Notification



Notification Issue Date:



Medical Policy Bulletin


Title:Patisiran (Onpattro™)

Policy #:08.01.50a

This policy is applicable to the Company’s commercial products only. Policies that are applicable to the Company’s Medicare Advantage products are accessible via a separate Medicare Advantage policy database.


The Company makes decisions on coverage based on Policy Bulletins, benefit plan documents, and the member’s medical history and condition. Benefits may vary based on contract, and individual member benefits must be verified. The Company determines medical necessity only if the benefit exists and no contract exclusions are applicable.

When services can be administered in various settings, the Company reserves the right to reimburse only those services that are furnished in the most appropriate and cost-effective setting that is appropriate to the member’s medical needs and condition. This decision is based on the member’s current medical condition and any required monitoring or additional services that may coincide with the delivery of this service.

This Medical Policy Bulletin document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy Bulletin will be reviewed regularly and be updated as scientific and medical literature becomes available. For more information on how Medical Policy Bulletins are developed, go to the About This Site section of this Medical Policy Web site.



Policy

Coverage is subject to the terms, conditions, and limitations of the member's contract.

MEDICALLY NECESSARY

Patisiran (Onpattro) is considered medically necessary and, therefore, covered for individuals 18 years of age or older with hereditary transthyretin-mediated (hATTR) amyloidosis with polyneuropathy when all of the following criteria, including Dosing and Frequency Requirements listed below, are met:
  • Diagnosis of hATTR amyloidosis with polyneuropathy is confirmed by molecular genetic testing that reveals pathogenic variation(s) in the transthyretin (TTR) gene (e.g., variation of V30M)
  • Documentation of one of the following baseline ambulation parameters in either the Familial Amyloid Polyneuropathy (FAP) Stage or Polyneuropathy Disability (PND) Score:
    • Stage 1 (unimpaired ambulation) or 2 (assisted ambulation) on the Familial Amyloid Polyneuropathy (FAP) staging tool
    • Score I, II, IIIa, or IIIb on the Polyneuropathy Disability (PND) scoring tool (see Guidelines Section for description of scores)
  • Documented presence of cardiac or renal manifestations, or motor, sensory, or autonomic neuropathy related to the hATTR amyloidosis with polyneuropathy (e.g., neuropathic pain, muscle weakness that affects daily living, orthostatic hypotension, diarrhea, nausea, vomiting, heart failure, arrhythmias, proteinuria, renal failure; vision disorders, such as vitreous opacity, dry eyes, glaucoma, or pupils with an irregular or scalloped appearance)
  • Prescribed by or in consultation with a neurologist
  • Individual has not had a liver transplant

CONTINUATION THERAPY (AFTER 18 MONTHS OF THERAPY)
Patisiran (Onpattro) is considered medically necessary and, therefore, covered for continuation therapy following at least 18 months of therapy for the treatment of hATTR amyloidosis with polyneuropathy when the individual meets both of the following criteria:
  • Recent documentation of one of the following ambulation parameters:
    • Stage 1 (unimpaired ambulation) or 2 (assisted ambulation) on the Familial Amyloid Polyneuropathy (FAP) staging tool
    • Score I, II, IIIa, or IIIb on the Polyneuropathy Disability (PND) scoring tool (see Guidelines Section for description of scores)
  • Documented improvement or stability in the signs and symptoms hATTR amyloidosis with polyneuropathy (e.g., neuropathic pain, muscle weakness that affects daily living, orthostatic hypotension, diarrhea, nausea, vomiting, heart failure, arrhythmias, proteinuria, renal failure; vision disorders, such as vitreous opacity, dry eyes, glaucoma, or pupils with an irregular or scalloped appearance), based on objective or standard evaluation scales.

DOSING AND FREQUENCY REQUIREMENTS

The following dosage and frequency information was taken from the Prescribing Information for this product:
  • Individuals weighing less than 100 kg, the dosage is 0.3 mg/kg once every three weeks via intravenous infusion
  • Individuals weighing 100 kg or more, the dosage is 30 mg once every three weeks via intravenous infusion

The Company reserves the right to modify the Dosing and Frequency Requirements listed in this policy to ensure consistency with the most recently published recommendations for the use of patisiran (Onpattro). Changes to these guidelines are based on a consensus of information obtained from resources such as, but not limited to: the US Food and Drug Administration (FDA); Company-recognized authoritative pharmacology compendia; or published peer-reviewed clinical research. The professional provider must supply supporting documentation (i.e., published peer-reviewed literature) in order to request coverage for an amount of patisiran (Onpattro) outside of the Dosing and Frequency Requirements listed in this policy. For a list of Company-recognized pharmacology compendia, view our policy on off-label coverage for prescription drugs and biologics.

