Abstract
PurposePrimary hyperoxaluria type 1 (PH1) is a rare, progressive, genetic disease with limited treatment options. We report the efficacy and safety of lumasiran, an RNA interference therapeutic, in infants and young children with PH1. MethodsThis single-arm, open-label, phase 3 study evaluated lumasiran in patients aged <6 years with PH1 and an estimated glomerular filtration rate >45 mL/min/1.73 m2, if aged ≥12 months, or normal serum creatinine, if aged <12 months. The primary end point was percent change in spot urinary oxalate to creatinine ratio (UOx:Cr) from baseline to month 6. Secondary end points included proportion of patients with urinary oxalate ≤1.5× upper limit of normal and change in plasma oxalate. ResultsAll patients (N = 18) completed the 6-month primary analysis period. Median age at consent was 50.1 months. Least-squares mean percent reduction in spot UOx:Cr was 72.0%. At month 6, 50% of patients (9/18) achieved spot UOx:Cr ≤1.5× upper limit of normal. Least-squares mean percent reduction in plasma oxalate was 31.7%. The most common treatment-related adverse events were transient, mild, injection-site reactions. ConclusionLumasiran showed rapid, sustained reduction in spot UOx:Cr and plasma oxalate and acceptable safety in patients aged <6 years with PH1, establishing RNA interference therapies as safe, effective treatment options for infants and young children.
Highlights
Primary hyperoxaluria type 1 (PH1) is a rare, progressive, autosomal recessive genetic disease characterized by increased hepatic oxalate production caused by a deficiency of the liver peroxisomal enzyme alanine-glyoxylate aminotransferase, encoded by AGXT
We present results from the 6-month primary analysis period of ILLUMINATE-B, a phase 3 trial designed to evaluate the efficacy of lumasiran as measured by changes in spot urinary oxalate (UOx) to creatinine ratio (UOx:Cr) in patients aged 45 mL/min/1.73 m2
Baseline spot urinary oxalate to creatinine ratio (UOx):Cr, plasma oxalate, and plasma glycolate were highest in patients who weighed
Summary
Primary hyperoxaluria type 1 (PH1) is a rare, progressive, autosomal recessive genetic disease characterized by increased hepatic oxalate production caused by a deficiency of the liver peroxisomal enzyme alanine-glyoxylate aminotransferase, encoded by AGXT. Excess oxalate combines with calcium to form crystals, resulting in nephrocalcinosis and nephrolithiasis, leading to progressive kidney disease and kidney failure in many patients. Treatment options for PH1 have been limited to hyperhydration and crystallization inhibitors, as well as pyridoxine for a specific subset of patients with PH1, all with varying degrees of efficacy and tolerability. Despite these interventions, many patients continue to experience serious and life-threatening manifestations of this disease. Liver transplantation corrects the metabolic overproduction of oxalate in patients with PH1 but is associated with significant risks and morbidities, including lifelong immunosuppression.[7]
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