Premera Bluecross ATTR therapy Coverage Update

Coverage Criteria by Indication and Agent

Amvuttra — hATTR polyneuropathy

Amvuttra (vutrisiran) may be considered medically necessary for hATTR polyneuropathy when ALL of the following are met:

Amvuttra hATTR polyneuropathy criteria: Individual is aged >= 18 years; diagnosis of hereditary transthyretin-mediated amyloidosis verified by documentation of a mutation in the TTR gene OR tissue biopsy showing amyloid deposition; presence of symptoms consistent with polyneuropathy of hereditary transthyretin amyloidosis (peripheral sensorimotor OR autonomic); PND score IIIb or less OR FAP stage 2 or less; medication is not used in combination with Attruby (acoramidis), Onpattro (patisiran), Vyndamax (tafamidis), Vyndaqel (tafamidis meglumine), or Wainua (eplontersen); individual does not have NYHA class III or IV heart failure, sensorimotor/autonomic neuropathy not related to hATTR (e.g., monoclonal gammopathy or autoimmune disease), or prior liver transplantation; medication prescribed by or in consultation with physicians experienced in the treatment of ATTR amyloidosis (e.g., neurologist, cardiologist, geneticist); dose = 25 mg subcutaneously every 3 months.PND <= IIIb or FAP <= stage2

Includes prohibition on combination therapy and provider specialty requirement

Amvuttra — ATTR cardiomyopathy

Amvuttra (vutrisiran) may be considered medically necessary for ATTR-CM when ALL of the following are met:

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

Combination therapy prohibited; specific exclusions listed

Attruby (acoramidis) — ATTR cardiomyopathy

Attruby (acoramidis) may be considered medically necessary for ATTR-CM when ALL of the following are met:

Attruby ATTR-CM criteria: Individual is aged >= 18 years; diagnosis of wild-type or hereditary transthyretin-mediated amyloidosis verified by documentation of a mutation in the TTR gene OR tissue biopsy showing amyloid deposition OR non-biopsy nuclear scintigraphy; evidence of cardiac involvement with end-diastolic interventricular septal wall thickness > 12 mm on transthoracic echocardiography; clinical history of heart failure with at least one prior hospitalization for heart failure OR clinical evidence of heart failure warranting diuretic treatment; 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 6-minute walk test >= 150 meters; medication is not used in combination with Amvuttra (vutrisiran), Onpattro (patisiran), Vyndamax (tafamidis), Vyndaqel (tafamidis meglumine), or Wainua (eplontersen); medication prescribed by or in consultation with physicians experienced in ATTR amyloidosis; dose = 712 mg orally twice daily.NT-proBNP >=300 pg/mL; 6MWT >=150 m; LV septal thickness >12 mm

Managed under pharmacy benefit; combination therapy prohibited

Onpattro — hATTR polyneuropathy

Onpattro (patisiran) may be considered medically necessary for hATTR polyneuropathy when ALL of the following are met:

Onpattro hATTR polyneuropathy criteria: Individual is aged >= 18 years; diagnosis of hereditary transthyretin-mediated amyloidosis verified by documentation of a mutation in the TTR gene OR tissue biopsy showing amyloid deposition; presence of symptoms consistent with polyneuropathy of hereditary transthyretin amyloidosis (peripheral sensorimotor OR autonomic); PND score IIIb or less OR FAP stage 2 or less; medication is not used in combination with Attruby (acoramidis), Amvuttra (vutrisiran), Vyndamax (tafamidis), Vyndaqel (tafamidis meglumine), or Wainua (eplontersen); individual does not have NYHA class III or IV heart failure, sensorimotor/autonomic neuropathy not related to hATTR, or prior liver transplantation; medication prescribed by or in consultation with physicians experienced in 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.PND <= IIIb or FAP <= stage2

Weight-based dosing specified

Vyndamax/Vyndaqel — ATTR cardiomyopathy

Vyndamax (tafamidis) and Vyndaqel (tafamidis meglumine) may be considered medically necessary for ATTR-CM when ALL of the following are met:

