Hereditary Transthyretin-Mediated (hATTR) Amyloidosis

Number: 0939

Policy

Note: REQUIRES PRECERTIFICATIONFootnotes*

Note: Site of Care Utilization Management Policy applies.  For information on site of service for patisiran (Onpattro), see Utilization Management Policy on Site of Care for Specialty Drug Infusions.

Patisiran (Onpattro)

Aetna considers patisiran (Onpattro) intravenous infusion medically necessary for the treatment of symptomatic polyneuropathy caused by hereditary transthyretin-mediated amyloidosis (hATTR) in adults (18 years of age and older) who have a documented TTR gene mutation.

Continued use of patisiran is considered medically necessary with documentation of disease stability or improvement in symptoms (e.g., decrease in neuropathic pain, improved motor function, quality of life assessment, and/or serum TTR levels).

Concurrent use of patisiran (Onpattro) with inotersen (Tegsdei) is considered experimental and investigational because the safety and effectiveness of this combination has not been established.

Aetna considers patisiran (Onpattro) experimental and investigational for all other indications (e.g., sensorimotor or autonomic neuropathy not related to hATTR amyloidosis) because of insufficient evidence in peer-reviewed published literature.

Inotersen (Tegsedi)

Aetna considers inotersen (Tegsedi) subcutaneous injection medically necessary for the treatment of symptomatic polyneuropathy caused by hereditary transthyretin-mediated (hATTR) amyloidosis in adults (18 years of age and older) and meet all of the following criteria:

• The following are documeted at treatment initiation
   
  • The member has stage 1 or stage 2 familial amyloid polyneuropathy (FAP) (see Appendix); and
  • The member has a TTR gene mutation by genotyping, and
  • The member has an amyloid deposit by biopsy, and
  • The platelet count is above 100 x 10⁹/L, and
  • Urinary protein to creatinine ratio (UPCR) is below 1000 mg/g, and
  • The estimated glomerular filtration rate (eGFR) above 45 mL/minute/1.73 m², and
     
    
• The member is enrolled in the Tegsedi Risk Evaluation and Mitigation Strategy (REMS) program; and 
• The initial subcutaneous injection is administered under supervision of a qualified healthcare provider; and
• Inotersen (Tegsdei) is not used concomitantly with patisiran (Onpattro).

Continued use of inotseren is considered medically necessary with documentation of disease stability or improvement in symptoms (e.g., decrease in neuropathic pain, improved motor function, quality of life assessment, and/or serum TTR levels).

Aetna considers inotersen (Tegsedi) experimental and investigational for all other indications (e.g., sensorimotor or autonomic neuropathy not related to hATTR amyloidosis) because of insufficient evidence in peer-reviewed published literature for these indications.

See Appendix for additional information on dosing and administration recommendations.

Footnotes*Precertification of patisiran (Onpattro) and inotersen (Tegsedi) are required of all Aetna participating providers and members in applicable plan designs. For precertification of patisiran (Onpattro) or inotersen (Tegsedi), call (866) 503-0857, or fax (866) 267-3277.

Background

Hereditary transthyretin amyloidosis (hATTR amyloidosis), formerly known as familial amyloid polyneuropathy (FAP) or familial amyloid cardiomyopathy, now identified by the amyloid fibril-forming protein rather than clinical presentation, is a rare, progressive, autosomal dominant disease primarily characterized by adult-onset sensory, motor, and autonomic neuropathy associated with cardiac, gastrointestinal, ocular, and renal symptoms that can be fatal within 2–15 years from onset. There are more than 50,000 people affected worldwide. Hereditary ATTR amyloidosis is caused by mutations in the TTR gene (chromosome 18q11.2–12.1) that results in misfolded TTR proteins that accumulate as amyloid fibrils in the body’s organs and tissues, such as the nerves, heart and gastrointestinal track. Since hATTR amyloidosis involves many systems in the body, it can result in a wide variety of symptoms, including peripheral and autonomic neuropathy. The amyloid buildup most frequently occurs in the peripheral nervous system, which can result in a loss of sensation, pain, or immobility in the arms, legs, hands and feet. hATTR amyloidosis is a physically debilitating disease that can contribute to significant morbidity and a decline in quality of life, negatively affecting activities of daily living. Available treatment options have focused on symptom management; however, a new drug, in a new drug class called small interfering ribonucleic acid (siRNA) treatment, was FDA approved in August 2018 to target the root cause of the symptoms itself (Akcea Therapeutics, 2018; FDA, 2018; Gonzalez‑Duarte, 2018).

