FC069: Pharmacokinetics and Pharmacodynamics of Lumasiran: Analysis of Four Clinical Studies

Abstract BACKGROUND AND AIMS Primary hyperoxaluria type 1 (PH1) is a rare genetic disorder characterized by hepatic oxalate overproduction that leads to progressive kidney disease. As kidney function declines, oxalate elimination is compromised and plasma oxalate (POx) increases, leading to systemic oxalosis. Lumasiran, an RNA interference therapeutic designed to reduce hepatic oxalate production, is indicated for the treatment of PH1 in all age groups. We describe lumasiran pharmacokinetics (PK) and pharmacodynamics (PD) in patients with PH1 from four clinical studies. METHOD Data from a Phase 1/2 study and three Phase 3 studies of lumasiran (ILLUMINATE-A, B and C) were included in the PK analyses, and data from the ILLUMINATE studies were included in the PD analyses. The studies included patients of all ages with the full spectrum of kidney function, from normal kidney function to patients with severely impaired kidney function or on hemodialysis (HD). Patients received weight-based dosing of subcutaneous lumasiran. PD parameters of efficacy included spot urinary oxalate: creatinine (UOx: Cr) and POx. Target engagement was evaluated using plasma glycolate. RESULTS A total of 90 patients were included, 15 of whom were on HD. Median (range) age was 11 (2‒60) years, median (range) body weight was 34 (5‒121) kg, and median (range) eGFR in patients not on HD was 85 (9‒174) mL/min/1.73 m2. In patients with normal to moderately impaired kidney function, on Day 1, the recommended dose regimen for lumasiran led to comparable plasma concentration and exposure across body weight categories. Median Cmax (ng/mL) was 890, 912, and 446 in the < 10, 10 to < 20, and ≥20 kg weight categories, respectively. Median AUC0-last (h*ng/mL) was 6270, 8110, and 6210 in the same weight categories. Patients weighing <20 kg exhibited faster plasma clearance, consistent with allometric principles. In patients with severely impaired kidney function or on HD, on Day 1, plasma concentrations of lumasiran were slightly increased compared to patients with normal to moderately impaired kidney function. Median Cmax (ng/mL) was 3190, 2670, and 811 in the < 10, 10 to < 20, and ≥20 kg weight categories, respectively. Median AUC0-last (h*ng/mL) was 16 200, 24 800, and 10 100 in the same weight categories. At 24 h postdose, many patients had lumasiran plasma concentrations below the lower limit of quantitation, indicating rapid liver uptake, regardless of kidney function. Mean % reduction in spot UOx: Cr at Month 6 ranged from 44.1 to 71.7% across studies. Mean % reduction in POx at Month 6 ranged from 20.3 to 40.3% across studies. The time course and persistence of reduction in spot UOx: Cr and POx were similar across the studies. Plasma glycolate levels showed an approximately 2-fold elevation at Month 6, consistent with the mechanism of action of lumasiran, suggesting comparable liver exposure and target engagement across studies. CONCLUSION The recommended weight-based dosing regimens of lumasiran achieved comparable target engagement and efficacy for patients of all ages and degrees of kidney function, including patients on HD.