Tafamidis ATTR-CM criteria: Individual is aged >= 18 years; diagnosis of wild-type or hereditary transthyretin-mediated amyloidosis verified by documentation of a mutation in the TTR gene OR tissue biopsy showing amyloid deposition OR non-biopsy nuclear scintigraphy; evidence of cardiac involvement with end-diastolic interventricular septal wall thickness > 12 mm on transthoracic echocardiography; clinical history of heart failure with at least one prior hospitalization for heart failure OR clinical evidence of heart failure warranting diuretic treatment; baseline NT-proBNP >= 600 pg/mL (policy-specified threshold for tafamidis); 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 6-minute walk test >= 150 meters; medication is not used in combination with Attruby (acoramidis), Amvuttra (vutrisiran), Onpattro (patisiran), or Wainua (eplontersen); medication prescribed by or in consultation with physicians experienced in ATTR amyloidosis; dose: Vyndaqel 80 mg orally once daily (Vyndamax dosing specified in policy); quantity limits applied per policy.NT-proBNP >=600 pg/mL; 6MWT >=150 m; LV septal thickness >12 mm

Managed under pharmacy benefit; combination therapy prohibited

Wainua — hATTR polyneuropathy

Wainua (eplontersen) may be considered medically necessary for hATTR polyneuropathy when ALL of the following are met:

Wainua hATTR polyneuropathy criteria: Individual is aged >= 18 years; diagnosis of hereditary transthyretin-mediated amyloidosis verified by documentation of a mutation in the TTR gene OR tissue biopsy showing amyloid deposition; presence of symptoms consistent with polyneuropathy of hereditary transthyretin amyloidosis; PND score IIIb or less OR FAP stage 2 or less; medication is not used in combination with Attruby (acoramidis), Amvuttra (vutrisiran), Onpattro (patisiran), Vyndamax (tafamidis), or Vyndaqel (tafamidis meglumine); individual does not have NYHA class III or IV heart failure, sensorimotor/autonomic neuropathy not related to hATTR, or prior liver transplantation; medication prescribed by or in consultation with physicians experienced in ATTR amyloidosis; dose = 45 mg subcutaneously every 4 weeks; note that Wainua may not be used in combination with Amvuttra, Onpattro, or Tegsedi.PND <= IIIb or FAP <= stage2

Managed under both pharmacy and medical benefits; investigational uses not outlined are considered investigational

Covered indications (agent-level)

Therapies discussed with evidence and indications in this section

Approved indications: Patisiran (Onpattro), vutrisiran (Amvuttra), and eplontersen (Wainua) are indicated for treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults; vutrisiran and other agents have approvals for ATTR-CM (vutrisiran, tafamidis, acoramidis) as described in regulatory summaries.

See Regulatory Status for agent-specific FDA approvals.

Drug-specific coverage groups (hATTR polyneuropathy, ATTR-CM)

Policy covers specific listed medications when diagnostic and clinical criteria are met.

hATTR (polyneuropathy) coverage: For Amvuttra, Onpattro, and Wainua: require documentation of a mutation in the TTR gene or tissue biopsy showing amyloid deposition; Wainua may not be used in combination with Amvuttra, Onpattro, or Tegsedi; prescribing by or in consultation with an experienced clinician is required.

Removed prior requirement for two confirmatory diagnostic tests.

ATTR-CM (cardiomyopathy) coverage: For Amvuttra, Attruby, Vyndamax/Vyndaqel and others: require documentation of a mutation in the TTR gene, tissue biopsy showing amyloid deposition, or non-biopsy nuclear scintigraphy; ensure cardiac involvement (e.g., septal thickness >12 mm, history of heart failure) and baseline NT-proBNP thresholds where specified (e.g., >= 600 pg/mL for tafamidis) and completed 6MWT where required; absence of LVAD and other exclusions as specified.NT-proBNP >= 600 pg/mL; septal thickness >12 mm

NYHA class IV exclusion removed for tafamidis; implanted cardiac device wording changed to LVAD.