Patisiran (Onpattro)

On August 10, 2018, the U.S. Food and Drug Administration (FDA) announced the approval of Onpattro (patisiran) infusion for the treatment of adults with peripheral nerve disease (polyneuropathy) caused by hereditary transthyretin-mediated amyloidosis (hATTR). Onpattro (patisiran), an RNA interference (RNAi) therapeutic, contains a transthyretin-directed small interfering RNA and has been classified by the FDA as an siRNA drug. siRNAs work by silencing a portion of RNA involved in causing the disease. More specifically, patisiran encases the siRNA into a lipid nanoparticle to deliver the drug directly into the liver, in an infusion treatment, to alter or halt the production of disease-causing proteins. Patisiran is designed to interfere with RNA production of an abnormal form of the protein transthyretin (TTR). By preventing the production of TTR, patisiran can help reduce the accumulation of amyloid deposits in peripheral nerves, improving symptoms and helping adults better manage the condition. (Alnylam Pharmaceuticals, 2018; FDA, 2018; Gonzalez-Duarte, 2018).

The FDA granted Onpattro the Fast Track, Priority Review and Breakthrough Therapy designations. Onpattro also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

FDA approval was based on the APOLLO trial (NCT01960348), which was a randomized, double-blind, placebo-controlled, global, phase 3 study that found that Onpattro improved multiple clinical manifestations of hereditary ATTR amyloidosis. The study included a total of 225 adult patients (18 to 85 years of age) with hATTR and polyneuropathy. Eligibility criteria also included an estimated survival greater than or equal to 2 years, documented TTR mutation, a Neuropathy Impairment Score (NIS) of 5–130, polyneuropathy disability (PND) score ≤IIIb, and adequate biochemical liver function. Patients were randomized 2:1 to receive either intravenous patisiran (n=148) 0.3 mg/kg or placebo (n=77) once every 3 weeks for 18 months. The primary endpoint was to determine the efficacy of patisiran (between the patisiran and placebo groups) based on the difference in the change in the modified Neuropathy Impairment Score+7, which assessed motor strength, reflexes, sensation, nerve conduction and postural blood pressure. Secondary objectives were to evaluate the effect of patisiran on Norfolk-Diabetic Neuropathy quality of life questionnaire score, nutritional status (as evaluated by modified body mass index), motor function (as measured by NIS-weakness and timed 10-m walk test), and autonomic symptoms (as measured by the Composite Autonomic Symptom Score-31 questionnaire). The authors found that patients treated with patisiran had a mean 6.0-point decrease (improvement) in the modified Neuropathy Impairment Score compared to a mean 28.0-point increase (worsening) for patients in the placebo group, resulting in a mean 34.0-point difference relative to placebo, after 18 months of treatment. Fifty-six percent of patisiran-treated patients at 18 months of treatment experienced reversal of neuropathy impairment (as assessed by the modified Neuropathy Impairment Score) relative to their own baseline, compared to 4% of patients who received placebo. Patients also had a mean 6.7-point decrease (improvement) in the Norfolk Quality of Life Diabetic Neuropathy score from baseline compared to a mean 14.4-point increase (worsening) for patients in the placebo group, resulting in a mean 21.1-point difference relative to placebo, after 18 months of treatment. Fifty-one percent of patisiran-treated patients experienced improvement in quality of life at 18 months relative to their own baseline, compared to 10 percent of the placebo-treated patients (per Norfolk QOL-DN questionnaire). Furthermore, the patisiran-treated patients experienced significant benefit vs. placebo for all other secondary efficacy endpoints, including measures of activities of daily living, walking ability, nutritional status, and autonomic symptoms over the 18 months of treatment (Adams et al., 2018; Adams et al., 2017; Alnylam, 2018; FDA, 2018).

