CurrentPremera BluecrossPolicy 5.01.593

Pharmacologic Treatment of Transthyretin-Mediated Amyloidosis

Defines medical necessity, site-of-service review, age limits, drug-specific coverage criteria (Amvuttra/vutrisiran, Onpattro/patisiran, Attruby/acoramidis, Vyndamax/Vyndaqel/tafamidis, Wainua/eplontersen) for hereditary and wild-type transthyretin-mediated amyloidosis for medical and pharmacy benefits, including initial authorization and re-authorization requirements and coding guidance.

Policy Summary

PayerPremera Bluecross

PolicyPharmacologic Treatment of Transthyretin-Mediated Amyloidosis

Policy CodePolicy 5.01.593

Change TypeCriteria updates & additions (2024-2026)

Effective DateJul 2, 202626d

Next Review Date

Key ActionDocument diagnostic confirmation (TTR gene mutation, tissue biopsy, or PYP scintigraphy for ATTR-CM) and meet drug-specific clinical criteria prior to prior authorization; initial approvals up to 12 months.

SourceLink

POLICY UPDATE CHANGES

Added coverage criteria for Wainua (eplontersen) for treatment of hATTR-PN (2024 update).

Updated diagnostic confirmation requirements to allow TTR gene mutation or tissue biopsy and removed requirement for two confirmatory tests (2026 update).

Added coverage criteria for Attruby (acoramidis) for treatment of ATTR-CM (2025 update).

Changed exclusion from 'implanted cardiac device' to 'left ventricular assist device' for several agents (2026 update).

Added site-of-service review for Amvuttra and Onpattro effective July 2, 2026.

Removed Tegsedi (inotersen) from the medical policy after market withdrawal (2024-2025 updates).

Policy effective date updated to Jul. 2, 2026; last revised Mar. 10, 2026.

6Drugs with specific criteria in this part

12Key clinical thresholds/requirements listed

4Benefit management assignments

6Medications referenced historically/approved

2026-07-02Upcoming effective date of substantive changes

Coverage Summary

Policy 5.01.593 (effective Jul. 2, 2026; last revised Mar. 10, 2026) is CURRENT and defines medical necessity and site-of-service review for pharmacologic treatments that target transthyretin (TTR) for both hereditary (hATTR) and wild-type ATTR presenting with neuropathy and cardiomyopathy phenotypes. The scope includes drug-specific coverage criteria, initial authorization and re-authorization requirements, and coding guidance. The policy distinguishes benefit management: certain agents are managed under the medical benefit (e.g., Onpattro, Amvuttra), others under the pharmacy benefit (e.g., Attruby, Vyndamax/Vyndaqel), and at least one agent (Wainua) is managed under both medical and pharmacy benefits.

Key clinical thresholds

PND scoreCovered neuropathy indications require PND score ≤ IIIb

FAP stageCovered neuropathy indications require FAP stage ≤ 2

Echocardiography septal thicknessATTR-CM requires end-diastolic interventricular septal wall thickness > 12 mm

NT‑proBNP (Amvuttra/Attruby)Baseline NT‑proBNP ≥ 300 pg/mL for Amvuttra/Attruby cardiomyopathy criteria

NT‑proBNP (Vyndamax/Vyndaqel)Baseline NT‑proBNP ≥ 600 pg/mL for Vyndamax/Vyndaqel cardiomyopathy criteria

6‑Minute Walk Test (6MWT)Completed 6MWT of at least 150 meters required for ATTR-CM coverage

Age — site-of-service reviewSite-of-service medical necessity review applies to individuals aged ≥13 years

Age — drug-specific indicationsMost drug-specific covered indications apply to adults aged ≥18 years

Diagnostic non-biopsy option (ATTR-CM)ATTR‑CM may be confirmed by non‑biopsy nuclear scintigraphy (eg, 99mTc‑PYP) in lieu of biopsy/genetic testing

Medical Necessity Criteria (grouped by indication / purpose)

Investigational / Not Medically Necessary

All other uses not outlined in this policy are considered investigational

Investigational uses: Any use of Amvuttra, Attruby, Onpattro, Vyndamax, Vyndaqel, or Wainua for conditions not specifically covered in this policy is investigational.

Not Covered / Investigational Uses

All other uses not outlined in this policy are considered investigational

Investigational statement: All other uses not outlined in this policy are considered investigational.

Policy history and code groups note that Tegsedi (inotersen) was removed from the medical policy after manufacturer withdrawal (discontinued September 27, 2024) and that prior coding entries referencing Tegsedi and other products may be historical or removed. Examples of historical/removed HCPCS entries include codes previously used to report Tegsedi and other agents (e.g., J3490/J3590) and the J-codes currently referenced for patisiran and vutrisiran (J0222, J0225) and unclassified reporting for Wainua (C9399).

