Hereditary Transthyretin-Mediated (hATTR) Amyloidosis

Number: 0939

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Brand Selection for Medically Necessary Indications for Commercial Medical Plans

Polyneuropathy of Hereditary Transthyretin-Mediated (hATTR) Amyloidosis

As defined in Aetna commercial policies, health care services are not medically necessary when they are more costly than alternative services that are at least as likely to produce equivalent therapeutic or diagnostic results. Amvuttra (vutrisiran), Tegsedi (inotersen), and Wainua (eplontersen) are more costly to Aetna than other medications in the treatment of polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis. There is a lack of reliable evidence that Amvuttra (vutrisiran), Tegsedi (inotersen), and Wainua (eplontersen) are superior to the lower cost medications in the treatment of polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis: Onpattro (patisiran). Therefore, Aetna considers Amvuttra (vutrisiran), Tegsedi (inotersen), and Wainua (eplontersen) to be medically necessary only for members who have a contraindication, intolerance or ineffective response to the available equivalent alternative medication in the treatment of polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis: Onpattro (patisiran). 

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses hereditary transthyretin-mediated (hATTR) amyloidosis for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Note: Requires Precertification:

Precertification of patisiran (Onpattro), eplontersen (Wainua), inotersen (Tegsedi), and vutrisiran (Amvuttra) are required of all Aetna participating providers and members in applicable plan designs. For precertification of patisiran (Onpattro), inotersen (Tegsedi), or vutrisiran (Amvuttra), call (866) 752-7021 or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see Specialty Pharmacy Precertification.

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

Patisiran (Onpattro)

1. Prescribing Information

   This medication must be prescribed by or in consultation with a neurologist, geneticist, or physician specializing in the treatment of amyloidosis.

2. Criteria for Initial Approval

   Aetna considers the initiation of patisiran (Onpattro) intravenous infusion medically necessary for the treatment of polyneuropathy of hereditary transthyretin-mediated amyloidosis (hATTR), also called transthyretin-type familial amyloid polyneuropathy (ATTR-FAP), when all of the following criteria are met:

   1. The diagnosis is confirmed by detection of a mutation in the TTR gene; and
   2. Member exhibits clinical manifestations of ATTR-FAP (e.g., amyloid deposition in biopsy specimens, TTR protein variants in serum, progressive peripheral sensory-motor polyneuropathy); and
   3. The requested medication will not be used in combination with any other medication approved for the treatment of hereditary transthyretin-mediated amyloidosis (e.g., Amvuttra, Tegsedi, Vyndamax, Vyndaqel, Wainua). 

   Aetna considers all other indications as experimental, investigational, or unproven.

3. Continuation of Therapy

   Aetna considers the continuation of patisiran (Onpattro) therapy medically necessary in members requesting reauthorization for an indication listed in Section II when all of the following criteria are met:

   1. Member must have met all initial authorization criteria, and
   2. Member must have demonstrated a beneficial response to treatment with the requested medication compared to baseline (e.g., improvement of neuropathy severity and rate of disease progression as demonstrated by the modified Neuropathy Impairment Scale+7 [mNIS+7] composite score, the Norfolk Quality of Life-Diabetic Neuropathy [QoL-DN] total score, polyneuropathy disability [PND] score, FAP disease stage, manual grip strength). 

Eplontersen (Wainua)

1. Prescriber Specialties

   This medication must be prescribed by or in consultation with a neurologist, geneticist, or physician specializing in the treatment of amyloidosis.

2. Criteria for Initial Approval

   Aetna considers the initiation of eplontersen (Wainua) subcutaneous injection medically necessary for the treatment of polyneuropathy of hereditary transthyretin-mediated amyloidosis (also called transthyretin-type familial amyloid polyneuropathy [ATTR-FAP]) when all of the following criteria are met:

   1. The diagnosis is confirmed by detection of a mutation in the TTR gene; and
   2. Member exhibits clinical manifestations of ATTR-FAP (e.g., amyloid deposition in biopsy specimens, TTR protein variants in serum, progressive peripheral sensory-motor polyneuropathy); and
   3. Member is not a liver transplant recipient; and
   4. The requested medication will not be used in combination with any other medication approved for the treatment of hereditary transthyretin-mediated amyloidosis (e.g., Amvuttra, Onpattro, Tegsedi, Vyndamax, Vyndaqel).

