Meaningful Improvement In Disease Activity Research Articles

P52 Efficacy of guselkumab in bionaive psoriatic arthritis patients with severe disease activity: post hoc analysis of Phase 3, randomized, double-blind, placebo-controlled study

Abstract The efficacy and safety of guselkumab, a fully human IL-23p19-subunit inhibitor, has been established in DISCOVER-1 and -2 studies. This post hoc analysis evaluates guselkumab efficacy through Week (W)100 in Bionaive psoriatic arthritis (PsA) patients with severe disease activity (DA) based on a range of composite and patient-reported outcomes. In DISCOVER-2, Bionaive adults with active PsA (≥5 swollen and ≥5 tender joints, CRP ≥0.6 mg/dL) received (1:1:1) guselkumab 100 mg every 4W (Q4W); guselkumab 100 mg at W0, W4, Q8W; or placebo with crossover to guselkumab Q4W at W24. Severe DA was defined by clinical DA Index for PsA (cDAPSA >27), PsA DA Score (PASDAS ≥5.4), and patient global assessment (PtGA ≥80 mm) criteria. Least square mean (LSM) changes from baseline were estimated with mixed models for repeated measures, adjusted for treatment group, baseline outcome levels, and study stratification factors (baseline csDMARD use, high-sensitivity serum CRP). Among 739 DISCOVER-2 patients, 648 (88%), 639 (86%), and 218 (29%) met cDAPSA (mean = 49.5), PASDAS (mean = 6.8), and PtGA (mean = 89.0) criteria for severe DA. Baseline characteristics and treatment groups were generally consistent across severe DA cohorts, except guselkumab Q4W group had a higher proportion of males and dactylitis than placebo. In multivariate analyses, irrespective of the severe DA cohort, significantly greater improvements were observed in guselkumab-treated patients vs. placebo in all evaluated endpoints (largest effect observed in severe PtGA cohort). Guselkumab showed clinically meaningful improvements at W2 for cDAPSA (guselkumab Q4W: −5.9; Q8W: −7.2; placebo: −5.0) and W8 for PASDAS (guselkumab Q4W: −1.5; Q8W: −1.5; placebo: −0.9) and PtGA (guselkumab Q4W: −30.0; Q8W: −32.1; placebo: −17.4). The LSM differences between guselkumab Q4W/Q8W and placebo were enhanced through W24 across severe DA cohorts, at which time further improvements with guselkumab occurred, resulting in significant (P < 0.001) differences of −9.8/−9.0 for cDAPSA, −1.1/−1.1 for PASDAS, and −24.0/−20.2 for PtGA. Further improvements were observed through 2 years of guselkumab treatment in all evaluated outcomes (LSM difference from BL: ΔcDAPSA, ∼−36; ΔPASDAS, ∼−3.6; ΔPtGA, ∼−56) representing ∼73%, ∼53%, and ∼63% improvements in joint DA, PsA activity across domains, and patient-reported overall DA. Guselkumab demonstrated rapid (W2 for joint and W8 for overall DA) and clinically meaningful improvements in DA in Bionaive PsA patients with severe DA in a range of joint-focused and multi-domain outcomes; these improvements were further enhanced by W24 and sustained through 2 years. Overall, findings support the use of guselkumab in PsA patients with severe DA.

Denifanstat for the treatment of metabolic dysfunction-associated steatohepatitis: a multicentre, double-blind, randomised, placebo-controlled, phase 2b trial

Denifanstat, an oral fatty acid synthase (FASN) inhibitor, blocks de-novo lipogenesis, a key pathway driving progressive lipotoxicity, inflammation, and fibrosis in metabolic dysfunction-associated steatohepatitis (MASH). This study aimed to examine the safety and efficacy of denifanstat for improving liver histology in individuals with MASH and moderate to advanced fibrosis. This multicentre, double-blind, randomised, placebo-controlled, phase 2b trial was conducted at 100 clinical sites in the USA, Canada, and Poland. After a screening period of up to 90 days, participants aged 18 years and older with biopsy-confirmed MASH and stage F2 or F3 fibrosis were randomly assigned (2:1) to receive either 50 mg oral denifanstat or placebo once per day for 52 weeks. Participants were dynamically allocated to treatment groups via a centrally administered interactive web-based response system and stratified by type 2 diabetes, region, and fibrosis stage. Investigators, patients, and the sponsor were masked to group allocation until database lock. The primary efficacy endpoints were a 2-point or greater improvement in non-alcoholic fatty liver disease activity score (NAS) without a worsening of fibrosis or MASH resolution with a 2-point or greater improvement in NAS without a worsening of fibrosis at week 52, assessed by intention to treat. Safety was assessed in all participants who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT04906421, and is closed for enrolment. Of the 1087 individuals screened between June 2, 2021, and June 28, 2022, 168 eligible participants were randomly assigned to receive a dose of 50 mg denifanstat once per day (n=112) or placebo (n=56). All 168 participants (100 female, 68 male) received at least one dose of study treatment. In the ITT population, 42 (38%) of 112 participants in the denifanstat group had a 2-point or greater improvement in NAS without a worsening of fibrosis versus nine (16%) of 56 participants in the placebo group (common risk difference 21·0%, 95% CI 8·1-33·9; p=0·0035). 29 (26%) of 112 participants in the denifanstat group showed MASH resolution with a 2-point or greater improvement in NAS without a worsening of fibrosis compared with six (11%) of 56 participants in the placebo group (common risk difference 13·0%, 0·7-25·3; p=0·0173). The most common treatment-emergent adverse events were COVID-19 (19 [17%] of 112 in the denifanstat group vs six [11%] of 56) in the placebo group, dry eye symptoms (ten [9%] of 112 vs eight [14%] of 56), and alopecia (21 [19%] of 112 vs two [4%] of 56). All adverse events considered to be related to the study drug were of grade 1 or grade 2. None of the serious adverse events (13 [12%] of 112 participants in the denifanstat group vs three [5%] of 56 in the placebo group) were considered drug-related. Treatment with denifanstat resulted in statistically significant and clinically meaningful improvements in disease activity, MASH resolution, and fibrosis. The results of this phase 2b trial support the advancement of denifanstat to phase 3 development. Sagimet Biosciences.

