Modifiedsierra health and lifePolicy 2025D0072N

RNA-Targeted Therapies (Amvuttra and Onpattro)

Defines medical necessity and coverage criteria for Amvuttra (vutrisiran) and Onpattro (patisiran) for cardiomyopathy and polyneuropathy of transthyretin-mediated (ATTR) amyloidosis for UnitedHealthcare Commercial members.

Policy Summary

Payersierra health and life

PolicyRNA-Targeted Therapies (Amvuttra and Onpattro)

Policy CodePolicy 2025D0072N

Change TypeCoverage criteria added and clarifiedmaterial clinical updates

Effective DateJun 1, 2025

Next Review DateN/A

Key ActionSubmit prior authorization with diagnostic confirmation of ATTR-CM, cardiology prescribing/consultation, FDA-consistent dosing, and documentation supporting NYHA I–III and authorization period up to 12 months.

SourceLink

POLICY UPDATE CHANGES

Removed language indicating Amvuttra (vutrisiran) and Onpattro (patisiran) are unproven and not medically necessary for the treatment of transthyretin (ATTR)-mediated amyloidosis with cardiomyopathy (ATTR-CM).

Added language to indicate Amvuttra (vutrisiran) is proven for the treatment of cardiomyopathy of wild-type (wtATTR) or hereditary transthyretin-mediated (hATTR) amyloidosis and is medically necessary when specific criteria are met.

Added detailed initial and continuation therapy coverage criteria for Amvuttra including diagnostic evidence, NYHA class I-III, NT-proBNP documentation, prior therapies or intolerance, prohibition on combination with other RNAi agents or TTR stabilizers, cardiology prescribing requirement, dosing per FDA, and authorization limits.

Added applicable ICD-10 diagnosis codes E85.0, E85.4, and E85.82.

Continuation of therapy requirements were added, including need for prior treatment with Amvuttra and documentation of positive clinical response.

Policy clarifies that Amvuttra must not be used in combination with RNA interference agents or transthyretin stabilizers.

12 monthsauthorization period

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J0225/J0222listed J-codes

Coverage Criteria for Amvuttra (vutrisiran) and Onpattro (patisiran)

Initial therapy — cardiomyopathy (Amvuttra/vutrisiran)

Amvuttra (vutrisiran) is medically necessary for treatment of cardiomyopathy of wild-type (wtATTR) or hereditary transthyretin-mediated (hATTR) amyloidosis when ALL of the following are met

Diagnosis of wild-type or hereditary ATTR-mediated amyloidosis with cardiomyopathy (ATTR-CM)

Diagnostic confirmation: One of: pathogenic TTR mutation (e.g., V30M); cardiac or noncardiac tissue biopsy confirming ATTR deposits; OR all of: echocardiogram or cardiac MRI suggestive of amyloidosis AND radionuclide imaging (99mTc-DPD, 99mTc-PYP, or 99mTc-HMDP) showing grade 2 or 3 cardiac uptake AND absence of light-chain (AL) amyloidosisgrade 2 or 3 uptake

Functional status and exclusions: Patient has NYHA Functional Class I, II, or III heart failure; patient is not receiving Amvuttra in combination with other RNA interference agents (e.g., patisiran, eplontersen, inotersen) or transthyretin stabilizers (e.g., tafamidis); prescribed by or in consultation with a cardiologist; dosing in accordance with FDA prescribing information; initial authorization for no more than 12 monthsNYHA I-III

NT-proBNP when combined with signs/symptoms may be required for diagnosis

Continuation therapy — cardiomyopathy (Amvuttra/vutrisiran)

Continuation is medically necessary when ALL of the following are met

Prior treatment: Patient has previously received treatment with Amvuttra for wtATTR or hATTR amyloidosis

Clinical response: Documentation of positive clinical response to Amvuttra (e.g., improved symptoms, quality of life, slowing of disease progression, decreased hospitalizations)

Functional status and exclusions: Patient continues to have NYHA Functional Class I, II, or III; patient is not receiving Amvuttra in combination with RNA interference agents or transthyretin stabilizers; prescribed by or in consultation with a cardiologist; dosing in accordance with FDA prescribing information; authorization for no more than 12 monthsNYHA I-III

Initial and continuation therapy — polyneuropathy (Amvuttra/vutrisiran and Onpattro/patisiran)

Medically necessary for hATTR amyloidosis with polyneuropathy when ALL of the following are met

Diagnosis and mutation: Diagnosis of hereditary (hATTR) amyloidosis with polyneuropathy AND documentation of a pathogenic TTR mutation (e.g., V30M)