   Aetna considers all other indications as experimental, investigational, or unproven.

3. Continuation of Therapy

   Aetna considers continuation of eplontersen (Wainua) therapy medically necessary in members requesting reauthorization for an indication listed in Section II when all of the following criteria are met:

   1. Member must have met all initial authorization criteria; and
   2. Member must have demonstrated a beneficial response to treatment with the requested medication compared to baseline (e.g., improvement of neuropathy severity and rate of disease progression as demonstrated by the modified Neuropathy Impairment Scale+7 [mNIS+7] composite score, the Norfolk Quality of Life-Diabetic Neuropathy [QoL-DN] total score, polyneuropathy disability [PND] score, FAP disease stage, manual grip strength).

Inotersen (Tegsedi)

1. Prescriber Specialties

   This medication must be prescribed by or in consultation with a neurologist, geneticist, or physician specializing in the treatment of amyloidosis.

2. Criteria for Initial Approval

   Aetna considers the initiation of inotersen (Tegsedi) subcutaneous injection medically necessary for the treatment of polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis, also called transthyretin-type familial amyloid polyneuropathy (ATTR-FAP), when all of the following are met:

   1. The diagnosis is confirmed by detection of a mutation in the TTR gene; and
   2. Member exhibits clinical manifestations of ATTR-FAP (e.g., amyloid deposition in biopsy specimens, TTR protein variants in serum, progressive peripheral sensory-motor polyneuropathy); and
   3. The requested medication will not be used in combination with any other medication approved for the treatment of hereditary transthyretin-mediated amyloidosis (e.g., Amvuttra, Onpattro, Vyndamax, Vyndaqel, Wainua). 

   Aetna considers all other indications as experimental, investigational, or unproven. 

3. Continuation of Therapy

   Aetna considers continuation of inotersen (Tegsedi) therapy medically necessary in members requesting reauthorization for an indication listed in Section II when all of the following criteria are met: 

   1. Member must have met all initial authorization criteria; and
   2. Member must have demonstrated a beneficial response to treatment with the requested medication compared to baseline (e.g., improvement of neuropathy severity and rate of disease progression as demonstrated by the modified Neuropathy Impairment Scale+7 [mNIS+7] composite score, the Norfolk Quality of Life-Diabetic Neuropathy [QoL-DN] total score, polyneuropathy disability [PND] score, FAP disease stage, manual grip strength). 

Vutrisiran (Amvuttra)

1. Prescriber Specialties

   This medication must be prescribed by or in consultation with a neurologist, geneticist, or physician specializing in the treatment of amyloidosis.  

2. Criteria for Initial Approval

   Aetna considers the initiation of vutrisiran (Amvuttra) subcutaneous injection medically necessary for treatment of polyneuropathy of hereditary transthyretin-mediated amyloidosis (also called transthyretin-type familial amyloid polyneuropathy [ATTR-FAP]) when all of the following criteria are met:

   1. The diagnosis is confirmed by detection of a mutation in the TTR gene; and
   2. Member exhibits clinical manifestations of ATTR-FAP (e.g., amyloid deposition in biopsy specimens, TTR protein variants in serum, progressive peripheral sensory-motor polyneuropathy); and
   3. Member is not a liver transplant recipient; and
   4. The requested medication will not be used in combination with any other medication approved for the treatment of hereditary transthyretin-mediated amyloidosis (e.g., Onpattro, Tegsedi, Vyndamax, Vyndaqel, Wainua). 

   Aetna considers all other indications as experimental, investigational, or unproven. 

3. Continuation of Therapy

   Aetna considers the continuation of vutrisiran (Amvuttra) therapy medically necessary in members requesting reauthorization for an indication listed in Section II when all of the following criteria are met: 

   1. Member must have met all initial authorization criteria; and
   2. Member must have demonstrated a beneficial response to treatment with the requested medication compared to baseline (e.g., improvement of neuropathy severity and rate of disease progression as demonstrated by the modified Neuropathy Impairment Scale+7 [mNIS+7] composite score, the Norfolk Quality of Life-Diabetic Neuropathy [QoL-DN] total score, polyneuropathy disability [PND] score, FAP disease stage, manual grip strength).

