Nedosiran (Rivfloza)

Number: 1047

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses nedosiran (Rivfloza) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Rivfloza has been identified as an Aetna Gene-based, Cellular & Other Innovative Therapies (GCIT®) product that receives dedicated review by the Aetna GCIT team for Commercial lines of business.

Note: Requires Precertification: 

Precertification of nedosiran (Rivfloza) is required of all Aetna participating providers and members in applicable plan designs. For precertification of nedosiran (Rivfloza), call (866) 752-7021, or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see Specialty Pharmacy Precertification. 

Note: Site of Care Utilization Management Policy applies. For information on site of service for Rivfloza, see Utilization Management Policy on Site of Care for Specialty Drug Infusions. 

1. Prescriber Specialties

   This medication must be prescribed by or in consultation with a geneticist, nephrologist, or urologist.

2. Criteria for Initial Approval

   Aetna considers nedosiran (Rivfloza) medically necessary for the treatment of primary hyperoxaluria type 1 (PH1) when all of the following criteria are met:

   1. Member is 2 years of age or older; and
   2. Member has a diagnosis of PH1 confirmed by either of the following:
      
      
      1. Molecular genetic test results demonstrating a pathogenic variant in the alanine:glyoxylate aminotransferase (AGXT) gene; or
      2. Liver enzyme analysis results demonstrating absent or significantly reduced alanine:glyoxylate aminotransferase (AGT) activity; and
   3. Member has elevated urinary oxalate, urinary oxalate:creatinine ratio, or plasma oxalate levels prior to initiating therapy with the requested medication, per laboratory performing the test; and
   4. Member has relatively preserved kidney function (e.g., eGFR of greater than or equal to 30 mL/min/1.73 m²); and
   5. Member has not previously received a liver transplant; and
   6. The requested medication will not be used in combination with lumasiran (Oxlumo).

   Aetna considers all other indications as experimental, investigational, or unproven.

3. Continuation of Therapy

   Aetna considers continuation of nedosiran (Rivfloza) therapy medically necessary for members who meet all initial authorization criteria and demonstrate a positive response to therapy (e.g., decrease or normalization in urinary and/or plasma oxalate levels, improvement in kidney function).

4. Related Policies 

   1. CPB 0983 - Lumasiran (Oxlumo)

Dosage and Administration

Rivfloza injection 160 mg/mL is available as follows:

• 80 mg (0.5 mL) single-dose vial
• 128 mg (0.8 mL) single-dose pre-filled syringe
• 160 mg (1 mL) single-dose pre-filled syringe.

A healthcare professional, caregiver, or person 12 years of age and older may inject Rivfloza using the pre-filled syringe. In pediatrics 2 to 11 years of age who weigh 39 kg or more, a healthcare professional or caregiver may inject Rivfloza using the pre-filled syringe.

Primary Hyperoxaluria Type 1

Per the label for Rivfloza, the recommended dosage is based on actual body weight and administered as a subcutaneous injection once monthly.

Table: Recommended Dosage of Rivfloza as Subcutaneous Injection for Persons 2 years of Age or Older

Age	Body Weight	Dosing Regimen
Adults and adolescents 12 years and older	Greater than or equal to 50 kg	160 mg once monthly
	Less than 50 kg	128 mg once monthly
Children 2 to 11 years	50 kg and above	160 mg once monthly
	39 kg to less than 50 kg	128 mg once monthly
	Less than 39 kg	3.3 mg/kg once monthly

Source: Dicerna Pharmaceuticals, Inc., 2025

Experimental, Investigational, or Unproven

Aetna considers nedosiran (Rivfloza) experimental, investigational, or unproven for treatment of primary hyperoxaluria type 2 (PH2) and primary hyperoxaluria type 3 (PH3).

