Final Results of the ILLUMINATE-A Phase 3 Clinical Trial of Lumasiran for Primary Hyperoxaluria 1

Background Primary hyperoxaluria type 1 (PH1) is characterized by hepatic oxalate overproduction, kidney stones, and progressive kidney disease. Lumasiran is the first approved treatment for PH1. Methods ILLUMINATE-A (NCT03681184) was a 60-month pivotal, phase 3, multinational clinical trial of lumasiran which consisted of a six-month double-blind, placebo-controlled period (6M DB) followed by a treatment extension period of up to 54 months in which all patients received lumasiran. Eligible patients were aged ≥6 years with genetically confirmed PH1, estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73m 2 , and mean 24-hour urinary oxalate (UOx) excretion ≥0.70 mmol/24h/1.73m 2 . Results Of 39 patients enrolled, 24 out of 26 randomized to lumasiran in the 6M DB (lumasiran/lumasiran group) and 13 out of 13 randomized to placebo in the 6M DB (placebo/lumasiran group) completed the study. Sustained reductions in 24-hour UOx were observed in both treatment groups. At Month 60 relative to study baseline, mean (standard error of the mean SEM) 24-hour UOx percentage reductions were 54% (6%) and 54% (8%) in the lumasiran/lumasiran and placebo/lumasiran groups, respectively, and mean (SEM) plasma oxalate concentrations had decreased by 35% (5%) and 38% (7%). Estimated glomerular filtration rate remained stable through the end of the study in both treatment groups. Kidney stone event rates during the study were 0.47 (95% confidence interval CI, 0.36, 0.62) and 0.54 (0.37, 0.78) per patient-year in the lumasiran/lumasiran group and placebo/lumasiran group, respectively. Medullary nephrocalcinosis grade improved at the end of the study in 21 out of 28 (75%) patients with nephrocalcinosis at baseline and an end of study assessment. The safety profile of lumasiran was acceptable. Injection site reactions were the most common adverse events during lumasiran treatment. Most adverse events were mild or moderate in severity. Conclusions Lumasiran treatment for up to 60 months in ILLUMINATE-A was associated with sustained reductions in UOx excretion and plasma oxalate concentration, and encouraging clinical outcomes including stable eGFR in a population that would be expected to show eGFR decline, reduced kidney stone event rates, improved medullary nephrocalcinosis, and indications of improved quality of life.