For oral acoramidis (Attruby), see Caremark Specialty Guideline Management (SGM) Attruby SGM 6744-A or pharmacy benefit plan. 

For oral tafamidis (Vyndaqel and Vyndamax), see Specialty Pharmacy Clinical Policy Bulletin - Vyndaqel-Vyndamax 3076-A SGM

Dosage and Administration

Onpattro (patisiran)

• Onpattro (patisiran) is available as a lipid complex injection as 10 mg/5 mL (2 mg/mL) in a single-dose vial. Onpattro is administered via intravenous (IV) infusion by a healthcare professional.
• Dosing is based on actual body weight
  
  
  • For members weighing less than 100 kg, the recommended dosage is 0.3 mg/kg every 3 weeks by IV infusion. 
  • For members weighing 100 kg or more, the recommended dosage is 30 mg IV once every 3 weeks.

Source: Alnylam Pharmaceuticals, 2023

Wainua (eplontersen)

• Wainua (eplontersen) is available for injection as 45 mg/0.8 mL in a single-dose autoinjector for subcutaneous use.
• The recommended dosage of Wainua is 45 mg administered by subcutaneous injection once monthly.
• Wainua is administered into the abdomen or upper thigh region; the back of the upper arm can be used if a healthcare provider or caregiver administers the injection.

Source: AstraZeneca, 2023b

Tegesdi (inotersen)

• Tegsedi (inotersen) is available for injection as 284 mg / 1.5 mL in a single-dose prefilled syringe for subcutaneous use.
• The recommended dose of Tegsedi is 284 mg injected subcutaneously once weekly. For consistency of dosing, individuals should be instructed to give the injection on the same day every week. 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.

Source: Sobi, 2024

Amvuttra (vutrisiran)

• Amvuttra (vutrisiran) is available for injection as 25 mg/0.5 mL in a single-dose prefilled syringe for subcutaneous use and should be administered by a healthcare professional.
• The recommended dosage of Amvuttra is 25 mg administered by subcutaneous injection once every 3 months.

Source: Alnylam Pharmaceuticals, 2023

Experimental, Investigational, and Unproven

1. Aetna considers concurrent use of patisiran (Onpattro) with eplontersen (Wainua), inotersen (Tegsedi), and/or vutrisiran (Amvuttra) experimental, investigational, or unproven because the safety and effectiveness of this combination has not been established.

2. Aetna considers patisiran (Onpattro), eplontersen (Wainua), inotersen (Tegsedi), or vutrisiran (Amvuttra) experimental, investigational, or unproven for sensorimotor or autonomic neuropathy not related to hATTR amyloidosis because of insufficient evidence in peer-reviewed published literature.

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Patisiran (Onpattro):
Other CPT codes related to the CPB:
96365 - 96368	Intravenous infusion administration
HCPCS codes covered if selection criteria are met:
J0222	Injection, patisiran, 0.1 mg
Other HCPCS codes related to the CPB:
Vyndamax, Vyndaqel - no specific code
ICD-10 codes covered if selection criteria are met:
E85.1	Neuropathic heredofamilial amyloidosis [transthyretin-type familial amyloid polyneuropathy (ATTR-FAP), Polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis]
ICD-10 codes not covered for indications listed in the CPB:
T86.40 - T86.49	Complications of liver transplant
Eplontersen (Wainua):
HCPCS codes covered if selection criteria are met:
Eplontersen (Wainua) subcutaneous injection- no specific code
Other CPT codes related to the CPB:
96369 - 96372	Subcutaneous infusion administration
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:
Other HCPCS codes related to the CPB:
Vyndamax, Vyndaqel - no specific code
ICD-10 codes covered if selection criteria are met:
E85.1	Neuropathic heredofamilial amyloidosis [transthyretin-type familial amyloid polyneuropathy (ATTR-FAP)]
ICD-10 codes not covered for indications listed in the CPB:
T86.40 - T86.49	Complications of liver transplant
Vutrisiran (Amvuttra):
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:
J0225	Injection, vutrisiran, 1 mg
Other HCPCS codes related to the CPB:
Vyndamax, Vyndaqel -no specific code
ICD-10 codes covered if selection criteria are met:
E85.1	Neuropathic heredofamilial amyloidosis [transthyretin-type familial amyloid polyneuropathy (ATTR-FAP)]

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Background

Hereditary transthyretin amyloidosis (hATTR amyloidosis), formerly known as transthyretin-type familial amyloid polyneuropathy (ATTR-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, 2019).

