Exposure–response analysis for selection of optimal dosage regimen of anifrolumab in patients with systemic lupus erythematosus. (25th February 2021)

• Record Type: Journal Article
• Authors: Chia, Yen Lin; Santiago, Linda; Wang, Bing; Kuruvilla, Denison; Wang, Shiliang; Tummala, Raj; Roskos, Lorin
• Is Part Of: Rheumatology. Volume 60:Number 12(2021)
• Page Start: 5854
• Page End: 5862
• Publication Date: 2021-02-25
• Subjects: systemic lupus erythematosus and autoimmunity -- clinical trials and methods -- pharmacology -- biological therapies -- study design; Rheumatism -- Periodicals; Rheumatology -- Periodicals; 616.723005
• DOI: 10.1093/rheumatology/keab176
• Languages: English
• ISSNs: 1462-0324

Abstract

Abstract: Objectives: The randomized, double-blind, phase 2 b MUSE study evaluated the efficacy and safety of the type I IFN receptor antibody anifrolumab (300 mg or 1000 mg every 4 weeks) compared with placebo for 52 weeks 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. Methods: The 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. Results: The population PK model found that type I IFNGS–high patients, and patients with a higher body weight, had significantly greater clearance of anifrolumab. Stochastic clinical simulations demonstrated that doses <300 mg would lead to a greater-than-proportional reduction in drug exposure owing to type I IFN alpha receptor-mediated drug clearance (antigen-sink effect, more rapid drug clearance at lower concentrations) and suboptimal SRI(4) responses with wider confidence intervals. Conclusions: Based on PK, efficacy and safety considerations, anifrolumab 300 mg every 4 weeks was recommended as the optimal dosage for pivotal phase 3 studies in patients with SLE.