P165 Sustained improvement in clinical outcomes and long-term safety of bimekizumab in patients across the spectrum of axial spondyloarthritis up to week 52: results from two phase 3 studies

Abstract Background/Aims Bimekizumab (BKZ), a monoclonal IgG1 antibody that selectively inhibits IL-17F in addition to IL-17A, has shown rapid and clinically meaningful improvements in disease activity across the axial spondyloarthritis spectrum (axSpA; active non-radiographic axSpA [nr-axSpA; BE MOBILE 1, NCT03928704] and ankylosing spondylitis [AS] / radiographic axSpA [r-axSpA; BE MOBILE 2, NCT03928743]). Here we present outcomes from these two phase 3 studies up to Week (Wk)52. Methods BE MOBILE 1 and 2 have similar study designs: 16-Wk double-blind period followed by 36-Wk maintenance period. Patients were randomised (1:1 in BE MOBILE 1; 2:1 in BE MOBILE 2) to BKZ 160 mg every 4Wks (Q4W) or placebo (PBO). All patients received BKZ 160 mg Q4W from Wk16 up to Wk52. Sustained improvements in ASAS40, BASDAI50 responses, BASDAI, BASFI and ASDAS-CRP scores were assessed up to Wk52. Missing data were imputed using non-responder or multiple imputation for binary and quantitative variables, respectively. Results 254 nr-axSpA (BKZ: 128; PBO: 126) and 332 r-axSpA (BKZ: 221; PBO: 111) patients were randomised; 86.6% and 89.8% completed Wk52, respectively. ASAS40 responses increased from Wk16 to Wk52 with similar efficacy across TNF-naïve/IR patients (Table). Approximately 47% of patients on BKZ achieved BASDAI50 at Wk16, increasing to ∼54% at Wk52 (NRI, Table). All improvements at Wk16 in BASDAI, BASFI and ASDAS were sustained up to Wk52 (Table). Efficacy was similar between treatment arms at Wk52. During the overall study period, 75% (183/244, nr-axSpA) and 75.5% (249/330, r-axSpA) patients reported ≥1 treatment-emergent adverse events (TEAEs). Most common TEAEs included nasopharyngitis, upper respiratory tract infection and oral candidiasis. Incidence of serious TEAEs were low (3.7% [nr-axSpA] and 6.1% [r-axSpA]); no incidence of systemic candidiasis, adjudicated MACE or deaths were reported. ‘Any definite or probable adjudicated IBD TEAE’ was reported in 0.8% (2/240, nr-axSpA) and 0.6% (2/326, r-axSpA) patients with no history of IBD and 25% (1/4, r-axSpA) patients with prior history of IBD. Incidence of uveitis (1.2% [3/244, nr-axSpA]; 2.1% [7/330, r-axSpA]) was low. Conclusion Across the axSpA disease spectrum, bimekizumab demonstrated sustained improvements in clinical outcomes up to Wk52 with no new safety signals. Disclosure K. Gaffney: Shareholder/stock ownership; KG is a shareholder of Rheumatology events. Grants/research support; KG received grant/research support from NASS, Versus Arthritis, AbbVie, Pfizer, UCB Pharma, Novartis, Lilly, Cellgene, Celltrion, Janssen, Gilead and Biogen. Other; KG has received honoraria/ consultation fees from Novartis, AbbVie, UCB Pharma, Lilly and Pfizer, KG has received speaker’s bureau from Novartis, UCB Pharma, AbbVie and Lilly; meeting expenses from AbbVie, Lilly, Roche, Novartis, Pfizer and UCB Pharma. N.D. McKay: Other; NDM received travel fees from UCB Pharma and Gilead, and Speaker’s bureau from Gilead. R. Sengupta: Grants/research support; RS received grants/ research support from AbbVie, Celgene, Novartis and UCB Pharma. Other; RS recevied honoraria or consultancy fees from Abbvie, Biogen, Novartis, Celgene, Lilly, Chugai, MSD and UCB Pharma, RS is on the advisory boards for AbbVie, Biogen, Chugai, Lilly, Novartis and UCB Pharma. C. Fleurinck: Other; CF is an employee of UCB Pharma. C. de la Loge: Consultancies; CdlL is a consultant to UCB Pharma, Brussels, Belgium. U. Massow: Other; UM is an employee of UCB Pharma. V. Taieb: Other; VT is an employee of UCB Pharma. S. Zhao: Honoraria; SSZ received honoraria from UCB Pharma. H. Marzo-Ortega: Grants/research support; HMO received grants/research support from Janssen, Novartis and UCB Pharma. Other; HMO received honoraria and/or consultancy and/or speaker fees from Abbvie, Biogen, Celgene, Janssen, Eli-Lilly, Moonlake, Novartis, Pfizer and UCB Pharma.

E071 Bimekizumab demonstrates sustained improvement in quality of life up to week 52 in patients across the full spectrum of axial spondyloarthritis: results from two phase 3 studies

