Exposure-Response Analysis for Selection of Optimal Dosage Regimen of Anifrolumab in Patients With Systemic Lupus Erythematosus.

Abstract

OBJECTIVES\nThe randomized, double-blind, phase 2\u2009b MUSE study evaluated the efficacy and safety of the type I interferon receptor antibody anifrolumab (300\u2009mg or 1000\u2009mg every 4\u2009weeks) compared with placebo for 52\u2009weeks in patients with chronic, moderate to severe SLE. Characterizing the exposure-response relationship of anifrolumab in MUSE will enable selection of its optimal dosage regimen in two phase 3 studies in patients with SLE.\n\n\nMETHODS\nThe exposure-response relationship, pharmacokinetics (PK), and SLE Responder Index (SRI[4]) efficacy data were analysed using a population approach. A dropout hazard function was also incorporated into the SRI(4) model to describe the voluntary patient withdrawals during the 1-year treatment period.\n\n\nRESULTS\nThe population PK model found that type I IFN test-high patients, and patients with a higher body weight, had significantly greater clearance of anifrolumab. Stochastic clinical simulations demonstrated that doses <300\u2009mg would lead to a greater-than-proportional reduction in drug exposure owing to type I interferon alpha receptor-mediated drug clearance (antigen-sink effect, more rapid drug clearance at lower concentrations) and suboptimal SRI(4) responses with wider confidence intervals.\n\n\nCONCLUSIONS\nBased on PK, efficacy, and safety considerations, anifrolumab 300\u2009mg every 4\u2009weeks was recommended as the optimal dosage for pivotal phase 3 studies in patients with SLE.