Coverage Policy Manual
Policy #: 2022042
Category: Pharmacy
Initiated: November 2022
Last Review: November 2025
Treatment of Hereditary Transthyretin-mediated Amyloidosis [Patisiran (e.g., Onpattro) and Vutrisiran (e.g., Amvuttra)]
Description:
The policy applies to the following medications: Patisiran (e.g., Onpattro) and Vutrisiran (e.g., Amvuttra).
Policy/
Coverage:
Prior approval is required for Patisiran (e.g., Onpattro).
 
Prior approval is required for Vutrisiran (e.g., Amvuttra).
 
The initial use of this drug requires documentation of direct physician involvement (MD/DO) in the ordering and evaluation, as well as signature, in the medical records submitted for prior approval. Concurrent review will require continued evidence of appropriate physician involvement.
 
INITIAL AND CONTINUATION APPROVAL will be for duration of the treatment course or 12 months (whichever comes first). Approval timeframes may differ for members/participants of Self-Insured plans.
 
PATISIRAN (E.G., ONPATTRO)
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
INITIAL APPROVAL
 
Patisiran (e.g., Onpattro) meets member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes or for members with contracts without Primary Coverage Criteria, is considered Medically Necessary and is covered, when ALL the following criteria are met:
 
Initial Approval and Continuation of Therapy:
 
Member receives a “recommended” determination from InterQual® Criteria review for Patisiran (e.g., Onpattro), based on diagnosis and requested product. Click the following link to view the InterQual® criteria: https://prod.ds.interqual.com/service/connect/transparency?tid=27b0a724-ca06-4b22-846b-598b8dae52fc
 
Does Not Meet Primary Coverage Criteria Or Is Not Covered For Contracts Without Primary Coverage Criteria
 
Patisiran (e.g., Onpattro) does not meet member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes and is not covered for any indication or circumstance not described above.
 
For contracts without Primary Coverage Criteria, Patisiran (e.g., Onpattro), is considered not Medically Necessary and is not covered or is investigational for any indication or circumstance not described above. Not Medically Necessary or Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Please refer to a separate policy on Maximum Dosage and Frequency (policy #2025031) for pharmacologic/biologic medications.
 
VUTRISIRAN (E.G., AMVUTTRA)
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Vutrisiran (e.g., Amvuttra) meets member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes or for members with contracts without Primary Coverage Criteria, is considered Medically Necessary and is covered, when ALL the following criteria are met:
 
Initial Approval and Continuation of Therapy:
 
Member receives a “recommended” determination from InterQual® Criteria review for Vutrisiran (e.g., Amvuttra), based on diagnosis and requested product. Click the following link to view the InterQual® criteria: https://prod.ds.interqual.com/service/connect/transparency?tid=27b0a724-ca06-4b22-846b-598b8dae52fc
 
Does Not Meet Primary Coverage Criteria Or Is Not Covered For Contracts Without Primary Coverage Criteria
 
Vutrisiran (e.g., Amvuttra) does not meet member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes and is not covered for any indication or circumstance not described above.
 
For contracts without Primary Coverage Criteria, Vutrisiran (e.g., Amvuttra), is considered not Medically Necessary and is not covered or is investigational for any indication or circumstance not described above. Not Medically Necessary or Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Please refer to a separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Please refer to a separate policy on Maximum Dosage and Frequency (policy #2025031) for pharmacologic/biologic medications.
 
