Medicare Advantage
Advanced Search

patisiran (Onpattro®) and vutrisiran (Amvuttra™)
MA08.100c

Policy

The Company reserves the right to reimburse only those services that are furnished in the most appropriate and cost-effective setting that is appropriate to the member’s medical needs and condition.​  

MEDICALLY NECESSARY

 INITIAL THERAPY ​
Patisiran (Onpattro) or vutrisiran (Amvuttra)​​ are considered medically necessary and, therefore, covered for individuals 18 years of age or older with hereditary transthyretin-mediated (hATTR) amyloidosis with polyneuropathy when all of the following criteria, including dosing and frequency requirements listed below, are met:
  • Diagnosis of hATTR amyloidosis with polyneuropathy is confirmed by molecular genetic testing that reveals pathogenic variation(s) in the transthyretin (TTR) gene (e.g., variation of V30M, which is the most common pathogenic variant consisting of a point mutation)​
  • Documentation of one of the following baseline ambulation parameters in either the Familial Amyloid Polyneuropathy (FAP) Stage or Polyneuropathy Disability (PND) Score (see Guidelines Section for description of scores):
    • Stage 1 (unimpaired ambulation) or 2 (assisted ambulation) on the FAP staging tool 
    • Score 0, I, II, IIIa, or IIIb on the PND scoring tool 
  • Documented presence of cardiac or renal manifestations, or motor, sensory, or autonomic neuropathy related to the hATTR amyloidosis with polyneuropathy (e.g., neuropathic pain, muscle weakness that affects daily living, orthostatic hypotension, diarrhea, nausea, vomiting, heart failure, arrhythmias, proteinuria, renal failure; vision disorders, such as vitreous opacity, dry eyes, glaucoma, or pupils with an irregular or scalloped appearance)
  • Prescribed by or in consultation with a neurologist, geneticist, or professional provider specializing in the treatment of amyloidosis​
  • Individual has not had a liver transplant ​or is unlikely to be a candidate   ​
  • Patisiran (Onpattro) or vutrisiran (Amvuttra)​​​ will not be used in combination with each other, any other RNA interference agents (e.g., inotersen [Tegsedi]), or transthyretin stabilizers (e.g., tafamidis [Vyndaqel, Vyndamax])

CONTINUATION THERAPY (AFTER 18 MONTHS OF THERAPY)
Patisiran (Onpattro) or vutrisiran (Amvuttra)​​ ​are considered medically necessary and, therefore, covered for continuation therapy following at least 18 months of therapy for the treatment of hATTR amyloidosis with polyneuropathy when the individual meets both of the following criteria:
  • Recent documentation of one of the following ambulation parameters (see Guidelines Section for description of scores):
    • Stage 1 (unimpaired ambulation) or 2 (assisted ambulation) on the FAP staging tool 
    • Score ​0, I, II, IIIa, or IIIb on the PND scoring tool  ​
  • Documented improvement or stability in the signs and symptoms of hATTR amyloidosis with polyneuropathy (e.g., neuropathic pain, muscle weakness that affects daily living, orthostatic hypotension, diarrhea, nausea, vomiting, heart failure, arrhythmias, proteinuria, renal failure; vision disorders, such as vitreous opacity, dry eyes, glaucoma, or pupils with an irregular or scalloped appearance), based on objective or standard evaluation scales 
​
DOSING AND FREQUENCY REQUIREMENTS

​PATISIRAN (ONPATTRO)  
The following dosage and frequency information was taken from the prescribing information for this product:
  • Individuals weighing less than 100 kg: the dosage is 0.3 mg/kg once every 3 weeks via intravenous infusion
  • Individuals weighing 100 kg or more, the dosage is 30 mg once every 3 weeks via intravenous infusion
VUTRISIRAN (AMVUTTRA) 
​The following dosage and frequency information was taken from the prescribing information for this product:​ The recommended dosage is 25 mg administered by subcutaneous injection by a professional provider once every 3 months.

REQUIREMENTS
​The Company reserves the right to modify the dosing and frequency requirements listed in this policy to ensure consistency with the most recently published recommendations for the use of patisiran (Onpattro) or vutrisiran (Amvuttra)​. Changes to these guidelines are based on a consensus of information obtained from resources such as, but not limited to, the US Food and Drug Administration (FDA); Company-recognized authoritative pharmacology compendia; or published peer-reviewed clinical research. The professional provider must supply supporting documentation (i.e., published peer-reviewed literature) in order to request coverage for an amount of patisiran (Onpattro) or vutrisiran (Amvuttra)​​ outside of the dosing and frequency requirements listed in this policy. For a list of Company-recognized pharmacology compendia, view our policy on off-label coverage for prescription drugs and biologics.

Accurate member information is necessary for the Company to approve the requested dose and frequency of this drug. If the member’s dose, frequency, or regimen changes (based on factors such as changes in member weight or incomplete therapeutic response), the provider must submit those changes to the Company for a new approval based on those changes as part of the utilization management activities. The Company reserves the right to conduct postpayment review and audit procedures for any claims submitted for patisiran (Onpattro) or vutrisiran (Amvuttra)​​​.

NOT MEDICALLY NECESSARY
​
When molecular genetic testing reveals results showing established benign variation(s) or wild-type genotype in the transthyretin (TTR) gene, patisiran (Onpattro) or vutrisiran (Amvuttra)​ are considered not medically necessary and, therefore, not covered because the available published peer-reviewed literature does not support their uses as treatments.​

EXPERIMENTAL/INVESTIGATIONAL

When molecular genetic testing reveals likely pathogenic or variations of unknown significance (VUS) in the transthyretin (TTR) gene, the use of patisiran (Onpattro) or vutrisiran (Amvuttra)​ are considered experimental/investigational and, therefore, not covered because the safety and/or effectiveness of this service cannot be established by review of the available published peer-reviewed literature. 

The use of patisiran (Onpattro) or vutrisiran (Amvuttra)​ ​for hATTR amyloidosis with cardiomyopathy in those who are not experiencing polyneuropathy is considered experimental/investigational and, therefore, not covered because the safety and/or effectiveness of this service cannot be established by review of the available published peer-reviewed literature.

All other uses for patisiran (Onpattro) and vutrisiran (Amvuttra) are considered experimental/investigational and, therefore, not covered unless the indication is supported as an accepted off-label use, as defined in the Company medical policy on off-label coverage for prescription drugs and biologics.

REQUIRED DOCUMENTATION

The individual's medical record must reflect the medical necessity for the care provided. These medical records may include, but are not limited to: records from the professional provider's office, hospital, nursing home, home health agencies, therapies, and test reports.

The Company may conduct reviews and audits of services to our members, regardless of the participation status of the provider. All documentation is to be available to the Company upon request. Failure to produce the requested information may result in a denial for the drug.

When coverage of patisiran (Onpattro) or vutrisiran (Amvuttra)​ are requested outside of the dosing and frequency requirements listed in this policy, the prescribing professional provider must supply documentation (i.e., published peer-reviewed literature) to the Company that supports this request.​

Guidelines

There is no Medicare coverage determination addressing patisiran (Onpattro) or vutrisiran (Amvuttra); therefore, the Company policy is applicable.

BENEFIT APPLICATION

Subject to the terms and conditions of the applicable Evidence of Coverage, patisiran (Onpattro) and vutrisiran (Amvuttra) are covered under the medical benefits of the Company’s Medicare Advantage products when the medical necessity criteria listed in this medical policy are met.

However, services that are identified in this policy as experimental/investigational or not medically necessary are not eligible for coverage or reimbursement by the Company.

PATISIRAN (ONPATTRO) ​
Patisiran (Onpattro) was approved by the U.S. Food and Drug Administration (FDA) on August 10, 2018, for for the treatment of polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults. The safety and effectiveness have not been established in pediatric individuals.

In accordance with FDA prescribing information, patisiran (Onpattro) is administered as an intravenous infusion every 3 weeks. Because of infusion-related reactions, each of the following premedications should be given on the day of infusion, at least 60 minutes prior to the start of infusion (see prescribing information for modifications):
  • Intravenous corticosteroid (e.g., dexamethasone 10 mg, or equivalent)
  • Oral acetaminophen (500 mg)
  • Intravenous H1 blocker (e.g., diphenhydramine 50 mg, or equivalent)
  • Intravenous H2 blocker (e.g., ranitidine 50 mg, or equivalent)
​VUTRISIRAN (AMVUTTRA)  ​​
Vutrisiran (Amvuttra) was approved by the FDA on June 13, 2022, for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults. The safety and effectiveness have not been established in pediatric individuals.

