Anifrolumab dose optimization for LN: Phase II TULIP-LN pharmacometric analysis

Results from a pharmacometric analysis of data from the randomized, double-blind, placebo-controlled phase II TULIP-LN trial (NCT02547922), investigating anifrolumab dosing regimens in patients with lupus nephritis (LN), were published in Clinical Pharmacology & Therapeutics by Almquist et al. Pharmacokinetic (PK; n = 95) and urine protein–creatinine ratio (UPCR; n = 145) analyses were performed. The analyses investigated the impact of a prolonged intensified regimen of anifrolumab on drug exposure, 24-hour UPCR (UPCR24) responses, and patient dropout, thereby guiding dose selection for the ongoing phase III IRIS trial (NCT05138133) of anifrolumab in patients with LN.

Key data: A combined PK–UPCR24–dropout model revealed that each mg/mg reduction in UPCR24 resulted in a 21.0% decrease (95% confidence interval [CI], 18.9–23.0) in linear anifrolumab clearance. Patients with a higher UPCR (2.8 mg/mg vs 0.5 mg/mg) or lower drug exposure (no exposure [NE] vs 21.0 μg/mL) were more likely to discontinue anifrolumab treatment. Simulations demonstrated that only the proposed phase III regimen (6 × 900 mg every 4 weeks [Q4W], then 300 mg thereafter) achieved anifrolumab exposure non-inferior to non-renal systemic lupus erythematosus (SLE), with 37% of patients achieving UPCR24 < 0.5 mg/mg at Week 52 and a reduced dropout rate of approximately one in nine patients. 

Key learning: Pharmacometric modeling of data from the TULIP-LN trial supported selection of a prolonged, intensified anifrolumab regimen (6 × 900 mg Q4W, then 300 mg thereafter) for the ongoing phase III IRIS trial, demonstrating that extended initial high-dose treatment optimizes drug exposure and proteinuria reduction in patients with LN.