diaz ◽

...

Keyword(s):

Disease Activity ◽

Lupus Erythematosus ◽

Response Rate ◽

Small Sample ◽

Statistical Testing ◽

Type I ◽

Phase 2 ◽

Systemic Lupus ◽

Research Support ◽

Chemokine Production

Background:Type I interferons and other inflammatory mediators derived from plasmacytoid dendritic cells (pDCs) are implicated in systemic lupus erythematous (SLE) pathology. BIIB059 is a humanized monoclonal antibody that targets blood dendritic cell antigen 2 (BDCA2), a pDC-specific receptor. The binding of BIIB059 to BDCA2 leads to rapid internalization of BDCA2 from the surface of pDCs and subsequent inhibition of interferon, cytokine, and chemokine production. In Part A of the 2-part, phase 2 LILAC study (NCT02847598), BIIB059 significantly reduced SLE activity, as evidenced by reduced total active joint count (primary endpoint) and higher SLE Responder Index (SRI-4)1 response (a secondary endpoint) versus placebo.2Objectives:To evaluate SRI-4 response for BIIB059 versus placebo at Week 24 in SLE participant subgroups.Methods:Enrollment in LILAC Part A was open to adults fulfilling ≥ 4 of 11 revised 1997 ACR criteria for classification of SLE, with ≥ 4 tender and ≥ 4 swollen joints, active skin disease, and positive lupus antibodies. Participants were randomized to receive either BIIB059 450 mg or placebo subcutaneously every 4 weeks for 20 weeks (with an additional dose at Week 2). SRI-4 response at Week 24 was analyzed in subgroups, though analyses were limited by small sample sizes and were not powered for statistical testing.Results:In LILAC Part A, 64 and 56 participants were dosed with BIIB059 450 mg and placebo, respectively. At week 24, SRI-4 response rate was observed in favor of BIIB059 regardless of the baseline disease activity, such as SLEDAI-2K <10 versus ≥10, presence of BILAG-2004 grade A or B arthritis, oral corticosteroid usage, positivity for anti-ds DNA autoantibody and/or complement status, with point estimates for least-squares mean differences as well as corresponding 95% CIs consistently favoring BIIB059 (Figure 1). The incidence of adverse events in the overall study population was similar between the placebo and BIIB059 groups.2Conclusion:BIIB059 treatment was associated with greater SRI-4 response rate, consistent among different subgroups of baseline disease activity as measured by SLEDAI-2K and BILAG-2004, glucocorticoid dosage, and serology. These findings provide additional evidence of the potential benefit of BIIB059 for the treatment of patients with active SLE.References:[1]Furie RA, et al. Arthritis Rheum. 2009;61(9):1143-1151. 2. Furie RA, et al. Arthritis Rheumatol. 2020;72(suppl 10). Abstract 0935.Acknowledgements:This study was sponsored by Biogen (Cambridge, MA, USA). Writing and editorial support was provided by Excel Scientific Solutions (Fairfield, CT, USA); funding was provided by Biogen.Disclosure of Interests:Ronald van Vollenhoven Consultant of: AbbVie, AstraZeneca, Biotest, Bristol Myers Squibb, Celgene, GlaxoSmithKline, Janssen, Lilly, Medac, Merck, Novartis, Pfizer, Roche, UCB, Grant/research support from: AbbVie, Arthrogen, Bristol Myers Squibb, GlaxoSmithKline, Lilly, Pfizer, UCB, Richard Furie Consultant of: Biogen, Grant/research support from: Biogen, Kenneth Kalunian Consultant of: AbbVie, Amgen, AstraZeneca, Biogen, Bristol Myers Squibb, Eli Lilly, Equillium, Genentech, Gilead, ILTOO, Janssen, Nektar, Roche, Viela, Grant/research support from: Lupus Research Alliance, Pfizer, Sanford Consortium, Sandra Navarra Speakers bureau: Astellas, Johnson & Johnson, Novartis, Pfizer, Consultant of: Biogen, Grant/research support from: Biogen, Juanita Romero-Diaz Consultant of: Biogen, Boehringer Ingelheim, Victoria Werth Consultant of: AbbVie, Amgen, AstraZeneca, Biogen, Bristol Myers Squibb, Eli Lilly, EMD Serono, Gilead, GlaxoSmithKline, Janssen, Kyowa Kirin, Resolve, Viela, Grant/research support from: Biogen, Celgene, Gilead, Janssen, Viela, XIAOBI HUANG Shareholder of: Biogen, Employee of: Biogen, HUA CARROLL Shareholder of: Biogen, Employee of: Biogen, Cristina Musselli Shareholder of: Biogen, Employee of: Biogen, Catherine Barbey Shareholder of: Biogen, Employee of: Biogen, NATHALIE FRANCHIMONT Shareholder of: Biogen, OMass Therapeutics, Employee of: Biogen