Baseline neurologic/functional criteria: One of: baseline PND score ≤ IIIb; FAP Stage 1 or 2; NIS score ≥ 5 and ≤ 130; KPS score ≥ 60%PND ≤ IIIb; NIS 5–130; KPS ≥ 60%

Other criteria: Presence of clinical signs/symptoms of polyneuropathy; patient has not had a liver transplant (for initiation); patient is not receiving excluded combination therapies (specific exclusions differ by drug as noted in policy); prescribed by or in consultation with a neurologist; dosing in accordance with FDA prescribing information; initial authorization for no more than 12 months; continuation requires maintenance of baseline scores and documentation of clinical benefit

Not medically necessary / unproven indications

Unproven indications: Treatment of sensorimotor or autonomic neuropathy not related to hATTR amyloidosis; primary or leptomeningeal amyloidosis

Initial Therapy for Amvuttra (vutrisiran) — Medically Necessary

Covered when ALL of the following are met:

Diagnosis of wild-type or hereditary ATTR-mediated amyloidosis with cardiomyopathy (ATTR-CM)

Diagnostic evidence: Documentation of one of: pathogenic TTR mutation; cardiac or noncardiac tissue biopsy demonstrating histologic confirmation of ATTR deposits; OR echocardiogram or cardiac MRI suggestive of amyloidosis; OR radionuclide imaging (99mTc-DPD, 99mTc-PYP, or 99mTc-HMDP) showing grade 2 or 3 cardiac uptakegrade 2 or 3

Exclude AL amyloidosis: Absence of light-chain (AL) amyloidosis

Functional class: Patient has NYHA Functional Class I, II, or III heart failureNYHA I-III

Continuation of Therapy for Amvuttra (vutrisiran)

Covered when ALL of the following are met:

Prior treatment: Patient has previously received treatment with Amvuttra for wtATTR or hATTR amyloidosis

Clinical response: Documentation that the patient has experienced a positive clinical response to Amvuttra (e.g., improved symptoms, quality of life, slowing of disease progression, decreased hospitalizations)

Functional class maintained: Documentation that the patient continues to have NYHA Functional Class I, II, or III heart failureNYHA I-III

No combination therapy: Patient is not receiving Amvuttra in combination with RNA interference agents or transthyretin stabilizers

Initial and Continuation Therapy Criteria

Coverage for Amvuttra is provided when ALL of the following are met for initial therapy, and separate continuation criteria apply for ongoing authorization.

Initial Authorization: Prescribed by or in consultation with a cardiologist; dosing per FDA prescribing information; patient is not receiving Amvuttra in combination with RNA interference agents or transthyretin stabilizers; initial authorization is for no more than 12 months12 months

From policy requirements for initial therapy

Continuation of Therapy: Patient previously received Amvuttra for wtATTR or hATTR; documentation of positive clinical response (e.g., improved symptoms, QoL, slowed progression, decreased hospitalizations); patient continues to have NYHA Functional Class I, II, or III; not receiving excluded combination therapies; prescribed by or in consultation with a cardiologist; dosing per FDA labeling; authorization up to 12 months12 months

Continuation criteria require documented benefit

Clinical evidence summaries (informational)

Selected trial outcomes supporting use:

HELIOS-B (vutrisiran, ATTR-CM): Phase 3 randomized HELIOS-B (NCT04153149): 655 patients randomized; vutrisiran 25 mg every 12 weeks reduced risk of death and recurrent cardiovascular events versus placebo (HR 0.72; 95% CI 0.56–0.93; p=0.01) and improved 6-minute walk distance and KCCQ-OS versus placebo

Patients could be on tafamidis as background therapy; trial not powered for tafamidis subgroup

APOLLO (patisiran, hATTR polyneuropathy): Phase 3 APOLLO: patisiran improved mNIS+7 and multiple secondary endpoints versus placebo; cardiac subpopulation showed improvements in GLS, wall thickness, and NT-proBNP

Vutrisiran polyneuropathy study: Phase 3 randomized/open-label studies showed vutrisiran improved mNIS+7 and Norfolk QoL-DN at 9 months versus external/placebo comparisons; common adverse reactions included arthralgia, dyspnea, and decreased vitamin A; rare serious atrioventricular conduction events reported

The following uses are considered unproven and not medically necessary: treatment of sensorimotor or autonomic neuropathy that is not related to hereditary transthyretin-mediated (hATTR) amyloidosis, and treatment of primary or leptomeningeal amyloidosis. Requests for coverage for these indications do not meet the policy's medical necessity criteria and are considered non-covered.