Coverage is denied when the individual has conditions explicitly excluded by the policy. The policy lists light-chain (AL) amyloidosis and sensorimotor or autonomic neuropathy not related to hATTR (for example, monoclonal gammopathy or autoimmune disease) as exclusions; these must be absent for coverage. The policy also excludes individuals with advanced heart failure: specifically New York Heart Association (NYHA) class III or IV is cited as an exclusion for neuropathy indications and remains an exclusion in several agent-specific criteria unless otherwise noted in later tafamidis updates.

Prior organ transplantation is an exclusion for certain agents: the policy requires that the individual not have a history of prior liver transplantation (and for some cardiomyopathy criteria not have a history of heart or liver transplantation). The presence of a mechanical circulatory support device is also excluded where specified — the guidance was updated to refer to an implanted cardiac device as a left ventricular assist device (LVAD) in the ATTR-CM criteria.

The policy prohibits combination therapy with other listed, ATTR-targeted agents. For all included products the medication must not be used in combination with other listed ATTR therapies (examples named in the policy include Amvuttra, Attruby, Onpattro, Vyndamax/Vyndaqel, and Wainua), and use in combination may trigger noncoverage or denial.

The policy requires objective confirmation of ATTR before approving ATTR-directed therapies. For hATTR indications this means documented evidence of amyloid deposition on tissue biopsy or identification of a pathogenic TTR gene mutation. Biopsy confirmation may include Congo red staining with supportive studies (e.g., immunohistochemistry or mass spectrometry) as described in the diagnostic section.

For ATTR cardiomyopathy (ATTR-CM) the policy allows diagnosis by tissue biopsy, documented pathogenic TTR mutation, or non-biopsy nuclear scintigraphy (e.g., 99mTc-PYP) when used in the absence of a monoclonal protein. The policy cites the established non-biopsy imaging criterion of grade 2/3 cardiac uptake or heart-to-contralateral-lung (H/CL) ratio > 1.5 when monoclonal protein is absent.

The policy emphasizes that lack of appropriate diagnostic confirmation — specifically absence of biopsy-proven amyloid deposition or a pathogenic TTR variant, or failure to demonstrate absence of a monoclonal protein when relying on 99mTc-PYP — may lead to denial of coverage for ATTR-targeted therapy.

The policy explicitly prohibits concurrent use of certain agents. Of note, Wainua (eplontersen) may not be used in combination with Amvuttra (vutrisiran), Onpattro (patisiran), or Tegsedi (inotersen); the 2024 update added this specific combination exclusion and combination use is a trigger for denial.

More generally, each drug-specific section reiterates that the medication must not be used in combination with other listed ATTR agents (examples across the policy include Attruby, Amvuttra, Onpattro, Vyndamax, Vyndaqel, and Wainua). Use in combination with another listed agent is an exclusion and may result in noncoverage.

The policy also calls out device-related exclusions in ATTR-CM criteria: individuals must not have an implanted mechanical circulatory support device. The wording in recent updates uses left ventricular assist device (LVAD) as the device exclusion for cardiomyopathy-related drug coverage.

The policy states that any use of the listed agents that is not specifically described in the coverage criteria is considered investigational and not medically necessary. This applies to Amvuttra, Attruby, Onpattro, Vyndamax, Vyndaqel, Wainua and other listed products when used outside the documented, agent-specific indications and criteria.

The policy also reminds providers that medications are subject to the product's FDA dosing and administration prescribing information, and investigational classification will apply where the use falls outside those approved or policy-specified indications.

Tegsedi (inotersen) has been removed from the policy because the manufacturer withdrew the product from the market. The policy notes that Tegsedi was discontinued by the manufacturer on September 27, 2024, and the removal from the medical policy reflects that market withdrawal.

The document clarifies the removal was due to manufacturer discontinuation (reported as low utilization) and not related to manufacturing, quality, or safety concerns; as a result, Tegsedi is no longer included among covered or criteria-specified therapies in this policy.