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SAT0189 SAMPLE SIZES AND RECRUITMENT RATES ARE DECREASING WHILE PLACEBO RESPONSE RATES ARE INCREASING IN CLINICAL TRIALS FOR SYSTEMIC LUPUS ERYTHEMATOSUS - A MANDATE FOR NEW STRATEGIES

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.3414 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 1036.2-1037

Author(s):

E. Olech ◽

E. Van Rijen ◽

F. Hussain ◽

G. Dennis ◽

A. Ashrafzadeh ◽

...

Keyword(s):

Phase Ii ◽

Primary Endpoint ◽

Lupus Erythematosus ◽

Placebo Response ◽

Response Rates ◽

Phase Iii ◽

Systemic Lupus ◽

Research Support ◽

Primary Endpoints ◽

Over Time

Background:Randomized controlled trials in Systemic Lupus (SLE) have shown disappointing results for decades. Key challenges may include the heterogenous population coupled with high placebo response rates.Objectives:To evaluate trends in SLE study metrics over time and explore associations between primary endpoint failure and response in placebo/standard of care arms.Methods:Data from Phase II or III trials which enrolled ≥ 100 patients with SLE and reported SRI-4 and/or BICLA responses after a minimum of 24 weeks were included in the analysis. Sample size, recruitment rates, regional patient distributions, and results in placebo arms (at 24-36 weeks or 48-52 weeks) were examined according to the start date of each study in order to determine trends over time. Placebo group SRI-4 response rates in studies that met their primary endpoint were compared with those that did not.Results:Twenty-seven (14 phase II and 13 phase III) studies met the search criteria. Eleven of them met their primary endpoints. The study start dates ranged from Dec 2006 to Jan 2017. Mean/median total subject numbers were 461/349. Mean/median placebo subjects’ age at baseline were 39.9/39.2 and SLEDAI: 10.6/10.6. Mean/median placebo SRI-4 responses at Week 24-36 were 47.2%/45.8% and 42.8%/43% at Week 48-52. For BICLA, the rates were 40.3%/37.2% at Week 24-36 and 33.2%/33.5% at Week 48-52.As expected, lower placebo response was found in trials that met primary endpoints vs studies that did not (p=0.005). Total subject numbers and recruitment rates decreased over time while placebo SRI-4 response rates increased overall (Figure). However, there has been a greater range of placebo responses in more recent trials. Similar trends were observed in BICLA responses at Week 24-36 and 48-52, and in a corticosteroid reduction endpoint (percent of patients with reduction in steroid dose by ≥25% and to ≤7.5 mg/day prednisone/equivalent) at Week 48-52. Enrollment of patients from North America decreased while proportions of Eastern Europeans increased over time (Figure).Conclusion:High placebo response rates pose a continuing challenge in SLE studies and are associated with primary endpoint failures.Clinical trial metrics have been changing over time, with declining size and recruitment rates, possibly due to competition from increasing numbers of studies.These trends should be considered while designing and conducting future trials. Attention to site training and data quality may be particularly important to control high placebo rates, especially as trial sizes decrease.Figure.Disclosure of Interests:Ewa Olech Grant/research support from: BMS, Consultant of: Abbvie, Amgen, Remegen, Employee of: IQVIA, Speakers bureau: Abbvie, Amgen, Merck, Pfizer, UCB, Eduard van Rijen Employee of: IQVIA, Faizi Hussain Employee of: IQVIA, Gregory Dennis Employee of: IQVIA, Ali Ashrafzadeh Employee of: IQVIA, Joan T Merrill Grant/research support from: Xencor, Bristol Myers Squibb, Glaxo Smith Kline, Consultant of: Xencor, Abbvie, UCB, Glaxo Smith Kline, EMD Serono, Astellas, Remegen, Celgene/Bristol Myers Squibb, Exagen, Astra Zeneca, Amgen, Jannsen, Servier, ILTOO, Daitchi Sankyo, Lilly, Paid instructor for: Abbvie, Bristol Myers Squibb

