Transthyretin-Mediated (ATTR) 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.

These medications have been identified as Aetna Gene-based, Cellular & Other Innovative Therapies (GCIT®) products. They receive dedicated review by the Aetna GCIT team for Commercial and Medicare lines of business.

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 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. Member is 18 years of age or older; and
   2. The diagnosis is confirmed by detection of a pathogenic variant in the TTR gene; and
   3. 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
   4. The requested medication will not be used in combination with vutrisiran (Amvuttra), inotersen (Tegsedi), eplontersen (Wainua), tafamidis meglumine (Vyndaqel), tafamidis  (Vyndamax), or acoramidis (Attruby).

   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. Member is 18 years of age or older; and
   2. The diagnosis is confirmed by detection of a pathogenic variant in the TTR gene; and
   3. 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
   4. Member is not a liver transplant recipient; and
   5. The requested medication will not be used in combination with vutrisiran (Amvuttra), patisiran (Onpattro), inotersen (Tegsedi), tafamidis meglumine (Vyndaqel), tafamidis  (Vyndamax), or acoramidis (Attruby). 

   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. Member is 18 years of age or older; and
   2. The diagnosis is confirmed by detection of a pathogenic variant in the TTR gene; and
   3. 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
   4. The requested medication will not be used in combination with vutrisiran (Amvuttra), patisiran (Onpattro), eplontersen (Wainua), tafamidis meglumine (Vyndaqel), tafamidis  (Vyndamax), or acoramidis (Attruby). 

   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, cardiologist, 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 the following indications when criteria are met:
   
   Polyneuropathy of hereditary transthyretin-mediated amyloidosis (also called transthyretin-type familial amyloid polyneuropathy [ATTR-FAP]) when all of the following criteria are met:

   1. Member is 18 years of age or older; and
   2. The diagnosis is confirmed by detection of a pathogenic variant in the TTR gene; and
   3. 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
   4. Member is not a liver transplant recipient; and
   5. The requested medication will not be used in combination with patisiran (Onpattro), inotersen (Tegsedi), eplontersen (Wainua), acoramidis (Attruby), tafamidis meglumine (Vyndaqel), or tafamidis (Vyndamax); 

   Cardiomyopathy of wild-type or hereditary transthyretin-mediated amyloidosis (ATTR-CM) when all of the following criteria are met:

   1. Member is 18 years of age or older; and
   2. Member has medical history of heart failure with at least one prior hospitalization for heart failure (not due to arrhythmia or a conduction system disturbance treated with a permanent pacemaker), or exhibits clinical symptoms of heart failure (e.g., volume overload, dyspnea, fatigue, orthostatic hypotension, syncope, peripheral edema) at baseline; and
   3. The diagnosis is confirmed by either of the following criteria:

      1. Member meets both of the following criteria for biopsy proven disease:

         1. Presence of transthyretin amyloid deposits on analysis of biopsy from cardiac or noncardiac sites; and
         2. Presence of transthyretin precursor proteins was confirmed by immunohistochemical analysis, mass spectrometry, tissue staining, or polarized light microscopy; or

      2. Member meets both of the following criteria for technetium-labeled bone scintigraphy proven disease:

         1. Presence of amyloid deposits confirmed by technetium-labeled bone scintigraphy tracing; and
         2. Systemic light chain amyloidosis is ruled out by showing the absence of monoclonal proteins by all of the following tests:
            
            
            1. serum kappa/lambda free light chain ratio, and
            2. serum protein immunofixation, and
            3. urine protein immunofixation; and
   4. For members with hereditary ATTR-CM, the diagnosis must also be confirmed by detection of a pathogenic or likely pathogenic variant in the TTR gene; and
   5. Member does not have prior or anticipated heart, liver, or other organ transplant or implantation of left-ventricular assist device; and 
   6. The requested medication will not be used in combination with patisiran (Onpattro), inotersen (Tegsedi), eplotersen (Wainua), acoramidis (Attruby), tafamidis meglumine (Vyndaqel), or tafamidis (Vyndamax).

   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; 
   2. For polyneuropathy of hereditary transthyretin-mediated amyloidosis (hATTR-PN), 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);
   3. For cardiomyopathy of wild-type or hereditary transthyretin-mediated amyloidosis (ATTR-CM), member must have demonstrated a beneficial response to treatment with the requested medication compared to baseline (e.g., improvement in rate of disease progression as demonstrated by distance walked on the 6-minute walk test, the Kansas City Cardiomyopathy Questionnaire-Overall Summary [KCCQ-OS] score, cardiovascular-related hospitalizations, New York Heart Association [NYHA] classification of heart failure, left ventricular stroke volume, N-terminal B-type natriuretic peptide [NT-proBNP] level).

Related Policies

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, 2025

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, 2025b

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:
81404	Molecular pathology procedure, Level 5 [full gene sequence TTR (transthyretin)]
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, Inotersen (Tegsedi), Eplontersen (Wainua), Acoramidis (Attruby) - no specific code
J0225	Injection, vutrisiran, 1 mg
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):
Other CPT codes related to the CPB:
81404	Molecular pathology procedure, Level 5 [full gene sequence TTR (transthyretin)]
96369 - 96372	Subcutaneous infusion administration
HCPCS codes covered if selection criteria are met:
Eplontersen (Wainua) subcutaneous injection- no specific code
Other HCPCS codes related to the CPB:
Tafamidis meglumine (Vyndaqel), Inotersen (Tegsedi), Tafamidis (Vyndamax), Acoramidis (Attruby)- no specific code
J0222	Injection, patisiran, 0.1 mg
J0225	Injection, vutrisiran, 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:
81404	Molecular pathology procedure, Level 5 [full gene sequence TTR (transthyretin)]
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, Eplontersen (Wainua), Acoramidis (Attruby) - no specific code
J0222	Injection, patisiran, 0.1 mg
J0225	Injection, vutrisiran, 1 mg
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:
78800-78804, 78830-78832	Radiopharmaceutical localization of tumor, inflammatory process or distribution of radiopharmaceutical agent(s) (includes vascular flow and blood pool imaging, when performed)
81404	Molecular pathology procedure, Level 5 [full gene sequence TTR (transthyretin)]
82542	Column chromatography, includes mass spectrometry, if performed (eg, HPLC, LC, LC/MS, LC/MS-MS, GC, GC/MS-MS, GC/MS, HPLC/MS), non-drug analyte(s) not elsewhere specified, qualitative or quantitative, each specimen
83521	Immunoglobulin light chains (ie, kappa, lambda), free, each
83789	Mass spectrometry and tandem mass spectrometry (eg, MS, MS/MS, MALDI, MS-TOF, QTOF), non-drug analyte(s) not elsewhere specified, qualitative or quantitative, each specimen
86334	Immunofixation electrophoresis; serum
86335	Immunofixation electrophoresis; other fluids with concentration (eg, urine, CSF)
88312-88319	Special stain including interpretation and report
88341-88344	Immunohistochemistry or immunocytochemistry, per specimen
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, Inotersen (Tegsedi), Eplontersen (Wainua), Acoramidis (Attruby) -no specific code
A9500-A9504, A9510-A9568	Technetium tc-99m
J0222	Injection, patisiran, 0.1 mg
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

Transthyretin amyloidosis (ATTR) is a frequently unrecognized systemic disorder caused by the misfolding of the transthyretin protein, leading to the formation of fibrils that accumulate in various tissues and organs. A specific form of this condition is hereditary transthyretin amyloidosis (hATTR amyloidosis), formerly known as transthyretin-type familial amyloid polyneuropathy (ATTR-FAP). This rare, progressive autosomal dominant disorder is characterized by adult-onset sensory, motor, and autonomic neuropathy, along with complications affecting the heart, gastrointestinal system, eyes, and kidneys, which can be fatal within 2 to 15 years of symptom onset. Over 50,000 individuals worldwide are affected by hATTR amyloidosis, which results from mutations in the TTR gene on chromosome 18q11.2–12.1, causing misfolded proteins to accumulate in organs and tissues, particularly impacting the peripheral nervous system and leading to symptoms such as loss of sensation, pain, or mobility issues. A notable manifestation of ATTR is transthyretin amyloid cardiomyopathy (ATTR-CM), which poses serious health risks and affects approximately 150,000 people in the United States. In ATTR-CM, the misfolded protein builds up in the heart, resulting in stiffened muscle walls that impair the heart's ability to pump blood, potentially leading to heart failure. ATTR-CM is classified into hereditary (hATTR-CM) and wild-type (wATTR-CM) forms. This debilitating condition significantly diminishes quality of life and daily functioning. While traditional treatments have focused on symptom management, a new class of medication, small interfering ribonucleic acid (siRNA) therapy, was approved by the FDA in August 2018 to address the root cause of the disease.

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, marketed as Onpattro (Alnylam Pharmaceuticals, Inc.), is a double-stranded small interfering ribonucleic acid (siRNA) that degrades both mutant and wild-type TTR mRNA through RNA interference. This process results in a reduction of serum TTR protein levels and decreases 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, marketed as Wainua (AstraZeneca Pharmaceuticals LP), is a transthyretin-directed antisense oligonucleotide that degrades both mutant and wild-type TTR mRNA by binding to it. This action leads to a reduction in serum TTR protein levels and decreases 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 decrease in vitamin A and vomiting.

There are no available data on eplontersen use in pregnant women to inform drug-associated risk of adverse developmental outcomes. Moreover, 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, marketed as Tegsedi (developed by Ionis Pharmaceuticals and distribution by Sobi, Inc.), is an antisense oligonucleotide that degrades both mutant and wild-type TTR mRNA by binding to it. This action results in a reduction of serum TTR protein levels and decreases TTR protein deposits in tissues. Therefore, Tegsedi is classified as 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.

Akcea Therapeutics, Inc., the manufacturer of Tegsedi, announced they will discontinue commercial availability of Tegsedi effective September 27, 2024 based on low utilization of the product. No issues with the effectiveness of the drug or its safety were involved in the decision (VativoRx, 2024)

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 (hATTR-PN) in adults;
• The cardiomyopathy of wild-type or hereditary transthyretin-mediated amyloidosis (ATTR-CM) in adults to reduce cardiovascular mortality, cardiovascular hospitalizations, and urgent heart failure visits.

Vutrisiran, marketed as Amvuttra (Alnylam Pharmaceuticals, Inc.), is a double-stranded small interfering RNA (siRNA) conjugated with GalNAc that mediates the degradation of both mutant and wild-type transthyretin (TTR) mRNA via RNA interference (RNAi). This mechanism leads to a reduction in circulating TTR protein levels and diminishes TTR deposition in tissues. As a transthyretin-targeting siRNA therapeutic, Amvuttra is engineered for enhanced potency and metabolic stability, enabling subcutaneous administration once every three months.

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 decreased vitamin A.

Polyneuropathy of Hereditary Transthyretin-Mediated Amyloidosis (hATTR-PN)

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).

Cardiomyopathy of Wild-Type or Hereditary Transthyretin-Mediated Amyloidosis (ATTR-CM)

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a serious and potentially life-threatening heart condition that impacts around 150,000 individuals in the United States. In ATTR-CM, the misfolded transthyretin protein accumulates in the heart, causing the muscle walls to stiffen, which impairs the heart's ability to pump blood effectively and can ultimately lead to heart failure. ATTR-CM is divided into two types: hereditary ATTR-CM (hATTR-CM), where a variant in the transthyretin gene leads to amyloid deposits in the heart, nerves, and sometimes other organs, with symptoms potentially beginning as early as age 30, and wild-type ATTR-CM (wATTR-CM), which occurs without a genetic variant and primarily affects the heart. Unfortunately, there is no cure for ATTR-CM, and the accumulation of misfolded transthyretin fibrils causes irreversible damage over time, which can result in premature death.

In March 2025, the FDA granted approval for use of Amvuttra for the treatment of cardiomyopathy of wild-type or hereditary transthyretin-mediated amyloidosis (ATTR-CM) in adults to reduce cardiovascular mortality, cardiovascular hospitalizations, and urgent heart failure visits. FDA approval is based on the results from the phase 3 HELIOS-B trial which achieved statistical significance compared to placebo on all 10 pre-specified primary and secondary endpoints. "In the overall population, Amvuttra reduced the risk of all-cause mortality (ACM) and recurrent cardiovascular (CV) events by 28% during the double-blind treatment period of up to 36 months. Mortality in this population was significantly reduced by 36% through 42 months in a pre-specified secondary endpoint analysis which included up to 36 months of the double-blind period plus six months of open-label extension. In the monotherapy population, Amvuttra significantly reduced the risk of ACM and recurrent CV events by 33% in the double-blind period and significantly reduced the risk of mortality by 35% through 42 months. As compared to patients treated with placebo, patients treated with Amvuttra also experienced preservation of functional capacity and quality of life, as well as early improvements in biomarkers NT-proBNP and troponin I, which are predictive of cardiovascular outcomes. The safety and tolerability of Amvuttra are well-established, as demonstrated in the positive HELIOS-A clinical trial for Amvuttra in hATTR-PN which resulted in FDA approval in 2022 and over 5,000 patient-years exposure to-date, globally. In that study, the most common adverse reactions in patients treated with Amvuttra were pain in extremity (15%), arthralgia (11%), dyspnea (7%), and vitamin A decreased (7%). No new safety concerns were identified in the HELIOS-B clinical trial of patients with ATTR-CM" (Alnylam Pharmaceuticals, 2025a).

In a multicenter, international, randomized, double-blind, placebo-controlled trial (HELIOS-B, NCT04153149), Fontana and colleagues (2025) evaluated the efficacy and safety of subcutaneous vutrisiran, an RNA interference therapeutic agent, in patients with ATTR-CM. A total of 655 patients underwent randomization (vutrisiran, n=326; placebo, n=329). Patients with ATTR-CM were randomized to receive vutrisiran (25 mg) or placebo every 12 weeks for up to 36 months. The primary end point was a composite of death from any cause and recurrent cardiovascular events. Secondary end points included death from any cause, the change from baseline in the distance covered on the 6-minute walk test, and the change from baseline in the Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS) score. The efficacy end points were assessed in the overall population and in the monotherapy population (the patients who were not receiving tafamidis at baseline) and were tested hierarchically. The investigators found that vutrisiran treatment led to a lower risk of death from any cause and recurrent cardiovascular events than placebo (hazard ratio in the overall population, 0.72; 95% confidence interval [CI], 0.56 to 0.93; P = 0.01; hazard ratio in the monotherapy population, 0.67; 95% CI, 0.49 to 0.93; P = 0.02) and a lower risk of death from any cause through 42 months (hazard ratio in the overall population, 0.65; 95% CI, 0.46 to 0.90; P = 0.01). Among the patients in the overall population, 125 in the vutrisiran group and 159 in the placebo group had at least one primary end-point event. In the overall population, treatment with vutrisiran resulted in less of a decline in the distance covered on the 6-minute walk test than placebo (least-squares mean difference, 26.5 m; 95% CI, 13.4 to 39.6; P<0.001) and less of a decline in the KCCQ-OS score (least-squares mean difference, 5.8 points; 95% CI, 2.4 to 9.2; P<0.001). Similar benefits were observed in the monotherapy population. The incidence of adverse events was similar in the two groups (99% in the vutrisiran group and 98% in the placebo group); serious adverse events occurred in 62% of the patients in the vutrisiran group and in 67% of those in the placebo group. The investigators concluded that among patients with ATTR-CM, treatment with vutrisiran led to a lower risk of death from any cause and cardiovascular events than placebo and preserved functional capacity and quality of life.

HELIOS-B inclusion criteria required patients to have a documented diagnosis of ATTR amyloidosis with cardiomyopathy, classified as either hereditary ATTR (hATTR) amyloidosis with cardiomyopathy or wild-type ATTR (wtATTR) amyloidosis with cardiomyopathy meeting pre-specified diagnostic criteria; and have a medical history of heart failure (HF) with at least 1 prior hospitalization for HF or clinical evidence of HF.

HELIOS-B exclusions were: 

• Known primary amyloidosis or leptomeningeal amyloidosis
• Having New York Heart Association (NYHA) Class IV heart failure
• Having NYHA Class III heart failure and is at high risk based on pre-specified criteria
• Having a polyneuropathy disability (PND) Score IIIa, IIIb, or IV at the screening visit
• Having estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m^2
• Having received prior TTR-lowering treatment
• Having other non-TTR cardiomyopathy, hypertensive cardiomyopathy, cardiomyopathy due to valvular heart disease, or cardiomyopathy due to ischemic heart disease.

In the HELIOS-B trial, safety was evaluated in 654 patients with ATTR-CM, which included 257 patients treated with vutrisiran for greater than or equal to 30 months, and 77 patients treated with vutrisiran for greater than or equal to 36 months. No new safety issues  were identified. Eighty-two percent of patients treated with vutrisiran had normal vitamin A levels at baseline, and 80% of those with a normal baseline developed low vitamin A levels.

Witteles et al (2025) presented data from HELIOS-B evaluating the impact of vutrisiran on survival with additional patient follow-up through 42 months, and cardiovascular (CV) events that included hospitalizations and urgent heart failure visits. The HELIOS-B trial enrolled 655 participants who received vutrisiran 25 mg or placebo subcutaneously every three months for up to 36 months, followed by an open-label extension. The authors found that vutrisiran was associated with a 36% reduction in all-cause mortality (HR: 0.64) and a 33% reduction in CV mortality (HR: 0.67) compared to placebo. Additionally, it lowered the risk of CV hospitalizations (RR: 0.75), heart failure (HF) hospitalizations (RR: 0.67), and urgent HF visits (RR: 0.54). These benefits were consistent regardless of baseline tafamidis use. Limitations of this data include the open-label extension and potential confounding from concurrent therapies.

In summary, the safety and efficacy of vutrisiran (Amvuttra) has been established for the use of cardiomyopathy of wild-type or hereditary transthyretin-mediated amyloidosis in adults to reduce cardiovascular mortality, cardiovascular hospitalizations and urgent heart failure visits.

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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