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Other CPT codes related to the CPB:
Alanine:glyoxylate aminotransferase (AGXT) gene test – no specific code
0259U	Nephrology (chronic kidney disease), nuclear magnetic resonance spectroscopy measurement of myo-inositol, valine, and creatinine, algorithmically combined with cystatin C (by immunoassay) and demographic data to determine estimated glomerular filtration rate (GFR), serum, quantitative
0602T	Glomerular filtration rate (GFR) measurement(s), transdermal, including sensor placement and administration of a single dose of fluorescent pyrazine agent
0603T	Glomerular filtration rate (GFR) monitoring, transdermal, including sensor placement and administration of more than one dose of fluorescent pyrazine agent, each 24 hours
80069	Renal function panel
82540	Creatine
82565	blood
82570	other source
82575	clearance
83945	Oxalate
84460	Transferase; alanine amino (ALT) (SGPT)
96372	Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular
HCPCS codes covered if selection criteria are met :
Nedosiran (Rivfloza) – no specific code
Other HCPCS codes related to the CPB:
J0224	Injection, lumasiran, 0.5 mg
ICD-10 codes covered if selection criteria are met:
E72.530	Primary hyperoxaluria, type 1
ICD-10 codes not covered if selection criteria are met:
E72.538	Other specified primary hyperoxaluria
Z94.4	Liver transplant status

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Background

U.S. Food and Drug Administration (FDA)-Approved Indications 

• Rivfloza is indicated to lower urinary oxalate levels in children 2 years of age and older and adults with primary hyperoxaluria type 1 (PH1) and relatively preserved kidney function, e.g., estimated glomerular filtration rate (eGFR) greater than or equal to 30 mL/min/1.73 m².

Nedosiran, branded as Rivfloza by Dicerna Pharmaceuticals, Inc., a Novo Nordisk company, is a small interfering ribonucleic acid (siRNA) that targets lactate dehydrogenase (LDHA). As an RNA interference (RNAi) therapy, nedosiran is administered via subcutaneous injection and works by inhibiting the production of the hepatic lactate dehydrogenase (LDH) enzyme, leading to a reduction in urinary oxalate levels. By blocking LDH, nedosiran has been shown to decrease the accumulation of oxalate associated with the genetic mutation linked to primary hyperoxaluria type 1 (PH1).

There are no known contraindications for use of nedosiran therapy. The most common adverse reaction reported in 20 percent or more of patients in clinical trials includes injection site reactions. 

Primary Hyperoxaluria Type 1 (PH1)

Primary hyperoxalurias (PHs) are rare inherited disorders characterized by a defect in glyoxylate metabolism, leading to the overproduction of oxalate by the liver. Primary hyperoxaluria type 1 (PH1) is the most common type, accounting for approximately 80 percent of all PH cases, with an estimated prevalence of 1 to 3 individuals per million in Europe and North America. PH1 is caused by autosomal recessive variants of the AGXT gene, which encodes the hepatic peroxisomal enzyme alanine:glyoxylate aminotransferase (AGT). This enzyme catalyzes the conversion of glyoxylate to glycine. In the absence of AGT activity, glyoxylate is converted to oxalate, resulting in the formation of insoluble calcium oxalate crystals that accumulate in the kidneys and other organs (Milliner et al., 2024).

PH1 is considered the most severe form of primary hyperoxaluria and can lead to nephrolithiasis, nephrocalcinosis, and renal failure (end-stage renal disease [ESRD]). Symptoms can manifest at any time between infancy and adulthood, with a median age at diagnosis of approximately 5 to 5.5 years, and the severity of symptoms can vary. As kidney function deteriorates, oxalate can accumulate and cause damage to other organs (Cochat and Rumsby, 2013; Milliner, 2005; Niaudet, 2023).

In September 2023, the U.S. Food and Drug Administration (FDA) approved a once-monthly subcutaneous injection of Rivfloza (nedosiran) to lower urinary oxalate levels in children 9 years of age and older and adults with PH1 who have relatively preserved kidney function (e.g., eGFR ≥ 30 mL/min/1.73 m²). FDA approval was based on the results of the PHYOX2 trial which met its primary endpoint, showing that patients treated with Rivfloza achieved a marked reduction from baseline in 24-hour urinary oxalate (Uox) excretion from Day 90 to Day 180.

