CurrentColorado Rocky Mountain Health PlansPolicy CS2026D0072R

RNA-Targeted Therapies (Amvuttra and Onpattro)

Defines medical necessity, coverage criteria, and coding for Amvuttra (vutrisiran) and Onpattro (patisiran) for treatment of ATTR cardiomyopathy and hereditary ATTR polyneuropathy; applies to UnitedHealthcare Community Plan medical benefit drug policy populations except listed state-specific exceptions.

Policy Summary

PayerColorado Rocky Mountain Health Plans

PolicyRNA-Targeted Therapies (Amvuttra and Onpattro)

Policy CodePolicy CS2026D0072R

Change TypeNo material change

Effective DateApr 1, 2026

Next Review Date

Key ActionSubmit prior authorization with documentation of diagnosis, genetic or biopsy/radionuclide confirmation, baseline severity measures, and prior therapies or intolerance as applicable.

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

J0222, J0225HCPCS codes referenced

655Patients randomized (HELIOS-B)

0.72Vutrisiran primary HR (HELIOS-B)

87.8%Patisiran mean TTR reduction (APOLLO)

≤12 moAuth duration

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Coverage Criteria for Amvuttra and Onpattro

Amvuttra for ATTR cardiomyopathy — Initial Therapy

Covered 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; OR cardiac or noncardiac tissue biopsy demonstrating histologic confirmation of ATTR amyloid 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) amyloidosis

Functional status and biomarkers: New York Heart Association (NYHA) Functional Class I, II, or III AND physician attestation that NT-proBNP level combined with signs and symptoms is definitive for ATTR-CM

Prior therapy / disease course: One of: documentation of progressive worsening or hospitalization related to hATTR-mediated amyloidosis; OR documentation of intolerance or contraindication to tafamidis and acoramidis when step-therapy applies

Commercial step therapy/prior treatment requirement may apply

Concomitant therapy and prescriber: 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 per FDA prescribing information; initial authorization for no more than 12 months

Amvuttra for ATTR cardiomyopathy — Continuation of Therapy

Covered when ALL of the following are met for continuation:

Prior treatment: Patient has previously received treatment with Amvuttra for ATTR-CM

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

Functional status: Patient continues to have NYHA Functional Class I, II, or III heart failure

Concomitant therapy and prescriber: Patient is not receiving Amvuttra in combination with other RNA interference agents or transthyretin stabilizers; prescribed by or in consultation with a cardiologist; dosing per FDA prescribing information; authorization for no more than 12 months

Amvuttra or Onpattro for hATTR polyneuropathy — Initial Therapy

Covered when ALL of the following are met:

Diagnosis and genetics: Diagnosis of hereditary transthyretin-mediated (hATTR) amyloidosis with polyneuropathy AND documentation of a pathogenic TTR mutation

Baseline severity: One of: baseline PND score ≤ IIIb; OR FAP Stage 1 or 2; OR NIS ≥ 5 and ≤ 130; OR Karnofsky performance status (KPS) ≥ 60%

Clinical signs: Presence of clinical signs and symptoms of polyneuropathy (e.g., peripheral sensorimotor polyneuropathy, autonomic neuropathy, motor disability)

Transplant status: Patient has not had a liver transplant

Amvuttra or Onpattro for hATTR polyneuropathy — Continuation of Therapy

Covered when ALL of the following are met:

Prior treatment: Patient has previously received treatment with Amvuttra or Onpattro

Ongoing severity: Patient continues to meet one of: PND score ≤ IIIb; OR FAP Stage 1 or 2; OR NIS ≥ 5 and ≤ 130; OR KPS ≥ 60%

Clinical response: Documentation that the patient has experienced a positive clinical response to Amvuttra or Onpattro (e.g., improved neurologic impairment, motor function, quality of life, slowing of disease progression)

Concomitant therapy and prescriber: Patient is not receiving Amvuttra or Onpattro in combination with other RNA interference agents or transthyretin stabilizers; prescribed by or in consultation with a neurologist; dosing per FDA prescribing information; authorization for no more than 12 months