The most frequently reported adverse reactions (that occurred in at least 10% of Onpattro-treated patients and at least 3% more frequently than on placebo) were upper respiratory tract infections and infusion-related reactions. To reduce the risk of infusion-related reactions, patients received premedications prior to infusion. Per FDA and Prescribing Information (2018), persons may also experience vision problems including dry eyes, blurred vision and eye floaters (vitreous floaters). It is recommended that individuals are referred to an ophthalmologist if ocular symptoms suggestive of vitamin A deficiency occur. Onpattro (patisiran) leads to a decrease in serum vitamin A levels, so it is recommended that patients take a daily Vitamin A supplement at the recommended daily allowance as per physician/ophthalmologist instructions (FDA, 2018). The administration and dosing recommendations are included in the appendix section.

Inotersen (Tegsedi)

On October 5, 2018, Akcea Therapeutics, Inc, an affiliate of Ionis Pharmaceuticals, Inc, announced the U.S. Food and Drug Administration (FDA) approval of Tegsedi (inotersen), a once-weekly subcutaneous injection, for the treatment of adults with polyneuropathy of hereditary transthyretin-mediated amyloidosis (hATTR).  Tegsedi, a transthyretin-directed antisense oligonucleotide, targets the disease by reducing the production of TTR proteins.

FDA-approval was based on the NEURO-TTR study which showed Tegsedi produced up to a 79% mean decrease from baseline in serum TTR protein regardless of TTR mutation, sex, age, or race (Akcea, 2018). The NEURO-TTR trial was an international, randomized, double-blind, placebo-controlled, 15-month phase 3 trial that comprehensively evaluated the use of inotersen  in a cohort of  172 adults with stage 1 (ambulatory) or stage 2 (ambulatory with assistance) hereditary transthyretin (ATTRm) amyloidosis with symptoms polyneuropathy. Patients were randomly assigned, in a 2:1 ratio, to receive weekly subcutaneous injections of inotersen (300 mg) or placebo. The primary end points were the change in the modified Neuropathy Impairment Score+7 and the change in the score on the patient-reported Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) questionnaire. A decrease in scores indicated improvement. Both primary efficacy assessments favored inotersen: the difference in the least-squares mean change from baseline to week 66 between the two groups (inotersen minus placebo) was -19.7 points (p<0.001) for the mNIS+7 and -11.7 points (p<0.001) for the Norfolk QOL-DN score. These improvements were independent of disease stage, mutation type, or the presence of cardiomyopathy. There were 5 deaths in the inotersen group and none in the placebo group. The most frequent serious adverse events in the inotersen group were glomerulonephritis (3%) and thrombocytopenia (3%), with one death associated with grade 4 thrombocytopenia. All patients received enhanced monitoring. The authors concluded that inotersen improved the course of neurologic disease and quality of life in patients with hereditary ATTRm amyloidosis. Thrombocytopenia and glomerulonephritis were managed with enhanced monitoring. The trial was funded by Ionis Pharmaceuticals; ClinicalTrials.gov NCT01737398) (Benson et al, 2018).

Study inclusion criteria consisted of a documented transthyretin variant by genotyping and documented amyloid deposit by biopsy (Ionis, 2018b).

Exclusion criteria (Ionis, 2018b) consisted of:

• Low Retinol level at screen
• Karnofsky performance status ≤50
• Poor Renal function
• Known type 1 or type 2 diabetes mellitus
• Other causes of sensorimotor or autonomic neuropathy (e.g., autoimmune disease)
• If previously treated with Vyndaqel, had discontinued treatment for 2 weeks prior to Study Day 1. If previously treated with Diflunisal, had discontinued treatment for 3 days prior to Study Day 1
• Previous treatment with any oligonucleotide or siRNA within 12 months of screening
• Prior liver transplant or anticipated liver transplant within 1 year of screening
• New York Heart Association (NYHA) functional classification of ≥3
• Acute Coronary Syndrome or major surgery within 3 months of screening
• Known Primary or Leptomeningeal Amyloidosis
• Anticipated survival less than 2 years.

The most common adverse reactions ( 20% more frequently than placebo) were injection site reactions, nausea, headache, fatigue, thrombocytopenia, and fever  (Ionis, 2018a).