Milliner et al. (2024) describe PH1 as a condition resulting from a deficiency of the liver enzyme alanine-glyoxylate aminotransferase (AGT), which is responsible for converting glyoxylate to glycine. When AGT activity is diminished or absent, glyoxylate is instead converted to oxalate, leading to its accumulation and subsequent excretion by the kidneys, where it forms insoluble calcium oxalate crystals. These crystals can aggregate, causing nephrolithiasis (calcium oxalate kidney stones) and nephrocalcinosis, with presentation occurring in infancy (10% of cases), childhood/adolescence (70%), and adulthood (20%). Untreated PH1 typically results in progressive kidney function decline due to complications from nephrolithiasis and nephrocalcinosis, and in advanced chronic kidney disease, high plasma oxalate levels can lead to systemic organ damage, particularly in the bones, heart, and retina, ultimately resulting in death from kidney failure or organ involvement. Diagnosis is confirmed through laboratory findings of excess urinary oxalate and biallelic pathogenic variants in AGXT via genetic testing. Management includes targeted therapies such as pyridoxine for certain AGXT variants, RNA interference therapeutics (lumasiran and nedosiran), and liver transplantation to restore AGT activity. Supportive care aims to minimize stone formation and preserve kidney function, with advanced cases potentially requiring dialysis or kidney transplantation. Lifelong surveillance is necessary, involving regular assessments of kidney function, urine oxalate excretion, and signs of systemic oxalosis. Patients should avoid certain agents and circumstances that could compromise kidney function, and family screening for PH1 is recommended due to intrafamilial variability and the effectiveness of available therapies. While pregnancy does not significantly increase the risk of end-stage kidney disease in most women with PH1, close monitoring by healthcare professionals is advised, and the use of recently approved therapies during pregnancy is not recommended until further data is available. Genetic counseling is important, as PH1 is inherited in an autosomal recessive manner, allowing for carrier testing and prenatal options for at-risk relatives once pathogenic variants are identified in an affected family member.

The PHYOX2 was a randomized, double-blind, phase 2 trial comparing nedosiran and placebo in patients aged 6 years or older with PH1 or PH2 and an eGFR ≥ 30 mL/min/1.73 m² (NCT03847909). However, findings for PH2 could not be established due to not enough participants with PH2 enrolled in the study. Nonetheless, all patients were randomized to receive either monthly doses of nedosiran (n=23) or placebo (n=12). Doses were weight-based. For patients 12 years of age and older weighing at least 50 kg, the dose was 160 mg. For patients at least 12 years of age weighing less than 50 kg, the dose was 128 mg. For children 6 to 11 years of age, the dose was 3.3 mg/kg (to a maximum of 128 mg). All patients were required to have PH1 or PH2 diagnosis confirmed by genotyping. The primary efficacy endpoint was the area under the curve, from Days 90 to 180, of the percent change from baseline in 24-hour urinary oxalate excretion (AUC_{24-hour Uox}). The least-squares (LS) mean AUC_{24-hour Uox} was -3486 (95% CI: -5025, -1947) in the nedosiran group compared to 1490 (95% CI: 781, 3761) in the placebo group, for a between group difference of 4976 (95% CI: 2803, 7149; p<0.0001), which was significant between the nedosiran and placebo groups over the 90 days. After 6 months of treatment in the PHYOX2 trial, patients could enroll in an ongoing single-arm extension, phase 3 study, PHYOX3 (NCT04042402). All patients were treated with nedosiran. Thus far,13 patients with PH1 who received an additional 6 months of treatment in the PHYOX3 trial have maintained a reduction in urinary oxalate.

In March 2025, the FDA approved a label expansion for the use of nedosiran (Rivfloza) in children 2 years of age or older. Safety and effectiveness in this population was based in part from a single-arm, open-label, multicenter study in pediatric patients 2 to less than 12 years of age with PH1 and an eGFR ≥30 mL/min/1.73 m2 (PHYOX8; NCT05001269).  A total of 15 patients completed treatment, of which 8 were age 2 to less than 6 years, 5 were age 6 to less than 9 years, and 2 were between 9 to 11 years of age. The mean spot urinary oxalate:creatinine ratio at baseline was 0.36 mmol/mmol. The primary endpoint was the percent change from baseline in spot urinary oxalate:creatinine ratio at Month 6. The study found that patients treated with nedosiran had a 64% (95% CI: 44, 84) reduction in spot urinary oxalate:creatinine ratio from baseline at Month 6. The corresponding absolute reduction in spot urinary oxalate:creatinine ratio at Month 6 was 0.25 mmol/mmol (95% CI: 0.21, 0.29). After 6 months of treatment in the PHYOX8 trial, patients could enroll in an ongoing single arm extension study, PHYOX3. The reduction in urinary oxalate:creatinine ratio was maintained in the 8 patients who received an additional 6 months of treatment in the PHYOX3 trial.

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References