Clinical evidence by indication

Evidence summaries supporting indications:

Vutrisiran for ATTR cardiomyopathy (HELIOS-B): Phase 3 HELIOS-B randomized study in adults with ATTR-CM (N=655) showed vutrisiran 25 mg q12w met the primary composite endpoint (death and recurrent cardiovascular events) with hazard ratio 0.72 (95% CI 0.56–0.93; p=0.01); secondary endpoints included improved 6-minute walk distance and KCCQ-OS.trial endpoints met

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

Patisiran for hATTR polyneuropathy (APOLLO): Phase 3 APOLLO (IV patisiran 0.3 mg/kg q3w) demonstrated significant improvement in mNIS+7 at 18 months and secondary endpoints (Norfolk QoL-DN, nutritional and motor measures); mean max serum TTR reduction ~87.8%.trial endpoints met

Cardiac subpopulation analyses showed improvements in GLS and LV wall thickness.

Vutrisiran for hATTR polyneuropathy (open-label study):

Use of Amvuttra (vutrisiran) or Onpattro (patisiran) for conditions that are not related to hereditary transthyretin-mediated (hATTR) amyloidosis is considered unproven. Specifically, treatment for sensorimotor or autonomic neuropathy not related to hATTR amyloidosis is classified as not medically necessary because there is insufficient evidence that these RNAi therapies provide clinical benefit in non‑hATTR neuropathies.

Similarly, use of these agents for primary or leptomeningeal amyloidosis is considered unproven and not medically necessary. Providers should document that the indication is hATTR polyneuropathy or ATTR cardiomyopathy per the policy’s diagnostic requirements; requests for treatment outside those indications are subject to denial.

The policy includes FDA approval information for reference only. FDA labeling for Amvuttra and Onpattro describes their marketed indications, but FDA approval alone is not a basis for coverage under this medical policy.

Coverage determinations are made using the clinical criteria and documentation requirements set forth in this policy (for example, diagnostic confirmation, baseline severity measures, prior therapies, and prescriber specialty); FDA indication is informational and does not automatically satisfy those requirements.

Requests to use Amvuttra or Onpattro for sensorimotor or autonomic neuropathy not related to hATTR amyloidosis will be considered not medically necessary and therefore not covered by this policy.

Therapy for primary or leptomeningeal amyloidosis is likewise classified as unproven and not medically necessary; clinicians should provide alternative evidence-based management or pursue other covered indications documented by the policy when seeking authorization.

Coding and Diagnosis Codes

HCPCS CodesHCPCS

J0222	Injection, patisiran, 0.1 mg
J0225	Injection, vutrisiran, 1 mg

ICD-10 Diagnosis CodesICD-10

E85.0	Non-neuropathic heredofamilial amyloidosis
E85.1	Neuropathic heredofamilial amyloidosis
E85.4	Organ-limited amyloidosis
E85.82	Wild-type transthyretin-related (ATTR) amyloidosis

PND score — severity threshold for polyneuropathy (≤ IIIb)

PND score thresholdBaseline polyneuropathy disability (PND) score ≤ IIIb

ContextUsed as a baseline severity measure to determine eligibility for Amvuttra or Onpattro in hATTR polyneuropathy

Continuation criterionContinued coverage requires patient continues to have PND score ≤ IIIb

FAP Stage — allowed stages for therapy (Stage 1 or 2)

Allowed FAP stagesFamilial amyloid polyneuropathy (FAP) Stage 1 or 2

ContextFAP stage is an alternate baseline severity measure for initial or continued therapy with Amvuttra or Onpattro

Provider Actions, Authorization, and Documentation

Prior Authorization

Prior Authorization Required

Prior authorization is required for Amvuttra and Onpattro for their indicated uses. Include clinical indication, prior therapies or documentation of intolerance/contraindication (e.g., prior tafamidis or acoramidis use or intolerance for ATTR-CM), and requested duration (initial authorization ≤ 12 months).

A copy of the clinical indication (ATTR-CM or hATTR polyneuropathy).
Documentation of prior therapies, progression or hospitalization while on tafamidis (Vyndaqel/Vyndamax) or acoramidis (Attruby) when required for ATTR-CM, or documentation of intolerance/contraindication to both when applicable.
Requested dosing and duration consistent with FDA prescribing information (initial authorization ≤ 12 months).

Denial Risk

Documentation and Indication-Related Denials

Coverage may be denied if required diagnostic or indication-related documentation is not provided. Examples include absence of pathogenic TTR mutation testing when required, lack of biopsy or radionuclide imaging confirming ATTR, or missing documentation of progression/hospitalization or intolerance to prior therapies for ATTR-CM.

Background on ATTR Amyloidosis

Transthyretin (TTR) amyloidosis results from misfolding of the TTR protein with subsequent formation of amyloid fibrils that deposit in extracellular tissues and impair organ function. The disease occurs in two major forms: hereditary ATTR (hATTR), caused by pathogenic TTR gene variants, and wild‑type ATTR (wtATTR), which occurs without a pathogenic TTR mutation.

Organ involvement varies by form and mutation: the peripheral nervous system is primarily affected in hATTR polyneuropathy, producing progressive sensorimotor and autonomic dysfunction, whereas the heart is commonly affected in both wtATTR and hATTR leading to restrictive cardiomyopathy with symptoms such as dyspnea, edema, and heart failure. Diagnostic confirmation relies on genetic testing for pathogenic TTR variants for hATTR and tissue biopsy or radionuclide imaging (with exclusion of light‑chain amyloidosis) for cardiac involvement.

Amvuttra (vutrisiran) and Onpattro (patisiran) are transthyretin‑directed small interfering RNA therapies that reduce circulating TTR produced by the liver; they have been studied and are addressed separately in this policy for ATTR cardiomyopathy and hATTR polyneuropathy, with indication‑specific criteria, baseline severity measures, and documentation requirements.

Definitions and Term Clarifications

ATTR-CM — definition

DefinitionCardiomyopathy due to wild-type (wtATTR) or hereditary transthyretin-mediated (hATTR) amyloidosis presenting with restrictive cardiomyopathy signs such as dyspnea, lower extremity edema, and/or ascites

Diagnostic confirmationDiagnosis may be supported by genetic testing, tissue biopsy demonstrating ATTR amyloid deposits, or supportive cardiac imaging and radionuclide uptake

Clinical manifestationsATTR-CM can result in progressive heart failure and may require evaluation of NT-proBNP and NYHA functional class as part of coverage criteria

hATTR polyneuropathy severity measures — PND, FAP Stage, NIS, KPS thresholds referenced

PND scoreBaseline PND score ≤ IIIb referenced as an eligibility measure for hATTR polyneuropathy

FAP Stage

Policy Summary

PayerColorado Rocky Mountain Health Plans

PolicyRNA-Targeted Therapies (Amvuttra and Onpattro)

Policy CodePolicy CS2026D0072R

Change TypeNo material change

Effective DateApr 1, 2026

Next Review Date

Key ActionSubmit prior authorization with documentation of diagnosis, genetic or biopsy/radionuclide confirmation, baseline severity measures, and prior therapies or intolerance as applicable.

SourceLink

On This Page

Concomitant therapy and prescriber:

For Amvuttra or Onpattro, patient is not receiving in combination with other RNA interference agents or transthyretin stabilizers; prescribed by or in consultation with a neurologist; dosing per FDA prescribing information; initial authorization for no more than 12 months

Open-label vutrisiran study in adults with hATTR polyneuropathy showed LS mean change in mNIS+7 at Month 9 of −2.2 vs +14.8 for external placebo (difference −17.0; p<0.001) and improvements in Norfolk QoL-DN, gait speed, and mBMI; safety signals include decreased vitamin A and rare AV heart block; vitamin A supplementation recommended.

Continuation criterionContinued coverage requires patient continues to have FAP Stage 1 or 2

NIS — numerical range referenced (≥ 5 and ≤ 130)

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

ContextNIS is an alternative baseline severity measure referenced for eligibility for Amvuttra or Onpattro

Continuation criterionContinued coverage requires patient continues to have NIS score within this range

Karnofsky performance status (KPS) — minimum performance status (≥ 60%)

Karnofsky performance status minimumKarnofsky performance status (KPS) score ≥ 60%

ContextKPS is an alternative baseline severity measure for initial or continued therapy with Amvuttra or Onpattro

Continuation criterionContinued coverage requires patient continues to have KPS score ≥ 60%

Missing genetic test confirming pathogenic TTR mutation (e.g., V30M) for hATTR indications.
No biopsy or radionuclide imaging (99mTc-DPD/PYP/HMDP grade 2–3) or echocardiogram/MRI suggestive of amyloidosis when required.
No documentation of progression or hospitalization while on tafamidis or acoramidis, or lack of documented intolerance/contraindication to both agents when step therapy is required.

Documentation Required

Contract and Regulatory Compliance Affects Coverage

Benefit plan, federal, state, and contractual requirements govern coverage and may supersede this policy. Confirm the member's specific plan terms and any applicable regulatory mandates before authorization; in case of conflict, the contractual or regulatory requirement prevails.

Reference the member's contract, state mandates, and federal requirements prior to approval.
This policy is informational; plan or regulatory requirements may require different coverage.
In event of conflict, federal/state/contract requirements govern.

Documentation Required

Documentation of Benefit Plan Requirements

Document the specific benefit plan requirements and include all requested clinical evidence in the authorization submission. Required supporting documentation may include genetic testing results, biopsy or radionuclide imaging reports, echocardiogram/CMR findings, NT‑proBNP values, NYHA class, and treating cardiologist attestation.

Genetic test results showing pathogenic TTR mutation when indicated.
Cardiac or noncardiac biopsy report or radionuclide imaging report (99mTc-DPD/PYP/HMDP) with grade 2–3 uptake when required.
Echocardiogram or cardiac MRI suggestive of amyloidosis and NT‑proBNP with clinician interpretation.
Physician attestation of NYHA class and that the prescriber is a cardiologist or consulted with one.

Step Therapy

Step Therapy / Prior Treatment Requirement

Step therapy applies for ATTR-CM: approval generally requires documentation of disease progression or hospitalization while on tafamidis (Vyndaqel/Vyndamax) or acoramidis (Attruby), or documentation of intolerance/contraindication to both agents. Render step-therapy criteria and prior-treatment requirements clearly in submissions.

Evidence of progression or hospitalization related to ATTR-CM while on tafamidis or acoramidis to satisfy step requirement.
OR documentation of intolerance or contraindication to both tafamidis and acoramidis to bypass step therapy.

Note

Use of Utilization Management Tools

Third-party utilization management tools (e.g., InterQual) may be used to assist in benefit administration and clinical decision support. Use these tools as supplemental guidance and ensure submitted documentation aligns with both tool output and the member's contract requirements.

InterQual or similar criteria may be referenced during review.
Ensure submitted clinical documentation matches tool-based criteria and the member's contractual/regulatory obligations.

Allowed baseline FAP Stage 1 or 2 for initial or continued therapy

NISNeuropathy Impairment Score (NIS) between ≥ 5 and ≤ 130 used as a baseline or continuation measure

KPSKarnofsky performance status (KPS) ≥ 60% referenced as an eligibility/continuation measure

vutrisiran — define Amvuttra (vutrisiran)

Proprietary and generic nameAmvuttra (vutrisiran)

Drug classTransthyretin-directed small interfering RNA (siRNA)

FDA indication summaryIndicated for polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults and for cardiomyopathy of wild-type or hereditary transthyretin-mediated amyloidosis in adults to reduce cardiovascular mortality and cardiovascular hospitalizations/urgent heart failure visits

patisiran — define Onpattro (patisiran)

Proprietary and generic nameOnpattro (patisiran)

Drug classTransthyretin-directed small interfering RNA (siRNA)

FDA indication summaryIndicated for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults