Nedosiran, a Candidate siRNA Drug for the Treatment of Primary Hyperoxaluria: Design, Development, and Clinical Studies

Abstract

Due to the lack of treatment options for the genetic disease primary hyperoxaluria (PH), including three subtypes PH1, PH2, and PH3, caused by accumulation of oxalate forming kidney stones, there is an urgent need for the development of a drug therapy aside from siRNA drug lumasiran for patients with PH1. After the recent success of drug therapies based on small interfering RNA (siRNA), nedosiran is currently being developed for the treatment of three types of PH as a siRNA-based modality. Through specific inhibition of lactate dehydrogenase enzyme, the key enzyme in biosynthesis of oxalate in liver, phase 1, 2, and 3 clinical trials of nedosiran have achieved the desired primary end point of reduction of urinary oxalate levels in patients with PH1. More PH2 and PH3 patients need to be tested for efficacy. It has also produced a favorable secondary end point on safety and toxicity in PH patients. In addition to common injection site reactions that resolved spontaneously, no severe nedosiran treatment-associated adverse events were reported. Based on the positive results in the clinical studies, nedosiran is a candidate siRNA drug to treat PH patients.

Inclisiran—Safety and Effectiveness of Small Interfering RNA in Inhibition of PCSK-9

“…In studies, vutrisiran significantly improved many disease-relevant outcomes compared to placebo, with an acceptable safety profile [ 77 ]. Research is underway to introduce further siRNA drugs—nedosiran, fitusiran, tivanisiran, and olpasiran [ 78 , 79 , 80 , 81 ].…”

Leveraging Prior Knowledge to Support Early Phase Clinical Trial Applications: Regulatory CMC Considerations and Case Studies

“…Dicerna Pharmaceuticals, Inc. (a Novo Nordisk company) has developed an siRNA platform technology consisting of a sense strand (passenger strand) and an antisense strand (guide strand) hybridized together to form a duplex siRNA drug substance (Figure ). The sense strand contains the multivalent GalNAc ligands that bind to the asialoglycoprotein receptor (ASGPR) that internalizes and delivers the siRNA into the endosome and ultimately cytoplasm where the sense strand is unwound, released, and degraded. The antisense strand loads into argonaute 2 (Ago2) to form the RNA-induced silencing complex (RISC) and the RISC/antisense strand complex binds to degrade the target mRNA .…”

“… The sense strand contains the multivalent GalNAc ligands that bind to the asialoglycoprotein receptor (ASGPR) that internalizes and delivers the siRNA into the endosome and ultimately cytoplasm where the sense strand is unwound, released, and degraded. The antisense strand loads into argonaute 2 (Ago2) to form the RNA-induced silencing complex (RISC) and the RISC/antisense strand complex binds to degrade the target mRNA . The arrangement of the chemical modifications of the nucleotide sequence in the drug substance has been selected to increase nuclease resistance, reduce recognition by the innate immune system, and promote efficient loading of the antisense strand into the RNA-induced silencing complex.…”

A Policy Call to Address Rare Kidney Disease in Health Care Plans

“…There have been therapeutic advances for some conditions, such as atypical hemolytic uremic syndrome, 19 lupus nephritis, 20 cystinosis, 21 membranous nephropathy, 22 primary hyperoxaluria, 23 and autosomal dominant polycystic kidney disease, 24 while other approaches are under consideration. [25][26][27] However, much more rare kidney diseases face therapeutic challenges, while currently accepted therapies may show differences in efficacy per individual patient, highlighting the need for more funding and investments in innovative therapies.…”