CurrentColorado Rocky Mountain Health PlansPolicy 2026D0072O

RNA-Targeted Therapies (Amvuttra and Onpattro) for ATTR amyloidosis

Medical necessity and prior authorization criteria for Amvuttra (vutrisiran) and Onpattro (patisiran) to treat transthyretin-mediated (ATTR) amyloidosis (cardiomyopathy and polyneuropathy) for UnitedHealthcare Commercial and Individual Exchange plans.

Policy Summary

PayerColorado Rocky Mountain Health Plans

PolicyRNA-Targeted Therapies (Amvuttra and Onpattro) for ATTR amyloidosis

Policy CodePolicy 2026D0072O

Change TypeTemplate update / transfer

Effective DateJun 1, 2026

Next Review Date

Key ActionObtain prior authorization and document diagnosis, supporting imaging/biopsy, and relevant baseline neurologic scores where applicable.

SourceLink

POLICY UPDATE CHANGES

Summary of Changes: Template Update — Transferred content to shared policy template that applies to UnitedHealthcare plans.

12 monthsmax initial auth

J0222, J0225listed HCPCS

I-IIINYHA classes

Grade 2–3radionuclide uptake

655HELIOS-B N

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Archivedprior versions

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 evidence: One of: pathogenic TTR mutation; cardiac or noncardiac tissue biopsy confirming ATTR deposits; OR all of: echocardiogram or cardiac MRI suggestive of amyloidosis AND radionuclide imaging showing grade 2 or 3 cardiac uptake AND absence of light-chain amyloidosis

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

Prior therapy or intolerance: Either 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 and acoramidis

For Medicare reviews, refer to CMS section

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

Amvuttra for ATTR cardiomyopathy — Continuation of Therapy

Covered when ALL of the following are met

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, quality of life, slowing of disease progression, decreased hospitalizations)

NYHA class: Patient continues to have New York Heart Association (NYHA) Functional Class I, II, or III heart failure

Amvuttra and Onpattro for hATTR polyneuropathy — Initial and Continuation Therapy

Covered when ALL of the following are met

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

Baseline neuro criteria: One of: PND score ≤ IIIb; FAP Stage 1 or 2; NIS ≥ 5 and ≤ 130; 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

Concomitant therapy restrictions:

Indications supported by FDA labeling

Clinical trial evidence and FDA indications referenced in the policy support use in the following populations when consistent with FDA labeling and member benefit:

FDA-indicated populations: Adults with polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis (patisiran indication); and adults with polyneuropathy of hATTR and adults with cardiomyopathy of wild-type or hereditary ATTR (vutrisiran indication).

Based on FDA indications cited in document.

Vutrisiran cardiomyopathy evidence

Efficacy evidence from HELIOS-B for vutrisiran cardiomyopathy:

HELIOS-B primary outcomes: In a phase 3 randomized, double-blind trial (HELIOS-B; N=655) vutrisiran 25 mg q12w reduced the risk of death from any cause and recurrent cardiovascular events versus placebo (hazard ratio 0.72; 95% CI 0.56–0.93; p=0.01); secondary analyses (death through 42 months and 6‑minute walk test change) also favored vutrisiran.

Trial allowed background tafamidis use; subgroup analyses underpowered.

Polyneuropathy and cardiac outcome evidence

Efficacy evidence for patisiran and vutrisiran in polyneuropathy and cardiac manifestations:

APOLLO (patisiran) neuropathy results: In APOLLO (IV patisiran 0.3 mg/kg q3w), patisiran reduced mNIS+7 at 18 months versus placebo (LS mean change -33.99; patisiran -6.03 vs placebo +27.96) and improved Norfolk QOL-DN and cardiac strain measures in a prespecified cardiac subpopulation; safety was acceptable with mostly mild infusion reactions.

Vutrisiran (hATTR polyneuropathy) results: In a phase 3 study, SC vutrisiran 25 mg q3 months improved mNIS+7 at 9 months versus an external placebo group (difference -17.0; 95% CI -21.8 to -12.2; p<0.001) and improved Norfolk QoL-DN, 10MWT, and mBMI; common adverse reactions included arthralgia, dyspnea, and decreased vitamin A; two serious AV heart block events (1.6%) were reported.

Use of Amvuttra (vutrisiran) or Onpattro (patisiran) for neuropathies that are not due to hereditary transthyretin-mediated (hATTR) amyloidosis is expressly identified as unproven and not medically necessary. This includes both sensorimotor or autonomic neuropathy not related to hATTR and primary or leptomeningeal amyloidosis.

