Nedosiran (Rivfloza) - Medical Clinical Policy Bulletins (2024)

Number:1047

Table Of Contents

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

Policy

Scope of Policy

This Clinical Policy Bulletin addressesnedosiran (Rivfloza) for commercial medical plans. For Medicare criteria, seeMedicare Part B Criteria.

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, seeSpecialty Pharmacy Precertification.

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

1. Criteria for Initial Approval

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

   1. Member is 9 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 mutation 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 relatively preserved kidney function (e.g., eGFR of greater than or equal to 30 mL/min/1.73 m²); and
   4. The requested medication will not be used in combination with lumasiran.

   Aetna considers all other indications as experimental and investigational.

2. Continuation of Therapy

   Aetna considers continuation of nedosiran (Rivfloza) therapy medically necessaryfor 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).

   See Also

   Extracorporeal Membrane Oxygenation (ECMO) - Medical Clinical Policy Bulletins

3. 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 mayinject Rivfloza using the pre-filled syringe. In pediatrics 9 to 11 years of age whoweigh 50 kg or more, a healthcare professional or caregiver may inject Rivfloza using the pre-filledsyringe.

Primary Hyperoxaluria Type 1

Per the label for Rivfloza, the recommended dosage is shown below and is administered as a subcutaneous injection once monthly.

Source: Dicerna Pharmaceuticals, Inc., a Novo Nordisk company (2023)

Background

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

• 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., estimated glomerular filtration rate (eGFR) of greater than or equal to 30 mL/min/1.73 m².

Nedosiran,anLDHA-directed small interfering ribonucleic acid (siRNA), is branded as Rivfloza (Dicerna Pharmaceuticals, Inc., a Novo Nordisk company).Nedosiranis considered an RNA interference (RNAi) therapy that, when injected subcutaneously, inhibits production of the hepatic lactate dehydrogenase (LDH) enzyme, resulting in reduction ofurinary oxalate levels.Blocking LDH has been shown to reduce accumulation of oxalate caused by the genetic mutation in the gene associatedprimary 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 rareinherited disorders in which there is a defect of glyoxylate metabolism resulting in the overproduction of oxalate levels by the liver. Primary hyperoxaluria type 1 (PH1) is considered the most common PH type, accounting for approximately 80 percent of all PH cases with estimated prevalence between 1 to 3 individuals per million in Europe and North America. PH1 iscaused by autosomal recessive variants of the AGXT genethat encodes the hepatic peroxisomal enzyme alanine:glyoxylate aminotransferase (AGT), which catalyzes the conversion of glyoxylate to glycine. When AGT activity is absent, glyoxylate is converted to oxalate, which forms insoluble calcium oxalate crystals that accumulate in the kidney and other organs (Milliner et al, 2022). PH1 is considered the most severe form of PH and can result in nephrolithiasis, nephrocalcinosis, and renal failure (end-stage renal disease [ESRD]). Manifestationscan begin at any time between infancy and adulthood (median age at diagnosis is approximately 5 to 5.5 years) with symptoms varying in severity. As kidney function worsens, oxalate can build up 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.

ThePHYOX2 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 nedosiranand 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 areduction in urinary oxalate.

It is not known if nedosiranis safe and effective in children younger than 9 years of age.

References