Identification
- Summary
Nedosiran is an antisense oligonucleotide used to treat primary hyperoxaluria type 1 in adults and high oxalate levels in children
- Brand Names
- Rivfloza
- Generic Name
- Nedosiran
- DrugBank Accession Number
- DB17635
- Background
Nedosiran is an RNA interference targeting hepatic lactate dehydrogenase, the enzyme responsible for the conversion of glyoxylate to oxalate.2 Oxalate, particularly calcium oxalate, precipitation is the main cause of kidney stones formation; therefore, blocking the production of oxalate can help alleviate renal symptoms.1
Nedosiran was approved by the FDA on October 2nd, 2023, under the brand name RIVFLOZA to lower urinary oxalate levels in children 9 years of age and older and adults with primary hyperoxaluria type 1 (PH1) and relatively preserved kidney function. This approval is based on the favorable results from the pivotal phase 2 PHYOXTM2 and interim data from the ongoing phase 3 PHYOXTM3 clinical trials.4
- Type
- Biotech
- Groups
- Approved, Investigational
- Biologic Classification
- Gene Therapies
Antisense oligonucleotides - Synonyms
- DCR-PHXC free acid
- Nedosiran
Pharmacology
- Indication
RIVFLOZA is indicated to lower urinary oxalate levels in children 9 years of age and older and adults with primary hyperoxaluria type 1 (PH1) and relatively preserved kidney function, e.g., eGFR ≥ 30 mL/min/1.73 m2.3
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Treatment of Primary hyperoxaluria type 1 (ph1) •••••••••••• ••••• •••• • •• ••••••••••• •• ••••••••• Prevention of Urine oxalate increased •••••••••••• •••••••• ••••••••• - Contraindications & Blackbox Warnings
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The pharmacodynamic effects of nedosiran were evaluated after single-dose and monthly-dose administration in patients with PH1. Dose-dependent reductions in urinary oxalate were observed in the single-dose range of 1.5 mg/kg to 6.0 mg/kg. With the recommended monthly dose regimen of nedosiran, the onset of the effect was observed at the first measurement (30 days after the first dose) and the effect persisted with continued monthly dosing.3
At the recommended dose, nedosiran does not lead to clinically relevant QT interval prolongation.3
- Mechanism of action
Nedosiran is a double-stranded siRNA, conjugated to GalNAc aminosugar residues. After subcutaneous administration, the GalNAc-conjugated sugars bind to asialoglycoprotein receptors (ASGPR) to deliver nedosiran to hepatocytes.3
Nedosiran reduces levels of hepatic lactate dehydrogenase (LDH) via the degradation of LDHA messenger ribonucleic acid (mRNA) in hepatocytes through RNA interference. The reduction of hepatic LDH by nedosiran reduces the production of oxalate by the liver, thereby reducing subsequent oxalate burden.3
Target Actions Organism UL-lactate dehydrogenase A chain antisense oligonucleotideHumans - Absorption
Nedosiran exhibited a dose-proportional increase in plasma exposure following single subcutaneous doses from 1.5 to 6.0 mg/kg.3
Nedosiran exhibited time-independent pharmacokinetics with multiple doses of 160 mg once monthly (body weight ≥ 50 kg), 128 mg once monthly (body weight < 50 kg), or 3.3 mg/kg once monthly in the age range of 6 to 11 years.3
Other pharmacokinetic parameters like Cmax, AUC0-last, and Tmax were calculated to be 844 ng/mL, 13600 ng*h/mL, and 6 hours respectively.3
- Volume of distribution
The volume of distribution was calculated to be 126 L.3
- Protein binding
The protein binding of nedosiran was estimated to be 85.6%.3
- Metabolism
As an antisense oligonucleotide, nedosiran is expected to be metabolized by endo- and exonucleases to shorter oligonucleotides.3
- Route of elimination
Approximately 27% of the administered nedosiran dose is excreted unchanged into the urine within 24 hours of dosing.3
- Half-life
The half-life of nedosiran was estimated to be 15 hours.3
- Clearance
The clearance of nedosiran was calculated to be 5.7 L/hr.3
- Adverse Effects
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In mice, subcutaneous administration of nedosiran at doses up to 2000 mg/kg/dose (approximately 58 times the maximum recommended human dose (MRHD) based on body surface area (BSA)) or a mouse-specific (pharmacologically active) analog (10 mg/kg/dose) during organogenesis (dosing on gestation days 6, 8, 10, 12, and 14 for nedosiran; gestation days 3 and 10 for the analog) did not have adverse effects on embryofetal development.3
Subcutaneous administration of nedosiran (0, 2, 6, or 20 mg/kg/dose) to pregnant rabbits during organogenesis (dosing on gestation days 7, 9, 11, 13, 15, 17, and 19) resulted in maternal toxicity on the basis of body weight loss of up to 6.5% following the first dose in the 6 and 20 mg/kg/dose groups. Higher post-implantation loss and lower numbers of live fetuses occurred at ≥ 6 mg/kg/dose (exposures equivalent to the MRHD based on BSA), and fetal cardiovascular and skeletal malformations occurred at the 20 mg/kg/dose (2 times the MRHD based on BSA). No adverse findings were seen at the 2 mg/kg/dose, which is below the MRHD.3
In a pre-and postnatal study in mice, subcutaneous administration of nedosiran (0, 250, 500, or 1000 mg/kg/dose) or a mouse-specific (pharmacologically active) analog (10 mg/kg/dose) from implantation (dosing on gestational days 6, 8, 10, 12, 14, 16) to weaning (dosing on lactation days 1, 8 15, 20) did not have adverse effects on the growth, viability, development and reproductive performance of the offspring.3
Long-term studies to assess the carcinogenic risk of nedosiran have not been conducted.3
Nedosiran was not genotoxic in the in vitro bacterial mutagenicity, in vitro micronucleus assays (human peripheral blood lymphocytes), and in vivo bone marrow micronucleus assay in mice.3
Weekly subcutaneous administration of nedosiran at doses of 500, 1000, or 2000 mg/kg or of a mouse-specific (pharmacologically active) analog at a dose of 10 mg/kg to male mice for 4 weeks prior to and throughout mating, and to female mice for 2 weeks prior to and throughout mating and to gestation day 7 did not affect male or female fertility or early embryonic development.3
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.Not Available
- Food Interactions
- No interactions found.