Abstract Background/Aims Bimekizumab (BKZ), a monoclonal IgG1 antibody that selectively inhibits IL-17F in addition to IL-17A, has demonstrated rapid and clinically meaningful improvements in disease activity in patients across the full spectrum of axial spondyloarthritis (axSpA; active non-radiographic axSpA [nr-axSpA; BE MOBILE 1, NCT03928704] and ankylosing spondylitis [AS]/ radiographic axSpA [r-axSpA; BE MOBILE 2, NCT03928743]). Here we report health-related quality of life (HRQoL) outcomes (ASQoL, SF-36 and EQ-5D-3L) from the two parallel phase 3 studies up to Week (Wk)52. Methods BE MOBILE 1 and 2 have similar study designs: 16-Wk double-blind placebo (PBO)-controlled period followed by 36-Wk maintenance period. Patients were randomised (1:1 in BE MOBILE 1; 2:1 in BE MOBILE 2) to receive BKZ 160 mg Q4W or PBO. All patients received BKZ 160 mg Q4W from Wk16 to Wk52. We report ASQoL, SF-36 - physical component summary (PCS) and SF-36 - mental component summary (MCS) scores up to Wk52 and proportion of patients with ’no problem’ in each of the 5 EQ- 5D-3L domains (mobility, selfcare, usual activity, pain/discomfort, and anxiety/ depression). The results are presented as observed cases (OC), and missing data were imputed using multiple imputation (MI). Results 254 nr-axSpA (BKZ: 128; PBO: 126) and 332 r-axSpA(BKZ: 221; PBO: 111) patients were randomised with 86.6% and 89.8% completing to Wk52, respectively. At Wk16, BKZ treated patients reported greater improvements in ASQoL and SF-36 PCS compared to PBO (p < 0.001, all comparisons, using Analysis of Covariance [ANCOVA]). By Wk52, these improvements across all HRQoL outcomes were sustained in BKZ treated patients and improved in patients who switched to BKZ at Wk16. (Table). The baseline SF-36 MCS levels indicated that on average patients had normal scores which remained unchanged throughout the study. The proportion of patients reporting ‘no problem’ across all five EQ-5D-3L domains improved over time up to Wk52. In patients with ASQoL ≥4 at baseline, >60% of patients had ≥4-point improvement in ASQoL at Wk52. Conclusion Across the axSpA disease spectrum, treatment with BKZ compared with PBO at Wk16 significantly improved quality of life outcomes measured by EQ-5D-3L, ASQoL and SF-36 PCS scores which were sustained to Wk52. Disclosure N.D. McKay: Consultancies; NDM has received consultancy fees from Gilead and UCB Pharma. Other; NDM has received a registration fees for attendance at a conference from Abbvie, Novartis and UCB Pharma, NDM has received a fee for lecturing from Gilead, NDM has taken part in education meetings, programmes and examinations for a wide range of pharmaceutical companies. A. Bennett: Honoraria; AB received teaching honorarium from Abbvie Ltd, Pfizer, UCB Pharma, Novartis and Biogen. Grants/research support; AB received research grants from Pfizer. Other; AB received advisory board fees from Abbvie Ltd, Pfizer, UCB Pharma, MSD, Novartis and Lilly. N. Goodson: Honoraria; NG has received honoraria from UCB Pharma and Novartis. C. Fleurinck: Other; CF is an employee of UCB Pharma. C. de la Loge: Consultancies; CdlL is a consultant to UCB Pharma, Brussels, Belgium. U. Massow: Other; UM is an employee of UCB Pharma. V. Taieb: Other; VT is employee of UCB Pharma. H. Marzo-Ortega: Grants/research support; HMO has received grants/research support from Janssen, Novartis and UCB Pharma. Other; HMO has received honoraria and/or consultancy and/or speaker fees from Abbvie, Biogen, Celgene, Janssen, Eli-Lilly, Moonlake, Novartis, Pfizer and UCB Pharma. K. Gaffney: Shareholder/stock ownership; KG is a shareholder of Rheumatology Events. Grants/research support; KG has received grants/research support from NASS, Versus Arthritis, AbbVie, Pfizer, UCB Pharma, Norvartis, Eli Lilly, Cellgene, Celltrion, Janssen, Gilead and Biogen. Other; KG has received honoraria/ consultation fees from Novartis, AbbVie, UCB Pharma, Lilly and Pfizer, KG has received speaker’s bureau from Novartis, UCB Pharma, AbbVie and Lilly; meeting expenses from AbbVie, Lilly, Roche, Novartis, Pfizer and UCB Pharma.

P658 Safety and efficacy of MH002, an optimized live biotherapeutic product, for the treatment of mild to moderate ulcerative colitis: a first-in-disease, double-blind, randomized clinical trial

Abstract Background Treatment options for patients with mild to moderate ulcerative colitis (UC) failing 5-ASA are limited. MH002 is an optimized consortium of 6 non-pathogenic, well-characterized commensal bacteria with immune modulating, wound healing and gut barrier protective effects. This study evaluated the safety, efficacy, and mechanistic effects of MH002 in mild to moderate UC. Methods In this 2:1-randomized, double-blind, placebo-controlled first-in-disease study (EudraCT 2020-001355-33), 45 patients with mild to moderate active UC (Modified Mayo Score [MMS] =4-8 but including Mayo Endoscopic Sub-score [MES] ≥2) received treatment with 400mg MH002 or placebo (PBO) once daily for 8 wks. Full colonoscopies with biopsies were performed at baseline and wk8, biopsies and endoscopy videos were scored by blinded central readers. The primary endpoint was the rate of treatment-emergent adverse events (TEAEs). Exploratory efficacy endpoints included clinical remission (MMS ≤2 with all sub-scores ≤1 and rectal bleeding sub-score =0), endoscopic improvement (MES ≤1), and UC-100 and biomarker normalisation (C-reactive protein [CRP] ≤5mg/L, faecal calprotectin [FCP] ≤250mg/kg). Changes from baseline (CFBL) in MES and stool consistency (Bristol Stool Form Scale) were also evaluated. Results MH002 was safe and well tolerated: a TEAE was reported in 11/31 (35%) patients with MH002 and in 8/14 (57%) with PBO. Most TEAEs were mild and unrelated to study treatment. Early discontinuations (7/45; 16%) occurred similarly in both groups. At wk8, patients achieved clinical remission, endoscopic improvement, and biomarker improvements at higher rates with MH002 vs PBO (Table 1). Clinical remission rates were 14% for MH002 vs 7% for PBO (Per-protocol Set [PPS]: 18% vs 0%). Significant differences in favour of MH002 over PBO were seen in the CFBL for MES at wk8 (P=0.05, 1-sided Wilcoxon) and for stool consistency at wk2 (P=0.0057, 1-sided Student t). In total, 14/45 (31%) and 36/42 (86%) patients had elevated CRP and FCP levels at baseline, resp. Of these, more patients treated with MH002 achieved normalisation at wk8 (CRP: 60% vs 25%; FCP: 36% vs 15%). Decreases in FCP and stool consistency with MH002 were observed as early as wk2 and were greater than with PBO through wk8 (Fig 1). Conclusion MH002 treatment was safe and well tolerated and resulted in clinically meaningful improvements in disease activity and inflammatory parameters. MH002 therefore represents a promising new treatment for mild to moderate UC patients insufficiently controlled with 5ASA. These results warrant further development in a phase 2/3 study.