Because of the risks of serious bleeding caused by severe thrombocytopenia and risk of glomerulonephritis, both of which require frequent monitoring, Tegsedi is only available through a restricted distribution program under a Risk Evaluation and Mitigation Strategy (REMS) called the TEGSEDI REMS Program (Ionis, 2018a). The REMS program requires persons to comply with ongoing monitoring requirements. 

Warnings and precautions per Prescribing Information (Ionis, 2018a) include:

• Thrombocytopenia: Tegsedi causes reductions in platelet count that may result in sudden and unpredictable thrombocytopenia, which can be life-threatening.
• Glomerulonephritis: Tegsedi can cause glomerulonephritis that may require immunosuppressive treatment and may result in dialysis-dependent renal failure.
• In clinical trials, cases of glomerulonephritis were accompanied by nephrotic syndrome, which can have manifestations of edema, hypercoagulability with venous or arterial thrombosis, and increased susceptibility to infection.
• Stroke and Cervicocephalic Arterial Dissection: These adverse events occurred within 2 days of first dose and with symptoms of cytokine release. Patients should be educated on symptoms of stroke and central nervous system arterial dissection.
• Inflammatory and Immune Effects: Serious neurologic adverse reactions consistent with inflammatory and immune effects occurred.
• Liver effects: Monitor alanine amino transferase, aspartate aminotransferase, and total bilirubin every 4 months during treatment and in case of symptoms of hepatic dysfunction.
• Hypersensitivity reactions: if these occur, discontinue and initiate appropriate therapy.
• Uninterpretable Platelet Counts: Reaction between Antiplatelet Antibodies and ethylenediaminetetra-acetic acid: Platelet clumping can cause uninterpretable platelet measurement; repeat test if this is suspected
• Reduced Serum Vitamin A Levels and Recommended Supplementation: Supplement with the recommended daily allowance of vitamin A. Refer to an ophthalmologist if ocular symptoms suggestive of vitamin A deficiency occur.

Inotersen (Tegsdei) should not be used concomitantly with patisiran (Onpattro) because the safety and effectiveness of this combination has not been established.

Appendix

Patisiran (Onpattro)

Available as a lipid complex injection: 10 mg/5 mL (2 mg/mL) in a single-dose vial and should be administered by a healthcare professional.

Dosage and Administration Recommendations

• For members weighing less than 100 kg, the recommended dosage is 0.3 mg/kg every 3 weeks by intravenous infusion (IV).
• For members weighing 100 kg or more, the recommended dosage is 30 mg IV once every 3 weeks.
• Premedicate with the following on the day of infusion at least 60 minutes prior to Onpattro infusion:
   
  • Intravenous (preferred) corticosteroid (e.g., dexamethasone 10 mg, or equivalent),
  • Oral acetaminophen (500 mg),
  • Intravenous (preferred) H1 blocker (e.g., diphenhydramine 50 mg, or equivalent),
  • Intravenous (preferred) H2 blocker (e.g., ranitidine 50 mg, or equivalent).
     
• Filter and dilute prior to administration
• Infuse over approximately 80 minutes

Note: For premedications not available or not tolerated intravenously, equivalents may be administered orally. For members who are tolerating their Onpattro infusions but experiencing adverse reactions related to the corticosteroid premedication, the corticosteroid may be reduced by 2.5 mg increments to a minimum dose of 5 mg of dexamethasone (intravenous), or equivalent.

Source: Prescribing Information (Alnylam Pharmaceuticals, revised 8/2018)

Inotersen (Tegsedi)

Available as 284 mg/1.5 mL in a single-dose prefilled syringe. The recommended dosage is 284 mg administered by subcutaneous injection once weekly. Laboratory tests must be measured prior to treatment, continue to be monitored after treatment initiation, and for 8 weeks following discontinuation of treatment, as directed.

The product labeling states that the first injection administered by the patient or caregiver should be performed under the guidance of an appropriately qualified healthcare professional. Patients and/or caregivers should be trained in the subcutaneous administration of Tegsedi. Sites for injection include the abdomen, or upper thigh region.  A trained person, other than the patient, should administer injection in the outer area of the upper arm.