The policy lists applicable HCPCS and ICD-10 codes for reference (for example, J0222 and J0225 and E85.x diagnosis codes) but states that listing a code does not guarantee coverage. Coverage and reimbursement determinations are made according to the member specific benefit plan document and any applicable laws or mandates.

When making coverage decisions, providers must reference the member specific benefit plan document, which governs when its terms conflict with this policy. Additionally, check for any applicable federal or state mandates that may supersede the plan or policy language before proceeding with authorization or treatment.

The policy reiterates that use of Amvuttra or Onpattro for neuropathy that is not attributable to hATTR amyloidosis is considered unproven and not medically necessary. It specifically calls out treatment for sensorimotor or autonomic neuropathy not related to hATTR and for primary or leptomeningeal amyloidosis as indications that may be denied.

Applicable Codes and Clinical Thresholds

Applicable 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

Referenced drug and diagnosis 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

Baseline clinical thresholds for polyneuropathy

Peripheral Neuropathy Disability (PND)Baseline PND score ≤ IIIb

Familial Amyloid Polyneuropathy (FAP) StageFAP Stage 1 or 2

Neuropathy Impairment Score (NIS)Baseline NIS ≥ 5 and ≤ 130

Karnofsky Performance Status (KPS)Baseline KPS ≥ 60%

Most actionable thresholdEnsure baseline PND ≤ IIIb (or FAP Stage 1–2, NIS 5–130, KPS ≥60%) documented before initiation

Provider Requirements, Prior Authorization, and Documentation

Prior Authorization

Prior Authorization Required

Prior authorization is required per the member-specific benefit plan. Providers must obtain prior authorization when applicable and note that initial and continuation authorizations are limited to no more than 12 months and dosing must follow FDA prescribing information.

Initial and continuation authorizations limited to <= 12 months
Dosing must follow FDA prescribing information
Obtain prior authorization per member-specific plan

Billing Rule

Coding Inclusion Is Not a Guarantee of Coverage

Listing of a procedure or diagnosis code in this policy does not guarantee coverage or payment. Inclusion of a code is for reference only and does not confer any right to reimbursement.

Background on ATTR Amyloidosis and Therapies

Transthyretin (ATTR) amyloidosis results from misfolded transthyretin (TTR) protein depositing as amyloid fibrils in multiple organs, most commonly the peripheral nerves and the heart. It occurs in wild-type (wtATTR) and hereditary (hATTR) forms. Cardiac involvement (ATTR-CM) produces a restrictive cardiomyopathy often manifesting with progressive heart failure symptoms such as dyspnea and peripheral edema. Vutrisiran (Amvuttra) and patisiran (Onpattro) are transthyretin-directed small interfering RNA (siRNA) therapies that reduce TTR production and are used to treat polyneuropathy of hATTR; vutrisiran also has an FDA indication for ATTR cardiomyopathy in adults.

Key Definitions

ATTR-CM (definition and diagnostic supports)

DefinitionCardiomyopathy due to wild-type or hereditary transthyretin-mediated (ATTR) amyloidosis

Diagnostic supports — geneticPresence of a pathogenic TTR mutation (e.g., V30M) can support the diagnosis

Diagnostic supports — tissue biopsyCardiac or noncardiac tissue biopsy demonstrating histologic confirmation of ATTR amyloid deposits

Diagnostic supports — imagingEchocardiogram or cardiac MRI suggestive of amyloidosis plus radionuclide imaging showing grade 2 or 3 cardiac uptake and exclusion of light-chain amyloidosis

ATTR (transthyretin) amyloidosis — overview

Nature of disorderA progressive, disabling, life‑threatening condition caused by misfolded transthyretin protein that accumulates as amyloid fibrils in multiple organs (nerves, heart, GI tract)

Policy Summary

PayerColorado Rocky Mountain Health Plans

PolicyRNA-Targeted Therapies (Amvuttra and Onpattro) for ATTR amyloidosis

Policy CodePolicy 2026D0072O

Change TypeTemplate update / transfer

Effective DateJun 1, 2026

Next Review Date

Key ActionObtain prior authorization and document diagnosis, supporting imaging/biopsy, and relevant baseline neurologic scores where applicable.

SourceLink

On This Page

For Amvuttra or Onpattro: patient is not receiving the agent in combination with other RNAi agents or transthyretin stabilizers

Prescriber/dosing/authorization: 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 maintained neuro scores and documented positive clinical response

Codes referenced in policy are informational only
Coverage and reimbursement determined by member-specific benefit plan

Note

Member-Specific Plan Governs

When there is any conflict between this policy and the member-specific benefit plan document (including Certificates of Coverage), the member-specific benefit plan governs. Providers should follow the benefit plan language and applicable state or federal mandates.

