SAT0243 Exposure-response (E-R) analysis for selection of optimal dosage regimen of anifrolumab in patients (PTS) with systemic lupus erythematosus (SLE)
Authors: LC Santiago, B Wang, P Brohawn, L Wang, G Illei, L Roskos
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Anifrolumab is a fully human IgG<sub>1</sub> monoclonal antibody directed against subunit 1 of the type I interferon–α receptor (IFNAR1). It is in development for treatment of SLE. <h3>Objectives</h3> To support dosage selection for pivotal anifrolumab studies, using an E−R model. <h3>Methods</h3> In the Phase IIb MUSE study (NCT01438489),<sup>1</sup> adult pts with moderate to severe SLE, who had inadequate responses to standard-of-care (SOC) medications, were randomized 1:1:1 to intravenous anifrolumab 300 or 1,000 mg or placebo every 4 weeks (Q4W), in addition to SOC medications, for 48 weeks. Pts were stratified by type I interferon gene signature (IFNGS) test status (high or low) using a validated 4-gene expression assay, oral corticosteroid dosage (&lt;10 or ≥10 mg/day of prednisone or equivalent), and SLE disease activity index−2K score (&lt;10 or ≥10) at screening. A mechanistic target-mediated drug disposition model<sup>2</sup> was used to describe the pharmacokinetics (PK) of anifrolumab. The dichotomous efficacy endpoint, SLE responder index [SRI (4)], was modeled using logistic regression. A dropout hazard function was used to describe voluntary withdrawals during treatment. Clinical simulations were conducted to assess dosing scenarios in virtual SLE pts. <h3>Results</h3> There was no PK difference between type I IFNGS test–high or –low pts (mean [standard deviation] C<sub>trough</sub> (Day 169): 17.0 [11.5] μg/mL and 23.3 [16.0] μg/mL, respectively). SRI (4) modeling demonstrated no anifrolumab treatment effect in type I IFNGS test–low pts compared with placebo; interpretation of this result may be limited by small sample size. In type I IFNGS test–high pts, a log-linear logistic model was used to describe the treatment effect of anifrolumab. Pt dropouts were more likely in nonresponders. Clinical simulations demonstrated dosages &lt;300 mg would result in inadequate PK exposure and suboptimal efficacy in some pts with SLE. In contrast, simulations indicated minimal efficacy improvement for dosages &gt;300 mg, consistent with the Phase IIb MUSE study outcomes. <h3>Conclusions</h3> Based on E−R analyses and overall risk assessment, a 300 mg Q4W, intravenous dosage regimen is recommended for pivotal anifrolumab studies in pts with SLE. <h3>References</h3> Furie R, et al. Arthritis Rheumatol. 2017;69:376–86. Wang B, et al. Clin Pharmacol Ther. 2013;93:483−92. <h3>Acknowledgements</h3> Funded by MedImmune. Medical writing support: R. Plant, QXV Comms, an Ashfield company, funded by MedImmune. <h3>Disclosure of Interest</h3> L. Santiago Shareholder of: AstraZeneca, Employee of: MedImmune LLC, B. Wang Shareholder of: AstraZeneca, Employee of: MedImmune LLC, P. Brohawn Shareholder of: AstraZeneca, Employee of: MedImmune LLC, L. Wang Employee of: MedImmune LLC, G. Illei Shareholder of: AstraZeneca, Employee of: MedImmune LLC, L. Roskos Shareholder of: AstraZeneca, Employee of: AstraZeneca