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.
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.
Authors: David Jayne; Brad Rovin; Eduardo F Mysler; Richard A Furie; Frederic A Houssiau; Teodora Trasieva; Jacob Knagenhjelm; Erik Schwetje; Yen Lin Chia; Raj Tummala; Catharina Lindholm Journal: Ann Rheum Dis Date: 2022-02-10 Impact factor: 27.973
Authors: Yen Lin Chia; Raj Tummala; Tu H Mai; Tomas Rouse; Katie Streicher; Wendy I White; Eric F Morand; Richard A Furie Journal: J Clin Pharmacol Date: 2022-05-21 Impact factor: 2.860