OP0001 The lupus low disease activity state (LLDAS) definition discriminates responders in a systemic lupus erythematosus (SLE) trial: post-hoc analysis of the phase iib muse trial of anifrolumab
Authors: E Morand, A Berglind, T Sheytanova, R Tummala, G Illei
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> A LLDAS definition has received preliminarily validation. Achieving low disease activity by this definition is associated with protection from damage accrual for patients (pts) with SLE.<sup>1</sup> However, it has not been evaluated as an endpoint in randomized controlled trials (RCTs). <h3>Objectives</h3> We evaluated LLDAS as an RCT endpoint in a <i>post-hoc</i> analysis of the MUSE trial of anifrolumab in pts with moderate to severe SLE.<sup>2</sup> <h3>Methods</h3> During the 52-week MUSE study, pts with active SLE received intravenous placebo, anifrolumab 300 mg, or 1,000 mg, in addition to standard of care, every 4 weeks for 48 weeks. LLDAS requires all of the following: SLEDAI–2K ≤4 without major organ activity, no new disease activity, PGA (0–3) ≤1, prednisolone ≤7.5 mg/day, and tolerance of standard immunosuppressant dosages.<sup>1</sup> LLDAS utility, its association with other endpoints, and discrimination between anifrolumab- and placebo-treated pts, were explored using descriptive statistics, logistic regression, and Gray9s test. All randomized pts in MUSE were included in the analyses, and non-response imputation was performed after dropout. <h3>Results</h3> For pts receiving placebo (n=102), anifrolumab 300 mg (n=99), or anifrolumab 1,000 mg (n=104), LLDAS criteria were met at least once by 35%, 52%, and 46% of pts, respectively (odds ratio [OR] vs. placebo; 300 mg: 1.97, 95% CI 1.08, 3.58; <i>p</i>=0.027; 1,000 mg: 1.63, 95% CI 0.90, 2.95; <i>p</i>=0.103). Positive associations were observed between LLDAS and both the SLE Responder Index (SRI[4]) and BILAG-based Composite Lupus Assessment (BICLA), with 87% and 74% of pts attaining LLDAS at Week 52 also being SRI(4) and BICLA responders, respectively (χ<sup>2</sup>=57.61 and 55.18; both <i>p</i>&lt;0.0001). However, only 47% and 51% of SRI(4) and BICLA responders reached LLDAS. Increased LLDAS attainment from Week 12 (300 mg) or 28 (1,000 mg) was associated with anifrolumab treatment, compared with placebo (OR range; 300 mg: 1.7–3.6; 1,000 mg: 1.7–2.5). LLDAS was attained earlier (300 mg: χ<sup>2</sup>=6.39, <i>p</i>=0.012; 1,000 mg: χ<sup>2</sup>=2.44, <i>p</i>=0.119) in anifrolumab-treated pts (Figure 1). At Week 52, more anifrolumab-treated pts attained a LLDAS (OR vs. placebo; 300 mg: 3.41, 95% CI 1.73, 6.76, <i>p</i>&lt;0.001; 1,000 mg: 2.03, 95% CI 1.01, 4.07, <i>p</i>=0.046). More anifrolumab-treated pts spent ≥50% of observed time in LLDAS (OR vs. placebo; 300 mg: 3.04, 95% CI 1.34, 6.92; <i>p</i>=0.008; 1,000 mg: 2.17, 95% CI 0.93, 5.03; <i>p</i>=0.072), and the OR of sustained LLDAS for at least six consecutive visits from Week 12 to 52 were 4.02 (95% CI 1.38, 11.73; <i>p</i>=0.011) (300 mg) and 2.95 (95% CI 0.99, 8.78; <i>p</i>=0.052) (1,000 mg). <h3>Conclusions</h3> LLDAS is associated with validated treatment response measures, SRI(4) and BICLA, but is more stringent than either. Anifrolumab was associated with ≤3.6-fold OR increases in LLDAS attainment, as well as greater aggregate and sustained time in LLDAS. This LLDAS definition should be considered as a study endpoint in SLE RCTs. <h3>References</h3> Franklyn K, et al. Ann Rheum Dis. 2015;75:1615–21. Furie R, et al. Arthritis Rheumatol. 2017;69:376–86. <h3>Acknowledgements</h3> Funded by MedImmune. Medical writing support: R Plant, QXV Comms, an Ashfield company, funded by MedImmune. <h3>Disclosure of Interest</h3> E. Morand Grant/research support from: Astra Zeneca, Janssen, UCB, BristoMyersSquibb, Consultant for: AstraZeneca, Pfizer, Merganser, Baxalta, BristoMyersSquibb, UCB, A. Berglind Shareholder of: AstraZeneca, Employee of: AstraZeneca, T. Sheytanova Employee of: AstraZeneca, R. Tummala Employee of: AstraZeneca, G. Illei Shareholder of: AstraZeneca, Employee of: MedImmune LLC