Effective February 19, 2026
 
PATISIRAN (E.G., ONPATTRO)
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Patisiran (e.g., Onpattro) meets member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes or for members with contracts without Primary Coverage Criteria, is considered Medically Necessary and is covered, when ALL the following criteria are met:
 
POLYNEUROPATHY OF HEREDITARY TRANSTHYRETIN-MEDIATED AMYLOIDOSIS
 
INITIAL APPROVAL:
 
1. Individual is 18 years or older; AND
2. Individual has a confirmatory diagnosis of hereditary transthyretin (hATTR) amyloidosis by a genetic test and tissue biopsy showing amyloid deposition (Adams, 2018); AND
3. Presence of clinical signs and symptoms of polyneuropathy characterized by 1 of the following:
a. Baseline polyneuropathy disability (PND)* IIIb or lower (Adams, 2018); OR
b. Baseline familial amyloidotic polyneuropathy (FAP)** Stage 1 or 2 (Adams, 2018); AND
4. Individual does not have ANY of the following:
a. New York Heart Association (NYHA) class III or IV heart failure (Adams, 2018); OR
b. Sensorimotor or autonomic neuropathy not related to hATTR amyloidosis (monoclonal gammopathy, autoimmune disease, etc.) (Adams, 2017); OR
c. Prior liver transplantation. (Adams, 2018); AND
5. The prescriber is a specialist in the area of the  individual’s diagnosis (e.g., neurologist) or the prescriber has consulted with a specialist in the area of the  individual’s diagnosis; AND
6. The individual does NOT have any U.S. FDA labeled contraindications to the requested agent; AND
7. Patisiran will not be used in combination with inotersen, tafamidis, or vutrisiran.
 
CONTINUATION OF THERAPY:
 
1. Individual has a documentation of diagnosis to hereditary mediated amyloidosis; AND
2. Individual has a documentation of stabilization or improvement via use of objective measurements, such as 10-MWT, COMPASS-31, PND Score or EQ-5D; AND
3. Patisiran will not be used in combination with inotersen, tafamidis, or vutrisiran.
 
Does Not Meet Primary Coverage Criteria Or Is Not Covered For Contracts Without Primary Coverage Criteria
 
Patisiran (e.g., Onpattro), for any indication or circumstance not described above, does not meet member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes and is not covered.
 
For members with contracts without Primary Coverage Criteria, Patisiran (e.g., Onpattro), for any indication or circumstance not described above, is considered not Medically Necessary or is investigational and is not covered. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
DOSAGE AND ADMINISTRATION
 
For FDA labeled indications, Patisiran (e.g., Onpattro) must be dosed in accordance with the indication specific recommended dose per FDA label unless otherwise specified below.
 
The recommended dose of patisiran is based on actual body weight. For individuals weighing less than 100 kg, the recommended dosage is 0.3 mg/kg once every 3 weeks. For individuals weighing 100 kg or more, the recommended dosage is 30 mg once every 3 weeks.
 
Patisiran is available as a 10mg/5mL single dose vial.
 
Patisiran should be administered as an intravenous infusion by a healthcare professional.  
 
Please refer to separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
VUTRISIRAN (E.G., AMVUTTRA)
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Vutrisiran (e.g., Amvuttra) meets member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes or for members with contracts without Primary Coverage Criteria, is considered Medically Necessary and is covered, when ALL the following criteria are met:
 
POLYNEUROPATHY OF HEREDITARY TRANSTHYRETIN-MEDIATED AMYLOIDOSIS
 
INITIAL APPROVAL:
 
1. Individual is 18 years or older (Amvuttra, 2025); AND
2. Individual has a confirmatory diagnosis of hereditary transthyretin (hATTR) amyloidosis by a genetic test and tissue biopsy showing amyloid deposition (Adams, 2022); AND
3. Presence of clinical signs and symptoms of polyneuropathy characterized by 1 of the following:
a. Baseline PND *(see policy guidelines) IIIb or lower (Adams, 2022); OR
b. Baseline FAP**(see policy guidelines) Stage 1 or 2 (Adams, 2022); AND
4. Individual does not have ANY of the following:
a. New York Heart Association (NYHA) class III or IV heart failure (Adams, 2022); OR
b. Sensorimotor or autonomic neuropathy not related to hATTR amyloidosis (monoclonal gammopathy, autoimmune disease, etc.) (Adams, 2017); OR
c. Prior liver transplantation. (Adams, 2022); AND
5. The prescriber is a specialist in the area of the individual’s diagnosis (e.g., neurologist) or the prescriber has consulted with a specialist in the area of the individual’s diagnosis; AND
6. The individual does NOT have any U.S. FDA labeled contraindications to the requested agent; AND
7. Vutirsiran will not be used in combination with inotersen, tafamidis, or patisiran.
 
