Primary hyperoxaluria type 1 (PH1) is a rare metabolic disease that leads to oxalate overproduction and results in kidney stones, nephrocalcinosis, kidney failure, and eventually systemic oxalosis. Garrelfs et al. (1) recently published results of the multinational, randomized, double-blind, placebo-controlled ILLUMINATE-A clinical trial evaluating the effectiveness of treating PH1 with lumasiran, an RNA interference (RNAi) agent directed against the mRNA encoding glycolate oxidase in the liver. The trial included 39 participants with PH1, ages 6-60 years (median age 14 years, including 22 pediatric participants), with an estimated glomerular filtration rate (eGFR) greater than or equal to 30 mL/min/1.73 m2, 26 of whom were randomized to lumasiran treatment. After 6 months of treatment, the least-squares mean percent change in 24-hour urinary oxalate excretion decreased 65.4% in the lumasiran group compared to 11.8% in the placebo group. Moreover, 84% of patients in the lumasiran group had 24-hour urinary oxalate levels no higher than 1.5 times the upper limit of normal compared to 0% of patients in the placebo group (p < 0.001). The most common side effect of lumasiran was injection-site reactions (38%), and no severe or serious adverse events occurred. Lumasiran is the first US Food and Drug Administration (FDA)-approved specific treatment for patients with PH1. Lumasiran has not been tested in other genetic forms of PH1 and would not be expected to be efficacious in secondary hyperoxaluria.
Prior to lumasiran, treatment strategies for PH1 focused on preventing oxalate stone formation and slowing disease progression and included hyperhydration, high-dose pyridoxine, and citrate. Despite these burdensome treatments, patients with PH1 often experienced progressive kidney failure. Liver transplant is curative, and patients often receive combined liver and kidney transplants after kidney failure. However, organ transplantation carries many periand post-operative risks, and many patients and their families experience transplantation as trading one disease for another. The findings of the ILLUMINATE-A clinical trial offer an apparently safe and effective subcutaneous treatment with the opportunity to improve both disease control and quality of life in patients with PH1.
Garrelfs SF, et al. Lumasiran, an RNAi therapeutic for primary hyperoxaluria type 1. N Engl J Med 2021; 384:1216–1226. doi: 10.1056/NEJMoa2021712