This policy prohibits concurrent administration of Amvuttra with other transthyretin-directed RNA interference agents (for example, Onpattro/patisiran, Wainua/eplontersen, Tegsedi/inotersen) or with transthyretin stabilizers (for example, tafamidis/Vyndaqel or Vyndamax). Use in combination with these agents is an explicit exclusion and will trigger non-coverage or denial.

Amvuttra must not be used in combination with any other RNA interference agents (e.g., Onpattro/patisiran, Wainua/eplontersen, Tegsedi/inotersen) or with transthyretin stabilizers (e.g., Vyndaqel/Vyndamax [tafamidis]). Concurrent use with these specified agents is excluded under the policy.

Use of Amvuttra or Onpattro for neuropathies that are not caused by hATTR amyloidosis (for example, other sensorimotor or autonomic neuropathies) and use for primary or leptomeningeal amyloidosis are considered not medically necessary and are excluded from coverage.

Prior policy language stating that Amvuttra and Onpattro were unproven and not medically necessary for transthyretin-mediated cardiomyopathy (ATTR-CM) has been removed. The revised policy states that Amvuttra (vutrisiran) is proven for treatment of cardiomyopathy of wild-type (wtATTR) or hereditary (hATTR) transthyretin-mediated amyloidosis when the specified coverage criteria are met.

Operationally, concurrent administration of Amvuttra with the listed RNA interference agents or transthyretin stabilizers is not permitted and is an explicit coverage exclusion. Requests showing simultaneous use of Amvuttra with these agents will be denied; documentation must confirm the patient is not receiving combination therapy to meet authorization requirements.

Applicable Codes and Clinical Thresholds

Applicable HCPCS and ICD-10 Codesmixed

J0222	Injection, patisiran, 0.1 mg
J0225	Injection, vutrisiran, 1 mg
E85.0	Non-neuropathic heredofamilial amyloidosis
E85.1	Neuropathic heredofamilial amyloidosis
E85.4	Organ-limited amyloidosis
E85.82	Wild-type transthyretin-related (ATTR) amyloidosis

Applicable ICD-10 Diagnosis CodesICD-10

E85.0	Hereditary ATTR amyloidosis
E85.4	Organ-limited amyloidosis
E85.82	Other transthyretin-related amyloidosis

Added ICD-10 diagnosis codesICD-10

E85.0	Hereditary systemic amyloidosis
E85.4	Organ-limited amyloidosis
E85.82	Cardiac amyloidosis

Radionuclide cardiac uptake — key diagnostic threshold (grade 2 or 3)

Radionuclide cardiac uptake thresholdGrade 2 or 3 cardiac uptake on 99mTc-DPD, 99mTc-PYP, or 99mTc-HMDP imaging

Imaging modalities specified99mTc-DPD, 99mTc-PYP, or 99mTc-HMDP radionuclide imaging

Diagnostic contextRequired as part of diagnostic confirmation when echocardiogram or cardiac MRI is suggestive of amyloidosis

PND score — initiation and continuation threshold (≤ IIIb)

PND score for initiationBaseline polyneuropathy disability (PND) score ≤ IIIb

PND score for continuation

Provider Requirements, Prior Authorization, and Denial Triggers

Prior Authorization

Prior Authorization Required

Prior authorization is required for Amvuttra (vutrisiran) for the treatment of transthyretin-mediated (ATTR) amyloidosis with cardiomyopathy. Providers must obtain prior authorization before initiation and for continuation; initial and continuation authorizations are limited to no more than 12 months.

Prior authorization required for initial and continuation therapy
Initial and continuation authorizations limited to ≤ 12 months

Prior Authorization

Prior Authorization Requirements for Amvuttra

Specific prior authorization requirements for Amvuttra: requests must document diagnosis, prior treatment history (when applicable), prescribing clinician specialty or documented cardiology consultation, and that dosing follows FDA prescribing information. Initial and renewal requests should include evidence supporting medical necessity for cardiomyopathy indication.

Prescribed by or in consultation with a cardiologist
Dosing consistent with FDA prescribing information

Background and Definitions

Transthyretin (TTR) amyloidosis results from misfolded TTR protein forming extracellular amyloid fibrils that deposit in organs including the heart and peripheral nerves. The disease presents as either wild-type (wtATTR) or hereditary (hATTR) forms and can cause a restrictive cardiomyopathy characterized by symptoms such as dyspnea and edema, and/or a progressive sensorimotor and autonomic polyneuropathy. Small interfering RNA therapies (such as vutrisiran and patisiran) act by reducing hepatic TTR production through targeted degradation of TTR mRNA, lowering circulating TTR and potentially reducing further tissue amyloid deposition.