CONTINUATION OF THERAPY:
 
1. Individual has a documentation of hereditary mediated amyloidosis; AND
2. Individual has a documentation of stabilization or improvement via use of objective measurements, such as 10-MWT, COMPASS-31, PND Score or EQ-5D; AND
3. Vutrisiran will not be used in combination with inotersen, tafamidis, or patisiran.
 
CARDIOMYOPATHY OF WILD-TYPE OR HEREDITARY TRANSTHYRETIN-MEDIATED AMYLOIDOSIS (ATTR-CM)
 
INITIAL APPROVAL:
 
1. Individual is 18 years or older; AND
2. Documentation is provided that the diagnosis was confirmed by ONE of the following:
a. A technetium pyrophosphate scan (i.e., nuclear scintigraphy) showing grade 2 or 3 cardiac uptake AND cardiac uptake AND Systemic light chain amyloidosis is ruled out by showing the absence of monoclonal proteins by ALL of the following tests:
i. Serum kappa/lambda free light chain ratio; AND
ii. Serum protein immunofixation; AND
iii. Urine protein immunofixation; OR
b. A tissue biopsy with confirmatory transthyretin (TTR) amyloid typing by mass spectrometry, immunoelectron microscopy, or immunohistochemistry; OR
c. Individual had genetic testing which, according to the prescriber, identified transthyretin (TTR) pathogenic variant; AND
 
Note: Examples of TTR variants include Val122Ile variant and Thr60Ala variant. If the individual has wild-type amyloidosis, this is not a TTR pathogenic variant.
 
3. Diagnostic cardiac imaging has demonstrated cardiac involvement; AND
 
Note: Examples of cardiac imaging include echocardiogram and cardiac magnetic imaging. Examples of cardiac involvement on imaging include increased thickness of the ventricular wall or interventricular septum.
 
4. Individual has New York Heart Association (NYHA) Functional Class I, II or III Heart Failure; AND
5. The medication is prescribed by or in consultation with a cardiologist or a physician who specializes in the treatment of amyloidosis; AND
6. Vutrisiran will not be used in combination with other medications indicated for the treatment of polyneuropathy of hereditary transthyretin-mediated amyloidosis or transthyretin-mediated amyloidosis-cardiomyopathy (eg. acoramidis, eplontersen, inotersen,  tafamidis products, or patisiran.
 
CONTINUATION OF THERAPY:
 
1. Individual has a documentation of cardiomyopathy due to transthyretin-mediated amyloidosis; AND
2. Individual has a documentation of stabilization of disease; AND
3. Vutrisiran will not be used in combination with inotersen, tafamidis, or patisiran.
 
Does Not Meet Primary Coverage Criteria Or Is Not Covered For Contracts Without Primary Coverage Criteria
 
Vutrisiran (e.g., Amvuttra), for any indication or circumstance not described above, does not meet member benefit certificate Primary Coverage Criteria that there be scientific evidence of effectiveness in improving health outcomes and is not covered.
 
For members with contracts without Primary Coverage Criteria, Vutrisiran (e.g., Amvuttra), for any indication or circumstance not described above, is considered not Medically Necessary or is investigational and is not covered. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
POLICY GUIDELINES
 
Polyneuropathy disability staging:
    •  0 No symptoms
    •  1 Unimpaired ambulation; mostly mild sensory and motor neuropathy in the lower limbs
    •  2 Assistance with ambulation needed; mostly moderate impairment progression to the lower limbs, upper limbs, and trunk
    •  3 Wheelchair-bound or bedridden; severe sensory and motor neuropathy of all limbs
 
Familial amyloidotic polyneuropathy scoring:
    •  0 No impairment
    •   I Sensory disturbances, preserved walking capability
    •  II Impaired walking capability but ability to walk without a stick or crutches
    •  IIa Walking only with the help of 1 stick or crutch
    •  IIIb Walking with the help of 2 sticks or crutches
    •  IV Confined to a wheelchair or bedridden
 
DOSAGE AND ADMINISTRATION
 
For FDA labeled indications, Vutrisiran (e.g., Amvuttra) must be dosed in accordance with the indication specific recommended dose per FDA label unless otherwise specified below.
 