P077 The Immunometabolic Bimodal Mechanism of NLRX1 Agonist NX-13 in a Pig Model of Ulcerative Colitis

Abstract Background In mouse models, NX-13 is an orally active, gut-restricted NLRX1 agonist that has been shown to reduce severity of disease in multiple UC models through a novel immunometabolic, bimodal mechanism. Most preclinical UC studies rely upon rodent models, the human gastrointestinal physiology, microbiome, and immune system bear a greater similarity to that of pigs. Therefore, we sought to expand and validate our preclinical NX-13 results in mice using the dextran sulfate sodium (DSS) pig model of colitis. Here, we describe the disease severity, cellular, and biomarker results, and confirm the immunometabolic MOA observed in other species. Methods Pigs were randomized by weight (n=6 per group) and were administered tablets of excipient alone (placebo), NX-13 10 mg, NX-13 50 mg, or NX-13 100mg once daily. Pigs were challenged with 1% DSS in drinking water for 6 days and monitored daily for weight gain (loss). Composite disease activity score (0-12) was taken based on the sum of three subscores (0-4) for rectal bleeding, stool consistency and overall health/activity. Necropsy was conducted on day 7. Feces were collected for fecal calprotectin (FCP) quantification. Colonic tissue was macroscopically scored and collected for analysis by flow cytometry, histopathology and gene expression. Results Oral NX-13 treatment protected against weight loss and reduced colitis development with differences as early as day 2, becoming significant between days 4 and 6 as disease worsens in placebo treated pigs (Fig1A). NX-13 yielded a dose-dependent improvement in macroscopic lesion severity and microscopic immune cell infiltration (Fig1B). Specifically, Th1 cells (Fig1C) and TNF producing myeloid cells in the colonic lamina propria were reduced by NX-13, as well as FCP levels in stool (Fig1D) and mRNA expression in the colon (Fig1E). Oral NX-13 treatment reduced inflammatory markers including TNF, monocyte and neutrophil chemo attractants, IL-6, and IL-23 (Fig3F). Additionally, NX-13 treatment affected markers specific to the bimodal immunometabolic MOA of NLRX1 activation, namely upregulation of NLRX1 and mitochondrial metabolism gene COX3 (Fig1G), and reduction of NFkB and NLRP3 (Fig1H). Conclusion NX-13 demonstrated fast and clinically meaningful improvement in disease activity, and significantly impacted on key inflammatory markers in a DSS colitis model in pigs. These results align with previous murine results and observations in the phase 1b clinical program. Therefore, they can be used to generate additional mechanistic hypotheses for translational studies in the ongoing NEXUS phase 2 trial in moderate to severe UC.

Clinical Pharmacokinetics, Pharmacodynamics, and Immunogenicity of Anifrolumab.

The type I interferon (IFN) signaling pathway is implicated in the pathogenesis of systemic lupus erythematosus (SLE). Anifrolumab is a monoclonal antibody that targets the type I IFN receptor subunit 1. Anifrolumab is approved in several countries for patients with moderate to severe SLE receiving standard therapy. The approved dosing regimen of anifrolumab is a 300-mg dose administered intravenously every 4 weeks; this was initially based on the results of the Phase 2b MUSE and further confirmed in the Phase 3 TULIP-1 and TULIP-2 trials, in which anifrolumab 300-mg treatment was associated with clinically meaningful improvements in disease activity with an acceptable safety profile. There have been several published analyses of the pharmacokinetic and pharmacodynamic profile of anifrolumab, including a population-pharmacokinetic analysis of 5 clinical studies of healthy volunteers and patients with SLE, in which body weight and type I IFN gene expression were significant covariates identified for anifrolumab exposure and clearance. Additionally, the pooled Phase 3 SLE population has been used to evaluate how serum exposure may be related to clinical responses, safety risks, and pharmacodynamic effects of the 21-gene type I IFN gene signature (21-IFNGS). The relevance of 21-IFNGS with regard to clinical efficacy outcomes has also been analyzed. Herein, the clinical pharmacokinetics, pharmacodynamics, and immunogenicity of anifrolumab as well as results of population-pharmacokinetics and exposure-response analyses are reviewed.

P193 Bimekizumab improves key symptoms, disease activity and function in patients across the full spectrum of axial spondyloarthritis up to week 24: results from two phase 3 studies

Abstract Background/Aims Bimekizumab (BKZ) is a monoclonal IgG1 antibody that selectively inhibits IL-17F in addition to IL-17A. BKZ demonstrated rapid and clinically meaningful improvements in disease activity across the full spectrum of axial spondyloarthritis (axSpA; active non-radiographic axSpA [nr-axSpA; BE MOBILE 1, NCT03928704] and ankylosing spondylitis [AS] / radiographic axSpA [r-axSpA; BE MOBILE 2, NCT03928743]). Here we present clinical outcomes from the ongoing phase 3 studies up to week (wk) 24. Methods BE MOBILE 1 and 2 have similar study designs: 16-wk double-blind period followed by a 36-wk maintenance period. Patients were randomised (1:1 in BE MOBILE 1 and 2:1 in BE MOBILE 2) to BKZ 160 mg every 4 wks (Q4W) or placebo (PBO). All patients received BKZ 160 mg Q4W from wk16. ASAS40 and BASDAI50 rates, mean change from baseline (CfB) in BASDAI (total and components) and BASFI scores are reported up to wk24. Missing data is imputed using non-responder or multiple imputation. Results Overall, 240/254 (94.5%; nr-axSpA) and 313/332 (94.3%; r-axSpA) patients completed the studies up to wk24. Both studies met their primary (ASAS40) and ranked secondary endpoints at wk16. Higher BASDAI50 response rates and larger mean reduction in BASDAI and BASFI scores were seen at wk16 for BKZ versus PBO (Table). After switching to BKZ, mean changes in BASDAI and BASFI scores for patients in the PBO group reached levels similar to BKZ-treated patients. 50.8% of nr-axSpA and 55.5% of r-axSpA patients had ≥1 treatment emergent adverse events (TEAE) and incidence of serious TEAEs was low up to wk24 (0.4% and 3.6%). No systemic candidiasis, MACE or deaths were reported with BKZ in either study up to wk24. No IBD was reported in BE MOBILE 1 (nr-axSpA), there was low incidence of adjudicated IBD in BE MOBILE 2 (r-axSpA: 0.3%). Incidence of uveitis was low in both studies (nr-axSpA: 4.8% [PBO], 1.6% [BKZ]; r-axSpA: 4.5% [PBO], 0% [BKZ]) at wk16. Conclusion Dual inhibition of IL-17A and IL-17F with BKZ provided significant improvement in key signs and symptoms, disease activity and physical function across the full spectrum of axSpA. No new safety signals were observed. Disclosure K. Gaffney: Consultancies; KG has received honoraria or consultancy fees from Novartis, AbbVie, UCB Pharma, Eli Lilly and Pfizer. Shareholder/stock ownership; KG is a shareholder of Rheumatology Events. Member of speakers’ bureau; KG has paticipated in speaker's bureau for Novartis, UCB Pharma, AbbVie and Eli Lilly. Grants/research support; KG has received grants/research support from NASS, Versus Arthritis, AbbVie, Pfizer, UCB Pharma, Norvartis, Eli Lilly, Cellgene, Celltrion, Janssen, Gilead and Biogen. Other; KG has received meeting expenses from AbbVie, Eli Lilly, Roche, Novartis, Pfizer and UCB Pharma. N. McKay: Member of speakers’ bureau; NM has received Speaker' bureau from Gilead. Other; NM has received travel fees from UCB Pharma and Gilead. R. Sengupta: Consultancies; RS has honoraria or consultancy fees from Abbvie, Biogen, Novartis, Celgene, Lilly, Chugai, MSD and UCB Pharma. Grants/research support; RS has received grants/ research support from AbbVie, Celgene, Novartis and UCB Pharma. Other; RS is on the advisory boards for AbbVie, Biogen, Chugai, Lilly, Novartis and UCB Pharma. C. Fleurinck: Other; CF is an employee of UCB Pharma. C. de la Loge: Consultancies; CdlL is a consultant to UCB Pharma, Brussels, Belgium. U. Massow: Other; UM is an employee of UCB Pharma. V. Taieb: Other; VT is employee of UCB Pharma. S. Zhao: Honoraria; SZ has received honoraria from UCB Pharma. H. Marzo-Ortega: Grants/research support; HMO has received grants/research support from Janssen, Novartis and UCB Pharma. Other; HMO has received honoraria and/or consultancy and/or speaker fees from Abbvie, Biogen, Celgene, Janssen, Eli-Lilly, Moonlake, Novartis, Pfizer and UCB Pharma.

