Background Anifrolumab is a fully human IgG1 monoclonal antibody directed against subunit 1 of the type I interferon–α receptor (IFNAR1). It is in development for treatment of SLE.
Objectives To support dosage selection for pivotal anifrolumab studies, using an E−R model.
Methods In the Phase IIb MUSE study (NCT01438489),1 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 (<10 or ≥10 mg/day of prednisone or equivalent), and SLE disease activity index−2K score (<10 or ≥10) at screening. A mechanistic target-mediated drug disposition model2 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.
Results There was no PK difference between type I IFNGS test–high or –low pts (mean [standard deviation] Ctrough (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 <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 >300 mg, consistent with the Phase IIb MUSE study outcomes.
Conclusions 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.
Furie R, et al. Arthritis Rheumatol. 2017;69:376–86.
Wang B, et al. Clin Pharmacol Ther. 2013;93:483−92.
Acknowledgements Funded by MedImmune. Medical writing support: R. Plant, QXV Comms, an Ashfield company, funded by MedImmune.
Disclosure of Interest 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