Premera Bluecross ATTR therapy Coverage Update

Coverage Criteria

Amvuttra (vutrisiran) — hATTR polyneuropathy

Covered when ALL of the following are met:

Amvuttra for hATTR polyneuropathy: The individual is aged >=18 years; diagnosis of hereditary transthyretin-mediated amyloidosis (hATTR) is verified by documentation of a mutation in the TTR gene OR tissue biopsy showing amyloid deposition; presence of symptoms consistent with polyneuropathy (peripheral sensorimotor or autonomic neuropathy); polyneuropathy disability (PND) score IIIb or less OR familial amyloid polyneuropathy (FAP) stage 2 or less; medication is not used in combination with Attruby (acoramidis), Onpattro (patisiran), Vyndamax (tafamidis), Vyndaqel (tafamidis meglumine), or Wainua (eplontersen); the individual does not have NYHA class III or IV heart failure, sensorimotor or autonomic neuropathy not related to hATTR (e.g., monoclonal gammopathy or autoimmune disease), or prior liver transplantation; medication is prescribed by or in consultation with physicians experienced in the treatment of ATTR amyloidosis (e.g., neurologist, cardiologist, geneticist); dose prescribed is 25 mg subcutaneously every 3 months.

Amvuttra (vutrisiran) — ATTR cardiomyopathy

Covered when ALL of the following are met:

Amvuttra for ATTR-CM: The individual is aged >=18 years; diagnosis of wild-type or hereditary transthyretin-mediated amyloidosis (ATTR-CM) is verified by documentation of a mutation in the TTR gene OR tissue biopsy showing amyloid deposition OR non-biopsy nuclear scintigraphy (e.g., PYP); echocardiographic evidence of cardiac involvement with end-diastolic interventricular septal wall thickness > 12 mm; clinical history of heart failure with at least one prior hospitalization for heart failure OR clinical evidence of heart failure requiring diuretics for volume overload/elevated intracardiac pressures; baseline NT-proBNP >= 300 pg/mL; NYHA class I-III heart failure; does not have light-chain amyloidosis, history of liver or heart transplantation, or a left ventricular assist device; completed a 6-minute walk test (6MWT) of at least 150 meters; medication is not used in combination with Attruby (acoramidis), Onpattro (patisiran), Vyndamax (tafamidis), Vyndaqel (tafamidis meglumine), or Wainua (eplontersen); medication is prescribed by or in consultation with physicians experienced in the treatment of ATTR amyloidosis; dose prescribed is 25 mg subcutaneously every 3 months.NT-proBNP >=300 pg/mL; septal thickness >12 mm; 6MWT >=150 m

Onpattro (patisiran) — hATTR polyneuropathy

Covered when ALL of the following are met:

Onpattro for hATTR polyneuropathy: The individual is aged >=18 years; diagnosis of hereditary transthyretin-mediated amyloidosis (hATTR) is verified by documentation of a mutation in the TTR gene OR tissue biopsy showing amyloid deposition; presence of symptoms consistent with polyneuropathy (peripheral sensorimotor or autonomic neuropathy); polyneuropathy disability (PND) score IIIb or less OR familial amyloid polyneuropathy (FAP) stage 2 or less; medication is not used in combination with Attruby (acoramidis), Amvuttra (vutrisiran), Vyndamax (tafamidis), Vyndaqel (tafamidis meglumine), or Wainua (eplontersen); the individual does not have NYHA class III or IV heart failure or prior liver transplantation; medication is prescribed by or in consultation with physicians experienced in the treatment of ATTR amyloidosis; dose based on actual body weight: <100 kg = 0.3 mg/kg IV every 3 weeks; >=100 kg = 30 mg IV every 3 weeks.

Infusion-related reaction risk noted in evidence; site-of-service review applies for IV administration.

Tafamidis (Vyndamax/Vyndaqel) — ATTR cardiomyopathy

Covered when ALL of the following are met:

Tafamidis for ATTR-CM: The individual is aged >=18 years; diagnosis of wild-type or hereditary transthyretin-mediated amyloidosis (ATTR-CM) is verified by documentation of a mutation in the TTR gene OR tissue biopsy showing amyloid deposition OR non-biopsy nuclear scintigraphy (e.g., PYP); echocardiographic evidence with end-diastolic interventricular septal wall thickness > 12 mm; clinical history of heart failure with at least one prior hospitalization OR clinical evidence requiring diuretics; baseline NT-proBNP >= 600 pg/mL; NYHA class I-III heart failure; does not have light-chain amyloidosis, history of liver or heart transplantation, or a left ventricular assist device; completed a 6-minute walk test (6MWT) of at least 150 meters; medication is not used in combination with Attruby (acoramidis), Amvuttra (vutrisiran), Onpattro (patisiran), or Wainua (eplontersen); medication is prescribed by or in consultation with physicians experienced in the treatment of ATTR amyloidosis; dose for Vyndamax is 61 mg orally once daily (Vyndaqel dosing specified separately).NT-proBNP >=600 pg/mL; septal thickness >12 mm; 6MWT >=150 m

Wainua (eplontersen) — hATTR polyneuropathy

Covered when ALL of the following are met:

Wainua for hATTR polyneuropathy: The individual is aged >=18 years; diagnosis of hereditary transthyretin-mediated amyloidosis (hATTR) is verified by documentation of a mutation in the TTR gene OR tissue biopsy showing amyloid deposition; presence of symptoms consistent with polyneuropathy (peripheral sensorimotor or autonomic neuropathy); polyneuropathy disability (PND) score IIIb or less OR familial amyloid polyneuropathy (FAP) stage 2 or less; medication is not used in combination with Attruby (acoramidis), Amvuttra (vutrisiran), Onpattro (patisiran), Vyndamax (tafamidis), or Vyndaqel (tafamidis meglumine); the individual does not have NYHA class III or IV heart failure or prior liver transplantation; medication is prescribed by or in consultation with physicians experienced in the treatment of ATTR amyloidosis; dose prescribed is 45 mg subcutaneously every 4 weeks.

Wainua is self-administered per product labeling.

Common exclusion criteria

The following conditions or histories exclude coverage for the agents addressed in this policy:

Exclusion conditions: Presence of light-chain (AL) amyloidosis; prior liver transplantation (for neuropathy indications); NYHA class III or IV heart failure for neuropathy indications where specified; sensorimotor or autonomic neuropathy not related to hATTR (e.g., monoclonal gammopathy or autoimmune disease); prior heart transplantation or left ventricular assist device for cardiomyopathy indications; use in combination with other listed ATTR agents contrary to the policy; other contraindications specified by drug-specific criteria.

Agent-specific evidence summaries

Informational summaries of key clinical trial evidence relevant to coverage:

Vutrisiran (Amvuttra) - evidence: HELIOS-A demonstrated vutrisiran improved neuropathy outcomes (mNIS+7) in hATTR-PN versus APOLLO placebo; HELIOS-B in ATTR-CM reduced all-cause mortality and recurrent cardiovascular events (28% overall risk reduction; 33% in monotherapy population) and improved 6MWT and KCCQ-OS at Month 30. Vutrisiran can reduce serum vitamin A; vitamin A supplementation and ophthalmology referral for suggestive symptoms are recommended.

Informational only; does not alter criteria logic.

Patisiran (Onpattro) - evidence: Patisiran 0.3 mg/kg IV Q3W demonstrated significant TTR knockdown and improvements in mNIS+7 and quality-of-life measures in the APOLLO and Phase 2 studies; common adverse events include infusion-related reactions and peripheral edema.

Informational only.

Tafamidis (Vyndamax/Vyndaqel) - evidence: The ATTR-ACT trial (30 months) showed pooled tafamidis reduced all-cause mortality and cardiovascular hospitalizations versus placebo (30% mortality reduction) and improved 6MWT and KCCQ-OS; subgroup benefit varied by NYHA class.

Diagnostic and prescriber criteria (updates)

Updated diagnostic confirmation and prescriber requirements (effective per policy history):

Diagnosis confirmation for hATTR: Documentation of a pathogenic mutation in the TTR gene OR tissue biopsy showing amyloid deposition is required for hATTR indications; the prior requirement for two confirmatory diagnostic tests has been removed.N/A

Applies to hATTR polyneuropathy indications.

Diagnosis confirmation for ATTR-CM: Documentation of a pathogenic mutation in the TTR gene OR tissue biopsy showing amyloid deposition OR non-biopsy nuclear scintigraphy (e.g., 99mTc-PYP) is required for ATTR-CM indications; the prior requirement for two confirmatory diagnostic tests has been removed.N/A

Applies to cardiomyopathy indications.

Prescriber qualifications: Medications must be prescribed by or in consultation with physicians experienced in the treatment of ATTR amyloidosis (e.g., neurologist, cardiologist, geneticist).

The following products are considered investigational when used for indications not explicitly described in this policy: Amvuttra (vutrisiran), Attruby (acoramidis), Onpattro (patisiran), Vyndamax (tafamidis), Vyndaqel (tafamidis meglumine), and Wainua (eplontersen). Coverage is limited to the conditions and specific clinical criteria detailed in this policy; use outside those criteria is not supported and will be treated as investigational.

Diagnosis of hereditary transthyretin-mediated amyloidosis (hATTR) should not rely on clinical signs alone because presentation is heterogeneous and nonspecific; misdiagnosis or delayed diagnosis is common. Definitive confirmation requires demonstration of amyloid deposition in tissue biopsy specimens (e.g., Congo red stain with supporting immunohistochemistry or mass spectrometry) and/or identification of a pathogenic transthyretin (TTR) gene variant by sequence analysis. For cardiomyopathy presentations (ATTR-CM), a non-biopsy diagnostic pathway using nuclear scintigraphy (e.g., 99mTc-PYP) is acceptable when interpreted with the required adjunct testing and absence of a monoclonal protein, as specified in the policy updates.

For cardiomyopathy indications, the policy explicitly excludes individuals with a left ventricular assist device (LVAD) or prior heart transplant from coverage for the listed therapies. The policy language was revised to replace broader wording about implanted cardiac devices with the specific exclusion for an LVAD. Additionally, providers should note that site-of-service review requirements for Amvuttra (vutrisiran) and Onpattro (patisiran) were added effective July 2, 2026.

The policy prohibits concurrent use of Wainua (eplontersen) with other approved TTR-lowering agents listed in this policy (for example, Amvuttra or Onpattro). Requests for combination therapy involving Wainua and any of the other named agents will be considered not medically necessary and are not eligible for coverage under this policy.

Coding and Diagnostic Thresholds

HCPCS / Billing codesHCPCS

C9399	Unclassified drugs or biologicals (used to report: Wainua)
J0222	Injection, patisiran (Onpattro), 0.1 mg
J0225	Injection, vutrisiran (Amvuttra), 1 mg
J3490	Unclassified drugs (use to report: Wainua)

Relevant HCPCS and coding historyHCPCS

J0225	HCPCS code for Amvuttra (vutrisiran) added
J0222	HCPCS code added (noted in history)
J3490	HCPCS misc code referenced in history
J3590	HCPCS misc code previously used for Amvuttra (removed)

inv-15: NT-proBNP baseline — thresholds

NT-proBNP baseline (Amvuttra - ATTR-CM)>= 300 pg/mL

NT-proBNP baseline (Tafamidis - ATTR-CM)>= 600 pg/mL

ContextBaseline NT-proBNP required as part of cardiac eligibility for ATTR-CM indications

inv-16: 6-Minute Walk Test (6MWT)

6-Minute Walk Test (6MWT)>= 150 meters

ApplicabilityRequired baseline functional assessment for ATTR-CM eligibility

Use in re-authorization

Provider Actions, Authorization, and Billing

Prior Authorization

Prior Authorization and Site-of-Service

Prior authorization required for the drugs listed in this policy. Documentation must verify the diagnosis and meet the specific diagnostic criteria described in the policy. Site-of-service determinations apply; certain hospital-based outpatient sites are considered not medically necessary when the site-of-service criteria in this policy are not met.

Prior authorization required for listed medications (see Coding block for HCPCS codes such as J0222, J0225, C9399, J3490).
Hospital-based outpatient infusion or clinic sites are considered not medically necessary for infusion/injectable therapy when the site-of-service criteria in this policy are not met. Exceptions exist for specific inpatient-level indications (e.g., grade 3–4 cytokine release syndrome requiring inpatient admission).
Medications may be managed under the pharmacy benefit (Attruby, Vyndaqel, Vyndamax) or medical benefit (Onpattro, Amvuttra); Wainua may be managed under either. Site-of-service review applies to Amvuttra and Onpattro.

Documentation Required

Required Diagnostic Documentation

Background

Hereditary transthyretin-mediated amyloidosis (hATTR) is an autosomal dominant disorder caused by pathogenic variants in the TTR gene that produce misfolded transthyretin protein. Abnormal TTR deposits systemically, most commonly causing a progressive sensorimotor and autonomic polyneuropathy and/or cardiomyopathy. Clinical presentation is variable in age of onset and rate of progression; therefore, objective diagnostic confirmation (tissue biopsy with demonstration of amyloid deposition and/or genetic testing) is required to establish the diagnosis and guide therapy. Pharmacologic treatment approaches in this policy include TTR gene-silencing agents and TTR stabilizers, which aim to reduce circulating TTR or stabilize the tetramer to slow disease progression and mitigate neuropathic and cardiac dysfunction.

Definitions

inv-33: hATTR — Hereditary transthyretin-mediated amyloidosis definition

DefinitionHereditary transthyretin-mediated amyloidosis (hATTR) is a disorder caused by mutation(s) in the TTR gene leading to misfolded transthyretin protein that deposits systemically (nerves, heart, GI tract, kidneys)

InheritanceTypically autosomal dominant

Clinical manifestationsMay present with polyneuropathy, cardiomyopathy, autonomic and other systemic symptoms

inv-34: PND score — Polyneuropathy Disability staging

PND score overviewPolyneuropathy Disability (PND) score stages neuropathy from 0 (no symptoms) to IV (wheelchair/bedridden)

Key stages0: no symptoms; I: sensory disturbances with preserved walking; II: impaired walking without aids; IIIA: walking with one stick/crutch; IIIB: walking with two sticks/crutches; IV: confined to wheelchair/bedridden

Initial Therapy Criteria

Initial authorization

Initial authorization durations and expectations:

Initial authorization: All drugs listed in this policy may be approved for an initial period of up to 12 months when drug-specific criteria are met.

Initiation evidence

Initiation evidence context (informational):

Patisiran initiation context: Patisiran 0.3 mg/kg IV every 3 weeks demonstrated efficacy for hATTR-PN in APOLLO and Phase 2 studies and is the regimen associated with highest TTR knockdown.

Informational.

Vutrisiran initiation context: Vutrisiran 25 mg subcutaneously every 3 months showed efficacy in HELIOS-A for hATTR-PN and HELIOS-B for ATTR-CM.

Continuation / Re-authorization Criteria

Re-authorization

Re-authorization requires ongoing demonstration of clinical benefit:

Re-authorization: Requires documented clinical efficacy (improved or stable motor, neurologic, or cardiac function, or serum TTR levels) AND improvement or stability in PND score or FAP stage for neuropathy indications OR improvement/stability in 6MWT or KCCQ-OS for cardiomyopathy indications AND absence of treatment-limiting toxicity.

Approval periods may be for 12 months.

Step Therapy and Sequencing

Re-authorization requirement
Re-authorization requires documented clinical efficacy (improved or stable motor, neurologic, or cardiac function or serum TTR levels) AND improvement or stability in PND score or FAP stage (for neuropathy) or in 6MWT/KCCQ-OS (for cardiomyopathy) AND absence of treatment‑limiting toxicity.

Trial context / step-therapy note
In HELIOS‑B, patients were permitted to be taking a tafamidis product at baseline or to initiate tafamidis during the double‑blind period; the trial stratified treatment by baseline tafamidis use but does not prescribe an explicit step‑therapy ordering in this policy excerpt.

Prior‑fail sequencing for Amvuttra
Policy history documents removal of the prior requirement to try and fail Onpattro or Tegsedi before Amvuttra; the current policy does not mandate prior‑failure of listed agents for Amvuttra.

Quantity Limits

inv-46: Vyndamax / Vyndaqel (tafamidis products) — quantity limits

Products affectedVyndamax (tafamidis) and Vyndaqel (tafamidis meglumine)

Policy actionQuantity limits have been added for tafamidis products in updated coverage criteria

ReferenceQuantity limits noted in 2024 and 2025 updates to tafamidis coverage language

Site of Care and Medical Necessity Review

Note

OpenPayer

Pharmacologic Treatment of Transthyretin-Mediated Amyloidosis

Coverage Criteria

Coding and Diagnostic Thresholds

Provider Actions, Authorization, and Billing

Background

Definitions

Initial Therapy Criteria

Continuation / Re-authorization Criteria

Step Therapy and Sequencing

Quantity Limits

Site of Care and Medical Necessity Review