P194 Bimekizumab is associated with improvement in quality of life in patients across the full spectrum of axial spondyloarthritis at week 16: results from two phase 3 studies

Abstract Background/Aims Bimekizumab (BKZ) is a monoclonal IgG1 antibody that selectively inhibits IL-17F in addition to IL-17A and has demonstrated rapid and clinically meaningful improvements in disease activity (ASAS40, primary outcome measure) in patients across the full spectrum of axial spondyloarthritis (axSpA; active non-radiographic axSpA [nr-axSpA; BE MOBILE 1, NCT03928704] and ankylosing spondylitis [AS] / radiographic axSpA [r-axSpA; BE MOBILE 2, NCT03928743]). Here we report results related to HRQoL instruments (EQ-5D-3L, ASQoL and SF-36) from the two ongoing phase 3 studies at week (wk) 16. Methods BE MOBILE 1 and 2 were conducted in parallel with similar study designs: 16-wk double-blind placebo-controlled period followed by a 36-wk maintenance period. Patients were randomised (1:1 in BE MOBILE 1 and 2:1 in BE MOBILE 2) to BKZ 160 mg Q4W or placebo (PBO). All patients received BKZ 160 mg Q4W from wk16. We report change from baseline (CfB) in the overall EQ-5D-3L utility index, ASQoL and SF-36 Physical component Summary (PCS) scores at wk16 compared to PBO. Missing data is imputed using multiple imputation. Results Overall, 240/254 (94.5%; nr-axSpA) and 313/332 (94.3%; r-axSpA) patients completed the studies up to wk24. Both studies met their primary and all ranked secondary endpoints at wk16. In both studies, BKZ treatment resulted in improved health status as measured with the EQ-5D-3L utility score versus PBO. This improvement at wk16 was consistent across both tumour necrosis factor inhibitor (TNFi)-naive and TNFi-inadequate responders (IR) patients. Significantly greater improvements were also observed with BKZ compared to PBO in ASQoL and SF-36 PCS in both studies (p < 0.001, all comparisons) at wk16 (Table). At wk16, a higher proportion of BKZ- versus PBO-treated patients achieved ≥5-point improvement in SF-36 PCS (nr-axSpA: 64.8% vs 41.3% and r-axSpA: 63.8% vs 49.5%) and ≥4-point improvement in ASQoL (nr-axSpA: 58.6% vs 33.3% and r-axSpA: 57.5% vs 45.0%), respectively. Conclusion Dual inhibition of IL-17A and IL-17F with BKZ improved quality of life measured by EQ-5D-3L, ASQoL and SF-36 PCS scores compared with PBO in patients across the full spectrum of axSpA. Disclosure N. McKay: Member of speakers’ bureau; NM has received Speaker' bureau from Gilead. Other; NM has received travel fees from UCB Pharma and Gilead. A. Bennett: Honoraria; AB has received teaching honorarium from Abbvie Ltd, Pfizer, UCB Pharma, Novartis and Biogen. Grants/research support; AB has received research grants from Pfizer. Other; AB has received advisory board fees from Abbvie Ltd, Pfizer, UCB Pharma, MSD, Novartis and Eli Lilly. N. Goodson: Honoraria; NG has received honoraria from UCB Pharma and Novartis. C. Fleurinck: Other; CF is an employee of UCB Pharma. C. de la Loge: Consultancies; CdlL is a consultant to UCB Pharma, Brussels, Belgium. U. Massow: Other; UM is an employee of UCB Pharma. V. Taieb: Other; VT is employee of UCB Pharma. H. Marzo-Ortega: Grants/research support; HMO has received grants/research support from Janssen, Novartis and UCB Pharma. Other; HMO has received honoraria and/or consultancy and/or speaker fees from Abbvie, Biogen, Celgene, Janssen, Eli-Lilly, Moonlake, Novartis, Pfizer and UCB Pharma. K. Gaffney: Consultancies; KG has received honoraria or consultancy fees from Novartis, AbbVie, UCB Pharma, Eli Lilly and Pfizer. Shareholder/stock ownership; KG is a shareholder of Rheumatology Events. Member of speakers’ bureau; KG has paticipated in speaker's bureau for Novartis, UCB Pharma, AbbVie and Eli Lilly. Grants/research support; KG has received grants/research support from NASS, Versus Arthritis, AbbVie, Pfizer, UCB Pharma, Norvartis, Eli Lilly, Cellgene, Celltrion, Janssen, Gilead and Biogen. Other; KG has received meeting expenses from AbbVie, Eli Lilly, Roche, Novartis, Pfizer and UCB Pharma.

Effect of Upadacitinib on Disease Activity, Pain, Fatigue, Function, Health-Related Quality of Life and Work Productivity for Biologic Refractory Ankylosing Spondylitis.