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OP0003 EARLY AND SUSTAINED RESPONSES WITH ANIFROLUMAB TREATMENT IN PATIENTS WITH ACTIVE SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IN 2 PHASE 3 TRIALS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.3538 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 2.1-3 ◽

Cited By ~ 1

Author(s):

E. F. Morand ◽

R. Furie ◽

I. N. Bruce ◽

K. Kalunian ◽

R. Kalyani ◽

...

Keyword(s):

Placebo Group ◽

Lupus Erythematosus ◽

Time Course ◽

Proportional Hazards Model ◽

Treatment Time ◽

Cox Proportional Hazards Model ◽

Type I ◽

Research Support ◽

Phase 3 ◽

Time To Onset

Background:In the phase 3 TULIP-2 and TULIP-1 trials in SLE, treatment with the type I interferon receptor antibody anifrolumab resulted in higher percentages of patients with BICLA responses vs placebo at Week 52, with differences of 16.3% (primary endpoint; P=0.001, 95% CI 6.3–26.3) and 16.4% (secondary endpoint; 95% CI 6.7–26.2), respectively.1,2Objectives:To better understand the time course of BICLA responses to anifrolumab, we examined responses over time compared with placebo in TULIP-2 and TULIP-1, including those that were sustained from attainment through Week 52.Methods:The TULIP-2 and TULIP-1 randomized, double-blind, placebo-controlled trials evaluated the efficacy and safety of anifrolumab (300 mg Q4W) over 52 weeks in patients with moderately to severely active SLE who were receiving standard-of-care treatment. Time to onset of BICLA response that was sustained from attainment through Week 52 was evaluated using a Cox proportional hazards model. For TULIP-1, BICLA response rate and time to onset of BICLA response were analyzed using the amended restricted medication rules.2Results:Overall, 180 patients each in TULIP-2 and TULIP-1 received anifrolumab compared with 182 and 184 patients in the placebo arms, respectively. At the first 3 assessments in TULIP-2 (Weeks 4, 8, and 12), numerically greater percentages of patients treated with anifrolumab (26.8%, 35.3%, and 42.9%, respectively) were classified as having a BICLA response compared with placebo (21.3%, 21.6%, and 31.8%). A similar trend was observed in TULIP-1 with anifrolumab (23.3%, 34.2%, and 36.5%) vs placebo (18.3%, 23.2%, and 27.5%). The time to onset of BICLA response sustained from onset through Week 52 favored anifrolumab in both TULIP-2 (HR 1.55, 95% CI 1.11–2.18) and TULIP-1 (HR 1.93, 95% CI 1.38–2.73) (Figure). In TULIP-2, 86 (47.8%) patients treated with anifrolumab had BICLA responses that were sustained from time of onset through Week 52 compared with 57 (31.3%) patients in the placebo group. In TULIP-1, 85 (47.2%) patients in the anifrolumab treatment arm had BICLA responses that were sustained from time of onset through Week 52 compared with 55 (29.9%) patients in the placebo group.Conclusion:In 2 Phase 3 studies, a greater proportion of patients achieved BICLA responses sustained from onset through Week 52 with anifrolumab treatment compared with placebo. Anifrolumab resulted in numerically favorable differences in time to onset of BICLA responses maintained through Week 52 across the TULIP studies. These data support the sustainability of clinical benefit derived from anifrolumab treatment of patients with active SLE.References:[1]Morand EF, et al.N Engl J Med. 2020;382:211–221.[2]Furie RA, et al.Lancet Rheumatol. 2019;1:e208–e219.Disclosure of Interests:Eric F. Morand Grant/research support from: AstraZeneca, Consultant of: AstraZeneca, Speakers bureau: AstraZeneca, Richard Furie Grant/research support from: AstraZeneca, Biogen, Consultant of: AstraZeneca, Biogen, Ian N. Bruce Grant/research support from: Genzyme Sanofi, GSK, and UCB, Consultant of: Eli Lilly, AstraZeneca, UCB, Iltoo, and Merck Serono, Speakers bureau: UCB, Kenneth Kalunian Grant/research support from: Pfizer, UCB, Resolve, Takeda, Idorsia, BMS, and Kirin, Consultant of: AstraZeneca, Nektar, Amgen, Eli Lilly, Janssen, GSK, AbbVie, Chemocentryx, Genentech-Roche, Biogen, and Equillium, Rubana Kalyani Employee of: AstraZeneca, Gabriel Abreu Employee of: AstraZeneca, Lilia Pineda Employee of: AstraZeneca, Raj Tummala Employee of: AstraZeneca

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THU0029 IDENTIFICATION AND COMPARING OF HUB GENES IN SYSTEMIC LUPUS ERYTHEMATOSUS T AND B CELLS BY BIOINFORMATIC ANALYSIS

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.2525 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 228.1-228

Author(s):

Q. Zhou ◽

L. Long

Keyword(s):

Systemic Lupus Erythematosus ◽

T Cells ◽

B Cells ◽

Lupus Erythematosus ◽

Type I ◽

T And B Cells ◽

Systemic Lupus ◽

Hub Genes ◽

Link Type ◽

Ppi Networks

Background:Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder that can virtually involve any organ system of the body. Many efforts have been made to elucidate the pathogeny, but the molecular mechanisms are still not understood. Lymphocytes are considered to play an important role in SLE pathogenesis. Aberrantly activated T cells mediate inflammatory responses and activate B cells to differentiate and produce autoantibodies, resulting in multisystem manifestations [1, 2]. With the wide use of gene technique, more genetic studies on SLE were performed and differentially expressed genes (DEGs) were identified. Integrating and re-analyzing these data can help us understand the molecular mechanisms and identify diagnostic and therapeutic targets of SLE.Objectives:In this study, we downloaded the microarray datasets GSE4588 and GSE10325 from Gene Expression Omnibus (GEO) database to identify the candidate genes in T and B cells respectively.Methods:Datasets GSE4588 and GSE10325 were downloaded from GEO (http://www.ncbi.nlm.nih.gov/geo). The DEGs between T or B cells and control samples were screened using GEO2R (http://www.ncbi.nlm.nih.gov/geo/geo2r). logFC |fold change| >1 and P-value <0.05 were considered statistically significant. To analyze the function of DEGs, biological analyses were performed using DAVID database (http://david.ncifcrf.gov). P<0.05 was considered statistically significant. The PPI networks of DEGs were constructed using STRING database, and an interaction with a combined score >0.4 was considered statistically significant. The PPI networks were drawn using Cytoscape and the most significant module was identified using MCODE. The criteria for selection were: MCODE scores >5, degree cut-off=2, node score cut-off=0.2, Max depth=100 and k-score=2. The hub genes were selected with degrees ≥10.Results:After standardization of the microarray results, DEGs in T and B cells were identified respectively (Fig. 1).Changes in biological processes in T and B cells were both mainly enriched in type I interferon signalling pathway, defense response to virus, and negative regulation of viral genome replication. Changes in cell component in T cells was enriched in the cytosol while in B cells it was in cytoplasm. KEGG pathway analysis revealed that the DEGs of T cells were mainly enriched in influenza A, measles, herpes simplex infection and hepatitis C, while DEGs of B cells were mainly enriched in measles. Changes in molecular function were not listed because the p values were ≥0.05.4 genes were identified as hub genes (2 in each cell population). In T cells, the hub genes are PLSCR1 and GINS2. PLSCR1 may contribute to the prothrombotic tendency in SLE. GINS2 is involved in the initiation of DNA replication and cell cycle progression. In B cells, the hub genes are ISG15 and TOP2A. Increased ISG15 is correlated with lymphocytopenia in SLE patients. TOP2A encodes a DNA topoisomerase and anti-topoisomerase II antibody could be found in SLE.Conclusion:In our study, 2 mRNA microarray datasets were analyzed to obtain DEGs between SLE T and B cells versus healthy controls. A total of 56 DEGs were identified in T cells and 83 in B cells. Most of the DEGs were upregulated. Changes in biological processes in T and B cells were mainly related to type I interferon signalling pathway and anti-virus function. KEGG also showed the same. PLSCR1 and GINS2 were hub genes in T cells while ISG15 and TOP2A were hub genes in B cells. Overexpression of these genes might play an important role in the pathogenesis of SLE.References:[1]Ohl, K. and K. Tenbrock,Regulatory T cells in systemic lupus erythematosus.Eur J Immunol, 2015.45(2): p. 344-55.[2]Moulton, V.R. and G.C. Tsokos,T cell signaling abnormalities contribute to aberrant immune cell function and autoimmunity.J Clin Invest, 2015.125(6): p. 2220-7.Disclosure of Interests:None declared

