Nedosiran

Nedosiran – Description

• Nedosiran is a subcutaneously administered lactate dehydrogenase A-directed small interfering ribonucleic acid (siRNA) indicated for the treatment of primary hyperoxaluria type 1 (PH1) in individuals with relatively preserved kidney function (e.g., eGFR of 30 mL/minute/1.73 m² or more) to lower urinary oxalate concentrations.⁶⁹⁵⁷¹ 
• PH1 is an autosomal recessive disease caused by mutations in the AGXT gene that encodes the hepatic peroxisomal enzyme alanine-glyoxylate aminotransferase (AGT). Defects in the AGT enzyme increase glyoxylate and oxalate production. An increase in oxylate production leads to the development of kidney stones and nephrocalcinosis due to low solubility when it combines with calcium in the kidney.
• Symptoms and age at diagnosis of PH1 vary from severe forms that present in infants and lead to kidney failure during the first months of life to forms that present in adults with moderate to advanced chronic kidney disease, including kidney failure, nephrocalcinosis, and recurrent bilateral kidney stones.⁶⁹⁵⁹³ 
• The efficacy and safety of nedosiran were established in a double-blind, placebo-controlled trial in 35 patients 6 years and older with primary hyperoxaluria type 1 (PH1) or type 2 (PH2). The primary endpoint was the percent change from baseline in 24-hour urinary oxalate excretion, measured by the area under the curve (AUC) from days 90 to 180.
• The least-squares mean AUC was 3,507 (95% CI: 1,962 to 5,053) in the nedosiran group, compared to -1,664 (95% CI: -3,397 to -668) in the placebo group, with a between-group difference of 5,172 (95% CI: 2,929 to 7,414; p less than 0.001).
• The reduction in urinary oxalate was maintained in 13 patients with PH1 who received an additional 6 months of nedosiran treatment.^6957169592 
• Additionally, in a single-arm, open-label, multicenter study involving 15 pediatric patients 2 to 11 years with PH1, nedosiran treatment resulted in a 64% (95% CI: 44 to 84) reduction in spot urinary oxalate: creatinine ratio from baseline at month 6, with an absolute reduction of 0.25 mmol/mmol (95% CI: 0.21 to 0.29).
• This reduction was maintained in 8 patients who received an additional 6 months of nedosiran treatment. Nedosiran has not been studied in individuals with severe renal impairment or moderate to severe hepatic impairment.⁶⁹⁵⁷¹

Indications & Dosage

•  primary hyperoxaluria type 1

For the treatment of primary hyperoxaluria type 1

Note: Nedosiran has been designated as an orphan drug for this indication by the FDA.

Subcutaneous dosage

Adults weighing 50 kg or more:

160 mg subcutaneously once monthly.⁶⁹⁵⁷¹

Adults weighing less than 50 kg:

128 mg subcutaneously once monthly.⁶⁹⁵⁷¹

Children and Adolescents 12 to 17 years weighing 50 kg or more:

160 mg subcutaneously once monthly.⁶⁹⁵⁷¹

Children and Adolescents 12 to 17 years weighing less than 50 kg:

128 mg subcutaneously once monthly.⁶⁹⁵⁷¹

Children 2 to 11 years weighing 50 kg or more:

160 mg subcutaneously once monthly.⁶⁹⁵⁷¹

Children 2 to 11 years weighing 39 to 49 kg:

128 mg subcutaneously once monthly.⁶⁹⁵⁷¹

Children 2 to 11 years weighing less than 39 kg:

3.3 mg/kg/dose subcutaneously once monthly.⁶⁹⁵⁷¹

Maximum Dosage Limits:

•Adults

weighing 50 kg or more: 160 mg/month subcutaneously.

weighing less than 50 kg: 128 mg/month subcutaneously.

•Geriatric

weighing 50 kg or more: 160 mg/month subcutaneously.

weighing less than 50 kg: 128 mg/month subcutaneously.

•Adolescents

weighing 50 kg or more: 160 mg/month subcutaneously.

weighing less than 50 kg: 128 mg/month subcutaneously.

•Children

12 years weighing 50 kg or more: 160 mg/month subcutaneously.

12 years weighing less than 50 kg: 128 mg/month subcutaneously.

2 to 11 years weighing 50 kg or more: 160 mg/month subcutaneously.

2 to 11 years weighing 39 to 49 kg: 128 mg/month subcutaneously.

2 to 11 years weighing less than 39 kg: 3.3 mg/kg/month subcutaneously.

younger than 2 years: Safety and efficacy have not been established.

•Infants

Safety and efficacy have not been established.

•Neonates

Safety and efficacy have not been established.

Patients with Hepatic Impairment Dosing

No dosage adjustment is recommended for persons with mild hepatic impairment (total bilirubin of the upper limit of normal (ULN) or less and aspartate aminotransferase (AST) more than ULN or total bilirubin more than 1 to 1.5 times ULN and any AST elevation). Nedosiran has not been studied in persons with moderate or severe hepatic impairment (total bilirubin more than 1.5 times ULN and any AST).⁶⁹⁵⁷¹

Precautions

•  breast-feeding
•  pregnancy

Interactions

There are no drug interactions associated with Nedosiran products.

Adverse Reactions

•  erythema
•  injection site reaction
•  rash
•  skin atrophy

Mechanism of Action

Nedosiran is a double-stranded small interfering ribonucleic acid (siRNA) that is conjugated to GalNAc aminosugar residues. The GalNAc-conjugated sugars bind to asialoglycoprotein receptors (ASGPR) to deliver nedosiran to hepatocytes after subcutaneous administration. Nedosiran reduces concentrations of hepatic lactate dehydrogenase (LDH) by the degradation of lactate dehydrogenase A (LDHA) messenger ribonucleic acid (mRNA) in hepatocytes through RNA interference. The reduction of hepatic LDH by nedosiran decreases the production of oxalate by the liver and leads to a reduction in oxalate burden.⁶⁹⁵⁷¹

Monitoring Parameters

Monitoring Parameters

•  laboratory monitoring not necessary

Classifications

• Alimentary Tract and Metabolism
  • Metabolic Disorder Agents
    •  Primary Hyperoxaluria Type 1 (PH1) Agents

References

69571.Rivfloza (nedosiran) injection package insert. Costa Mesa, CA: Pyramid Laboratories; 2025 Mar.

69592.Baum MA, Langman C, Cochat P, et al. PHYOX2: a pivotal randomized study of nedosiran in primary hyperoxaluria type 1 or 2. Kidney Int 2023;103:207-17.

69593.Bacchetta J, Lieske JC. Primary hyperoxaluria type 1: novel therapies at a glance. Clin Kidney J 2022;15:i17-i22.