Patients with ankylosing spondylitis (AS) have significant unmet treatment needs, despite advancements in biologic therapies. This study evaluated the impact of upadacitinib on clinically meaningful improvement in patient-reported outcomes (PROs) assessing disease activity, pain, fatigue, function, health-related quality of life (HRQoL), and work productivity in patients with AS with inadequate responses or intolerance to biologic disease-modifying antirheumatic drugs (bDMARD-IR). Patients enrolled in the phase 3 SELECT-AXIS 2 AS bDMARD-IR study received blinded once-daily oral upadacitinib 15mg or placebo for 14weeks. The percentage of patients achieving improvements ≥ minimum clinically important differences (MCID) at week 14 were compared between treatment groups for disease activity (Bath Ankylosing Spondylitis Disease Activity Index, BASDAI), patient global assessment of disease activity (PtGA), total and nocturnal back pain, fatigue (Functional Assessment of Chronic Illness Therapy-Fatigue, FACIT-F), physical function (Bath Ankylosing Spondylitis Functional Index, BASFI), HRQoL (Assessment of SpondyloArthritis international Society Health Index [ASAS HI], Ankylosing Spondylitis Quality of Life [ASQoL], Short form-36 [SF-36] physical [PCS] and mental [MCS] component summary scores), and work productivity (Work Productivity and Activity Impairment [WPAI] Questionnaire). Mean changes from baseline through week 14 in fatigue and HRQoL were compared between treatment groups. A total of 420 patients with active AS who were bDMARD-IR were included. A higher proportion of patients reported MCIDs at week 14 across all PROs with upadacitinib compared with placebo (nominal p ≤ 0.05). Greater improvements in mean change from baseline through week 14 were reported with upadacitinib compared with placebo across FACIT-F, HRQoL, and WPAI, with improvements differentiated as early as week 1 for ASAS HI, ASQoL and SF-36 PCS and week 4 for SF-36 MCS. Upadacitinib 15mg demonstrated rapid and clinically meaningful improvements in disease activity, pain, FACIT-F, function, HRQoL, and WPAI among bDMARD-IR patients with active AS. Clinical Registration number: NCT04169373, SELECT-AXIS 2.

P268 Development and validation of a novel composite index for the assessment of endoscopic and histologic disease activity in pouchitis: The Atlantic pouchitis index.

Abstract Background Several instruments have been used in clinical trials of pouchitis to define eligibility criteria and outcome measures but have not been formally validated. A need remains for a validated pouchitis instrument that is suitable for use in novel drug development. We developed and internally validated the novel composite Atlantic pouchitis index (API) for the assessment of endoscopic and histologic disease activity in patients with pouchitis. Methods Paired baseline and week 10 endoscopic videos and histologic images were obtained from 98 patients with chronic antibiotic-refractory pouchitis who participated in a randomised placebo-controlled trial of alicaforsen enema (ClinicalTrials.gov identifier: NCT02525523). For each pair, 4 endoscopists and 3 pathologists scored 59 items. These items included 51 component items from 11 indices (4 endoscopic, 4 histologic, 3 composite) identified in a prior systematic review and 8 additional items identified in a prior Research and Development/University of California Los Angeles appropriateness methodology exercise. The reliability of all measures was assessed using intraclass correlation coefficients (ICCs) and interpreted according to Landis and Koch benchmarks (slight, 0.00-0.20; fair, 0.21-0.40; moderate, 0.41-0.60; substantial, 0.61-0.80; almost perfect, 0.81-1.00). Responsiveness was evaluated using the area under the receiver operating characteristic curve (AUC). The API was developed using linear regression with a 100-mm visual analogue scale (VAS) of pouchitis activity as an anchor. Results Among all measures assessed for reliability and responsiveness, the simple endoscopic score for Crohn’s disease (SES-CD) and the Robarts histopathology index (RHI) were selected for inclusion in the API. The total API score ranges from 0 to 69, with higher scores indicating more severe disease activity, and can be calculated as API = (3 × SES-CD [0 to 12]) + (1 × RHI [0 to 33]). The API demonstrated almost perfect intra-rater reliability (ICC, 0.88 [95% CI: 0.81, 0.92]), substantial inter-rater reliability (ICC, 0.72 [95% CI: 0.60, 0.79]), and a high correlation with the VAS (r = 0.84 [95% CI: 0.76, 0.89]). Index responsiveness in detecting meaningful improvements in disease activity was higher for the API (AUC, 0.95 [95% CI: 0.89, 0.98]) than for existing endoscopic indices (∆AUC, 0.09-0.24; P≤0.005) (Table). Conclusion The novel API is a composite index of endoscopic (SES-CD) and histologic disease activity (RHI) that is reliable and significantly more responsive than existing endoscopic pouchitis scoring systems. The API is a promising tool for use in clinical trials of novel therapies for pouchitis. Further validation is needed in independent datasets.

345 Treatment with amlitelimab—a novel non-depleting, non-cytotoxic anti-OX40Ligand monoclonal antibody—reduces IL-22 serum levels in a phase 2a randomized, placebo-controlled trial in patients with moderate-to-severe atopic dermatitis