Contraindications include platelet count less than 100 x 10⁹/L, history of acute glomerulonephritis caused by Tegsedi, and history of hypersensitivity reaction to Tegsedi. Tegsedi should generally not be initiated in patients with urinary protein to creatinine ratio (UPCR) of 1000 mg/g or higher.

Lab recommendations prior to treatment include measurement of platelet count, serum creatinine, estimated glomerular filtration rate (eGFR), urine protein to creatinine ratio (UPCR), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin, and perform urinalysis.

During treatment, monitor serum creatinine, eGFR urinalysis, and UPCR every 2 weeks. Tegsedi should not be given to patients who develop a UPCR of 1000 mg/g or higher, or eGFR below 45 mL/minute/1.73 m², pending further evaluation of the cause. Monitor ALT, AST, and total bilirubin every 4 months during treatment with Tegsedi.

Following discontinuation of treatment, monitor platelet count, serum creatinine, estimated glomerular filtration rate (eGFR), urinalysis, urine protein to creatinine ratio (UPCR), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin for 8 weeks.

Persons who are not able to adhere to the recommended laboratory monitoring or to the related treatment recommendations must not receive Tegsedi.

Table 1: Platelet Monitoring and Dosing Recommendations for Tegsedi

Platelet count (x109/L)	Monitoring Frequency	Dosing
At least 100	Weekly	Continue to dose weekly.
75 to less than 100	Weekly	Stop treatment. Do not restart unless platelet count is greater than 100.
50 to less than 75	Twice weekly until 3 successive values above 75; then weekly monitoring.	Stop treatment. Do not restart in persons with thrombocytopenia, unless there have been 3 successive values above 100 and the benefit of Tegsedi outweighs the risk of thrombocytopenia and potential bleeding.
25 to less than 50	Twice weekly until 3 successive values above 75; then weekly monitoring. Consider more frequent monitoring if additional risk factors for bleeding are present (i.e., age greater than 60 years, receiving anticoagulant or antiplatelet products, prior history of major bleeding events).	Stop treatment. Do not restart in persons with thrombocytopenia, unless there have been 3 successive values above 100 and the benefit of Tegsedi outweighs the risk of thrombocytopenia and potential bleeding. Corticosteroids recommended. Consider discontinuation of any antiplatelet agents or anticoagulants.
Less than 25	Daily until 2 successive values above 25. Then monitor twice weekly until 3 successive values above 75. Then weekly monitoring until stable.	Stop Tegsedi. Corticosteroids recommended. Consider discontinuation of any antiplatelet agents or anticoagulants. Note: persons who discontinue therapy with Tegsedi because of platelets below x109/L should not reinitiate therapy.

Table adapted from Prescribing Information (Ionis, 2018a).

Source: Prescribing Information (Ionis, 2018a)

Table 2: Clinical Staging of TTR-FAP

Stage 0	No symptoms
Stage 1	Unimpaired ambulation; mostly mild sensory, motor, and autonomic neuropathy in the lower limbs.
Stage 2	Assistance with ambulation required; mostly moderate impairment progression to the lower limbs, upper limbs, and trunk.
Stage 3	Wheelchair-bound or bedridden; severe sensory, motor, and autonomic involvement of all limbs

Table based on Coutinho et al. (Ando et al., 2013)

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+" :
CPT codes covered if selection criteria are met:
Patisiran (Onpattro) - no specific code:
Other CPT codes related to the CPB:
96365 - 96368	Intravenous infusion administration
HCPCS codes covered if selection criteria are met:
C9036	Injection, patisiran, 0.1 mg
ICD-10 codes covered if selection criteria are met:
E85.1	Neuropathic heredofamilial amyloidosis
Inotersen (Tegsedi):
Other CPT codes related to the CPB:
96372	Therapeutic, prophylactic, or diagnostic injection (specify substance or drug); subcutaneous or intramuscular.
HCPCS codes covered if selection criteria are met:
Inotersen (Tegsedi) - no specific code:
ICD-10 codes covered if selection criteria are met:
E85.1	Neuropathic heredofamilial amyloidosis

The above policy is based on the following references: