Background/Purpose: Anifrolumab is a fully human IgG₁ monoclonal antibody directed against subunit 1 of the type I interferon–α receptor (IFNAR1) currently in development for the treatment of systemic lupus erythematosus (SLE). An exposure-response (E-R) model was developed to support the rational dosage selection for the pivotal anifrolumab studies.

Methods: In the Phase IIb MUSE study (NCT01438489),¹ adult patients with seropositive moderate to severe SLE, who had inadequate responses to standard-of-care (SOC) medications, were randomized 1:1:1 to receive anifrolumab 300 or 1,000 mg or placebo intravenously every 4 weeks, in addition to SOC medications, for 48 weeks. Patients were stratified by interferon (IFN) test status as IFN high or IFN low based on a validated 4-gene expression assay, dosage of oral corticosteroid (<10 or ≥10 mg/day of prednisone or equivalent), and SLEDAI−2K score (<10 or ≥10) at screening. A mechanistic target-mediated drug disposition model, previously developed for a first-in-human study in scleroderma patients,² 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 introduced to describe the voluntary patient withdrawals during the treatment period. Clinical simulations were conducted to evaluate different dosing scenarios in patients with SLE.

Results: There was no PK difference between patients classified as IFN high or IFN low. SRI(4) modeling suggested there was no treatment effect of anifrolumab in IFN-low patients, although the interpretation of this result could be limited by the small sample size. In IFN-high patients, a log-linear logistic model was selected to describe the treatment effect of anifrolumab. Patient dropouts were more likely in nonresponders. Clinical simulations demonstrated dosages less than 300 mg would result in inadequate PK exposure and suboptimal efficacy in some patients with SLE. In contrast, simulations indicated minimal improvement in efficacy for dosages higher than 300 mg, consistent with the outcome observed in the Phase IIb MUSE study.

Conclusion: Based on E-R analyses and overall risk assessment, an every-4-week 300-mg intravenous dosage regimen is recommended for pivotal anifrolumab trials in patients with SLE. References: ¹Furie R et al. Arthritis Rheumatol 2015;67(Suppl 10):Abs 3223. ²Wang B et al. Clin Pharmacol Ther 2013;93(6):483-92.