Abstract OX40Ligand (OX40L) upregulation on antigen-presenting cells (APCs) following antigen presentation contributes to the survival and functional activation of T helper (Th) 2 and Th1/17/22 cells, which are central to the inflammation and pathological outcomes in atopic dermatitis (AD). In a Phase 2a trial (NCT03754309), amlitelimab, a fully human, non-depleting, non-cytotoxic anti-OX40L monoclonal antibody, was effective in treating patients with moderate-to-severe AD. To assess the effects of amlitelimab on interleukin (IL)-22, an important Th22-associated disease mediator of AD. 89 patients with moderate-to-severe AD were enrolled in a Phase 2a randomized, double-blind, placebo-controlled, multicentre trial and randomized 1 : 1 : 1 to intravenous amlitelimab low dose (200 mg loading/100 mg maintenance every 4 weeks [Q4W]; n = 29), high dose (500 mg/250 mg Q4W; n = 30) or placebo (Q4W; n = 29) until week 12. The primary efficacy endpoint was the percentage change in Eczema Area and Severity Index (EASI) from baseline to week 16. Other disease severity measurements included SCORing of Atopic Dermatitis (SCORAD) and validated Investigator Global Assessment (vIGA). Serum was collected at baseline, week 4 and week 16, and further collected at week 24 and week 36 in responders, defined as patients who reached vIGA 0/1 at week 16. IL-22 levels were determined by ultrasensitive single-molecule immunoassay (Simoa). Of 88 subjects who received study treatment, 59 were evaluable at week 16. Amlitelimab was well tolerated with an unremarkable safety profile. The mean percentage change in EASI from baseline at week 16 was −80.12% for amlitelimab low dose and −69.97% for amlitelimab high dose vs. −49.37% for placebo (nominal P-values: 0.009 [amlitelimab low dose vs. placebo] and 0.072 [amlitelimab high dose vs. placebo]). Amlitelimab-treated patients who achieved vIGA 0/1 at week 16 had sustained clinical responses up to week 36. No difference in IL-22 serum levels was found between groups at baseline. IL-22 levels correlated with disease severity at baseline, as measured by EASI and SCORAD (r = 0.53, P < 0.0001; and r = 0.36, P = 0.001; respectively). A significant reduction in IL-22 levels was observed at week 16 in amlitelimab-treated patients (low dose P < 0.0001; high dose P = 0.001), but not in the placebo group (P = 0.381). The amlitelimab-induced decrease in IL-22 levels was maintained until week 36 in those defined as vIGA 0/1 responders at week 16. OX40L blockade on APCs represents a promising novel approach in the treatment of AD by effectively targeting underlying T-cell immune dysregulation. Amlitelimab monotherapy not only provided a sustained and clinically meaningful improvement in disease activity compared with placebo in patients with moderate-to-severe AD, but also significantly decreased serum levels of IL-22, a Th22 cell-associated cytokine involved in the underlying immunopathogenesis of AD.

Discrepancy Between Multibiomarker Disease Activity and Clinical Disease Activity Scores in Patients With Persistently Active Rheumatoid Arthritis.

Responsive assessment of disease activity in patients who have rheumatoid arthritis (RA) is necessary to evaluate therapeutic efficacy and guide treatment. We compared the utility of the multibiomarker disease activity (MBDA) score in the assessment of RA disease activity with that of the Disease Activity Score in 28 joints using the erythrocyte sedimentation rate (DAS28-ESR) score and the Clinical Disease Activity Index (CDAI) in a multicenter, randomized, placebo-controlled trial of repository corticotropin injection (RCI) in patients with persistently active RA. Patients received 80 units of RCI twice weekly during a 12-week open-label period; those who experienced low disease activity at week 12 were randomly assigned to receive either 80 units of RCI or placebo twice weekly during a 12-week double-blind period. Changes in disease activity (measured by DAS28-ESR, CDAI, and MBDA scores) and correlations between MBDA scores and both DAS28-ESR and CDAI scores were assessed. Changes from baseline in DAS28-ESR and CDAI scores suggested that RCI therapy led to clinically meaningful improvements in disease activity, but improvements from baseline in MBDA scores were below the minimally important difference threshold. For the DAS28-ESR and CDAI, correlations with total MBDA and individual component scores were generally low (r ≤ 0.3) and occasionally moderate (r > 0.3 but r < 0.5). The results of the present study suggest overall MBDA scores are not sufficiently responsive for assessing RA disease activity after RCI therapy. These findings are consistent with those seen with other RA drugs and, although they are from a clinical trial, suggest the MBDA should not be a preferred disease activity measure in clinical practice.

AB004. Evaluating differences in meaningful change in disease activity between different races and clinical subtypes affected by cutaneous lupus erythematosus

Cutaneous lupus erythematosus (CLE) has a profound impact on a patient’s quality of life (QoL), despite epidemiologic differences disease presentation. Disease activity, rather than damage, has a greater impact on QoL, and improvement in disease activity, defined by the Cutaneous Lupus Disease Area and Severity Index score for activity (CLASI-A), is correlated to improvement in QoL. We aimed to evaluate the differences between meaningful improvement in disease activity, experienced by Caucasian and African-American patients and disease subtypes. This study included 144 patients seen at the Hospital of the University of Pennsylvania who participated in a longitudinal research database of lupus patients. Patients with an initial CLASI-A ≥4 were included, and classified by their self-identified racial background and clinical disease subtype. Linear regression models were used to calculate change in disease activity needed to predict meaningful improvement in QoL, defined as a respective 9.38-point in the Emotions subscale of Skindex-29. Due to the limited number of patients with acute CLE, we compared meaningful improvement between patients with discoid lupus erythematosus (DLE) and patients with subacute CLE (SCLE). An improvement of disease activity by 58.6% and 52.5% is associated with a meaningful impact on the Emotions subscale of Caucasian and African-American patients, respectively. Decreasing disease activity by 52.1% and 55.2% is meaningful for patients with DLE and SCLE, respectively. Regardless of individual differences in disease activity and presentation of CLE, patients experience improvement in QoL, particularly in the emotional component, with similar meaningful changes in their disease activity.

AB005. Assessing meaningful changes in disease activity as clinical trial clinical efficacy measures for cutaneous lupus erythematosus

To date, there are no approved treatments for cutaneous lupus erythematosus (CLE), a disease known to significantly burden a patient’s quality of life (QoL). Clinical trials are important for the advancement of treatments and outcome measures of these trials should reflect clinically meaningful improvement in disease activity and its effect on QoL. Currently, clinical trials use an efficacy measure of ≥50% improvement in disease activity, defined by the Cutaneous Lupus Disease Area and Severity Index activity (CLASI-A) score, in patients with an initial CLASI-A score of ≥10. However, the degree of improvement in disease activity needed to predict a meaningful impact on QoL has not been defined. This is a retrospective study of 126 patients enrolled in a longitudinal research database. Using a linear regression model, we calculated the percent change and difference needed in CLASI-A to have an important impact on QoL, defined as a 9.38-point and a 7.37-point improvement in the Emotions and Symptoms subscales of Skindex-29, respectively. In patients with an initial CLASI-A score ≥8, a decrease by 42.1% and a decrease by 31.0% in disease activity is associated with a meaningful impact in the Emotions and the Symptoms subscales, respectively. Using a CLASI-A score ≥8 for trial entry allows for inclusion of patients with milder disease for whom improvement of CLASI-A by ≥50% has a meaningful impact on QoL, as determined by the Emotions and Symptoms subscales. In patients with moderate to severe initial disease, a respective decrease in activity by seven and five-points is not only clinically significant, but also has a meaningful impact on the Emotions and Symptoms subscales. Our findings establish appropriate trial endpoints by determining clinically significant change in disease activity associated with meaningful changes in patients’ QoL.