Member-specific benefit plan governs in event of conflict
State or federal mandates may supersede plan language

Documentation Required

Required Supporting Documentation

Required supporting documentation must be submitted with prior authorization requests. Provide clinically relevant records to substantiate the diagnosis and medical necessity.

Diagnosis of wtATTR or hATTR (use appropriate ICD-10 E85.x code)
Evidence of pathogenic TTR mutation OR tissue biopsy confirming ATTR amyloid OR imaging consistent with cardiac ATTR (echocardiogram or cardiac MRI and radionuclide imaging with grade 2–3 uptake) and absence of light-chain amyloidosis
History of heart failure (e.g., prior hospitalization) or signs/symptoms of heart failure for ATTR-CM indications
Documentation of prior treatments, intolerance, contraindication, or progression as applicable

Documentation Required

Documentation and Benefit Verification

Providers must perform benefit verification and include documentation of diagnosis codes and drug administration codes when submitting claims. Verify eligibility, benefits, and prior authorization requirements before initiating therapy.

Document relevant ICD-10 diagnosis codes (e.g., E85.0, E85.1, E85.4, E85.82) on authorization and claims
Include applicable HCPCS/J-codes for administered drugs (e.g., J0222 for patisiran, J0225 for vutrisiran) on claims
Verify member eligibility, benefits, and prior authorization requirements prior to treatment

Note

Verify Member Plan and Applicable Mandates

Before applying this policy, providers must check the member-specific benefit plan document and any applicable federal or state mandates. This policy is informational and may not reflect plan-specific coverage rules or legal requirements.

Check member-specific benefit plan document prior to authorization
Confirm any state or federal mandates that may affect coverage
This policy assists interpretation of standard plans but does not replace plan language

Step Therapy

Step Therapy / Prior Treatments

Step therapy and prior treatment requirements apply for cardiomyopathy indications. Document prior use, intolerance, contraindication, or disease progression while on specified prior therapies as required by the clinical criteria.

For ATTR-CM, document progression or hospitalization while on tafamidis (Vyndaqel/Vyndamax) or acoramidis (Attruby) OR intolerance/contraindication to both agents
Provide medical records showing clinical worsening, hospitalization, or intolerance as applicable

Note

Background Therapy Considerations

Background therapy considerations: clinical trials (e.g., HELIOS-B) allowed background use of tafamidis; the trial did not directly compare vutrisiran monotherapy to tafamidis monotherapy. Document concurrent therapies and consider trial context when assessing medical necessity.

HELIOS-B permitted background tafamidis use in both study arms
Trial was not powered to compare vutrisiran alone versus tafamidis alone
Document any concurrent transthyretin stabilizer (e.g., tafamidis) use

Note

Provider Actions and Verification Reminder

Providers must verify the member-specific benefit plan and follow plan-specific prior authorization and coverage rules. When in doubt, obtain prior authorization and submit comprehensive documentation to avoid delays or denials.

Member-specific plan terms and mandates take precedence over this policy
Obtain prior authorization when required and include full supporting documentation

FormsOccurs as wild‑type (wtATTR) often associated with aging, and hereditary/mutant forms (hATTR/ATTRv)

Clinical manifestationsCan cause peripheral sensorimotor and autonomic neuropathy and restrictive cardiomyopathy with symptoms such as dyspnea and edema

Vutrisiran (Amvuttra) — product and indications

ProductVutrisiran (Amvuttra) — a transthyretin‑directed small interfering RNA (siRNA)

FDA indicationsIndicated for treatment of polyneuropathy of hereditary ATTR in adults and for cardiomyopathy of wild‑type or hereditary ATTR in adults to reduce cardiovascular mortality, cardiovascular hospitalizations, and urgent heart failure visits

Mechanism/formulationsiRNA that reduces TTR production; formulated to target the liver, the primary source of circulating TTR

Patisiran (Onpattro) — product and indications

ProductPatisiran (Onpattro) — a transthyretin‑directed small interfering RNA (siRNA)

FDA indicationIndicated for the treatment of the polyneuropathy of hereditary transthyretin‑mediated (hATTR) amyloidosis in adults

MechanismsiRNA that targets TTR mRNA to decrease serum TTR and tissue deposits; formulated in lipid nanoparticles directed to the liver

InterQual — third‑party criteria tool

ToolInterQual — a third‑party criteria tool UnitedHealthcare may use to assist in administering health benefits

RoleUsed as an external resource to support coverage determinations and clinical criteria implementation

Application noteInterQual may be referenced alongside member‑specific benefit plan terms when determining coverage