Safety and efficacy of small interfering RNA agents (lumasiran) in therapy for primary hyperoxaluria type 1: A systematic review

Introduction. Primary hyperoxaluria type 1 (PH1) is an inherited disorder characterized by excessive oxalate production in the liver, leading to hyperoxaluria, kidney stone formation, nephrocalcinosis, and progressive kidney damage. PH1 is caused by mutations in the AGXT gene, whereas types 2 and 3 are associated with mutations in GRHPR and HOGA1, respectively. Lumasiran, an RNA interference (RNAi)-based therapeutic agent, targets the HAO1 gene (hydroxyacid oxidase 1), thus reducing the levels of glycolate oxidase. This action results in decreased hepatic oxalate production.

Objective. Evaluation of the efficacy, safety, and clinical use of lumasiran in adults and children with genetically confirmed primary hyperoxaluria type 1.

Materials and methods. The systematic review was conducted in accordance with the PRISMA 2020 guidelines. A comprehensive literature search was performed across four databases (PubMed, Scopus, Web of Science, and EMBASE). Studies were selected based on their focus on the use of lumasiran in pediatric or adult patients with genetically confirmed primary hyperoxaluria type 1. The quality and risk of bias were assessed using the Joanna Briggs Institute (JBI) critical appraisal tools. The final analysis included 11 studies: two randomized controlled trials, two prospective single-arm studies, one case series (involving five patients), and six individual clinical case reports involving both pediatric and adult populations.

Discussion. Lumasiran treatment was found to lead to a significant reduction in urinary oxalate (UOx) levels (approximately 60–75%) and plasma oxalate (POx) levels (approximately 30–60%). Patients across all age groups, from infants to adults, exhibited markedly stabilized or improved renal function, alongside reduced progression of nephrocalcinosis. Lumasiran demonstrated a favorable safety profile, with the most common adverse events being mild injection-site reactions. No serious treatment-related adverse events requiring discontinuation of therapy were reported.

Conclusions. By suppressing glycolate oxidase expression, lumasiran has consistently demonstrated significant efficacy in reducing oxalate levels. However, there exist differences in therapeutic approaches for adult patients and infants, as well as in treatment effects based on baseline renal function and dosing regimens. Both pediatric and adult populations showed substantial improvement and normalization of renal function, although infants and patients with advanced chronic kidney disease required dose adjustments. Studies also revealed a greater variability in renal outcomes, particularly regarding the progression of nephrocalcinosis. Although additional large-scale long-term studies are needed, our findings indicate that lumasiran may impede the progression of kidney disease and potentially reduce or delay the need for kidney transplantation in PH1.

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