Interferon blockade in systemic lupus erythematosus: Light at the end of the tunnel for novel therapies for lupus?

Interferon blockade in systemic lupus erythematosus: Light at the end of the tunnel for novel therapies for lupus?

Evaluating change in disease activity needed to reflect meaningful improvement in quality of life for clinical trials in cutaneous lupus erythematosus

Outcomemeasures of clinical trials in cutaneous lupus erythematosus (CLE) should reflect clinically meaningful improvement in disease activity, as measured by the Cutaneous Lupus Disease Area and Severity Index activity score (CLASI-A). We aimed to define the degree of improvement in disease activity meaningful to a patient's quality of life. The change in the CLASI-A in 126 patients needed to predict meaningful change in QoL, as defined by the Emotions and Symptoms subscales of the Skindex-29, was evaluated by linear regression models. In patients with an initial CLASI-A of ≥8, a 42.1% or ≥7-point and a 31.0% or ≥5-point decrease in CLASI-A predicts meaningful improvement in the Emotions and the Symptoms subscales, respectively. This is a retrospective study of prospectively collected data at a single site. A CLASI-A score of ≥8 for trial entry allows for inclusion of patients with milder disease where CLASI-A improvement by ≥50% is clinically significant and meaningful.

AB0774 TIME TO RESPONSE FOR CLINICAL AND PATIENT-REPORTED OUTCOMES IN PATIENTS WITH PSORIATIC ARTHRITIS TREATED WITH TOFACITINIB, ADALIMUMAB OR PLACEBO

Background:With multiple disease domains affected in PsA, clinical and patient-reported outcome (PRO) measures are important to assess disease improvement following treatment. Rapid, meaningful improvements in disease activity are a priority for physicians and patients (pts). Tofacitinib is an oral Janus kinase inhibitor for the treatment of PsA. Higher proportions of pts achieved responses in PROs and clinical measures when treated with tofacitinib for 3 months vs placebo (PBO).1-5Proportions of responders were also similar between tofacitinib and adalimumab (ADA) after 3, 6 and 12 months.2,3,5Objectives:To determine the time to initial response using responder definitions for selected PROs and clinical endpoints in pts with active PsA treated with tofacitinib, ADA or PBO switching to tofacitinib.Methods:In this post hoc analysis, data were collected from two Phase 3 studies (OPAL Broaden [12 months;NCT01877668]; OPAL Beyond [6 months;NCT01882439]).3,4Pts receiving tofacitinib 5 or 10 mg twice daily (BID), subcutaneous ADA 40 mg once every two weeks (Q2W; OPAL Broaden only), or PBO switching to tofacitinib 5 or 10 mg BID at Month (M)3, were included. Responder definitions included: HAQ-DI ≥0.35-point improvement from baseline (BL), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) total score ≥4-point improvement from BL, minimal disease activity (MDA) yes/no composite response (meeting at least 5 of 7 criteria) and PsA Disease Activity Score (PASDAS) post-BL score of ≤3.2 and &gt;1.6-point improvement from BL. First post-BL data were collected at Week 2 (eg for HAQ-DI) or M1. Time-to-event analyses were performed using the Kaplan-Meier (KM) method, with pts censored at the last observed visit. Log-rank tests compared time to initial response across treatment groups.Results:KM analyses show days to initial response (Figure 1, Figure 2). Time to initial HAQ-DI response was significantly different between treatment groups in OPAL Broaden (p&lt;0.01): faster response in pts receiving tofacitinib 5 mg BID, tofacitinib 10 mg BID and ADA 40 mg Q2W vs pts who switched from PBO to tofacitinib at M3 (Figure 1a). A similar, but not significant (ns), trend was observed for HAQ-DI responses in OPAL Beyond (Figure 1b). Generally, initial FACIT-F responses were achieved faster (ns) in pts receiving tofacitinib 5 mg BID vs other treatment in both studies (Figure 1c, Figure 1d). Times to initial MDA and PASDAS responses were similar between tofacitinib and ADA treatment groups (Figure 2).Conclusion:Times to initial response in functional ability and disease activity were similar in pts treated with either tofacitinib or ADA. Time to initial response prior to first post-BL observation (Week 2 or M1) was not estimable in this analysis. These results may help physicians better understand the time frame for a meaningful response in pts receiving tofacitinib.

Safety and efficacy of switching from adalimumab to sarilumab in patients with rheumatoid arthritis in the ongoing MONARCH open-label extension

ObjectiveEvaluate open-label sarilumab monotherapy in patients with rheumatoid arthritis switching from adalimumab monotherapy in MONARCH (NCT02332590); assess long-term safety and efficacy in patients continuing sarilumab during open-label extension (OLE).MethodsDuring the...

587 Evaluating meaningful change in disease activity as a clinical efficacy measure for clinical trials in cutaneous lupus erythematosus

To date, there are no approved treatments for cutaneous lupus erythematous (CLE), a disease known to significantly burden a patient’s quality of life (QoL). Clinical trials are important for the advancement of treatments and outcome measures of these trials should reflect clinically meaningful improvement in disease activity and its effect on QoL. Currently, clinical trials use an efficacy measure of ≥ 50% improvement in disease activity, defined by the Cutaneous Lupus Disease Area and Severity Index activity (CLASI-A) score, in patients with an initial CLASI-A score of ≥ 10. However, the degree of improvement in disease activity needed to predict a meaningful impact on QoL has not been defined. This is a retrospective study of 126 patients enrolled in a longitudinal research database. Using a linear regression model, we calculated the percent change and difference needed in CLASI-A to have an important impact on QoL, defined as a 9.38-point and a 7.37-point improvement in the Emotions and Symptoms subscales of Skindex-29, respectively. In patients with an initial CLASI-A score ≥ 8, a decrease by 42.1% and a decrease by 31.0% in disease activity is associated with a meaningful impact in the Emotions and the Symptoms subscales, respectively. Using a CLASI-A score ≥ 8 for trial entry allows for inclusion of patients with milder disease for whom improvement of CLASI-A by ≥ 50% has a meaningful impact on QoL, as determined by the Emotions and Symptoms subscales. In patients with moderate to severe initial disease, a respective decrease in activity by at least seven and five-points is not only clinically significant, but also has a meaningful impact on the Emotions and Symptoms subscales. Our findings establish appropriate trial endpoints by determining clinically significant change in disease activity associated with meaningful changes in patients’ QoL.