Products
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Ingredient UNII CAS InChI Key Nedosiran sodium EGR9KYM536 Not Available Not applicable - Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Rivfloza Injection, solution 128 mg/0.8mL Subcutaneous Novo Nordisk 2024-02-19 Not applicable US 
Rivfloza Injection, solution 160 mg/1mL Subcutaneous Novo Nordisk 2024-02-19 Not applicable US Rivfloza Injection, solution 80 mg/0.5mL Subcutaneous Novo Nordisk 2024-02-19 Not applicable US
Categories
- Drug Categories
- Not Available
- Classification
- Not classified
- Affected organisms
- Not Available
Chemical Identifiers
- UNII
- 13U9R5J3WL
- CAS number
- 2266591-83-5
References
- General References
- Khan SR, Pearle MS, Robertson WG, Gambaro G, Canales BK, Doizi S, Traxer O, Tiselius HG: Kidney stones. Nat Rev Dis Primers. 2016 Feb 25;2:16008. doi: 10.1038/nrdp.2016.8. [Article]
- Liu A, Zhao J, Shah M, Migliorati JM, Tawfik SM, Bahal R, Rasmussen TP, Manautou JE, Zhong XB: Nedosiran, a Candidate siRNA Drug for the Treatment of Primary Hyperoxaluria: Design, Development, and Clinical Studies. ACS Pharmacol Transl Sci. 2022 Sep 21;5(11):1007-1016. doi: 10.1021/acsptsci.2c00110. eCollection 2022 Nov 11. [Article]
- FDA Approved Drug Products: RIVFLOZA (nedosiran) injection, for subcutaneous use [Link]
- FDA approves Rivfloza™ for children ≥9 years old and adults living with primary hyperoxaluria type 1 (PH1), a rare genetic condition [Link]
- External Links
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 3 Enrolling by Invitation Treatment Genetic Disease / Kidney Diseases / Primary Hyperoxaluria Type 1 (PH1) / Primary Hyperoxaluria Type 2 (PH2) / Primary Hyperoxaluria Type 3 (PH3) / Urological Diseases 1 2 Completed Treatment Genetic Disease / Kidney Diseases / Primary Hyperoxaluria Type 1 (PH1) / Primary Hyperoxaluria Type 2 (PH2) / Urological Diseases 1 2 Recruiting Treatment End Stage Renal Disease (ESRD) / Primary Hyperoxaluria Type 1 (PH1) / Primary Hyperoxaluria Type 2 (PH2) 1 2 Recruiting Treatment Primary Hyperoxaluria / Primary Hyperoxaluria Type 1 (PH1) / Primary Hyperoxaluria Type 2 (PH2) / Primary Hyperoxaluria Type 3 (PH3) 1 1 Completed Treatment Primary Hyperoxaluria Type 3 (PH3) 1
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Injection, solution Subcutaneous 128 mg/0.8mL Injection, solution Subcutaneous 160 mg/1mL Injection, solution Subcutaneous 80 mg/0.5mL - Prices
- Not Available
- Patents
Patent Number Pediatric Extension Approved Expires (estimated) Region US11661604 No 2018-10-12 2038-10-12 US US11359203 No 2015-10-09 2035-10-09 US US11286488 No 2018-10-12 2038-10-12 US US10738311 No 2020-08-11 2035-10-09 US US11053502 No 2021-07-06 2035-10-29 US US10351854 No 2019-07-16 2035-10-09 US
Properties
- State
- Liquid
- Experimental Properties
Property Value Source water solubility Freely soluble FDA Label
Targets
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Antisense oligonucleotide
- General Function
- Nad binding
- Specific Function
- Not Available
- Gene Name
- LDHA
- Uniprot ID
- P00338
- Uniprot Name
- L-lactate dehydrogenase A chain
- Molecular Weight
- 36688.465 Da
References
- Goldfarb DS, Lieske JC, Groothoff J, Schalk G, Russell K, Yu S, Vrhnjak B: Nedosiran in primary hyperoxaluria subtype 3: results from a phase I, single-dose study (PHYOX4). Urolithiasis. 2023 Apr 28;51(1):80. doi: 10.1007/s00240-023-01453-3. [Article]
- FDA Approved Drug Products: RIVFLOZA (nedosiran) injection, for subcutaneous use [Link]
Drug created at April 17, 2023 20:45 / Updated at February 27, 2024 23:52