Patisiran (Onpattro)

U.S. Food and Drug Administration (FDA)-Approved Indication

• Onpattro is indicated for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults.

Patisiran is branded as Onpattro (Alnylam Pharmaceuticals, Inc.). Patisiran is a double-stranded small interfering ribonucleic acid (siRNA) that causes degradation of mutant and wild-type TTR mRNA through RNA interference, which results in a reduction of serum TTR protein and TTR protein deposits in tissues.

Onpattro label includes warnings and precautions for infusion-related reactions (IRR) and reduced serum vitamin A levels. In a controlled clinical study, 19% of Onpattro-treated patients experienced IRRs, compared to 9% of placebo-treated patients. Among Onpattro-treated patients who experienced an IRR, 79% experienced the first IRR within the first 2 infusions. The frequency of IRRs decreased over time. IRRs led to infusion interruption in 5% of patients. IRRs resulted in permanent discontinuation of Onpattro in less than 1% of patients in clinical studies. In addition, Onpattro therapy leads to a decrease in serum vitamin A levels. Supplementation at the recommended daily allowance of vitamin A is advised for patients taking Onpattro. Higher doses than the recommended daily allowance of vitamin A should not be given to try to achieve normal serum vitamin A levels during treatment with Onpattro, as serum vitamin A levels do not reflect the total vitamin A in the body.

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) included upper respiratory tract infections and infusion-related reactions.

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, 2019).

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 the diagnosis of hATTR amyloidosis 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, adequate biochemical liver function, and serum creatinine ≤ 2 x ULN. Patients were excluded if they had a prior liver transplant or planned to undergo liver transplant during the study period, Type 1 diabetes, Type 2 diabetes greater than or equal to 5 years, active hepatitis B or C, HIV infection, and NYHA heart failure classification greater than 2. Selected 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).

In the clinical trial, 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.

Milani and colleagues (2019) stated that hATTRv (v for variant) is a rare, progressive, fatal multi-systemic disease, autosomal dominantly inherited with heterogeneous clinical phenotype caused by mutations in the TTR gene.  Mutations promoting proteolytic re-modeling and tetramer dissociation result in fragmented and full-length TTR monomers that misfold, aggregate and deposit at multiple sites (mainly nerves and heart) causing peripheral neuropathy and/or cardiomyopathy.  These investigators discussed patisiran, the first FDA-approved RNA interference-based therapeutic agent that suppresses the circulating levels of the amyloidogenic protein TTR both wild-type and mutant.  This compound demonstrated a safe clinical profile in phase-I and -II clinical trials and showed a significant clinical effect in a phase-III (APOLLO) trial in ATTRv patients.  An open-label extension study is still underway but, based on the positive results, the regulatory agencies granted approval for the treatment of ATTRv with polyneuropathy in Stage I and II.  The authors concluded that the patisiran program has demonstrated that substantial TTR concentration reduction was associated with significant and sustained improvement in polyneuropathy scores, QOL profile and several outcome measures that capture the systemic burden of the disease.  The drug has also been reported to be safe in long-term follow-up studies; however its efficacy for ATTR with cardiomyopathy is under investigation.

Per a label update, age, race (non-Caucasian vs. Caucasian), sex, and prior liver transplantation had no impact on the steady state pharmacokinetics of patisiran or TTR reduction (Alnylam Pharmaceuticals, 2023).

Eplontersen (Wainua)

U.S. Food and Drug Administration (FDA)-Approved Indication

• Wainua is indicated for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults.

Eplontersen is branded as Wainua (AstraZeneca Pharmaceuticals LP). Eplontersen is a transthyretin-directed antisense oligonucleotide that causes degradation of mutant and wild-type TTR mRNA through binding to the TTR mRNA, which results in a reduction of serum TTR protein and TTR protein deposits in tissues.

Wainua label includes warnings and precautions for reduced serum vitamin A levels. Supplementation at the recommended daily allowance of vitamin A is advised. However, higher doses than the recommended daily allowance of vitamin A should not be given to try to achieve normal serum vitamin A levels during treatment with Wainua, as serum vitamin A levels do not reflect the total vitamin A in the body. Patients should be referred to an ophthalmologist if they develop ocular symptoms suggestive of vitamin A deficiency (e.g., night blindness, dry eyes).

The most common adverse reactions (that occurred in at least 9% of patients treated with Wainua) were vitamin A decreased and vomiting.

There is no information regarding the presence of eplontersen in human milk, the effects on the breast-fed infant, or the effects on milk production.

On December 21, 2023, the FDA approved Wainua (AstraZeneca Pharmaceuticals LP) for the treatment of the polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis in adults. Wainua is a once-monthly subcutaneous injection that can be self-administered via an auto-injector. Approval was based on the positive 35-week interim analysis from the NEURO-TTRansform phase 3 trial, which showed patients treated with Wainua demonstrated consistent and sustained benefit on the co-primary endpoints of serum transthyretin (TTR) concentration and neuropathy impairment measured by modified Neuropathy Impairment Score +7 (mNIS+7), and key secondary endpoint of quality of life (QoL) on the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QoL-DN) (AstraZeneca, 2023a). The neuropathy impairment score (NIS) objectively measures deficits in cranial nerve function, muscle strength, reflexes, and sensations, and the Modified +7 assesses heart rate response to deep breathing, quantitative sensory testing (touch-pressure and heat-pain), and peripheral nerve electrophysiology. The validated version of the mNIS+7 score used in the trial has a range of -22.3 to 346.3 points, with higher scores representing a greater severity of disease. The Norfolk QoL-DN scale is a patient-reported assessment that evaluates the subjective experience of neuropathy in the following domains: physical functioning/large fiber neuropathy, activities of daily living, symptoms, small fiber neuropathy, and autonomic neuropathy. The version of the Norfolk QoL-DN that was used in the trial has a range from -4 to 136 points, with higher scores representing greater impairment (AstraZeneca, 2023b).

NEURO-TTRansform was a randomized, open-label, multicenter, phase 3 trial that evaluated the safety and efficacy of eplontersen in 168 adult patients with polyneuropathy caused by hATTR amyloidosis. Patients were randomized in a 6:1 ratio to receive subcutaneous injections of either 45 mg of eplontersen (Wainua) once every 4 weeks (n=144), or 284 mg of inotersen (Tegsedi) once per week (n=24). Ninety-seven percent of eplontersen-treated patients and 83% of inotersen-treated patients completed at least 35 weeks of the assigned treatment. The efficacy endpoints were the change from baseline to Week 35 in the mNIS+7 composite score and the change from baseline to Week 35 in the Norfolk QoL-DN total score. Efficacy assessments compared the eplontersen study arm with the external placebo group (n=60) from the inotersen NEURO-TTR trial, which had similar eligibility criteria and endpoints. Treatment with eplontersen resulted in statistically significant improvements in the mNIS+7 and the Norfolk QoL-DN total scores, compared to the external placebo control (p<0.001) at Week 35.

Coelho et al (2023) compared the efficacy of eplontersen in the NEURO-TTRansform trial with the external placebo from the inotersen NEURO-TTR trial at Week 66. The authors found that in patients with hATTR polyneuropathy, the eplontersen treatment group demonstrated changes consistent with significantly lowered serum transthyretin concentration, less neuropathy impairment, and better quality of life compared with the external placebo group. All patients were followed on treatment until week 85, when they had the option to transition into an open- label extension study, which is still ongoing.

The safety and effectiveness in pediatric patients have not been established.

Eplontersen has not been studied in patients with severe renal impairment, end-stage renal disease, or in patients with moderate to severe hepatic impairment, or in patients with prior liver transplant.

Inotersen (Tegsedi)

U.S. Food and Drug Administration (FDA)-Approved Indication

• Tegsedi is indicated for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults.

Inotersen is branded as Tegsedi (developed by Ionis Pharmaceuticals and distributed by Sobi, Inc.). Inotersen is an antisense oligonucleotide that causes degradation of mutant and wild-type TTR mRNA through binding to the TTR mRNA, which results in a reduction of serum TTR protein and TTR protein deposits in tissues. Thus, Tegsedi is a transthyretin-directed antisense oligonucleotide.