DIAGNOSTIC TOOLS TO ASSESS AMBULATION

FAMILIAL AMYLOID POLYNEUROPATHY (FAP) STAGES*
The FAP Stages objectively categorize an individual's ability to ambulate into four stages: ​Stage 0, No symptoms; Stage 1, unimpaired ambulation; Stage 2, assisted ambulation; Stage 3, wheelchair bound or bedridden.

POLYNEUROPATHY DISABILITY (PND) SCORE*
The PND score objectively categorizes an individual's ability to ambulate into six stages.
  • Score 0: no impairment
  • Score I: preserved walking capacity with sensory disturbances
  • Score II: impaired walking, no walking stick or crutch is required
  • Score IIIa: one walking stick or crutch is required to walk
  • Score IIIb: two walking sticks or crutches are required to walk
  • Score IV: confined to wheelchair or bed
*Ando et al., 2013​

Description

Hereditary transthyretin-mediated (hATTR) amyloidosis is a progressive, degenerative, multisystemic, life-threatening disease in which insoluble fibril proteins (amyloid deposits) accumulate in various organs of the body, including the central nervous system, nerves, gastrointestinal tract, and heart. hATTR amyloidosis is caused by a variation in the transthyretin (TTR) protein, a protein that is produced in the liver. Pathogenic variation(s) of TTR causes the protein to misfold and form an insoluble fibril protein that deposits itself in various organs of the body. To date, over 120 TTR variants have been identified as a cause of hATTR, the most common being the p.Val30Met mutation. Symptoms commonly develop in the third to fifth decade of life and depend on several factors, including location of the deposits. ​The majority of TTR mutations cause a “neuropathic” or a “mixed” phenotype; yet, some variants typically manifest with a predominant or isolated cardiomyopathy (Luigetti et al., 2020). Polyneuropathy and cardiomyopathy are progressive and life-threatening, with survival approximately 2 to 15 years after onset of neuropathy and 2 to 5 years after onset of cardiomyopathy. Examples of symptoms associated with motor, sensory, and autonomic neuropathy include neuropathic pain, carpal tunnel syndrome, muscle weakness that affects daily living, orthostatic hypotension, recurrent urinary tract infections, diarrhea, nausea, vomiting, vision disorders (e.g., vitreous opacity, dry eyes, glaucoma, or pupils with an irregular or scalloped appearance), cardiac conduction blocks, and arrhythmias. Symptoms of hATTR can cause severe decreased ambulation, decline in daily function due to pain or discomfort, and anxiety or depression. ​

Patisiran (Onpattro) is the first pharmacologic treatment approved by the US Food and Drug Administration (FDA) for the treatment of adults with polyneuropathy associated with hereditary transthyretin-mediated amyloidosis. Prior to its approval, treatment options consisted of orthotopic liver transplant or a TTR tetramer stabilizer, such as diflunisal (as an off-label indication). Since its approval, ​other treatments have been approved by the FDA:  inotersen (Tegsedi), vutrisiran (Amvuttra).  

Patisiran (Onpattro) and vutrisiran (Amvuttra) represent a class of drugs called double-stranded small interfering ribonucleic acid (siRNA) treatment that controls gene expression by silencing or interfering with a targeted portion of RNA to reduce the amount of disease-causing TTR, causing a reduction in the amount of amyloid deposits in the body. Patisiran (Onpattro) is administered by intravenous infusion every 3 weeks. Vutrisiran (Amvuttra) is administered by a professional provider by subcutaneous injection once every 3 months.​

PATISIRAN (ONPATTRO)  

PEER-REVIEWED LITERATURE
Summary

APOLLO was a Phase 3, multicenter, randomized, double-blind, placebo-controlled study that evaluated the safety and effectiveness of patisiran (Onpattro) in 225 adults with hATTR amyloidosis. Participants were required to have a documented pathogenic variant in TTR, a Neuropathy Impairment Score (NIS) of 5 to 130 (range, 0 to 244, with higher scores indicating more impairment) and a polyneuropathy disability score of IIIb or lower (with higher scores indicating more impaired walking ability). Participants were randomly assigned (2:1) to either patisiran (Onpattro), 0.3 mg/kg, or placebo via intravenous infusion once every 3 weeks for 18 months. The primary efficacy endpoint was the change from baseline to Month 18 in the modified Neuropathy Impairment Score +7 (mNIS+7). The study resulted in a reduction in TTR level by 81% in those treated with patisiran (Onpattro). There was a statistically significant improvement in polyneuropathy (mNIS+7 score) in those treated with patisiran (Onpattro) compared to placebo. At 18 months, 56% of participants treated with patisiran (Onpattro) had improvement in mNIS+7, compared with 4% treated with placebo.

