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

KEY POINTS: Primary hyperoxaluria type 1 is a genetic disorder associated with hepatic oxalate overproduction, kidney failure, and systemic oxalosis. Lumasiran treatment for up to 60 months was associated with sustained reductions in urinary and plasma oxalate and encouraging clinical outcomes. Lumasiran's safety profile was acceptable with mild injection site reactions being the most common adverse events.

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 6-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, eGFR ≥30 ml/min per 1.73 m 2 , and mean 24-hour urinary oxalate (UOx) excretion ≥0.70 mmol/24 h per 1.73 m 2 .

RESULTS

Of 39 patients enrolled, 24 of 26 randomized to lumasiran in the 6M DB (lumasiran/lumasiran group) and 13 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, the mean (SEM) 24-hour UOx percentage reductions were 54 (6) and 54% (8%) in the lumasiran/lumasiran and placebo/lumasiran groups, respectively, and the mean (SEM) plasma oxalate concentrations had decreased by 35 (5) and 38% (7%). eGFR 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, 0.36 to 0.62) and 0.54 (0.37 to 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 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, 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 health-related quality of life.Clinical Trial registry name and registration number: ClinicalTrials.gov NCT03681184 .