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.

Figure 1

Progression of primary hyperoxaluria (PH). Accumulation of calcium oxalate (CaOx) crystals that form stones in the kidneys and bladder is due to the excessive production of oxalate in the liver.

Figure 2

Biosynthesis pathways of oxalate in hepatocytes and pathological formation of PH1, PH2, and PH3 due to genetic mutations in the alanine-glycine aminotransferase (AGXT), glyoxylate reductase (GRHPR), and 4-hydroxy-2-oxoglutarate aldolase (HOGA1) genes, respectively. The overaccumulation of oxalate in the cytosol of hepatocytes is a result of overconversion from glyoxylate by the enzyme lactate dehydrogenase (LDH) encoded by the LDH gene. Deficiency of the AGT enzyme in the peroxisomes caused by the genetic mutations in the AGXT gene results in less conversion of glyoxylate to pyruvate in peroxisomes and more accumulation of oxalate in the cytosol (PH1). Lumasiran is approved to treat PH1 patients by inhibiting the overproduction of glyoxylate from glycolate in peroxisomes through inhibition of the glycolate oxidase (GO) enzyme. Deficiency of glyoxylate reductase (GR) in mitochondria caused by genetic mutations in the GRHPR gene can result in overaccumulation of glyoxylate (PH2). Functional loss of the HOGA1 enzyme in mitochondria encoded by the HOGA1 gene can result in the overaccumulation of glyoxylate (PH3). Nedosiran targets the degradation of the mRNA of LDH and reduces the production of oxalate from all types of PH patients.

Figure 3

Principle of drug action of nedosiran. After subcutaneous administration, nedosiran is transported across the interstitial space into the blood and then to the liver via asialoglycoprotein receptor (ASGPR)-mediated uptake. The GalNAc moiety of nedosiran binds to the ASGPR receptor expressed on the surface of hepatocytes followed by internalization via endocytosis. After endocytosis, nedosiran is trapped in endocytic vesicles, which fuse with endosomes/lysosomes. The GalNAc ligand of nedosiran is then degraded and the double stranded siRNA is slowly released into cytoplasm from endosomes/lysosomes, while ASGPR is recycled to the cell surface. The double-stranded siRNA component of nedosiran is then loaded into the RNA-induced silencing complex (RISC), containing Dicer, transactivating response RNA-binding protein (TRBP), and Argonaute 2 (AGO2), which removes the sense strand. The antisense strand retained in the RISC scans and binds to the complementary sequence in its target LDH mRNA. The RISC utilizes the catalytic slicer activity that degrades LDH mRNA, resulting in less mRNA available for translation. As a result, less LDH enzyme is available to convert glyoxylate to oxalate in hepatocytes and leading to less accumulation of CaOx in the kidneys for the PH progress.

Figure 4

Preclinical studies of nedosiran. (1) In vitro studies demonstrated that nedosiran could effectively reduce production of oxalate by inhibition of LDH. (2) A mouse PH1 model was used to prove the reduction of urinary oxalate (UOx) levels by treatment with nedosiran. (3) Nedosiran treatment with GRHPR-knockdown PH2 mice (HP2 model) showed increased oxalate clearance. (4) Transferability to humans was tested in non-human primates and humanized mice with human hepatocyte replacement.