Accurate member information is necessary for the Company to approve the requested dose and frequency of this drug. If the member’s dose, frequency, or regimen changes (based on factors such as changes in member weight or incomplete therapeutic response), the provider must submit those changes to the Company for a new approval based on those changes as part of the utilization management activities. The Company reserves the right to conduct post-payment review and audit procedures for any claims submitted for patisiran (Onpattro).

NOT MEDICALLY NECESSARY

When molecular genetic testing reveals established benign variation(s) or wild-type genotype in the transthyretin (TTR) gene, patisiran (Onpattro) is considered not medically necessary and, therefore, not covered because the available published peer-reviewed literature does not support its use in the treatment of this disease.

EXPERIMENTAL/INVESTIGATIONAL

When molecular genetic testing reveals likely pathogenic or variations of unknown significance (VUS) in the transthyretin (TTR) gene, the use of patisiran (Onpattro) is considered experimental/investigational and, therefore, not covered because the safety and/or effectiveness of this service cannot be established by review of the available published peer-reviewed literature.

The use of patisiran (Onpattro) for hereditary transthyretin-mediated (hATTR) amyloidosis with cardiomyopathy in those who are not experiencing polyneuropathy is considered experimental/investigational and, therefore, not covered because the safety and/or effectiveness of this service cannot be established by review of the available published peer-reviewed literature.

All other uses for patisiran (Onpattro) are considered experimental/investigational and, therefore, not covered unless the indication is supported as an accepted off-label use, as defined in the Company medical policy on off-label coverage for prescription drugs and biologics.

REQUIRED DOCUMENTATION

The individual's medical record must reflect the medical necessity for the care provided. These medical records may include, but are not limited to: records from the professional provider's office, hospital, nursing home, home health agencies, therapies, and test reports.

The Company may conduct reviews and audits of services to our members, regardless of the participation status of the provider. All documentation is to be available to the Company upon request. Failure to produce the requested information may result in a denial for the drug.

When coverage of patisiran (Onpattro) is requested outside of the Dosing and Frequency Requirements listed in this policy, the prescribing professional provider must supply documentation (i.e., published peer-reviewed literature) to the Company that supports this request.
Guidelines

DRUG INFORMATION

In accordance with US Food and Drug Administration (FDA) prescribing information, patisiran (Onpattro) is administered as an intravenous infusion every three weeks. Due to infusion-related reactions, each of the following premedications should be given on the day of infusion, at least 60 minutes prior to the start of infusion:
  • Intravenous corticosteroid (e.g., dexamethasone 10 mg, or equivalent)
  • Oral acetaminophen (500 mg)
  • Intravenous H1 blocker (e.g., diphenhydramine 50 mg, or equivalent)
  • Intravenous H2 blocker (e.g., ranitidine 50 mg, or equivalent)

BENEFIT APPLICATION

Subject to the terms and conditions of the applicable benefit contract, patisiran (Onpattro) is covered under the medical benefits of the Company’s products when the medical necessity criteria and Dosing and Frequency Requirements listed in this medical policy are met.

US FOOD AND DRUG ADMINISTRATION (FDA) STATUS

Patisiran (Onpattro) was approved by the FDA on August 10, 2018 for for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults. The safety and effectiveness have not been established in pediatric individuals.

DIAGNOSTIC TOOLS TO ASSESS AMBULATION

FAMILIAL AMYLOID POLYNEUROPATHY (FAP) STAGES
The FAP Stages objectively categorizes an individual's ability to ambulate into three stages. Stage 1 is unimpaired ambulation, Stage 2 is assisted ambulation, and Stage 3 is wheel-chair bound or bedridden.