Coding

HCPCS / J-codes referencedHCPCS

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

Covered HCPCS/J-codes (historical examples)HCPCSCovered

J0225	Amvuttra (vutrisiran) (historical coding update added 01/01/23)
J0222	Historical code added 10/01/19 (coding update)

Removed/withdrawn product codingHCPCSNot Covered

J3490	Tegsedi (inotersen) previously reported; Tegsedi removed from policy after market withdrawal
J3590	Previously used for Amvuttra; removed

Provider Actions / Prior Authorization & Documentation

Prior Authorization

Prior authorization required / medical necessity review

Prior authorization is required for medical necessity review before initiating therapy. Initial approvals may be issued for up to 12 months. Claims for the listed drugs may require site-of-service review per the policy effective Jul 2, 2026.

Initial approval: up to 12 months
Affected HCPCS/Codes: J0222, J0225, C9399, J3490
Site-of-service review effective: 2026-07-02

Documentation Required

Diagnostic verification required

Diagnostic verification of transthyretin-mediated amyloidosis must be provided with the prior authorization request. Acceptable documentation includes genetic testing, tissue pathology, or (for cardiac involvement) nuclear scintigraphy per related information. Include documentation that signs and symptoms align with neuropathy and/or cardiomyopathy as applicable.

Background, Evidence & Definitions

Background emphasizes the rationale for diagnostic methods and the clinical scope: confirmatory testing may include tissue biopsy with Congo red / mass spectrometry and/or genetic testing of the TTR gene, and for cardiomyopathy noninvasive diagnosis using 99mTc‑PYP (bone scintigraphy) with grade 2/3 uptake or H/CL >1.5 is diagnostic of ATTR-CM in the absence of a monoclonal protein. The policy covers both hereditary and wild-type ATTR with neuropathy and cardiomyopathy phenotypes and references pivotal trials supporting the agents (e.g., HELIOS-A/HELIOS-B for vutrisiran, APOLLO/patisiran, ATTR-ACT/tafamidis, NEURO-TTRansform/eplontersen, and trials for acoramidis) while noting safety considerations (e.g., infusion‑related reactions with patisiran, vitamin A reduction with vutrisiran, general AE profiles) that inform monitoring and management; efficacy details and trial results are addressed in the evidence section.

evidence	summary
HELIOS-A / HELIOS-B (vutrisiran)
HELIOS-A: improvement in mNIS+7 at 9 and 18 months versus APOLLO placebo; HELIOS-B: 28% reduction in composite all-cause mortality and recurrent CV events, improved 6MWT and KCCQ-OS at Month 30
APOLLO (patisiran)
Patisiran demonstrated improved mNIS+7 and Norfolk QoL-DN; associated with infusion-related reactions and peripheral edema
ATTR-ACT (tafamidis)
Tafamidis reduced all-cause mortality and CV hospitalizations over 30 months; improved 6MWT and KCCQ-OS
NEURO-TTRansform (eplontersen / Wainua)
35-week interim analysis: lowered serum TTR, lessened neuropathic impairment, improved quality of life versus placebo
Regulatory approvals
Onpattro (2018), Amvuttra (2022 for hATTR-PN; 2025 for ATTR-CM), Wainua (2023), Vyndaqel/Vyndamax (2019), Attruby (2024) — FDA approval dates summarized

Glossary:

• PND score: Polyneuropathy disability score (0 no symptoms; I sensory disturbances; II impaired walking without stick; IIIA walking with one stick; IIIB walking with two sticks; IV wheelchair/bedridden).

• FAP stage: Familial amyloid polyneuropathy staging (0 no symptoms; 1 unimpaired ambulation; 2 assistance with ambulation required; 3 wheelchair-bound or bedridden).

• ATTR-CM: Cardiomyopathy of wild-type or hereditary transthyretin-mediated amyloidosis.

• 6MWT: Six-minute walk test; distance walked in six minutes (policy threshold: ≥ 150 meters for cardiomyopathy coverage).

• NT‑proBNP: N-terminal pro b-type natriuretic peptide; baseline thresholds specified by agent (e.g., ≥ 300 pg/mL for some agents, ≥ 600 pg/mL for tafamidis formulations).

Revision History

2026-07-02revisedLatest

Policy effective date updated to Jul. 2, 2026; last revised Mar. 10, 2026. (Administrative effective date change)

2024-03-01added

Added coverage criteria for Wainua (eplontersen) for treatment of hATTR-PN; Wainua may not be used in combination with Amvuttra, Onpattro, or Tegsedi. (MATERIAL CHANGE)

2026-04-01revised

Updated diagnostic confirmation requirements to require documentation of a TTR gene mutation or tissue biopsy and removed requirement for two confirmatory tests; for ATTR-CM allowed non-biopsy nuclear scintigraphy (PYP). (MATERIAL CHANGE)

Policy Summary

PayerPremera Bluecross

PolicyPharmacologic Treatment of Transthyretin-Mediated Amyloidosis

Policy CodePolicy 5.01.593

Change TypeCriteria updates & additions (2024-2026)

Effective DateJul 2, 202626d

Next Review Date

SourceLink

On This Page

Documentation of a pathogenic/likely pathogenic TTR gene mutation OR
Tissue biopsy showing amyloid deposition with appropriate typing (e.g., mass spectrometry or immunohistochemistry) OR
For ATTR-CM: non-biopsy diagnostic nuclear scintigraphy (e.g., 99mTc-PYP/DPD/HMDP) consistent with ATTR when light-chain (AL) amyloidosis has been excluded

Documentation Required

Functional and biomarker data required for ATTR-CM

For ATTR-CM (cardiomyopathy) patients, provide baseline functional and biomarker data to support medical necessity and to enable re-authorization assessments.

Transthoracic echocardiography: interventricular septal wall thickness (end diastolic) > 12 mm
Baseline NT-proBNP: ≥ 300 pg/mL
NYHA functional class: I–III documented
History of prior heart failure hospitalization OR clinical evidence of heart failure with volume overload or need for diuretics
Completed 6-minute walk test (6MWT) with distance ≥ 150 meters

Documentation Required

Prescriber specialty requirement

Medications must be prescribed by, or in consultation with, clinicians experienced in ATTR amyloidosis management. Include specialty and consultant details in the documentation to ensure expertise (e.g., neurologist, cardiologist, geneticist).

Prescriber specialty: neurologist, cardiologist, geneticist, or other clinician experienced in ATTR amyloidosis
If prescribed in consultation, include consultant name, specialty, and consultation note

Denial Risk

Combination therapy exclusion

Use of an authorized agent in combination with other ATTR-directed therapies is excluded; claims may be denied when combination therapy with the listed agents is billed. Verify intended therapy and do not co-administer with prohibited agents without prior approval.

Combination therapy exclusion — claims may be denied if medication is used in combination with: Attruby (acoramidis), Onpattro (patisiran), Vyndamax (tafamidis), Vyndaqel (tafamidis meglumine), Wainua (eplontersen)
Wainua-specific prohibition: concurrent use of eplontersen with listed agents is not allowed

Documentation Required

Re-authorization evidence

For continuation/reevaluation (re‑authorization), submit objective evidence of clinical efficacy and tolerability. Documentation should demonstrate stabilization or improvement in neurologic or cardiac disease markers and absence of significant drug toxicity.

Neuropathy measures: PND/FAP stage or documented change in neuropathic symptoms/function
6MWT: distance and trend compared with baseline
Kansas City Cardiomyopathy Questionnaire – Overall Summary (KCCQ‑OS) when used for ATTR‑CM monitoring
Serum transthyretin (TTR) level if available to document pharmacodynamic effect
Document absence of treatment-limiting toxicity or serious adverse events

Prior Authorization

Prior authorization/site-of-service review

Prior authorization and site-of-service review apply to Amvuttra (vutrisiran) and Onpattro (patisiran) effective July 2, 2026. Providers will receive a 90‑day notification when site-of-service criteria affect coverage. Include the HCPCS codes for these agents in the request.

Site-of-service review effective date: 2026-07-02
Provider notification window: 90 days when site-of-service criteria apply
Affected codes: J0225 (Amvuttra), J0222 (Onpattro)

Billing Rule

Adherence to FDA dosing and administration

Dosing and administration must follow FDA-approved labeling. Non-formulary exceptions may be considered and, if approved, may be authorized for up to 12 months. Include prescribed dose, frequency, route, and rationale when requesting exceptions.

Adhere to FDA dosing and administration for each agent
Non-formulary exception approvals: may be granted up to 12 months

• Wild-type: TTR protein is normal, with no documented mutations.

2025-01-01added

Added coverage criteria for Attruby (acoramidis) for treatment of ATTR-CM; included agent-specific cardiac criteria, 6MWT requirement, and quantity limits. (MATERIAL CHANGE)

2026-04-01revised

Changed exclusion language from 'implanted cardiac device' to 'left ventricular assist device' for several agents and clarified wild-type definition and prescriber specialty requirements. (MATERIAL CHANGE)

2026-07-02addedLatest

Added site-of-service review for Amvuttra (vutrisiran) and Onpattro (patisiran) effective July 2, 2026 following 90-day provider notification. (MATERIAL CHANGE)

2024-09-27removed

Removed Tegsedi (inotersen) from the medical policy after manufacturer discontinued the product on September 27, 2024; removal not related to safety/quality. (MATERIAL CHANGE)