The recommended dose of Vutrisiran 25mg administered by subcutaneous injection once every 3 months.
 
Vutrisiran is available as a 25mg/0.5mL single-dose prefilled syringe.
 
Vutrisiran should be administered by a healthcare professional.  
 
Please refer to separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Effective Date November 2023 to February 18, 2026
 
Patisiran (e.g., Onpattro)
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
INITIAL APPROVAL STANDARD REVIEW for up to 12 months:
 
Patisiran (e.g., Onpattro) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when ALL the following criteria are met:
 
Polyneuropathy of hereditary transthyretin-mediated amyloidosis
 
    1. Individual is 18 years or older; AND
    2. Individual has a confirmatory diagnosis of hereditary transthyretin (hATTR) amyloidosis by a genetic test and tissue biopsy showing amyloid deposition (Adams, 2018) ; AND
    3. Presence of clinical signs and symptoms of polyneuropathy characterized by 1 of the following:
a. Baseline polyneuropathy disability (PND)* IIIb or lower (Adams, 2018); OR
b. Baseline familial amyloidotic polyneuropathy (FAP)** Stage 1 or 2 (Adams, 2018) ; AND
4. Individual does not have ANY of the following
a. New York Heart Association (NYHA) class III or IV heart failure (Adams, 2018); OR
b. Sensorimotor or autonomic neuropathy not related to hATTR amyloidosis (monoclonal gammopathy, autoimmune disease, etc.) (Adams, 2017); OR
c. Prior liver transplantation. (Adams, 2018) ; AND
5. The prescriber is a specialist in the area of the  individual’s diagnosis (e.g., neurologist) or the prescriber has consulted with a specialist in the area of the  individual’s diagnosis; AND
6. The individual does NOT have any U.S. FDA labeled contraindications to the requested agent; AND
7. Patisiran will not be used in combination with inotersen, tafamidis, or vutrisiran; AND
8. Must be dosed in accordance with the FDA label.
 
CONTINUED APPROVAL for 1 year:
 
    1. Documentation of diagnosis to hereditary mediated amyloidosis; AND
    2. Documentation of stabilization or improvement via use of objective measurements, such as 10-MWT, COMPASS-31, PND Score or EQ-5D; AND
    3. Patisiran will not be used in combination with inotersen, tafamidis, or vutrisiran.
 
Dosage and Administration
Dosing per FDA Guidelines
 
The recommended dose of patisiran is based on actual body weight. For individuals weighing less than 100 kg, the recommended dosage is 0.3 mg/kg once every 3 weeks. For individuals weighing 100 kg or more, the recommended dosage is 30 mg once every 3 weeks.
 
Patisiran is available as a 10mg/5mL single dose vial.
 
Patisiran should be administered as an intravenous infusion by a healthcare professional.  
 
Please refer to separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Patisiran, for any indication or circumstance not described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, patisiran, for any indication or circumstance not described above, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Vutrisiran (e.g., Amvuttra)
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
INITIAL APPROVAL STANDARD REVIEW for up to 12 months:
 
Vutrisiran (e.g., Amvuttra) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when ALL the following criteria are met:
 
Polyneuropathy of hereditary transthyretin-mediated amyloidosis
 
    1. Individual is 18 years or older; AND
    2. Individual has a confirmatory diagnosis of hereditary transthyretin (hATTR) amyloidosis by a genetic test and tissue biopsy showing amyloid deposition (Adams, 2022) ; AND
    3. Presence of clinical signs and symptoms of polyneuropathy characterized by 1 of the following:
a. Baseline PND* IIIb or lower (Adams, 2022); OR
b. Baseline FAP** Stage 1 or 2 (Adams, 2022) ; AND
4. Individual does not have ANY of the following:
a. New York Heart Association (NYHA) class III or IV heart failure (Adams, 2022); OR
b. Sensorimotor or autonomic neuropathy not related to hATTR amyloidosis (monoclonal gammopathy, autoimmune disease, etc.) (Adams, 2017); OR
c. Prior liver transplantation. (Adams, 2022) ; AND
5. The prescriber is a specialist in the area of the individual’s diagnosis (e.g., neurologist) or the prescriber has consulted with a specialist in the area of the individual’s diagnosis; AND
6. The individual does NOT have any U.S. FDA labeled contraindications to the requested agent; AND
7. Vutirsiran will not be used in combination with inotersen, tafamidis, or patisiran; AND
8. Must be dosed in accordance with the FDA label.
 
CONTINUED APPROVAL for 1 year:
Vutrisiran may be considered medically necessary in individuals 18 years of age and older for the treatment of hereditary mediated amyloidosis and if the conditions indicated below are met:
 
    1. Documentation of diagnosis to hereditary mediated amyloidosis; AND
    2. Documentation of stabilization or improvement via use of objective measurements, such as 10-MWT, COMPASS-31, PND Score or EQ-5D; AND
    3. Vutrisiran will not be used in combination with inotersen, tafamidis, or patisiran.
 
Dosage and Administration
Dosing per FDA Guidelines
 
The recommended dose of vutrisiran 25mg administered by subcutaneous injection once every 3 months.
 
Vutrisiran is available as a 25mg/0.5mL single-dose prefilled syringe.
 
Vutrisiran should be administered by a healthcare professional.  
 
Please refer to separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Vutrisiran, for any indication or circumstance not described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, vutrisiran, for any indication or circumstance not described above, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
* Polyneuropathy disability staging
    • 0 No symptoms
    • 1 Unimpaired ambulation; mostly mild sensory and motor neuropathy in the lower limbs
    • 2 Assistance with ambulation needed; mostly moderate impairment progression to the lower limbs, upper limbs, and trunk
    • 2 Assistance with ambulation needed; mostly moderate impairment progression to the lower limbs, upper limbs, and trunk
    • 2 Assistance with ambulation needed; mostly moderate impairment progression to the lower limbs, upper limbs, and trunk
    • 3 Wheelchair-bound or bedridden; severe sensory and motor neuropathy of all limbs
 
** Familial amyloidotic polyneuropathy scoring
    • 0 No impairment
    • I Sensory disturbances, preserved walking capability
    • II Impaired walking capability but ability to walk without a stick or crutches
    • IIa Walking only with the help of 1 stick or crutch
    • IIIb Walking with the help of 2 sticks or crutches
    • IV Confined to a wheelchair or bedridden
 
Effective Date November 9, 2022 to October 2023
 
Patisiran (e.g., Onpattro)
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
INITIAL APPROVAL STANDARD REVIEW for up to 12 months:
Patisiran (e.g., Onpattro) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when ALL the following criteria are met:
 
Polyneuropathy of hereditary transthyretin-mediated amyloidosis
1. Individual is 18 years or older
2. Individual has a confirmatory diagnosis of hATTR by a genetic test and tissue biopsy showing amyloid deposition (Adams, 2018)
3. Presence of clinical signs and symptoms of polyneuropathy characterized by 1 of the following:
a. Baseline polyneuropathy disability (PND)* IIIb or lower (Adams, 2018)
b. Baseline familial amyloidotic polyneuropathy (FAP)** Stage 1 or 2 (Adams, 2018)
4. Individual does not have ANY of the following
a. New York Heart Association (NYHA) class III or IV heart failure (Adams, 2018)
b. Sensorimotor or autonomic neuropathy not related to hATTR amyloidosis (monoclonal gammopathy, autoimmune disease, etc.) (Adams, 2017)
c. Prior liver transplantation. (Adams, 2018)
5. The prescriber is a specialist in the area of the patient’s diagnosis (e.g., neurologist) or the prescriber has consulted with a specialist in the area of the patient’s diagnosis
6. The individual does NOT have any U.S. FDA labeled contraindications to the requested agent
7. Patisiran will not be used in combination with inotersen, tafamidis, or vutrisiran
8. Must be dosed in accordance with the FDA label unless otherwise specified
 
CONTINUED APPROVAL for 1 year:
Patisiran may be considered medically necessary in individuals 18 years of age and older for the treatment of hereditary mediated amyloidosis and if the conditions indicated below are met:
1. Documentation of diagnosis to hereditary mediated amyloidosis
2. Documentation of stabilization or improvement via use of objective measurements, such as 10-MWT, COMPASS-31, PND Score or EQ-5D
3. Patisiran will not be used in combination with inotersen, tafamidis, or vutrisiran
 
Dosage and Administration
Dosing per FDA Guidelines
 
The recommended dose of patisiran is based on actual body weight. For patients weighing less than 100 kg, the recommended dosage is 0.3 mg/kg once every 3 weeks. For patients weighing 100 kg or more, the recommended dosage is 30 mg once every 3 weeks.
 
Patisiran is available as a 10mg/5mL single dose vial.
 
Patisiran should be administered as an intravenous infusion by a healthcare professional.  
 
Please refer to separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Patisiran, for any indication or circumstance not described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, patisiran, for any indication or circumstance not described above, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Vutrisiran (e.g., Amvuttra)
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
INITIAL APPROVAL STANDARD REVIEW for up to 12 months:
Vutrisiran (e.g., Amvuttra) meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when ALL the following criteria are met:
 
Polyneuropathy of hereditary transthyretin-mediated amyloidosis
1. Individual is 18 years or older
2. Individual has a confirmatory diagnosis of hATTR by a genetic test and tissue biopsy showing amyloid deposition (Adams, 2022)
3. Presence of clinical signs and symptoms of polyneuropathy characterized by 1 of the following:
a. Baseline PND* IIIb or lower (Adams, 2022)
b. Baseline FAP** Stage 1 or 2 (Adams, 2022)
4. Individual does not have ANY of the following
a. New York Heart Association (NYHA) class III or IV heart failure (Adams, 2022)
b. Sensorimotor or autonomic neuropathy not related to hATTR amyloidosis (monoclonal gammopathy, autoimmune disease, etc.) (Adams, 2017)
c. Prior liver transplantation. (Adams, 2022)
5. The prescriber is a specialist in the area of the patient’s diagnosis (e.g., neurologist) or the prescriber has consulted with a specialist in the area of the patient’s diagnosis
6. The patient does NOT have any U.S. FDA labeled contraindications to the requested agent
7. Vutirsiran will not be used in combination with inotersen, tafamidis, or patisiran
8. Must be dosed in accordance with the FDA label unless otherwise specified
 
CONTINUED APPROVAL for 1 year:
Vutrisiran may be considered medically necessary in individuals 18 years of age and older for the treatment of hereditary mediated amyloidosis and if the conditions indicated below are met:
1. Documentation of diagnosis to hereditary mediated amyloidosis
2. Documentation of stabilization or improvement via use of objective measurements, such as 10-MWT, COMPASS-31, PND Score or EQ-5D
3. Vutrisiran will not be used in combination with inotersen, tafamidis, or patisiran
 
Dosage and Administration
Dosing per FDA Guidelines
 
The recommended dose of vutrisiran 25mg administered by subcutaneous injection once every 3 months.
 
Vutrisiran is available as a 25mg/0.5mL single-dose prefilled syringe.
 
Vutrisiran should be administered by a healthcare professional.  
 
Please refer to separate policy on Site of Care or Site of Service Review (policy #2018030) for pharmacologic/biologic medications.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Vutrisiran, for any indication or circumstance not described above, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, vutrisiran, for any indication or circumstance not described above, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
* Polyneuropathy disability staging
0 No symptoms
1 Unimpaired ambulation; mostly mild sensory and motor neuropathy in the lower limbs
2 Assistance with ambulation needed; mostly moderate impairment progression to the lower limbs, upper limbs and trunk
2 Assistance with ambulation needed; mostly moderate impairment progression to the lower limbs, upper limbs and trunk
2 Assistance with ambulation needed; mostly moderate impairment progression to the lower limbs, upper limbs and trunk
3 Wheelchair-bound or bedridden; severe sensory and motor neuropathy of all limbs
 
** Familial amyloidotic polyneuropathy scoring
0 No impairment
I Sensory disturbances, preserved walking capability
II Impaired walking capability but ability to walk without a stick or crutches
IIa Walking only with the help of 1 stick or crutch
IIIb Walking with the help of 2 sticks or crutches
IV Confined to a wheelchair or bedridden
Rationale:
The efficacy of patisiran was demonstrated in a randomized, double-blind, placebo-controlled, multicenter clinical trial. Adult patients with polyneuropathy caused by hATTR were randomized in a 2:1 ratio to receive patisiran 0.3 mg/kg (N=148) or placebo (N=77), respectively, via intravenous infusion once every 3 weeks for 18 months. All patients received premedication with a corticosteroid, acetaminophen, and histamine 1 and histamine 2 blockers. Ninety-three percent of patisiran-treated patients and 62% of placebo-treated patients completed 18 months of the trial.
 
The primary efficacy endpoint was the change from baseline to Month 18 in the modified Neuropathy Impairment Score +7 (mNIS+7). The mNIS+7 is an objective assessment of neuropathy and comprises the NIS and Modified +7 (+7) composite scores. In the version of the mNIS+7 used in the trial, the NIS objectively measures deficits in cranial nerve function, muscle strength, and reflexes, and the +7 assesses postural blood pressure, quantitative sensory testing, and peripheral nerve electrophysiology. The clinical meaningfulness of effects on the mNIS+7 was assessed by the change from baseline to Month 18 in Norfolk Quality of Life-Diabetic Neuropathy (QoL-DN) total score. The Norfolk QoL-DN scale is a patient-reported assessment that evaluates the subjective experience of neuropathy in the following domains: physical functioning/large fiber neuropathy, activities of daily living, symptoms, small fiber neuropathy, and autonomic neuropathy.
 
Patisiran demonstrated statistically and clinically significant differences from placebo for both scores. (Alnylam, 2022)
 
The efficacy of vutrisiran was evaluated in a randomized, open-label clinical trial in adult patients with polyneuropathy caused by hATTR amyloidosis. Patients were randomized 3:1 to receive 25 mg of vutrisiran subcutaneously once every 3 months (N=122), or 0.3 mg/kg patisiran intravenously every 3 weeks (N=42) as a reference group. Ninety-seven percent of vutrisiran-treated patients and 93% of patisiran-treated patients completed at least 9 months of the assigned treatment.
 
Efficacy assessments were based on a comparison of the vutrisiran arm of Study 1 with an external placebo group in another study (NCT01960348) composed of a comparable population of adult patients with polyneuropathy caused by hATTR amyloidosis. The primary efficacy endpoint was the change from baseline to Month 9 in modified Neuropathy Impairment Score +7 (mNIS+7). The mNIS+7 is an objective assessment of neuropathy and comprises the NIS and Modified +7 composite scores. In the version of the mNIS+7 used in the trial, the NIS objectively measures deficits in cranial nerve function, muscle strength, and reflexes, and the +7 assesses postural blood pressure, quantitative sensory testing, and peripheral nerve electrophysiology. The mNIS+7 has a total score range from 0 to 304 points, with higher scores representing a greater disease severity.
 
The clinical meaningfulness of effects on the mNIS+7 was assessed by the change from baseline to Month 9 in NorfolkQuality of Life-Diabetic Neuropathy (QoL-DN) total score. The Norfolk QoL-DN scale is a patient-reported assessment that evaluates the subjective experience of neuropathy in the following domains: physical functioning/large fiber neuropathy, activities of daily living, symptoms, small fiber neuropathy, and autonomic neuropathy.
 
Additional endpoints were gait speed, as measured by the 10-meter walk test (10MWT), and modified body mass index (mBMI). Treatment with vutrisiran in Study 1 resulted in statistically significant improvements in the mNIS+7, Norfolk QoL-DN total score, and 10-meter walk test at Month 9 compared to placebo in the external study (p <0.001). The change from baseline to Month 9 in modified body mass index nominally favored vutrisiran. (Alnylam, 2022)
 
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through November 2023. No new literature was identified that would prompt a change in the coverage statement.
 
2024 Update
Annual policy review completed with a literature search using the MEDLINE database through November 2024. No new literature was identified that would prompt a change in the coverage statement.
 
2025 Update
Annual policy review completed with a literature search using the MEDLINE database through November 2025. No new literature was identified that would prompt a change in the coverage statement.
 
December 2025 Update
Addition of new indication for vutrisiran is based on the HELIOS-B Phase 3 clinical trial which evaluated vutrisiran for the treatment of ATTR-CM. The trial achieved statistical significance compared to placebo on all 10 pre-specified primary and secondary endpoints. The results were presented at the European Society of Cardiology Congress and simultaneously published in The New England Journal of Medicine. In the overall population, vutrisiran reduced the risk of all-cause mortality (ACM) and recurrent cardiovascular (CV) events by 28% during the double-blind treatment period of up to 36 months. Mortality in this population was significantly reduced by 36% through 42 months in a pre-specified secondary endpoint analysis which included up to 36 months of the double-blind period plus six months of open-label extension. In the monotherapy population, vutrisiran significantly reduced the risk of ACM and recurrent CV events by 33% in the double-blind period and significantly reduced the risk of mortality by 35% through 42 months. Compared to individuals treated with placebo, individuals treated with vutrisiran also experienced preservation of functional capacity and quality of life, as well as early improvements in biomarkers NT-proBNP and troponin I, which are predictive of cardiovascular outcomes. The safety and tolerability of vutrisiran are well-established, as demonstrated in the positive HELIOS-A clinical trial for vutrisiran in hATTR-PN which resulted in FDA approval in 2022 and over 5,000 patient-years exposure to-date, globally. In that study, the most common adverse reactions in individuals treated with vutrisiran were pain in extremity (15%), arthralgia (11%), dyspnea (7%), and vitamin A decreased (7%). No new safety concerns were identified in the HELIOS-B clinical trial of individuals with ATTR-CM.
CPT/HCPCS:
J0222Injection, patisiran, 0.1 mg
J0225Injection, vutrisiran, 1 mg
References:
Adams D, Gonzalez-Duarte A, O’Riordan WD, et al.(2018) Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis. N Engl J Med. 2018 Jul 5;379(1):11-21. doi: 10.1056/NEJMoa1716153.

Adams D, Suhr OB, Dyck PJ, et al.(2017) Trial design and rationale for APOLLO, a Phase 3, placebo-controlled study of patisiran in patients with hereditary ATTR amyloidosis with polyneuropathy. BMC Neurol. 2017;17(1):181.

Adams D, Tournev IL, Taylor MS, et al.(2022) Efficacy and safety of vutrisiran for patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy: a randomized clinical trial. Amyloid. 2022 Jul 23:1-9. doi: 10.1080/13506129.2022.2091985. [Epub ahead of print]

Alnylam Pharmaceuticals, Inc.(2022) Amvuttra (vutrisiran). Prescribing Information. Cambridge, MA: Alynlam Pharmaceuticals; Published: 6/2022.

Alnylam Pharmaceuticals, Inc.(2022) Onpattro (patisiran). Prescribing Information. Cambridge, MA: Alynlam Pharmaceuticals; Revised: 7/2022.
Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants.
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