POLYNEUROPATHY DISABILITY (PND) SCORE
The PND score objectively categorizes an individual's ability to ambulate into five stages.
  • Score I: preserved walking capacity with sensory disturbances
  • Score II: impaired walking, no walking stick or crutch is required
  • Score IIIa: one walking stick or crutch is required to walk
  • Score IIIb: two walking sticks or crutches are required to walk
  • Score IV: confined to wheelchair or bed

Description

Hereditary transthyretin-mediated (hATTR) amyloidosis is a progressive, degenerative, multisystemic, life-threatening disease where insoluble fibril proteins (amyloid deposits) accumulate in various organs of the body, including the central nervous system, nerves, GI tract, and heart. hATTR amyloidosis is caused by a variation in the transthyretin (TTR) protein, a protein that is produced in the liver. Pathogenic variation(s) of TTR causes the protein to misfold and form an insoluble fibril protein that deposits itself in various organs of the body. Symptoms commonly develop in the third to fifth decade of life and depend on several factors, including location of the deposits. Examples of symptoms associated with motor, sensory, and autonomic neuropathy: neuropathic pain, carpal tunnel syndrome, muscle weakness that affects daily living, orthostatic hypotension, recurrent UTIs, diarrhea, nausea, vomiting, vision disorders (e.g., vitreous opacity, dry eyes, glaucoma, or pupils with an irregular or scalloped appearance), cardiac conduction blocks, and arrhythmias. Symptoms of hATTR can cause severe decreased ambulation, decline in daily function due to pain or discomfort, and anxiety or depression. Polyneuropathy and cardiomyopathy are progressive and life-threatening, with survival approximately 2-15 years after onset of neuropathy and 2-5 years after onset of cardiomyopathy.

Patisiran (Onpattro) is the first pharmacologic treatment approved by the US Food and Drug Administration (FDA) for the treatment of adults with polyneuropathy associated with hereditary transthyretin-mediated amyloidosis. Prior to its approval, treatment options consisted of orthotopic liver transplant or a TTR tetramer stabilizer, such as diflunisal (as an off-label indication). Since its approval, a second treatment option, inotersen (Tegsedi), was also FDA approved.

Patisiran (Onpattro) represents a class of drugs called double-stranded small interfering ribonucleic acid (siRNA) treatment that controls gene expression by silencing or interfering with a targeted portion of RNA to reduce the amount of disease-causing TTR, causing a reduction in the amount of amyloid deposits in the body. Patisiran (Onpattro) is administered by intravenous infusion every three weeks.

PEER-REVIEWED LITERATURE
Summary

APOLLO was a Phase 3, multi-centered, randomized, double-blind, placebo-controlled study that evaluated the safety and effectiveness of patisiran (Onpattro) in 225 adults with hereditary transthyretin-mediated (hATTR) amyloidosis. Participants were required to have a documented pathogenic variant in TTR, a Neuropathy Impairment Score (NIS) of 5 to 130 (range, 0 to 244, with higher scores indicating more impairment) and a polyneuropathy disability score of IIIb or lower (with higher scores indicating more impaired walking ability). Participants randomized (2:1) to either patisiran (Onpattro) 0.3 mg/kg or placebo via intravenous infusion once every 3 weeks for 18 months. The primary efficacy endpoint was the change from baseline to Month 18 in the modified Neuropathy Impairment Score +7 (mNIS+7). The study resulted in a reduction in TTR level by 81% in those treated with patisiran (Onpattro). There was a statistically significant improvement in polyneuropathy (mNIS+7 score) in those treated with patisiran (Onpattro), compared to placebo. At 18 months, 56% of participants treated with patisiran (Onpattro) had improvement in mNIS+7, compared with 4% treated with placebo.

The following secondary endpoints showed statistically significant improvement in those treated with patisiran (Onpattro): quality of life (Norfolk Quality of Life–Diabetic Neuropathy [Norfolk QOL-DN] questionnaire), motor strength (NIS-weakness); disability (Rasch-built Overall Disability Scale [R-ODS]), gait speed (10-m walk test), nutritional status (modified body-mass index [BMI]), patient-reported autonomic symptoms (Composite Autonomic Symptom Score). Exploratory endpoints were evaluated in a predefined cardiac subpopulation which showed improvement in echocardiographic measures of cardiac structure and function and a reduction in N-terminal pro–brain natriuretic peptide (NT-proBNP) levels (a measure of cardiac stress that is an independent predictor of death in individuals with transthyretin cardiac amyloidosis) in those treated with patisiran (Onpattro). More randomized, double-blind studies will be needed to assess efficacy in those with hATTR who have cardiac manifestations. The frequency of severe adverse events and serious adverse events were similar between the two groups.

OFF-LABEL INDICATION

There may be additional indications contained in the Policy section of this document due to evaluation of criteria highlighted in the Company’s off-label policy, and/or review of clinical guidelines issued by leading professional organizations and government entities.
References


Adams D. Recent advances in the treatment of familial amyloid polyneuropathy. Ther Adv Neurol Disord. 2013;6(2):129-139.

