BACKGROUND AND OBJECTIVES: In the rare disease primary hyperoxaluria type 1, 
overproduction of oxalate by the liver causes kidney stones, nephrocalcinosis, 
kidney failure, and systemic oxalosis. Lumasiran, an RNA interference 
therapeutic, suppresses glycolate oxidase, reducing hepatic oxalate production. 
The objective of this first-in-human, randomized, placebo-controlled trial was 
to evaluate the safety, pharmacokinetic, and pharmacodynamic profiles of 
lumasiran in healthy participants and patients with primary hyperoxaluria type 
1.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This phase 1/2 study was 
conducted in two parts. In part A, healthy adults randomized 3:1 received a 
single subcutaneous dose of lumasiran or placebo in ascending dose groups (0.3-6 
mg/kg). In part B, patients with primary hyperoxaluria type 1 randomized 3:1 
received up to three doses of lumasiran or placebo in cohorts of 1 or 3 mg/kg 
monthly or 3 mg/kg quarterly. Patients initially assigned to placebo crossed 
over to lumasiran on day 85. The primary outcome was incidence of adverse 
events. Secondary outcomes included pharmacokinetic and pharmacodynamic 
parameters, including measures of oxalate in patients with primary hyperoxaluria 
type 1. Data were analyzed using descriptive statistics.
RESULTS: Thirty-two healthy participants and 20 adult and pediatric patients 
with primary hyperoxaluria type 1 were enrolled. Lumasiran had an acceptable 
safety profile, with no serious adverse events or study discontinuations 
attributed to treatment. In part A, increases in mean plasma glycolate 
concentration, a measure of target engagement, were observed in healthy 
participants. In part B, patients with primary hyperoxaluria type 1 had a mean 
maximal reduction from baseline of 75% across dosing cohorts in 24-hour urinary 
oxalate excretion. All patients achieved urinary oxalate levels ≤1.5 times the 
upper limit of normal.
CONCLUSIONS: Lumasiran had an acceptable safety profile and reduced urinary 
oxalate excretion in all patients with primary hyperoxaluria type 1 to 
near-normal levels.
CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Study of Lumasiran in 
Healthy Adults and Patients with Primary Hyperoxaluria Type 1, NCT02706886.