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Disease Control and Safety of Belimumab Plus Standard Therapy Over 7 Years in Patients with Systemic Lupus Erythematosus

The Journal of Rheumatology ◽

10.3899/jrheum.121368 ◽

2013 ◽

Vol 41 (2) ◽

pp. 300-309 ◽

Cited By ~ 99

Author(s):

Ellen M. Ginzler ◽

Daniel J. Wallace ◽

Joan T. Merrill ◽

Richard A. Furie ◽

William Stohl ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Disease Control ◽

Lupus Erythematosus ◽

Standard Therapy ◽

Initial Study ◽

Systemic Lupus ◽

Open Label ◽

Double Blind ◽

Link Type ◽

Auto Antibody

Objective.To evaluate the efficacy/safety of belimumab plus standard therapy in patients (n = 449) with active systemic lupus erythematosus (SLE) treated up to 7 years (n = 177 currently ongoing).Methods.Patients (n = 345) who completed a double-blind, placebo-controlled, 52-week study of belimumab 1, 4, or 10 mg/kg and 24-week extension of belimumab (placebo switched to 10 mg/kg; belimumab same dose or switched to 10 mg/kg) could receive belimumab 10 mg/kg in an open-label continuation study (n = 296). Disease activity was analyzed in patients with active SLE at baseline of the initial study. Biomarker and SLE medication changes were evaluated, and adverse events (AE) were monitored throughout the study.Results.Total belimumab exposure over 7 years (double-blind and open-label periods): 1746 patient-years. SLE Responder Index (SRI) response rates at Week 52 in autoantibody-positive patients: placebo, 29%; belimumab, 46% (p < 0.05). In the continuation study, 57% of auto-antibody-positive patients had an SRI response by Year 2 and 65% by Year 7; severe flares occurred in 19% with placebo and 17% with belimumab during the first year, with the annual rate declining to 2%–9% during years 2–7. Anti-dsDNA autoantibodies in patients positive for them at baseline had a progressive decline of 40%–60% from baseline over 2–7 years with belimumab. Corticosteroid use decreased over time with ≥ 50–55% reduction in median dose during years 5–7. Serious and overall annual AE rates, including infections, were generally stable or decreased during 7-year treatment.Conclusion.Disease control and safety profile were maintained in patients with active SLE taking belimumab plus standard therapy for up to 7 years. [ClinicalTrials.gov numbers: NCT00071487 and NCT00583362]

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