Adams D, Gonzalez-Duarte A, O'Riordan WD, et al. Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis. N Engl J Med. 2018;379(1):11-21.

Alnylam Pharmaceuticals, Inc. Clinical Profile for Onpattro (Patisiran). 2018. Available at: https://www.onpattro.com/wp-content/uploads/2018/08/Clinical-Profile-for-ONPATTRO.pdf . Accessed August 15, 2018.

Gertz MA. Hereditary ATTR amyloidosis: burden of illness and diagnostic challenges. Am J Manag Care. 2017;23(7 Suppl):S107-S112.

Lexi-Drugs Compendium. Patisiran (Onpattro). 08/13/18. [Lexicomp Online Web site]. Available at: http://online.lexi.com/lco/action/home [via subscription only]. Accessed August 14, 2018.

National Institutes of Health (NIH). Genetics Home Reference. Transthyretin amyloidosis. Reviewed 01/2009. Available at: https://ghr.nlm.nih.gov/condition/transthyretin-amyloidosis . Accessed August 17, 2018.

Patisiran (Onpattro). [prescribing information]. Cambridge, MA: Alnylam Pharmaceuticals, Inc.; 08/2018. Available at: https://www.onpattro.com/ . Accessed August 13, 2018.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. patisiran (Onpattro) prescribing information and approval letter [FDA Web site]. 08/10/2018. Available at: https://www.accessdata.fda.gov/scripts/cder/daf/ . Accessed August 13, 2018.





Coding

Inclusion of a code in this table does not imply reimbursement. Eligibility, benefits, limitations, exclusions, precertification/referral requirements, provider contracts, and Company policies apply.

The codes listed below are updated on a regular basis, in accordance with nationally accepted coding guidelines. Therefore, this policy applies to any and all future applicable coding changes, revisions, or updates.

In order to ensure optimal reimbursement, all health care services, devices, and pharmaceuticals should be reported using the billing codes and modifiers that most accurately represent the services rendered, unless otherwise directed by the Company.

The Coding Table lists any CPT, ICD-9, ICD-10, and HCPCS billing codes related only to the specific policy in which they appear.

CPT Procedure Code Number(s)

N/A


Professional and outpatient claims with a date of service on or before September 30, 2015, must be billed using ICD-9 codes. Professional and outpatient claims with a date of service on or after October 1, 2015, must be billed using ICD-10 codes.

Facility/Institutional inpatient claims with a date of discharge on or before September 30, 2015, must be billed with ICD-9 codes. Facility/Institutional inpatient claims with a date of discharge on or after October 1, 2015, must be billed with ICD-10 codes.


ICD - 10 Procedure Code Number(s)

N/A


Professional and outpatient claims with a date of service on or before September 30, 2015, must be billed using ICD-9 codes. Professional and outpatient claims with a date of service on or after October 1, 2015, must be billed using ICD-10 codes.

Facility/Institutional inpatient claims with a date of discharge on or before September 30, 2015, must be billed with ICD-9 codes. Facility/Institutional inpatient claims with a date of discharge on or after October 1, 2015, must be billed with ICD-10 codes.


ICD -10 Diagnosis Code Number(s)

E85.1 Neuropathic heredofamilial amyloidosis


HCPCS Level II Code Number(s)

C9036 Injection, patisiran, 0.1 mg


THE FOLLOWING CODE IS USED TO REPRESENT PATISIRAN (ONPATTRO)

J3490 Unclassified drugs



Revenue Code Number(s)

N/A

Coding and Billing Requirements

BILLING REQUIREMENTS

If there is no specific HCPCS code available for the drug administered, then the drug must be reported with the most appropriate unlisted code along with the corresponding National Drug Code (NDC).

Cross References


Policy History

Revisions from 08.01.50a
01/01/2019This policy has been identified for the HCPCS code update, effective 01/01/2019.

The following HCPCS code has been added to this policy:
C9036 Injection, patisiran, 0.1 mg

The following HCPCS code has been removed from this policy:
C9399 Unclassified drugs or biologicals

Revisions from 08.01.50
11/19/2018This new policy has been issued to communicate the Company’s coverage position.


Version Effective Date: 01/01/2019
Version Issued Date: 01/03/2019
Version Reissued Date: N/A

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