Patisiran (Onpattro^TM) is a RNA interference (RNAi) therapeutic targeting transthyretin for the treatment of hereditary transthyretin amyloidosis (TTR amyloidosis, hATTR or ATTR). RNAi is a cellular process of gene silencing. Patisiran (Onpattro) silences specific messenger RNA, blocking the production of transthyretin protein. This enables the clearance of TTR amyloid deposits from and restores function in peripheral tissues.

Vutrisiran (Amvuttra™) is a transthyretin-directed small interfering RNA for the treatment of heredity transthyretin amyloidosis (TTR amyloidosis, hATTR or ATTR) associated polyneuropathy and cardiomyopathy of wild-type or hereditary transthyretin-mediated amyloidosis.

Treatment with patisiran (Onpattro) or vutrisiran (Amvuttra) typically leads to a decrease in serum vitamin A levels. Supplementation at the recommended daily allowance of vitamin A is advised for individuals. Higher doses than the recommended daily allowance should not be given to try to achieve normal serum vitamin A levels during treatment, as serum vitamin A levels do not reflect the total vitamin A in the body. Individuals should be referred to an ophthalmologist if they develop ocular symptoms suggestive of vitamin A deficiency (eg. night blindness).

Hereditary transthyretin amyloidosis is a slowly progressive condition characterized by the buildup of abnormal deposits of amyloid protein in the body’s organs and tissues. It is caused by mutations in the TTR gene. The TTR gene provides instructions for producing a protein called transthyretin, which transports vitamin A and thyroxine throughout the body. Transthyretin is produced primarily in the liver. A small amount is produced in the choroid plexus of the brain and in the retina. In TTR amyloidosis, transthyretin builds up as amyloid fibrils in tissues (primarily liver), interfering with the normal function of these tissues. The ideal setting for evaluation of the individual with hereditary transthyretin amyloidosis is a multi-disciplinary Amyloid Program.

Patisiran (Onpattro) or Vutrisiran (Amvuttra) may be considered medically necessary for the treatment of individuals 18 years of age and older with a diagnosis of polyneuropathy associated with hereditary transthyretin-mediated (hATTR) amyloidosis when ALL of the following criteria are met:

• Prescribed by or in consultation with a neurologist or physician who specializes in the treatment of amyloidosis; and
• Diagnosis of polyneuropathy associated with hATTR amyloidosis and is not being used for sensorimotor or autonomic neuropathy unrelated to hATTR amyloidosis; and
• Documented mutation in TTR gene as confirmed by genetic testing; and
• A complete neurologic examination has been performed, showing clinical signs and symptoms of the disease (e.g., peripheral/autonomic neuropathy, motor disability, carpel tunnel, etc.); and
• Documentation of baseline functional ambulation performance (FAP) stage of 1 or 2; and
• Has documentation of ANY of the following:
  • Peripheral neuropathy impairment score (NIS) of five (5) or greater; or
  • Polyneuropathy disability (PND) score of IIIb or lower; and
• Has not had a prior liver transplant or scheduled liver transplant; and
• Individual is not simultaneously utilizing other TTR-lowering agents or TTR-stabilizing agents (for example, Attruby, Vyndaqel, Vyndamax, Onpattro, Wainua); and
• Initial authorization will be for a 12 month period.

Reauthorization Criteria

• Individual meets the above criteria; and
• Individual has documentation of a positive clinical response to patisiran (Onpattro) or vutrisiran (Amvuttra) (e.g., improved or stabilized neurologic impairment, motor function, quality of life assessment, serum TTR levels, etc.) as demonstrated by an improvement or stabilization in ANY of the following:
  • NIS; or
  • PND score; or
  • FAP stage; and
• The individual is not simultaneously utilizing other TTR-lowering agents or TTR-stabilizing agents (for example, Attruby, Vyndaqel, Vyndamax, Onpattro, Wainua); and
• Reauthorization will be for a 12 month period.

The use of patisiran (Onpattro) or Vutrisiran (Amvuttra) not meeting the criteria as indicated in this policy is considered not medically necessary.