The following secondary endpoints showed statistically significant improvement in those treated with patisiran (Onpattro): quality of life (Norfolk Quality of Life–Diabetic Neuropathy [Norfolk QOL-DN] questionnaire), motor strength (NIS-weakness); disability (Rasch-built Overall Disability Scale [R-ODS]), gait speed (10-meter walk test), nutritional status (modified body mass index [BMI]), patient-reported autonomic symptoms (Composite Autonomic Symptom Score). Exploratory endpoints were evaluated in a predefined cardiac subpopulation that showed improvement in echocardiographic measures of cardiac structure and function and a reduction in N-terminal pro–brain natriuretic peptide (NT-proBNP) levels (a measure of cardiac stress that is an independent predictor of death in individuals with transthyretin cardiac amyloidosis) in those treated with patisiran (Onpattro). More randomized, double-blind studies will be needed to assess efficacy in those with hATTR who have cardiac manifestations. The frequency of severe adverse events and serious adverse events were similar between the two groups.

VUTRISIRAN (AMVUTTRA) 

PEER-REVIEWED LITERATURE
Summary​

HELIOS-A was a Phase 3, global, multicenter​, randomized, open-label study that evaluated the safety and effectiveness of vutrisiran (Amvuttra) in 160 adults with hereditary transthyretin (ATTRv; v for variant) amyloidosis (also known as hATTR amyloidosis. Participants were required to have a documented pathogenic variant in TTR, a NIS of 5 to 130, a polyneuropathy disability (PND) score of IIIb or less, a Karnofsky Performance Status score of 60% or greater, and adequate liver and renal function. ​Participants were randomly assigned (3:1) to treatment with vutrisiran (Amvuttra) 25 mg SC every 3 months or patisiran (Onpattro)​ 0.3 mg/kg IV every 3 weeks for 18 months or external placebo group from the APOLLO study. The primary efficacy endpoint was the change from baseline to Month 18 in the modified Neuropathy Impairment Score +7 (mNIS+7) compared with the placebo group of the APOLLO study (external placebo group) at Month 9. The study resulted in with vutrisiran (Amvuttra) meeting the primary endpoint​, resulting in statistically significant improvement in mNIS+7 at Month 9 versus the external placebo group.  At Month 9, 50.4% of participants treated with vutrisiran (Amvuttra) had an improvement in mNIS+7 versus 18.2% in the external placebo group.​ Vutrisiran (Amvuttra) met all of its secondary efficacy endpoints: significant improvements versus external placebo were observed in Norfolk Quality of Life-Diabetic Neuropathy, 10-meter walk test (both at 9 and 18 months), mNIS+7, modified body-mass index, and Rasch-built Overall Disability Scale (all at 18 months). TTR reduction with vutrisiran (Amvuttra)​ every 3 months was noninferior to within-study patisiran (Onpattro)​ ​every 3 weeks. Most adverse events were mild or moderate in severity, and consistent with ATTRv amyloidosis natural history. There were no drug-related discontinuations or deaths. All secondary endpoints resulted in significant improvements with vutrisiran (Amvuttra)​ treatment compared with the external placebo group. ​

OFF-LABEL INDICATION

There may be additional indications contained in the Policy section of this document due to evaluation of criteria highlighted in the Company’s off-label policy, and/or review of clinical guidelines issued by leading professional organizations and government entities.

References

Adams D. Recent advances in the treatment of familial amyloid polyneuropathy. Ther Adv Neurol Disord. 2013;6(2):129-139.

Adams D, Gonzalez-Duarte A, O'Riordan WD, et al. Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis. N Engl J Med. 2018;379(1):11-21.

Adams D, Tournev IL, Taylor MS, et al; HELIOS-A Collaborators. Efficacy and safety of vutrisiran for patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy: a randomized clinical trial. Amyloid. 2022;23:1-9. 

American Hospital Formulary Service (AHFS). Drug Information 2023. Patisiran (Onpattro). [Lexicomp Online Web site]. 07/25/2022. Available at: http://online.lexi.com/lco/action/home [via subscription only]. Accessed January 25, 2023. 

American Hospital Formulary Service (AHFS). Drug Information 2023. vutrisiran (Amvuttra)​. [Lexicomp Online Web site]. 08/18/2022. Available at: http://online.lexi.com/lco/action/home [via subscription only]. Accessed January 25, 2023. 

Ando Y, Coelho T, Berk JL, et al. Guideline of transthyretin-related hereditary amyloidosis for clinicians. Orphanet J Rare Dis. 2013;8:31. 

Elsevier's Clinical Pharmacology Compendium. Patisiran (Onpattro). 01/18/2023. [Clinical Key Web site]. Available at: https://www.clinicalkey.com/pharmacology/ [via subscription only]. Accessed January 25, 2023. ​​

Elsevier's Clinical Pharmacology Compendium. vutrisiran (Amvuttra)​. 06/17/2022. [Clinical Key Web site]. Available at: https://www.clinicalkey.com/pharmacology/ [via subscription only]. Accessed January 25, 2023.

Gertz MA. Hereditary ATTR amyloidosis: burden of illness and diagnostic challenges. Am J Manag Care. 2017;23(7 Suppl):S107-S112.

Lexi-Drugs Compendium. Patisiran (Onpattro). 09/28/2022. [Lexicomp Online Web site]. Available at: http://online.lexi.com/lco/action/home [via subscription only]. Accessed January 25, 2023. 

Lexi-Drugs Compendium. vutrisiran (Amvuttra)​. 01/24/2023. [Lexicomp Online Web site]. Available at: http://online.lexi.com/lco/action/home [via subscription only]. Accessed January 25, 2023. 
​
Luigetti M, Romano A, Di Paolantonio A, Bisogni G, Sabatelli M. Diagnosis and treatment of hereditary transthyretin amyloidosis (hATTR) polyneuropathy: current perspectives on improving patient care. Ther Clin Risk Manag. 2020;16:109-123. ​

National Institutes of Health (NIH). Genetics Home Reference. Transthyretin amyloidosis. Reviewed 01/2009. Available at: https://ghr.nlm.nih.gov/condition/transthyretin-amyloidosis. Accessed January 23, 2023.​

Patisiran (Onpattro). [prescribing information]. Cambridge, MA: Alnylam Pharmaceuticals, Inc.; 01/2023. Available at: https://www.onpattro.com/. Accessed January 25, 2023. 

Truven Health Analytics. Micromedex® DrugDex® Compendium. Patisiran (Onpattro). 11/29/2022. Greenwood Village, CO. [Micromedex® Solutions Web site]. Available at: http://www.micromedexsolutions.com/micromedex2/librarian [via subscription only]. Accessed January 25, 2023. 

Truven Health Analytics. Micromedex® DrugDex® Compendium. Vutrisiran (Amvuttra). 07/19/2022. Greenwood Village, CO. [Micromedex® Solutions Web site]. Available at: http://www.micromedexsolutions.com/micromedex2/librarian [via subscription only]. Accessed January 25, 2023. ​

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. patisiran (Onpattro) prescribing information and approval letter [FDA Web site]. 01/2023. Available at: https://www.accessdata.fda.gov/scripts/cder/daf/. Accessed January 23, 2023.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. vutrisiran (Amvuttra)​ prescribing information and approval letter [FDA Web site]. 06/2022. Available at: https://www.accessdata.fda.gov/scripts/cder/daf/. Accessed January 23, 2023.

vutrisiran (Amvuttra)​. [prescribing information]. Cambridge, MA: Alnylam Pharmaceuticals, Inc.; 06/2022. Available at:​https://www.amvuttra.com/. Accessed January 24, 2023.

Coding

CPT Procedure Code Number(s)
N/A
ICD - 10 Procedure Code Number(s)
N/A
ICD - 10 Diagnosis Code Number(s)
E85.1 Neuropathic heredofamilial amyloidosis
HCPCS Level II Code Number(s)
J0222 Injection, Patisiran, 0.1 mg

​​​J0225 Injection, Vutrisiran, 1 mg
Revenue Code Number(s)
N/A


Coding and Billing Requirements

Policy History

6/12/2023
6/12/2023
MA08.100
Medical Policy Bulletin
Medicare Advantage
No
Connect with Us

2023 Independence Blue Cross

Independence Blue Cross is a subsidiary of Independence Health Group, Inc. — independent licensees of the Blue Cross and Blue Shield Association, serving the health insurance needs of Philadelphia and southeastern Pennsylvania.