Anifrolumab Dose Regimen Selection for a Phase 3 Trial in Lupus Nephritis.

In patients with systemic lupus erythematosus (SLE), increased type I interferon signaling is associated with increased disease activity across organs, including in the kidney, which can cause lupus nephritis (LN). Anifrolumab, which abrogates type I interferon signaling, is an approved treatment for moderate to severe SLE. In a phase 2 trial in patients with LN (TULIP-LN; NCT02547922), promising clinical benefit was observed with an intensified regimen (IR) of intravenous anifrolumab (3× 900 mg Q4W, 300 mg thereafter) compared with the approved SLE dose (basic regimen [BR], 300 mg Q4W). Anifrolumab clearance was greater with higher levels of proteinuria; however, the quantitative relationship between proteinuria and anifrolumab exposure was not fully characterized. Here, we describe a mathematical model of time-varying anifrolumab pharmacokinetics, 24-hour urine protein-creatinine ratio (UPCR24), and investigational product discontinuation in patients with LN. The model evaluated both TULIP-LN anifrolumab dosing regimens (IR and BR) and revealed a temporal association between clearance and proteinuria in patients with LN, with each mg/mg UPCR reduction resulting in a 21% decrease in linear anifrolumab clearance. Our model indicated that an intensified regimen including 6 initial anifrolumab 900 mg doses provided adequate exposure and rapid UPCR24 reduction. Higher anifrolumab exposure and reduced UPCR24 were each associated with decreased risk of treatment discontinuation. These model results guided the selection of an optimized, longer intensified anifrolumab dosing regimen (6× 900 mg Q4W, 300 mg thereafter) for the ongoing phase 3 IRIS trial (NCT05138133).