Vutrisiran (Amvuttra) may be considered medically necessary for the treatment of individuals 18 years of age and older with a diagnosis of cardiomyopathy transthyretin-mediated amyloidosis (ATTR-CM) when ALL of the following criteria are met:

• Prescribed by or in consultation with a cardiologist or physician who specializes in the treatment of amyloidosis; and
• The individual has a diagnosis of wild-type or hereditary ATTR-CM; and
• The individual has cardiac involvement supported by one (1) of the following tests:
  • Cardiac magnetic resonance; or
  • Echocardiography; or
  • Serum cardiac biomarker (for example, B-type natriuretic peptide, cardiac troponin); and
• The prescriber submits clinical documentation supporting ATTR-CM diagnosis including one (1) of the following:
  • Amyloid deposits on cardiac biopsy; or
  • Scintigraphy using radiotracers (for example, technetium pyrophosphate) with heart to contralateral lung ≥ 1.5 or visual grade 2-3; and
• Individual has New York Heart Association (NYHA) Class I, II, or III; and
• The individual is not simultaneously utilizing other TTR-lowering agents or TTR-stabilizing agents (for example, Attruby, Vyndaqel, Vyndamax, Onpattro, Wainua); and
• Initial authorization will be for a 12 month period.

Reauthorization Criteria

• Individual meets the above criteria; and
• Individual has documentation of a positive clinical response to vutrisiran (Amvuttra) as demonstrated by an improvement or delayed disease progression in ANY of the following:
  • Reduction in cardiovascular-related hospitalizations or urgent heart failure visits; or
  • 6-Minute Walk Test; or
  • Kansas City Cardiomyopathy Questionnaire-Overall Summary score; or
  • Cardiac function (for example, global longitudinal strain, LVEF, NYHA class); or
  • Serum cardiac biomarker (for example, B-type natriuretic peptide, cardiac troponin); and
• The prescriber attests that the member is not simultaneously utilizing other TTR-lowering agents or TTR-stabilizing agents (for example, Attruby, Vyndaqel, Vyndamax, Onpattro, Wainua); and
• Reauthorization will be for a 12 month period.

The use of vutrisiran (Amvuttra) not meeting the criteria as indicated in this policy is considered not medically necessary.

Patisiran (Onpattro) may be considered medically necessary for individuals 18 years of age and older when applicable clinical criteria for individual medication policies are met and when administered in a physician’s office not affiliated with a hospital, specialized infusion centers not affiliated with a hospital or in the home.

Outpatient facility (Outpatient Hospital IV Infusion Department or Hospital-based Outpatient Clinical Level of Care) administration may be considered medically necessary if ANY of the following criteria are present to indicate the member is medically unstable for infusions in other than an outpatient facility setting:

• Member’s home is considered unsuitable for care by the home infusion provider; or
• Individual’s medical status requires enhanced monitoring beyond that which would routinely be needed for infusion therapy; or
• Previous severe adverse reaction (including but not limited to anaphylaxis, seizure, thromboembolism, myocardial infarction, renal failure) during or following administration of prescribed medication despite standard pre-medication; or
• Individual is receiving other medications that require close monitoring with a higher level of care (e.g., cytotoxic chemotherapy or blood products); or
• Individual is at high risk for complications due to medication administration (e.g., at risk for post-transplant complications, increased risk of infusion reactions due to presence of circulating antibodies, unstable vascular access, cardiopulmonary condition at risk for severe adverse reactions, unstable renal function with inability to safely tolerate IV volume loads, etc.); or 
• Individual is initiating therapy or re-initiating therapy after a period of at least 6 months with no therapy; or
• Physically and/or cognitively impaired AND a home caregiver is not available to comply with the required treatment regimen and schedule.

Home health services may be considered medically necessary when utilized for the administration of home infusion therapy and when provided by licensed eligible provider. Each case will be addressed on an individual basis.

The medications identified in this policy will be considered not medically necessary if administered in an unapproved hospital outpatient setting when an approved site of care is a viable option for treatment.

NOTE: In addition to the above criteria, product specific dosage and/or frequency limits may apply in accordance with the U.S. Food and Drug Administration (FDA)-approved product prescribing information, national compendia, Centers for Medicare and Medicaid Services (CMS) and other peer reviewed resources or evidence-based guidelines. Highmark may deny, in full or in part, reimbursement for utilization that does not fall within the applicable dosage and/or frequency limits.

Evidence-based guidelines support the administration of injectable medications in alternative sites of care such as the non-hospital physician’s office, non-hospital infusion center or in the home.  Administration of the injectable medications subject to this policy at alternate sites of care is based upon the professional judgment of the provider, and takes into account the clinical appropriateness for each individual member. Requests for administration of any dose of the drugs listed in this policy received from a hospital-based facility, physician’s office or specialized infusion center will be assessed for meeting the policy exception criteria based on the clinical documentation provided by the requesting practitioner.

The use of vutrisiran (Amvuttra) is typically an outpatient procedure which is only eligible for coverage as an inpatient procedure in special circumstances, including, but not limited to, the presence of a co-morbid condition that would require monitoring in a more controlled environment such as the inpatient setting.