Coding and Diagnostic Thresholds

HCPCS/Billing codes referencedHCPCS

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)

Historical/Policy HCPCS updatesHCPCS

J0222	HCPCS code added Oct 1, 2019 (historical note)
J0225	HCPCS code for Amvuttra (added 01/01/23)

inv-16: Echocardiographic LV septal thickness — > 12 mm

Echocardiographic LV septal thickness> 12 mm

ContextRequired evidence of cardiac involvement on transthoracic echocardiography for ATTR-CM coverage

Applies toAmvuttra, Attruby, Vyndamax/Vyndaqel (per ATTR-CM criteria)

inv-17: 6-Minute Walk Test (6MWT) — >= 150 meters

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

RequirementCompleted 6MWT of at least 150 meters is required for ATTR-CM coverage

Prior Authorization, Documentation, and Denial Triggers

Prior Authorization

Benefit management and PA

Prior authorization is required for all drugs listed in this policy. Benefit routing depends on the medication: Attruby (acoramidis), Vyndaqel (tafamidis meglumine), and Vyndamax (tafamidis) are managed through the pharmacy benefit; Onpattro (patisiran) and Amvuttra (vutrisiran) are managed through the medical benefit; Wainua (eplontersen) is managed through both the pharmacy and medical benefits. Prior authorization approvals may be granted for up to 12 months. Non-formulary exception review authorizations for all listed drugs may also be approved up to 12 months.

Prior authorization required for all policy-listed medications
Pharmacy benefit: Attruby, Vyndaqel, Vyndamax
Medical benefit: Onpattro, Amvuttra
Both pharmacy and medical benefits: Wainua
Initial and reauthorization approvals: up to 12 months

Denial Risk

Combination therapy and exclusion conditions

Initial Therapy Authorization Criteria

Initial therapy authorization

Initial approvals

Initial authorization period: All drugs listed in the policy may be approved for up to 12 months initially when the applicable drug-specific criteria are met.

Initial therapy dosing evidence

Trial dosing regimens supporting initial therapy

Patisiran regimen: Patisiran (Onpattro) dosing used in trials: 0.3 mg/kg IV every 3 weeks demonstrated efficacy in hATTR-PN studies and produced the highest TTR knockdown in trials.

Supported by Phase 2 and APOLLO trials.

Vutrisiran regimen: Vutrisiran (Amvuttra) dosing used in trials: 25 mg subcutaneously every 3 months (HELIOS-A and HELIOS-B trials).

Re-authorization and Continuation Requirements

Re-authorization

Re-authorization for Amvuttra, Onpattro, and Wainua for hATTR; and for Amvuttra, Attruby, Vyndamax, and Vyndaqel for ATTR-CM

Re-authorization requirements: Continued approval (periods up to 12 months) requires documentation of clinical efficacy in the medical record indicating positive clinical response (e.g., improved or stable motor, neurologic, or cardiac function, or serum TTR levels) AND improvement or stability in PND score or FAP stage for hATTR OR improvement/stability in 6MWT/KCCQ-OS for ATTR-CM AND absence of treatment-limiting toxicity.

Continuation considerations

Safety monitoring and long-term use considerations noted in trials

Vitamin A monitoring for vutrisiran: Vutrisiran (Amvuttra) can cause reduced serum vitamin A levels; patients should supplement with the recommended daily allowance and be referred to ophthalmology for ocular symptoms suggestive of vitamin A deficiency.

Observed low vitamin A levels developed in ~80% of those with normal baseline in HELIOS-B.

Step Therapy and Prior Failures

Re-authorization requirement	Details
Evidence of clinical response or stability required for re-authorization	Continued approval for up to 12 months requires documentation in the medical record of positive clinical response (e.g., improved or stable motor, neurologic, or cardiac function, or serum TTR levels), improvement or stability in PND score or FAP stage for hATTR (or improvement/stability in 6MWT or KCCQ-OS for ATTR-CM), and absence of treatment-limiting toxicity.

Step therapy context	Policy note
Multiple agents available for ATTR-CM and hATTR-PN	Clinical context: several approved agents exist for polyneuropathy and cardiomyopathy (e.g., patisiran, vutrisiran, eplontersen, tafamidis, acoramidis). Specific step requirements are not specified in this policy excerpt and would depend on the member's benefit rules and comparative indications; trials supporting respective agents are summarized in the policy (e.g., HELIOS-B for vutrisiran, acoramidis and tafamidis trials).

Step therapy context

Policy note

Multiple agents available for ATTR-CM and hATTR-PN

Clinical context: several approved agents exist for polyneuropathy and cardiomyopathy (e.g., patisiran, vutrisiran, eplontersen, tafamidis, acoramidis). Specific step requirements are not specified in this policy excerpt and would depend on the member's benefit rules and comparative indications; trials supporting respective agents are summarized in the policy (e.g., HELIOS-B for vutrisiran, acoramidis and tafamidis trials).

Prior failure required	Policy change/history
No prerequisite failure required for Amvuttra	Policy history: as of 02/01/23 the prior requirement to try and fail Onpattro or Tegsedi before Amvuttra was removed; Amvuttra does not require prior failure of those agents per the updated policy wording.

Quantity Limits and Dosing Constraints

inv-51: Vyndamax/Vyndaqel — quantity limits added

Quantity limits addedVyndamax (tafamidis) and Vyndaqel (tafamidis meglumine) have quantity limits added to the policy

Benefit routingTafamidis formulations are managed under the pharmacy benefit per the policy

PurposeQuantity limits implemented as part of 2024–2025 coverage updates

Benefit Routing and Administration Setting

Billing Rule

Benefit routing — which agents are medical vs pharmacy benefit

Routing to medical versus pharmacy benefit depends on the agent: Onpattro and Amvuttra are managed under the medical benefit; Attruby, Vyndaqel, and Vyndamax are managed under the pharmacy benefit; Wainua may be managed under both.

Verify benefit (medical vs pharmacy) before submitting the authorization and billing claim.
Use the appropriate billing codes and claim type for the benefit managing the agent.

Note

Mixed administration settings — self‑administered vs infusion agents

Some agents are self-administered while others require infusion or administration in a clinical setting: Wainua is self-administered; patisiran (Onpattro) is administered as an IV infusion and requires an infusion setting.

Background and Clinical Context

Transthyretin-mediated (TTR) amyloidosis is caused by misfolding of the transthyretin protein, either due to pathogenic mutations (hereditary, hATTR) or age-related changes in the normal TTR protein (wild-type), leading to systemic deposition of amyloid fibrils in tissues.

Clinical manifestations center on two dominant phenotypes: polyneuropathy (progressive peripheral sensorimotor and autonomic neuropathy) and cardiomyopathy (restrictive cardiomyopathy with heart failure). Treatments addressed in this policy act by reducing hepatic TTR production (RNA-targeted therapies/antisense oligonucleotides) or stabilizing TTR to slow further fibril formation.

Diagnosis requires objective confirmation: for hATTR this is typically a pathogenic TTR gene mutation or biopsy-proven amyloid deposition; for ATTR-CM noninvasive diagnosis may be made with 99mTc-PYP imaging (grade 2/3 uptake or H/CL ratio > 1.5) when a monoclonal protein has been excluded. Early and accurate diagnosis is important because clinical presentation is heterogeneous and misdiagnosis or delay is common.

Definitions and Key Terms

inv-37: hATTR definition — hereditary transthyretin-mediated amyloidosis

DefinitionHereditary transthyretin-mediated amyloidosis (hATTR): disease caused by TTR gene mutation leading to systemic amyloid deposition

PathophysiologyMutations destabilize TTR causing misfolding and extracellular amyloid fibril deposition affecting nerves, heart, GI, kidneys

Clinical manifestationsMay include polyneuropathy, cardiomyopathy, autonomic dysfunction, and other multisystem symptoms

inv-38: PND score — polyneuropathy disability scoring details and permitted thresholds

PND score descriptionPND score ranges from 0 (no symptoms) to IV (confined to wheelchair or bedridden); clinical descriptors for 0–IV provided in policy

Permitted threshold for neuropathy indications

OpenPayer

Pharmacologic Treatment of Transthyretin-Mediated (ATTR) Amyloidosis