ATTR-CM definition — cardiomyopathy of wtATTR or hATTR and diagnostic approaches

DefinitionATTR-CM: cardiomyopathy of wild-type (wtATTR) or hereditary transthyretin-mediated (hATTR) amyloidosis

Diagnostic approachesDiagnosis may be by pathogenic TTR mutation, cardiac or noncardiac tissue biopsy confirming ATTR deposits, or imaging (echocardiogram/CMR) plus radionuclide imaging showing grade 2–3 uptake and absence of light-chain amyloidosis

Clinical significanceATTR-CM presents as restrictive cardiomyopathy with signs such as dyspnea and edema; therapies aim to reduce cardiovascular mortality and hospitalizations

Policy Summary

Payersierra health and life

PolicyRNA-Targeted Therapies (Amvuttra and Onpattro)

Policy CodePolicy 2025D0072N

Change TypeCoverage criteria added and clarifiedmaterial clinical updates

Effective DateJun 1, 2025

Next Review DateN/A

SourceLink

On This Page

NT-proBNP attestation: Physician attests that NT-proBNP level combined with signs and symptoms is definitive for a diagnosis of ATTR-CM

Heart failure evidence: Documentation of one of: history of heart failure with at least one prior hospitalization for heart failure; presence of signs and symptoms of heart failure (e.g., dyspnea, edema)

Prior therapy or intolerance: One of: documentation of progressive worsening or hospitalization related to ATTR-CM while on tafamidis (Vyndaqel/Vyndamax) or acoramidis (Attruby); OR documentation of intolerance or contraindication to both tafamidis formulations

No combination therapy: Patient is not receiving Amvuttra in combination with any RNA interference agents (e.g., patisiran, eplontersen, inotersen) or transthyretin stabilizers (e.g., tafamidis)

Prescriber and dosing: Prescribed by or in consultation with a cardiologist; dosing in accordance with FDA prescribing information

Initial authorization up to 12 months

Prescriber and dosing: Prescribed by or in consultation with a cardiologist; dosing in accordance with FDA prescribing information

Continuation authorization up to 12 months

Supportive heart failure evidence for consideration:

Documentation of one of: history of heart failure with at least one prior hospitalization OR presence of signs/symptoms of heart failure (dyspnea, edema); OR documentation of progressive worsening or hospitalization related to ATTR-CM while on tafamidis (or intolerance/contraindication to tafamidis)

From policy summary of changes

Patient continues to have PND score ≤ IIIb for continuation

Use contextPND used as one of the baseline neurologic/functional criteria for hATTR polyneuropathy coverage

NIS score — numeric range used in neuropathy criteria (≥ 5 and ≤ 130)

NIS score rangeNeuropathy Impairment Score (NIS) ≥ 5 and ≤ 130

Role in eligibilityNIS 5–130 used as an inclusion/baseline severity criterion in polyneuropathy trials and policy criteria

Continuation requirementFor continuation, patient must continue to have NIS within the documented range (≥5 and ≤130)

KPS score — functional threshold (≥ 60%)

KPS functional thresholdKarnofsky Performance Status (KPS) score ≥ 60%

Use in trialsKPS ≥ 60 required for eligibility in vutrisiran polyneuropathy studies

Continuation implicationPatients must continue to meet KPS threshold as part of ongoing therapy documentation when applicable

Radionuclide imaging uptake — cardiac uptake grade 2 or 3 cited

Cardiac uptake grade citedPolicy requires radionuclide imaging showing grade 2 or 3 cardiac uptake for diagnostic confirmation of ATTR-CM

Associated imaging modalities99mTc-DPD, 99mTc-PYP, or 99mTc-HMDP are the specified tracers for assessing uptake

Diagnostic combinationGrade 2–3 uptake is required along with echocardiogram/CMR suggestive of amyloidosis and absence of light-chain (AL) amyloidosis in defined diagnostic pathways

Authorization duration — initial and continuation authorization limits (up to 12 months)

Authorization duration (initial and continuation)Initial and continuation authorizations are each limited to no more than 12 months

Dosing requirementDosing must be in accordance with U.S. FDA prescribing information for duration determinations

Policy noteAuthorization limits are specified in the continuation and initial therapy sections and reflected in policy history

Initial and renewal requests require clinical justification and supporting documentation

Denial Risk

Diagnostic Confirmation and Combination-Therapy Exclusion

Diagnostic confirmation and combination-therapy exclusions must be documented. Requests lacking diagnostic confirmation or showing concurrent disallowed therapies may be denied.