Tegsedi label includes a black box warning for risk of thrombocytopenia and glomerulonephritis. Tegsedi causes reductions in platelet count that may result in sudden and unpredictable thrombocytopenia, which can be life-threatening. One clinical trial patient died from intracranial hemorrhage. Tegsedi is contraindicated in patients with a platelet count below 100 x 10⁹ /L. In addition, Tegsedi can cause glomerulonephritis that may require immunosuppressive treatment and may result in dialysis-dependent renal failure. One clinical trial patient who developed glomerulonephritis and did not receive immunosuppressive treatment remained dialysis-dependent. 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. Tegsedi should generally not be initiated in patients with urinary protein to creatinine ratio (UPCR) of 1000 mg/g or higher. Because of the risks of serious bleeding caused by severe thrombocytopenia and because of glomerulonephritis, both of which require frequent monitoring, Tegsedi is available only through a restricted distribution program under a Risk Evaluation and Mitigation Strategy (REMS) called the Tegsedi REMS Program.

Tegsedi label carries warnings and precautions for stroke and cervicocephalic arterial dissection, inflammatory and immune effects, liver injury, hypersensitivity reactions, uninterpretable platelet counts, and reduced serum vitamin A levels. In clinical studies, 1 of 161 (0.6%) Tegsedi-treated patients experienced carotid artery dissection and stroke. These events occurred within 2 days of the first Tegsedi dose, a time when the patient also had symptoms of cytokine release (e.g., nausea, vomiting, muscular pain and weakness) and a high sensitivity C-reactive protein level greater than 100 mg/L. In clinical studies, serious inflammatory and immune adverse reactions occurred in Tegsedi-treated patients, including immune thrombocytopenia and glomerulonephritis, as well as a single case of antineutrophil cytoplasmic autoantibody (ANCA)-positive systemic vasculitis. Additionally, in clinical studies, 8% of Tegsedi-treated patients had an increased alanine aminotransferase (ALT) at least 3 times the  upper limit of normal (ULN), compared to 3% of patients on placebo; 3% of Tegsedi-treated patients had an ALT at least 8 times the ULN, compared to no patient on placebo. One clinical study patient experienced an increased ALT more than 30 times the ULN. After a course of corticosteroids and discontinuation of Tegsedi, the patient’s ALT returned to normal levels. Some patients had resolution of the liver laboratory abnormalities with continued use of Tegsedi. In clinical studies, demonstrated or possible cases of immune-mediated biliary disease occurred in Tegsedi-treated patients. There was a single case of autoimmune hepatitis with primary biliary cirrhosis in a patient with a family history of primary biliary cirrhosis, as well as a single case of biliary obstruction of unclear etiology. In a clinical study, cases of liver transplant rejection were reported 2-4 months after starting Tegsedi in patients whose liver allografts had previously been clinically stable (for over 10 years) prior to starting Tegsedi. In these cases, the patients clinically improved and transaminase levels normalized after glucocorticoid administration and cessation of Tegsedi. In clinical studies, 6 of 161 (4%) Tegsedi-treated patients stopped treatment because of a hypersensitivity reaction. Antibodies to Tegsedi were present when the reactions occurred. These reactions generally occurred within 2 hours of administration of Tegsedi and included headache, chest pain, hypertension, chills, flushing, dysphagia, palmar erythema, eosinophilia, involuntary choreaform movements, arthralgia, myalgia, and flu-like symptoms. In a clinical study, 23% of Tegsedi-treated patients had at least 1 uninterpretable platelet count caused by platelet clumping, compared to 13% of patients on placebo. In 2 cases of severe thrombocytopenia with platelet count below 25 x 109 /L, one of which resulted in death, clumped platelet samples caused a delay in diagnosis and treatment. Both subjects had tested positive for treatment-emergent anti-platelet IgG antibodies detected shortly before, or at the time of the severe reduction in platelet count.

Tegsedi treatment leads to a decrease in serum vitamin A levels. Supplementation at the recommended daily allowance of vitamin A is advised for patients taking Tegsedi. Higher doses than the recommended daily allowance of vitamin A should not be given to try to achieve normal serum vitamin A levels during treatment with Tegsedi, as serum vitamin A levels do not reflect the total vitamin A in the body.

Labeling for Tegsedi states to monitor alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin monthly during treatment. In addition, monitor monthly for patients who have received a liver transplant. Tegsedi should be discontinued in patients suspected of developing liver injury induced by Tegsedi. 

The most common adverse reactions (those that occurred in at least 20% of Tegsedi-treated patients and more frequently than on placebo) included injection site reactions, nausea, headache, fatigue, thrombocytopenia, and fever.

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, 2018a). 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 (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.

Vutrisiran (Amvuttra)

U.S. Food and Drug Administration (FDA)-Approved Indication

• Amvuttra is indicated for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults.

Vutrisiran is branded as Amvuttra (Alnylam Pharmaceuticals, Inc.). Vutrisiran is a double-stranded siRNA-GalNAc conjugate that causes degradation of mutant and wild-type TTR mRNA through RNA interference, which results in a reduction of serum TTR protein and TTR protein deposits in tissues. Thus, Amvuttra contains a transthyretin-directed small interfering RNA. Amvuttra is designed for increased potency and high metabolic stability to allow for subcutaneous injection once every three months (quarterly).

Amvuttra carries labeled warnings and precautions for reduced serum vitamin A levels. Supplementation at the recommended daily allowance of vitamin A is advised for patients taking Amvuttra. Higher doses than the recommended daily allowance of vitamin A should not be given to try to achieve normal serum vitamin A levels during treatment with Amvuttra, as serum vitamin A levels do not reflect the total vitamin A in the body. Patients should be referred to an ophthalmologist if they develop ocular symptoms suggestive of vitamin A deficiency (e.g., night blindness). The most common adverse reactions (5% or more) were pain in extremity, arthralgia, dyspnea, and vitamin A decrease.

On June 13, 2022, Alnylam Pharmaceuticals, Inc. announced the FDA approval of Amvuttra (vutrisiran), an RNAi therapeutic administered via subcutaneous injection once every three months (quarterly), for the treatment of the polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis in adults. FDA approval is based on positive 9-month results from the HELIOS-A Phase 3 study, where Amvuttra significantly improved the signs and symptoms of polyneuropathy, with more than 50 percent of patients experiencing halting or reversal of their disease manifestations (Alnylam Pharmaceuticals, 2022b).

The HELIOS-A trial (NCT03759379) is a randomized, open-label clinical trial that evaluated the efficacy of vutrisiran in adult patients with polyneuropathy caused by hATTR amyloidosis. Patients were randomized 3:1 to receive 25 mg of vutrisiran subcutaneously once every 3 months (N=122), or 0.3 mg/kg patisiran intravenously every 3 weeks (N=42) as a reference group. Ninety-seven percent of vutrisiran-treated patients and 93% of patisiran-treated patients completed at least 9 months of the assigned treatment. Efficacy assessments were based on a comparison of the vutrisiran arm of the HELIOS-A trial with an external placebo group from the APOLLO trial (patisiran) composed of a comparable population of adult patients with polyneuropathy caused by hATTR amyloidosis. The primary efficacy endpoint was the change from baseline to Month 9 in modified Neuropathy Impairment Score +7 (mNIS+7). The clinical meaningfulness of effects on the mNIS+7 was assessed by the change from baseline to Month 9 in Norfolk Quality of Life-Diabetic Neuropathy (QoL-DN) total score. Additional endpoints were gait speed, as measured by the 10-meter walk test (10MWT), and modified body mass index (mBMI). Treatment with vutrisiran resulted in statistically significant improvements in the mNIS+7, Norfolk QoL-DN total score, and 10-meter walk test at Month 9 compared to placebo in the external study (p<0.001). The change from baseline to Month 9 in modified body mass index nominally favored vutrisiran. Patients receiving vutrisiran experienced similar improvements relative to those in the external placebo group in mNIS+7 and Norfolk QoL-DN total score across all subgroups including age, sex, race, region, NIS score, Val30Met genotype status, and disease stage (Alnylam Pharmaceuticals, 2022a, 2022b, 2023).

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Appendix

Table: Clinical Staging of TTR-FAP

Stage	Symptoms
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)

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References