Diagnostic confirmation options: pathogenic TTR mutation, tissue biopsy showing ATTR amyloid deposits, or compatible cardiac imaging plus radionuclide uptake (grade 2–3)
Patient must not be receiving Amvuttra in combination with RNAi agents (e.g., patisiran, eplontersen, inotersen) or transthyretin stabilizers (e.g., tafamidis, acoramidis)

Documentation Required

Required Clinical Documentation

Required clinical documentation for authorization includes confirmation of diagnosis, evidence of heart-failure status, prior treatment history or intolerance to stabilizers when applicable, and demonstration of clinical benefit for continuation requests.

Diagnosis of wild-type or hereditary ATTR-CM with one of: pathogenic TTR mutation; biopsy demonstrating ATTR deposits; or echocardiogram/CMR suggestive of amyloidosis plus radionuclide imaging (99mTc-DPD, 99mTc-PYP, or 99mTc-HMDP) showing grade 2–3 uptake and absence of light-chain amyloidosis
Documentation of NYHA Functional Class I–III and NT‑proBNP level supportive of ATTR‑CM diagnosis when combined with signs/symptoms
Evidence of prior hospitalization for heart failure or presence of signs/symptoms (e.g., dyspnea, edema)
Documentation of progressive worsening or hospitalization related to ATTR-CM while on tafamidis (Vyndaqel/Vyndamax) or acoramidis (Attruby), OR intolerance/contraindication to both tafamidis products when step-therapy considerations apply
For continuation: prior treatment with Amvuttra for wtATTR or hATTR cardiomyopathy and documentation of positive clinical response (e.g., improved symptoms, quality of life, slowed progression, decreased hospitalizations)

Step Therapy

Step Therapy / Prior Stabilizer Use

For patients with cardiomyopathy, step-therapy / prior-use considerations require documentation that either the patient experienced progressive worsening or a hospitalization while on transthyretin stabilizers (tafamidis or acoramidis), or that the patient has intolerance or contraindication to these agents.

Documentation of progression or hospitalization related to ATTR-CM while on Vyndaqel (tafamidis meglumine), Vyndamax (tafamidis), or Attruby (acoramidis)
Alternatively, documentation of intolerance or contraindication to both Vyndaqel/Vyndamax when applicable

ATTR-CM — definition and diagnostic support (duplicate/informational)

Definition (informational)Cardiomyopathy due to transthyretin amyloid deposition (wtATTR or hATTR); indication for vutrisiran includes reducing cardiovascular mortality and hospitalizations

Diagnostic supportSupported diagnostic methods include pathogenic TTR mutation, tissue biopsy, or imaging plus radionuclide uptake (grade 2–3)

Regulatory contextFDA indicates Amvuttra (vutrisiran) is indicated for cardiomyopathy of wild-type or hereditary ATTR to reduce CV mortality and events

PND, FAP, NIS, KPS — baseline neurologic/functional measures referenced for polyneuropathy

Baseline measures referencedPND score, FAP stage, NIS, and KPS are baseline neurologic/functional measures used for polyneuropathy criteria

Specific thresholdsPND ≤ IIIb; FAP Stage 1–2; NIS 5–130; KPS ≥ 60% are the policy-specified thresholds

Use for continuationContinuation requires maintenance of baseline scores (PND, FAP, NIS, or KPS) and documentation of positive clinical response

mNIS+7 — definition of modified Neuropathy Impairment Score +7 (informational)

mNIS+7 definitionModified Neuropathy Impairment Score +7 (mNIS+7) is a composite measure used to assess polyneuropathy severity (range 0–304; higher scores indicate greater severity)

Use in trialsmNIS+7 was the primary efficacy endpoint in APOLLO (patisiran) and in vutrisiran polyneuropathy studies

InterpretationChanges in mNIS+7 are used to demonstrate clinical benefit (improvement or slowed progression)

NYHA Functional Class — acceptable classes I–III cited for continuation

Acceptable NYHA classes for continuationNew York Heart Association (NYHA) Functional Class I, II, or III are acceptable for continuation of therapy

Documentation requirementContinuation documentation must show the patient continues to have NYHA class I–III

Functional status roleNYHA class is a required element in initial and continuation cardiomyopathy criteria

Combination exclusions — definition/summary of disallowed concurrent therapies

Combination therapy exclusionConcurrent use of Amvuttra with RNA interference agents (e.g., patisiran, eplontersen, inotersen) or transthyretin stabilizers (e.g., tafamidis) is not permitted and will trigger non-coverage/denial

Examples listedSpecifically names Onpattro (patisiran), Wainua (eplontersen), Tegsedi (inotersen), and tafamidis formulations as excluded agents

ApplicabilityExclusion applies to both initial and continuation therapy criteria for Amvuttra and relevant polyneuropathy agents