Medical Policy

Policy Num:       05.001.033
Policy Name:     Treatment of Hereditary Transthyretin-Mediated Amyloidosis in Adult Patients
Policy ID:           [05.001.033]  [Ac / B / M+ / P+]  [5.01.30]

Last Review:       January 14, 2025
Next Review:      January 20, 2026
 

Related Policies: None

Treatment of Hereditary Transthyretin-Mediated Amyloidosis in Adult Patients

Summary

Description

Hereditary transthyretin-mediated amyloidosis (hATTR) is a rare, progressive, and fatal autosomal dominant genetic disease in which a variant in the transthyretin gene results in the production of misfolded insoluble transthyretin protein which accumulates as amyloid fibrils (i.e., amyloidosis) in multiple organs of the body such as the liver, nerves, heart, and kidneys causing disruption of organ tissue structure and function. Historically, hATTR was classified into familial amyloid polyneuropathy or familial amyloid cardiomyopathy. However, it is now recognized that most patients manifest signs and symptoms of both syndromes over the course of their disease and therefore the current clinical approach treats familial amyloid polyneuropathy and familial amyloid cardiomyopathy as 1 hereditary disease (polyneuropathy of hATTR) with a spectrum of clinical manifestations.

Summary of Evidence

For individuals who are adults with polyneuropathy of hereditary transthyretin-mediated amyloidosis (hATTR) who receive patisiran, the evidence includes 1 pivotal randomized controlled trial (RCT). Relevant outcomes are symptoms, change in disease status, functional outcomes, quality of life (QOL), treatment-related morbidity, and treatment-related mortality. Data from the APOLLO III trial demonstrated a statistically significant mean improvement in neurologic function and neuropathy-related QOL with patisiran at 18 months compared to placebo. Post-hoc evidence also suggests a decreased risk of the composite endpoint of all-cause mortality and hospitalization among those with cardiac involvement. However, results of APOLLO trial have limited generalizability because only 20% of APOLLO participants were from the U.S. and included only 2 participants (0.9%) with Val122Ile variant, which is the most common variant observed in the U.S. There is also uncertainty regarding long-term benefits and harms for a treatment that is intended to be used lifelong. Studies on long-term safety and tolerability are ongoing. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome

For individuals who are adults with polyneuropathy of hATTR who receive vutrisiran, the evidence includes 1 pivotal RCT. Relevant outcomes are symptoms, change in disease status, functional outcome, QOL, treatment-related morbidity, and treatment-related mortality. Data from the HELIOS-A trials demonstrated a statistically significant improvement in neurological function and neuropathy related QOL with vutrisiran compared to the placebo arm of the previous pivotal trial for patisiran (APOLLO). There is uncertainty regarding long-term benefits and harms for a treatment that is intended to be used lifelong. Studies on long-term safety and tolerability are ongoing. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who are adults with polyneuropathy of hATTR who receive eplontersen, the evidence includes 1 pivotal RCT. Relevant outcomes are symptoms, change in disease status, functional outcome, QOL, treatment-related morbidity, and treatment-related mortality. Data from the NEURO-TTRansform trial demonstrated a statistically significant improvement in neurological function and neuropathy related QOL with eplontersen compared to the placebo arm of the pivotal trial for inotersen (NEURO-TTR). There is uncertainty regarding long-term benefits and harms for a treatment that is intended to be used lifelong. Studies on long-term safety and tolerability are ongoing. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who are adults with cardiomyopathy of hATTR who receive tafamidis or tafamidis meglumine, the evidence includes 1 pivotal RCT. Relevant outcomes are symptoms, change in disease status, functional outcome, QOL, treatment-related morbidity and treatment-related mortality. Data from the ATR-ACT trial demonstrated a significant reduction in all-cause mortality and frequency of cardiovascular-related hospitalizations in the pooled tafamidis meglumine 20-mg and 80-mg groups versus placebo. In addition, statistically significant treatment effect favoring tafamidis were observed for functional capacity and health status as assessed by the 6-minute walk test (6MWT) and Kansas City Cardiomyopathy Questionnaire (KCCQ-OS) scores. Data from an open-labeled extension study suggests durability of treatment effect up to a follow-up of 51 months. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.

Additional Information

Not applicable

Objective

The objective of this evidence review is to assess whether the use of patisiran, inotersen, vutrisiran, tafamidis and tafamidis meglumine improves the net health outcome in adults with hATTR.

Policy Statements

Initial Treatment - Hereditary Transthyretin-Mediated Amyloidosis Polyneuropathy

Patisiran, vutrisiran, and eplontersen are considered medically necessary for individuals if they meet criteria 1 through 5:

1. 18 years of age or older.

2. Confirmatory diagnosis of hATTR by a genetic test OR tissue biopsy showing amyloid deposition.

3. Presence of clinical signs and symptoms of polyneuropathy characterized by any one of the following:

   1. Baseline polyneuropathy disability (PND) IIIb or lower (see Table 1 in background section)

   2. Baseline familial amyloid polyneuropathy (FAP) Stage 1 or 2 (see Table 1 in background section).

4. Does not have ANY of the following:

   1. New York Heart Association (NYHA) class III or IV heart failure

   2. Sensorimotor or autonomic neuropathy not related to hATTR amyloidosis (monoclonal gammopathy, autoimmune disease, etc.)

5. Does not have any U.S. Food and Drug Administration (FDA) labeled contraindications to the requested agent and is intended to be used consistently with the FDA approved label (see policy guidelines).

Initial authorization period is for 12 months.

Continuation of Treatment - Hereditary Transthyretin-Mediated Amyloidosis Polyneuropathy

Incremental reauthorization of patisiran, vutrisiran, and eplontersen are considered medically necessary for individuals if they meet criteria 1 through 2:

1. Continues to meet the initial treatment criteria cited above.

2. Documentation of stabilization OR improvement via use of objective measurements, such as 10-MWT, COMPASS-31, PND Score or 5 EQ-5D.

Reauthorization period is for 12 months.

Patisiran, vutrisiran, and eplontersen are considered investigational when the above criteria are not met.

Initial Treatment - Hereditary Transthyretin-Mediated Amyloidosis Cardiomyopathy

Tafamidis and tafamidis meglumine are considered medically necessary for individuals if they meet criteria 1 through 5:

1. 18 years of age or older.

2. Confirmatory diagnosis of hereditary or wild-type transthyretin-mediated amyloidosis by a genetic test OR tissue biopsy showing amyloid deposition.

3. Presence of clinical signs and symptoms of cardiac involvement by all of the following:

   1. End-diastolic interventricular septal wall thickness exceeding 12 mm on echocardiography.

   2. History of heart failure, with at least one prior hospitalization for heart failure or clinical evidence of heart failure (without hospitalization) manifested in signs or symptoms of volume overload or elevated intracardiac pressures requiring treatment with a diuretic for improvement.

   3. Baseline NT-proBNP ≥ 600 pg/mL.

4. Does not have any of the following:

   1. NYHA class IV heart failure.

   2. Presence of light-chain amyloidosis.

   3. History of liver or heart transplantation.

   4. Implanted cardiac device.

5. Does not have any U.S. FDA labeled contraindications to the requested agent and is intended to be used consistently with the FDA approved label (see policy guidelines).

Initial authorization period is for 12 months.

Continuation of Treatment - Hereditary Transthyretin-mediated Amyloidosis Cardiomyopathy

Incremental reauthorization for tafamidis and tafamidis meglumine are considered medically necessary for individuals if they meet criteria 1 through 2:

1. Continues to meet the initial treatment criteria cited above.

2. Documentation of stabilization OR improvement via use of objective measurements, such as number of hospitalizations, 6-MWT, or KCCQ-OS.

Reauthorization period is for 12 months.

Tafamidis and tafamidis meglumine are considered investigational when the above criteria are not met.

Policy Guidelines

Patisiran Only

• It is given as intravenous infusion based on body weight.

  • For individuals less than 100 kg: 0.3 mg/kg once every 3 weeks

  • For individuals weighing 100 kg or more: 30 mg once every 3 weeks.

• Treatment requires premedication with intravenous corticosteroid, oral acetaminophen, intravenous H1 blocker, and intravenous H2 blocker prior to its administration to reduce the risk of infusion-related reactions. For premedications not available or not tolerated intravenously, equivalents may be administered orally.

Vutrisiran Only

• It is given as subcutaneous injection.

  • 25 mg once every 3 months (Quarterly)

  • Injection should be administered by a healthcare professional.

Eplontersen Only

• It is given as subcutaneous injection.

  • 45 mg once monthly

  • Injection can be administered by a healthcare provider or trained individual.

Patisiran, Vutrisiran, and Eplontersen

Treatment leads to a decrease in serum vitamin A levels and therefore vitamin A supplementation at the recommended daily allowance is advised. Individuals should be referred to an ophthalmologist if they develop ocular symptoms suggestive of vitamin A deficiency (e.g., night blindness).

Tafamidis and Tafamidis Meglumine

The recommended dose for tafamidis meglumine (brand name Vyndaqel) is 80 mg orally once daily as four 20 mg capsules. The recommended dose tafamidis (brand name Vyndamax) is 61 mg orally once daily as a single 61 mg capsule. Tafamidis and tafamidis meglumine are not substitutable on a per milligram basis.

Coding

See the Codes table for details.

Benefit Application

BlueCard/National Account Issues

State or federal mandates (eg, Federal Employee Program) may dictate that certain U.S. Food and Drug Administration approved devices, drugs, or biologics may not be considered investigational, and thus these devices may be assessed only by their medical necessity.

Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered. Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.

Background

Hereditary transthyretin-mediated amyloidosis (hATTR) is a rare, progressive, and fatal autosomal dominant genetic disease with variable penetrance. Transthyretin is a transporter protein that carries thyroxine and retinol (vitamin A) and is primarily synthesized in the liver (95%) but also choroid plexus. The gene for transthyretin is located on chromosome 18. Variance in the transthyretin gene results in the production of misfolded transthyretin protein. More than 120 variants have been described, including single variants, compound heterozygotes, and deletions. The valine-to-methionine substitution at position 30 (V30M) is the most common variant observed worldwide, while valine-to-

Hereditary transthyretin-mediated amyloidosis (hATTR) is a rare, progressive, and fatal autosomal dominant genetic disease with variable penetrance. Transthyretin is a transporter protein that carries thyroxine and retinol (vitamin A) and is primarily synthesized in the liver (95%) but also choroid plexus. The gene for transthyretin is located on chromosome 18. Variance in the transthyretin gene results in the production of misfolded transthyretin protein. More than 120 variants have been described, including single variants, compound heterozygotes, and deletions. The valine-to-methionine substitution at position 30 (V30M) is the most common variant observed worldwide, while valine-to-isoleucine substitution at position 122 (V122I) is the most common variant in the U.S. The misfolded protein generated because of a variant in the transthyretin gene is insoluble and accumulates as amyloid fibrils (i.e., amyloidosis) in multiple organs of the body, such as the liver, nerves, heart, and kidneys causing disruption of organ tissue structure and function.

Historically, hATTR was classified into 2 distinct syndromes—amyloidosis with polyneuropathy (previously known as familial amyloid polyneuropathy or FAP) and amyloidosis with cardiomyopathy (previously known as familial amyloid cardiomyopathy).^1, While hATTR patients may show predominance of polyneuropathy or cardiomyopathy, it is now recognized that most patients manifest signs and symptoms of both syndromes over the course of their disease and, therefore, the current clinical approach treats FAP and familial amyloid cardiomyopathy as 1 hereditary disease with a spectrum of clinical manifestations.^2, The first symptoms of hATTR amyloidosis typically appear between the mid-20s and the mid-60s, involving multiple tissues and organs and often seem unrelated. Neurologic symptoms include severe sensorimotor disturbances (loss of sensation, pain, muscle weakness and loss of ambulation) and autonomic dysfunction resulting in orthostatic hypotension, diarrhea, impotence, and bladder disturbances.^3, While the neurologic symptoms of hATTR are among the most physically disabling, cardiac manifestations are the most predictive of early death. Cardiac manifestations include arrhythmias, conduction disorders, cardiomegaly, and heart failure. If the disease is untreated, the median survival for patients with predominantly neuropathic symptoms is 5 to 15 years, while patients with predominantly cardiomyopathic symptoms have a median survival of 2.5 to 6 years.^4,5,

The FAP stage system and the polyneuropathy disability score are the 2 most used clinical staging systems and are summarized in Table 1. Higher scores on each of the staging systems are indicative of greater disease severity.

Table 1. Clinical Staging in Hereditary Transthyretin-Mediated Amyloidosis

    Adapted from Ando et al (2013)3, FAP: familial amyloid polyneuropathy; PND: polyneuropathy disability.

Diagnosis

Diagnosis of hATTR based on clinical signs and symptoms is difficult because of heterogeneity in clinical manifestations and the nonspecific nature of signs and symptoms that may mimic other conditions. Furthermore, the age of onset and rate of progression are highly variable from patient to patient.^2, As a result, many patients are misdiagnosed or their diagnosis is delayed, and patients often see physicians across multiple specialties before receiving an accurate diagnosis.^2,

  To confirm the diagnosis, proven amyloid deposition in biopsy specimens and identification of a pathogenic variant in the transthyretin gene are necessary.6,Amyloid deposition in the biopsied tissues can be confirmed by using Congo red staining and, ideally, immunohistochemical study as well as laser capture tandem mass spectrometry. However, mass spectrometry can only demonstrate a mass difference between wild-type and transthyretin protein variants in serum. It does not specify the site and kind of amino acid substitution in a number of disease-related transthyretin variants; thus, DNA sequencing is usually required. Sequence analysis of the transthyretin gene, the only gene in which mutation is known to cause hATTR, detects more than 99% of pathogenic variants.6,

There are currently 2 genetic test programs that offer no-cost, confidential genetic testing and genetic counseling services sponsored by the manufacturer of patisiran. It is summarized in Table 2.

Table 2. Characteristics of Genetic Testing Program Offered by Manufacturers in the U.S.

  Adapted from AlnylamActTM Program7,

  hATTR: hereditary transthyretin-mediated amyloidosis.

Epidemiology

It is estimated that the neuropathy-predominant form of hATTR affects at least 10,000 people worldwide,^8, and roughly 3,000-3,500 people in the United States (U.S.).^9, Due to under-diagnosis and a lack of population-based data, these numbers may underestimate the actual prevalence.^10, According to unpublished data from Alnylam, there may be 10,000 to 15,000 individuals with the neuropathy-predominant form of hATTR [AMCP dossier].

The prevalence of the cardiomyopathy form of hATTR is also problematic to estimate. About 50,000 people worldwide may have hATTR amyloidosis.^8,9, In the U.S. general population, the prevalence of V122I variant (which is the most common variant seen in the U.S.) is 3.4%.^11, However, phenotypic penetrance resulting in overt clinical cardiac disease depends on age and varies widely from 7% to 80%.^12, Higher estimates of clinical prevalence were reported in studies with very small samples of carriers. Characteristics of hATTR in the U.S. by different variants are summarized in Table 3.

Table 3. Characteristics of hATTR in the U.S. by Variants

  Adapted from Swiecicki et al 201513,

Treatment

Prior to the approval of patisiran and inotersen in 2018, there was no U.S. Food and Drug Administration (FDA) approved treatment available in the U.S. for the treatment of hATTR. As of September 27, 2024, inotersen (Tegsedi) was discontinued in the United States due to low utilization.^14,

Management approaches included the use of pharmacotherapy with tetramer stabilizers (such as diflunisal and tafamidis) and surgery (orthotopic liver transplant).

Diflunisal, a generic nonsteroidal anti-inflammatory drug, is not approved by the FDA for the treatment of hATTR but is available in the U.S. as a generic and has been used off-label for treatment. Diflunisal has been shown to stabilize transthyretin tetramers in a phase I study, ^15, and significantly reduced the progression of neurologic impairment and preserved the quality of life in a randomized controlled trial.^16, Although the results of the randomized controlled trial were positive, multiple limitations with long-term use of diflunisal such as gastrointestinal bleeding, worsening of renal insufficiency, and cardiovascular events (e.g., MI, stroke) preclude its long-term use. Furthermore, diflunisal does not reverse neurologic or cardiac impairment.

Tafamidis received FDA approval in 2019 for treatment of hATTR patients with cardiomyopathy.

As transthyretin is primarily formed in the liver, orthotopic liver transplantation has been the disease-modifying treatment available to most patients with hATTR. This procedure can remove approximately 95% of the production of variant transthyretin. However, limited organ availability, exclusion of older patients and those with advanced disease, the high costs of transplantation, the risks of lifelong immunosuppression, and reports of disease progression following liver transplantation limits it use. Furthermore, orthotopic liver transplantation is not recommended for patients with cardiac involvement due to the observed post-transplant progression of cardiac; making a considerable proportion of patients in the U.S. who will develop cardiomyopathy ineligible for transplantation.^17, As such the procedure is not commonly performed in the U.S.

Mechanism of Action

The function of small interfering ribonucleic acid (RNA) is to regulate gene expression, or how much protein will be made from a particular gene. Patisiran and vutrisiran are small interfering RNA that are designed to selectively target variant and wild-type transthyretin messenger RNA through RNA interference, which results in a reduction of serum transthyretin and transthyretin deposits in tissues. Eplontersen is an antisense oligonucleotide that causes degradation of variant and wild-type transthyretin messenger RNA through binding to the transthyretin messenger RNA, which results in a reduction of serum transthyretin and transthyretin deposits in tissues.

Regulatory Status

In August 2018, patisiran (Onpattro, Alnylam Pharmaceuticals, Inc.) was approved by the FDA for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults.

In June 2022, vutrisiran (Amvuttra, Alnylam Pharmaceuticals, Inc.) was approved by the FDA for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults.

In December 2023, eplontersen (Wainua, AstraZeneca Pharmaceuticals, LP) was approved by the FDA for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults.

In May 2019, Vyndaqel (tafamidis meglumine) and Vyndamax (tafamidis) capsules were approved by the FDA for the treatment of heart disease (cardiomyopathy) caused by transthyretin mediated amyloidosis in adults.

Rationale

This evidence review was created in December 2018 with a search of the PubMed database. The most recent literature update was performed through October 17, 2024.

Evidence reviews assess the clinical evidence to determine whether the use of technology improves the net health outcome. Broadly defined, health outcomes are the length of life, quality of life (QOL), and the ability to function¾including benefits and harms. Every clinical condition has specific outcomes that are important to patients and managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent 1 or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.

Population Reference No. 1, 2, 3 & 4

Polyneuropathy of Hereditary Transthyretin-Mediated Amyloidosis

Clinical Context and Therapy Purpose

The purpose of patisiran, inotersen, vutrisiran, and eplontersen for individuals with polyneuropathy of hereditary transthyretin-mediated amyloidosis (hATTR) is to provide a treatment option that is an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest are individuals with polyneuropathy of hATTR.

Interventions

The therapies being considered are patisiran, inotersen, vutrisiran, and eplontersen.

Comparators

Management approaches include the use of pharmacotherapy with tetramer stabilizers (such as diflunisal and tafamidis) and surgery (orthotopic liver transplant). Tafamidis is approved in the European Union and several South American and Asian countries, but not in the U.S for the treatment of polyneuropathy. Orthoptic liver transplantation has also shown to be beneficial but is less frequently used in the U.S.

Outcomes

The general outcomes of interest are related to assessing the impact of disease on sensorimotor, autonomic and cardiovascular manifestation and summarized in Table 4.

Table 4. Description of Health Outcome Measures Relevant to Polyneuropathy of Hereditary Transthyretin-Mediated Amyloidosis

    10-MWT: 10-meter walk test; COMPASS-31: Composite Autonomic Symptom Score-31; EQ-5D: Euro-QOL; FAP: familial amyloid polyneuropathy; hATTR: hereditary transthyretin-mediated; mBMI: modified body mass index; MCID: minimal clinically important difference; mNIS; modified neuropathy impairment score; NIS: neuropathy impairment score; PND: polyneuropathy disability; QOL: quality of life; R-ODS: Rasch-built-Overall Disability Scale.  

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Consistent with a 'best available evidence approach,' within each category of study design, studies with larger sample sizes and longer durations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Patisiran

Randomized Controlled Trials

In one pivotal RCT of patisiran (APOLLO, NCT01960348) in 225 adults with hATTR amyloidosis with polyneuropathy, participants were randomized to receive either patisiran or placebo (Table 5).^27, There were several differences in baseline characteristics between the 2 randomized arms. Compared to placebo, a lesser proportion of patients in the patisiran arm had the Val30Met variant (52% vs 38% respectively, p<0.05), and had more severe impairment as indicated by a 3.5 points higher mean neuropathy impairment score (NIS) score. Furthermore, there was a 14% absolute difference in the proportion of patients with cardiac involvement between the patisiran (61%) and placebo (47%) groups. These factors suggest the potential for imbalances in baseline disease severity and natural history between the 2 groups.

The results of the trial are summarized in Table 6. The trial met its primary endpoint. The proportion of responders was 56% in patisiran arm vs 4% in the placebo arm (odds ratio=39.9; 95% confidence interval; 11.0 to 144.4). Neuropathy-related QOL, measured by the Norfolk-QOL-DN, also improved significantly. Detailed analysis on QOL at 18 months reported that patisiran improved the Norfolk QOL-DN total score and three individual domains as well as COMPASS-31 total scores relative to baseline.^28,. However, neither the mNIS+7 nor the Norfolk-QOL-DN has a validated threshold of what magnitude of improvement or worsening is clinically relevant. The effect of patisiran was consistent and statistically significant for other secondary endpoints.

Cardiac outcomes (global longitudinal strain, left ventricular wall thickness and N-terminal pro b-type natiuretic peptide [NT-pro-BNP] levels) were assessed in a prespecified cardiac subpopulation that included patients with a left ventricle wall thickness ≥13 mm at baseline and with an absence of a history of hypertension or aortic valve disease. Disproportionately more patisiran patients met these criteria compared to placebo patients (90 [61%] vs. 36 [47%], respectively). Furthermore, in the subset with cardiac involvement, patients in the placebo arm had more severe polyneuropathy (NIS score) and familial amyloid polyneuropathy (FAP) stage 2 while more patients in the patisiran group had New York Heart Association class II heart failure. Higher NT-pro-BNP levels have been shown to predict mortality in hATTR patients with cardiac involvement.^9, Among patisiran treated patients, NT-pro-BNP decreased by a median of 49.9 ng/L, while among placebo-treated patients, levels increased by a median of 320.4 ng/L, yielding a statistically significant treatment difference of 370.2 (p<.0001). However, the median NT-pro-BNP levels were below the 3000 ng/L cut-off associated with increased risk of death both at baseline and after treatment.^29, In post-hoc composite outcome analyses (data not shown), patients receiving patisiran also had a lower composite rate of cardiac hospitalization and/or all-cause mortality, as well as a lower composite rate of any hospitalization and/or all-cause mortality. However, the results did not report on all-cause mortality alone.

Open Label Studies

Data from an open-labeled extension (OLE) study (NCT02510261) of the APOLLO as well as a phase II study suggests a sustained delay of progression of polyneuropathy and maintenance of QOL.^30, The published findings of this study are based on the interim analysis of the patients who had completed 12-month efficacy assessments as of the data cutoff (Sep 24, 2018). Study participants received patisiran for a mean of 20.5 months (±8.0) and had a cumulative drug exposure of 359.6 patient-years. The rapid polyneuropathy progression observed among patients in the APOLLO-placebo group halted upon treatment with patisiran in the global OLE. However, the mean mNIS+7 score did not return to APOLLO baseline. Furthermore, neurological disability and mortality remained higher in APOLLO placebo patients compared to participants who received patisiran in the parent studies, underscoring the importance of treatment at the earliest disease stage possible. This report, however, is an interim analysis and continued observation and reporting are needed to assess whether the clinical benefits are maintained to the end of the 5-year global OLE.

Schmidt et al (2022) reported the results of a single-arm open label study (NCT03862807) that enrolled 23 adults who had had received a liver transplant for treatment of hATTR ≥12 months before study entry and had experienced polyneuropathy progression post-liver transplant. ^31,The primary endpoint was median transthyretin reduction from baseline. Twenty-three study participants received patisiran for 12 months alongside immunosuppression regimens. The mean TTR level (±SEM) at baseline was 202.1 (±11.3) mg/l. Respective levels 3 weeks, 6-months and 12-months post treatment were 35.5 (±4.5), 21.2 (±3.7) and 24.9 (±2.7) which translates to mean (±SEM) percent reduction from baseline to 81.9% (±2.9), 89.2% (±2.0) and 87.1 (±1.7) respectively. Neuropathy, quality of life, and autonomic symptoms were assessed by measuring the change from baseline to month 12 in neuropathy impairment score, Norfolk quality of life-diabetic neuropathy questionnaire, and composite autonomic symptom score-31. Respective change was -3.7 (±2.7), -6.5 (±4.9]) and -5.0 (±2.6). Adverse events were mild or moderate; 5 patients experienced ≥1 serious adverse event.

Table 5. Summary of Key RCT Characteristics: Patisiran

    BMI, body mass index; hATTR: hereditary transthyretin-mediated; IV: intravenous; kg: kilogram; mNIS+7: modified Neuropathy Impairment Score +7; NIS: Neuropathy Impairment Score; NT-proBNP: N-terminal pro-B-type natriuretic peptide; OLE: open-label extension; PND: polyneuropathy disability; Q3W: every 3 weeks; QOL-DN: quality of life-diabetic neuropathy; R-ODS: Rasch-built overall disability scale; TTR, transthyretin.

Table 6. Summary of Key RCT Results: Patisiran

    10-MWT: 10-meter walk test; AE; adverse event; CI, confidence interval; COMPASS-31: Composite Autonomic Symptom Score-31; EQ-5D-5L; Euro-QOL 5-dimension 5-level; EQ-VAS: Euro-QOL Visual Analogue Scale; LSM: least squares mean; m: meters; mBMI: modified body mass index; mNIS+7: Modified Neuropathy Impairment Score; NIS-W: Neuropathy Impairment Score – Weakness; OLE; open label extension; PND, polyneuropathy disability; QOL, quality of life; QOL-DN: Quality of Life - Diabetic Neuropathy; R-ODS: Rasch-built-Overall Disability Scale; SE: standard error; SAE; serious adverse event a meter/seconds b kilogram/meter2 x albumin (gram/deciliter) c Missing includes all deaths prior to 18-month visit d Change from parent study baseline

The purpose of the study limitations tables (Table 7) is to display notable limitations identified in each study. This information is synthesized as a summary of the body of evidence following each table and provides conclusions on the sufficiency of evidence supporting the position statement. A gap in relevance for the APOLLO trial is related to the generalizability of its results to the U.S. population. Only 20% of APOLLO participants were from the U.S. and included only 2 patients (0.9%) with the Val122Ile variant, which is the most common variant observed in the U.S. This was likely due to the trial inclusion criterion of polyneuropathy-predominant hATTR. Secondly, while the OLE phase of the study has reported outcomes data up to 12 months, long-term safety data is inadequate as these drugs are intended for chronic use. In addition to these limitations, the impact of statistically significant imbalances, potentially clinically relevant differences in baseline characteristics, and a higher rate of trial discontinuation in the placebo arm vs patisiran arm in the APOLLO trial is unclear. No major gaps were identified in study design and conduct except in the open label extension study, since there could be selection bias as the population for this study was self-selected from previous patisiran studies.

Table 7. Study Relevance Limitations: Patisiran

    The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment. a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use. b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest. c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively. d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported. e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms. 

Vutrisiran

Randomized-Controlled Trials

The evidence includes one pivotal multicenter, randomized, open labeled trial, HELIOS-A^37,The trial randomized166 adults to vutrisiran or patisiran. Ninety-seven percent of vutrisiran-treated study participants and ninety-three percent of patisiran-treated study participants completed at least 9 months of the assigned treatment. Efficacy assessments were based on a comparison of the vutrisiran arm with an external placebo group in another study (APOLLO; NCT01960348. The APOLLO study was a randomized, double-blind, placebo-controlled trial which randomized 225 study participants with hATTR-PN to patisiran or placebo for 18 months. At 9 months, treatment with vutrisiran resulted in statistically significant treatment difference versus placebo in the mNIS+7 (-17.0 points, p<.001), Norfolk QoL-DN total score (-16.2 points, p<.001), and 10-meter walk test (0.13 points, p<.001). Vutrisiran was also compared to the patisiran group in the HELIOS-A extension trial for the secondary outcome of mean steady state transthyretin (TTR) reduction from baseline. Vutrisiran was noninferior to patisiran at 18 months (median TTR difference, 5.28%; 95% CI, 1.17 to 9.25; lower limit of CI >-10%).

Common adverse events occurring in > 10% of study participants were falls, pain extremities, diarrhea, peripheral edema, urinary tract infection (UTI), arthralgia, and dizziness. Arthralgia and pain in extremities occurred more frequently with vutrisiran than APOLLO placebo. Injection-site reactions occurred in 4.1% of study participants on vutrisiran. Serious AEs (SAEs) and severe AEs occurred numerically less frequently with vutrisiran than APOLLO placebo or patisiran (SAEs: 26% vutrisiran, 40% APOLLO placebo, 43% patisiran; severe AEs: 16%, 36% and 38% respectively). Two SAEs (dyslipidemia and UTI) were considered related to vutrisiran. No hepatic, hematologic, or renal safety signals were considered related to vutrisiran. No discontinuations due to AEs were considered related to vutrisiran. No drug-related deaths were identified. No major gaps were identified in the study design and conduct.

Table 11. Summary of Key RCT Characteristics: Vutrisiran

    hATTR: hereditary transthyretin-mediated; Q3W: every 3 weeks

Table 12. Summary of Key RCT Results: Vutrisiran

    10-MWT: 10-meter walk test; CI: confidence interval; LS mean: least squares mean; mBMI: modified body mass index; mNIS: modified Neuropathy Impairment Score; QoL-DN: Quality of Life-Diabetic Neuropathy; SEM: standard error of the mean a A lower number indicates less impairment/fewer symptoms b A higher number indicates less disability/less impairment c mBMI: nominal p-value; body mass index (BMI; kg/m2) multiplied by serum albumin (g/L) d External placebo group from another randomized controlled trial (NCT01960348)

The purpose of the study limitations tables (Table 13) is to display notable limitations identified in each study. This information is synthesized as a summary of the body of evidence following each table and provides the conclusions on the sufficiency of evidence supporting the position statement. A gap in relevance for HELIOS-A trial is related to the duration of the study which is insufficient to ascertain durability and safety. No major gaps were identified in study design and conduct.

Table 13. Study Relevance Limitations: Vutrisiran

    The study limitations in this table are those notable in the current review; this is not a comprehensive gaps assessment.

    a Population key: 1. Intended use population unclear; 2. Study population is unclear; 3. Study population not representative of intended use; 4, Enrolled populations do not reflect relevant diversity; 5. Other. b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest (e.g., proposed as an adjunct but not tested as such); 5: Other. c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively; 5. Other. d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. Incomplete reporting of harms; 4. Not establish and validated measurements; 5. Clinically significant difference not prespecified; 6. Clinically significant difference not supported; 7. Other. e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms; 3. Other.

Eplontersen

Randomized-Controlled Trials

The evidence includes one pivotal multicenter, randomized, open labeled trial, NEURO-TTRansform.^33, The trial randomized 168 adults to eplontersen or inotersen (Table 14). Efficacy assessments were based on a comparison of the eplontersen arm with an external placebo group from NEURO-TTR (NCT04136184) composed of a comparable population of adult patients with polyneuropathy caused by hATTR amyloidosis. Use of a placebo in NEURO-TTRansform was deemed unethical due to the study participants having a rapidly progressive and potentially fatal neurologic disease for which effective treatment options are available. The inotersen reference group in NEURO-TTRansform was used to ensure comparable disease progression and treatment response patterns between NEURO-TTR and NEURO-TTRansform trials. Ninety-seven percent of eplontersen-treated study participants and eighty-three percent of inotersen-treated study participants completed at least 35 weeks of the assigned treatment. Study results are summarized in Table 15. The trial met the primary endpoint. At 35 weeks, treatment with eplontersen resulted in a statistically significant treatment difference versus placebo in the mNIS+7 (-9.0 points, p<.001) and Norfolk QoL-DN total score (-11.2 points, p<.001).

Common adverse events occurring in >9% of study participants were decrease in levels of vitamin A and vomiting. Three serious adverse reactions of atrioventricular (AV) heart block (2%) occurred in eplontersen-treated patients, including 1 case of complete AV block. No drug-related deaths were identified. No major gaps were identified in the study design and conduct.

Table 14. Summary of Key RCT Characteristics: Eplontersen

    hATTR: hereditary transthyretin-mediated

Table 15. Summary of Key RCT Results: Eplontersen

    CI: confidence interval; LS mean: least squares mean; mNIS: modified Neuropathy Impairment Score; QoL-DN: Quality of Life-Diabetic Neuropathy; SEM: standard error of the mean a A lower number indicates less impairment/fewer symptoms b External placebo group from another randomized controlled trial (NCT01737398)

The purpose of the study limitations tables (Table 16) is to display notable limitations identified in each study. This information is synthesized as a summary of the body of evidence following each table and provides the conclusions on the sufficiency of evidence supporting the position statement. A gap in relevance for NEURO-TTRansform trial is related to the duration of the study which is insufficient to ascertain durability and safety. No major gaps were identified in study design and conduct.

Table 16. Study Relevance Limitations: Eplontersen

    The study limitations in this table are those notable in the current review; this is not a comprehensive gaps assessment.

    a Population key: 1. Intended use population unclear; 2. Study population is unclear; 3. Study population not representative of intended use; 4, Enrolled populations do not reflect relevant diversity; 5. Other. b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest (e.g., proposed as an adjunct but not tested as such); 5: Other. c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively; 5. Other. d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. Incomplete reporting of harms; 4. Not establish and validated measurements; 5. Clinically significant difference not prespecified; 6. Clinically significant difference not supported; 7. Other. e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms; 3. Other. 

Section Summary: Polyneuropathy of Hereditary Transthyretin-Mediated Amyloidosis

For individuals with polyneuropathy of hATTR, the U.S. FDA has approved 3 drugs- patisiran, inotersen, and vutrisiran. Pivotal RCTs that supported the approval of these products reported statistically significant improvement in neurologic function and neuropathy related QOL. No major limitations were identified except for the limited duration of the studies, which is insufficient to ascertain durability and safety.

Population Reference No. 4

Cardiomyopathy of Hereditary Transthyretin-Mediated Amyloidosis

Clinical Context and Therapy Purpose

The purpose of tafamidis and tafamidis meglumine for individuals with cardiomyopathy of hereditary transthyretin-mediated amyloidosis (hATTR) is to provide a treatment option that is an improvement on existing therapies.

The following PICO was used to select literature to inform this review.

Populations

The relevant population of interest are individuals with cardiomyopathy of hATTR.

Interventions

The therapies being considered are tafamidis and tafamidis meglumine. The recommended dose for tafamidis meglumine is 80 mg and four 20-mg tafamidis meglumine capsules be taken once daily. The recommended dose for tafamidis is 61 mg and a single 61-mg tafamidis capsule taken once daily.

Comparators

Management approaches include the use of pharmacotherapy.

Outcomes

The International Consortium for Health Outcomes Measurement has identified 3 domains of outcomes for a standard outcome set for patients with heart failure.^35,

• Survival and disease control (ie, mortality)

• Functioning and disease control (ie, symptom control including dyspnea, fatigue and tiredness, disturbed sleep, and peripheral edema, activities of daily living including health-related quality of life, maximum physical exertion, independence, and psychosocial health including depression and anxiety, confidence, and self-esteem)

• Burden of care to patient (ie, hospital visits including admissions and appointments, treatment side effects, complications)

The Heart Failure Association of the European Society of Cardiology has published a consensus document on heart failure outcomes in clinical trials.^36, They likewise categorize important outcomes for clinical trials as mortality outcomes (all-cause and cause-specific), morbidity and clinical composites (including hospitalizations, worsening of heart failure, implantable cardioverter device shocks) and symptoms and patient-reported outcomes. The consensus document recommends that hospitalization for heart failure be defined as a hospitalization requiring at least an overnight stay caused by substantive worsening of symptoms and/or signs requiring augmentation of therapy.

The HFC-ARC (Heart Failure Collaboratory and the Academic Research Consortium) expert panel published their findings on using functional and symptomatic clinical trial endpoints in the trial for heart failure.^37, Patient reported outcomes (PRO) that have been comprehensively evaluated and most used in heart failure trials include Kansas City Cardiomyopathy Questionnaire (KCCQ-12) and Minnesota Living With Heart Failure Questionnaire (MLHFQ). As therapeutic endpoints, these instruments complement assessment of major adverse cardiac events (MACE). However, their interpretation is complicated by difficulty in determining what change constitutes a minimal clinically important difference (MCID). A treatment effect on such measures that is undetectable by patients has no clear clinical or regulatory utility. The published MCIDs for the KCCQ and MLHFQ are 5 points; however, alternative MCIDs have been reported, and there is limited information on between group changes and durability of effect.^{38,39,40,41,42,} Responder analyses, in which benefit is defined by an individual’s improvement in PRO score crossing a threshold, can assist with interpretation of PRO endpoints; however, they are best avoided as primary analyses because they discard clinical information and statistical power by dichotomizing data and because individual patient responses may vary over time.^37, Patient global assessments is a generic PRO that assesses if an individual feels better, worse, or unchanged in response to treatment. Although it is widely used in clinical trials and it captures the overall disease impact, it is not heart failure specific and therefore may not capture HRQOL changes targeted by an investigational heart failure therapy.

Patient function can be measured in a variety of ways, including by daily movement metrics such as wakeful actigraphy, structured and timed submaximal metrics such as the 2-minute walk test or 6-minute walk test (6MWT), structured maximal exertion evaluations such as cardiopulmonary exercise testing (CPET), and other aggregations such as the Short Physical Performance Battery, which comprises evaluations of standing balance, 4-meter walk time, and time to complete 5 chair stands. The 6MWT is most suitable to measure the effects of interventions with mechanisms of action that improve functional capacity. Clinically meaningful difference in 6MWT distance has been reported to be thirty meters but alternative values, including a 10% change, may be more appropriate and merit further investigation.^43,44, CPET is more comprehensive than the 6MWT, as it integrates ventilatory measurements and evaluates contributions from noncardiac disease processes to dyspnea and functional limitation.^45, According to the panel, actigraphy is not currently suitable for use as a functional endpoint because of lack of standardization and validation for patients with heart failure, and there is no established framework for clinically meaningful change.^37,

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

• To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;

• In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.

• To assess long-term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

• Consistent with a 'best available evidence approach,' within each category of study design, studies with larger sample sizes and longer durations were sought.

• Studies with duplicative or overlapping populations were excluded.

Review of Evidence

Tafamidis and tafamidis meglumine

Randomized Controlled Trials

In the pivotal RCT of tafamidis (ATR-ACT, NCT01994889), 441 adults with cardiomyopathy of wild-type or hereditary transthyretin-mediated amyloidosis (ATTR-CM) were randomized to receive tafamidis meglumine 20 mg (n=88), tafamidis meglumine 80 mg (administered as four 20-mg capsules) (n=176), or matching placebo (n=177) once daily for 30 months, in addition to standard of care (e.g., diuretics) (Table 17). Treatment assignment was stratified by the presence or absence of a variant TTR genotype as well as baseline disease severity (NYHA Class). Transplant patients were excluded from this study.^51,

The results of the trial are summarized in Table 18. The trial met its primary endpoint. For the primary analysis, all-cause mortality was hierarchically assessed first followed by frequency of cardiovascular-related hospitalizations using Finkelstein-Schoenfeld method. This analysis demonstrated a significant reduction (p=.0006) in all-cause mortality and frequency of cardiovascular-related hospitalizations in the pooled tafamidis meglumine 20-mg and 80-mg groups versus placebo (Table 15). Analysis of the individual components of the primary analysis (all-cause mortality and cardiovascular-related hospitalization) also demonstrated significant reductions for the pooled tafamidis groups versus placebo. The hazard ratio from the all-cause mortality Cox-proportional hazard model for pooled tafamidis versus placebo was 0.70 (95% CI, 0.51 to 0.96), indicating a 30% relative reduction in the risk of death relative to the placebo group (p=.026). Approximately 80% of total deaths were cardiovascular-related in both treatment groups.^52,

The treatment effects of tafamidis meglumine on functional capacity and health status were assessed by the 6MWT and the KCCQ-OS score, respectively. The KCCQ-OS score is composed of four domains including total symptoms (symptom frequency and symptom burden), physical limitation, quality of life, and social limitation. The overall summary score and domain scores range from 0 to 100, with higher scores representing better health status. A significant treatment effect favoring tafamidis was first observed at month 6 and remained consistent through month 30 on both 6MWT distance and KCCQ-OS score. Further, all four domains of the KCCQ-OS score favored the pooled tafamidis meglumine groups compared to placebo at month 30 and demonstrated similar treatment effects to the total KCCQ-OS score. ^52, Data from an OLE study of the ATR-ACT suggests durability of treatment effect up to a follow-up of 51 months. ^53,

Table 17. Summary of Key RCT Characteristics: Tafamidis

    a Confirmed by the presence of amyloid deposits on analysis of biopsy specimens obtained from cardiac and noncardiac sites (e.g., fat aspirate, gastrointestinal sites, salivary glands, or bone marrow). In patients without pathogenic mutations in the transthyretin gene, cardiomyopathy was confirmed by the presence of transthyretin precursor protein confirmed on immunohistochemical analysis, scintigraphy, or mass spectrometry  eGFR: estimated glomerular filtration rate; hATTR: hereditary transthyretin-mediated; NT-proBNP: N-terminal pro-B-type natriuretic peptide; NYHA: New York Heart Association; ULN: upper limit of normal

Table 18. Summary of Key RCT Results: Tafamidis

^a Heart transplantation and cardiac mechanical assist device implantation are considered indicators of approaching end stage. As such, these individuals are treated in the analysis as equivalent to death. Therefore, such individuals are not included in the count of “Number of Subjects Alive at Month 30” even if such individuals are alive based on 30-month vital status follow-up assessment.

    b This analysis was based on a Poisson regression model with treatment, TTR genotype (variant and wild-type), New York Heart Association (NYHA), baseline classification (NYHA Classes I and II combined and NYHA Class III), treatment-by-TTR genotype interaction, and treatment-by-NYHA baseline classification interaction terms as factors. 6MWT: 6-minute walk test; CI: confidence interval; KCCQ-OS: Kansas City Cardiomyopathy Questionnaire-Overall Summary; LS: least squares; SD: standard deviation; SE: standard error

No notable limitations in study relevance or study design and conduct were noted.

Section Summary: Cardiomyopathy of Hereditary Transthyretin-Mediated Amyloidosis

For individuals with cardiomyopathy of hATTR, 2 oral formulations of tafamidis (tafamidis meglumine and tafamidis) drugs have been approved by the U.S. FDA. The pivotal RCT (ATR-ACT) demonstrated a significant reduction in all-cause mortality and frequency of cardiovascular-related hospitalizations in the pooled tafamidis meglumine 20-mg and 80-mg groups versus placebo. In addition, statistically significant treatment effects favoring tafamidis were observed for functional capacity and health status as assessed by the 6MWT and KCCQ-OS scores. Data from an open-labeled extension study suggests durability of treatment effect up to a follow-up of 51 months.

Supplemental Information

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Practice Guidelines and Position Statements

Guidelines or position statements will be considered for inclusion in ‘Supplemental Information' if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

No guidelines or statements from U.S. societies were identified.

Consensus Statements from European Network for Transthyretin-Mediated Amyloidosis-Familial Amyloid Polyneuropathy

Consensus statements from the European Network (2016) for transthyretin-mediated amyloidosis-familial amyloid polyneuropathy were published prior to the approval of patisiran, eplontersen, and vutrisiran and, therefore, do not include any recommendation for these drugs.^49, These guidelines recommend that following a clinical suspicion, positive results from both biopsy and genetic analysis are essential to distinguish transthyretin-mediated amyloidosis-familial amyloid polyneuropathy from a large number of peripheral neuropathies.

National Institute for Health and Care Excellence

On August 14, 2019 the NICE issued highly specialized technologies guidance on patisiran for treating hereditary transthyretin amyloidosis. Patisiran is recommended, within its marketing authorization, as an option for treating hereditary transthyretin amyloidosis in adults with stage 1 and stage 2 polyneuropathy. It is recommended only if the company provides patisiran according to the commercial arrangement.^50,

On February 15, 2023 the NICE issued technology appraisal guidance on vutrisiran for treating hereditary transthyretin amyloidosis. Vutrisiran is recommended, within its marketing authorization, as an option for treating hereditary transthyretin-related amyloidosis in adults with stage 1 or stage 2 polyneuropathy. It is only recommended if the company provides vutrisiran according to the commercial arrangement.^51,

On June 19, 2024 the NICE issued technology appraisal guidance on tafamidis for treating transthyretin amyloidosis with cardiomyopathy. Tafamidis is recommended, within its marketing authorization, as an option for treating wild-type or hereditary transthyretin amyloidosis with cardiomyopathy in adults. It is only recommended if the company provides vutrisiran according to the commercial arrangement.^52,

In January 2024, the NICE issued the scope for a technology appraisal on eplontersen for treating hereditary transthyretin amyloidosis [ID6337]. The expected date of publication has not been released as of October 16, 2024.

Institute for Clinical and Economic Review

The ICER (2018) published a Report on comparative effectiveness and value of patisiran for hereditary transthyretin-mediated amyloidosis.^10, Using criteria from the U.S. Preventive Services Task Force, the authors of the ICER rated the APOLLO trial to be of fair quality due to differential drop-out between treatment groups.

In summarizing the clinical evidence, the ICER Report observed that limitations in the clinical evidence include study populations that limit the generalizability of clinical outcomes to all hATTR patients, clinical outcome measures (mNIS+7 and Norfolk-QOL-DN) without defined thresholds for clinical significance, limited functional outcomes such as disease stage progression, and limited data on patients with cardiac involvement, especially among cardiac-dominant patients who are at a higher risk for mortality than patients with neuropathy-predominant hATTR. Further, there may be uncertainties related to the translation of neurologic outcomes to longer-term clinical benefit, the durability of such benefit, potential harms of treatment, and the costs associated with the use of patisiran.

The Report concluded that for patisiran, there is moderate certainty of a substantial net health benefit with a high certainty of at least a small net health benefit compared to best supportive care, and therefore rated the clinical evidence for patisiran to be incremental or better (“B+”).

U.S. Preventive Services Task Force Recommendations

Not applicable.

Medicare National Coverage

There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this review are listed in Table 19.

Table 19. Summary of Key Trials

    NCT: national clinical trial. a Denotes industry-sponsored or cosponsored trial.

References

1. Gertz MA, Benson MD, Dyck PJ, et al. Diagnosis, Prognosis, and Therapy of Transthyretin Amyloidosis. J Am Coll Cardiol. Dec 01 2015; 66(21): 2451-2466. PMID 26610878
2. Gertz MA. Hereditary ATTR amyloidosis: burden of illness and diagnostic challenges. Am J Manag Care. Jun 2017; 23(7 Suppl): S107-S112. PMID 28978215
3. Ando Y, Coelho T, Berk JL, et al. Guideline of transthyretin-related hereditary amyloidosis for clinicians. Orphanet J Rare Dis. Feb 20 2013; 8: 31. PMID 23425518
4. Arvanitis M, Chan GG, Jacobson DR, et al. Prevalence of mutant ATTR cardiac amyloidosis in elderly African Americans with heart failure. Amyloid. Dec 2017; 24(4): 253-255. PMID 29052438
5. Parman Y, Adams D, Obici L, et al. Sixty years of transthyretin familial amyloid polyneuropathy (TTR-FAP) in Europe: where are we now? A European network approach to defining the epidemiology and management patterns for TTR-FAP. Curr Opin Neurol. Feb 2016; 29 Suppl 1(Suppl 1): S3-S13. PMID 26734951
6. Sekijima Y. Familial Transthyretin Amyloidosis. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews((R)). Seattle (WA)1993. PMID 20301373
7. AlnylamAct. https://www.invitae.com/en/alnylam-act-hattr-amyloidosis/#eligibility. Accessed January 15, 2024.
8. Kato-Motozaki Y, Ono K, Shima K, et al. Epidemiology of familial amyloid polyneuropathy in Japan: Identification of a novel endemic focus. J Neurol Sci. Jul 15 2008; 270(1-2): 133-40. PMID 18410945
9. Plante-Bordeneuve V. Update in the diagnosis and management of transthyretin familial amyloid polyneuropathy. J Neurol. Jun 2014; 261(6): 1227-33. PMID 24888313
10. ICER. Inotersen and Patisiran for Hereditary Transthyretin Amyloidosis: Effectiveness and Value: Final Evidence Report (October 4, 2018). https://icer.org/wp-content/uploads/2020/10/ICER_Amyloidosis_Final_Evidence_Report_101718.pdf. Accessed January 15, 2024.
11. Jacobson DR, Alexander AA, Tagoe C, et al. Prevalence of the amyloidogenic transthyretin (TTR) V122I allele in 14 333 African-Americans. Amyloid. 2015; 22(3): 171-4. PMID 26123279
12. Quarta CC, Buxbaum JN, Shah AM, et al. The amyloidogenic V122I transthyretin variant in elderly black Americans. N Engl J Med. Jan 01 2015; 372(1): 21-9. PMID 25551524
13. Swiecicki PL, Zhen DB, Mauermann ML, et al. Hereditary ATTR amyloidosis: a single-institution experience with 266 patients. Amyloid. 2015; 22(2): 123-31. PMID 26017327
14. Drugs@FDA: FDA-Approved Drugs. Available at https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=BasicSearch.process Accessed on November 4, 2024.
15. Sekijima Y, Dendle MA, Kelly JW. Orally administered diflunisal stabilizes transthyretin against dissociation required for amyloidogenesis. Amyloid. Dec 2006; 13(4): 236-49. PMID 17107884
16. Berk JL, Suhr OB, Obici L, et al. Repurposing diflunisal for familial amyloid polyneuropathy: a randomized clinical trial. JAMA. Dec 25 2013; 310(24): 2658-67. PMID 24368466
17. Carvalho A, Rocha A, Lobato L. Liver transplantation in transthyretin amyloidosis: issues and challenges. Liver Transpl. Mar 2015; 21(3): 282-92. PMID 25482846
18. Adams D, Suhr OB, Dyck PJ, et al. Trial design and rationale for APOLLO, a Phase 3, placebo-controlled study of patisiran in patients with hereditary ATTR amyloidosis with polyneuropathy. BMC Neurol. Sep 11 2017; 17(1): 181. PMID 28893208
19. Diabetic polyneuropathy in controlled clinical trials: Consensus Report of the Peripheral Nerve Society. Ann Neurol. Sep 1995; 38(3): 478-82. PMID 7668839
20. Vinik EJ, Vinik AI, Paulson JF, et al. Norfolk QOL-DN: validation of a patient reported outcome measure in transthyretin familial amyloid polyneuropathy. J Peripher Nerv Syst. Jun 2014; 19(2): 104-14. PMID 24738700
21. Perera S, Mody SH, Woodman RC, et al. Meaningful change and responsiveness in common physical performance measures in older adults. J Am Geriatr Soc. May 2006; 54(5): 743-9. PMID 16696738
22. Roberts HC, Denison HJ, Martin HJ, et al. A review of the measurement of grip strength in clinical and epidemiological studies: towards a standardised approach. Age Ageing. Jul 2011; 40(4): 423-9. PMID 21624928
23. Sletten DM, Suarez GA, Low PA, et al. COMPASS 31: a refined and abbreviated Composite Autonomic Symptom Score. Mayo Clin Proc. Dec 2012; 87(12): 1196-201. PMID 23218087
24. Payakachat N, Ali MM, Tilford JM. Can The EQ-5D Detect Meaningful Change? A Systematic Review. Pharmacoeconomics. Nov 2015; 33(11): 1137-54. PMID 26040242
25. Coretti S, Ruggeri M, McNamee P. The minimum clinically important difference for EQ-5D index: a critical review. Expert Rev Pharmacoecon Outcomes Res. Apr 2014; 14(2): 221-33. PMID 24625040
26. McClure NS, Sayah FA, Xie F, et al. Instrument-Defined Estimates of the Minimally Important Difference for EQ-5D-5L Index Scores. Value Health. Apr 2017; 20(4): 644-650. PMID 28408007
27. Adams D, Gonzalez-Duarte A, O'Riordan WD, et al. Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis. N Engl J Med. Jul 05 2018; 379(1): 11-21. PMID 29972753
28. Obici L, Berk JL, González-Duarte A, et al. Quality of life outcomes in APOLLO, the phase 3 trial of the RNAi therapeutic patisiran in patients with hereditary transthyretin-mediated amyloidosis. Amyloid. Sep 2020; 27(3): 153-162. PMID 32131641
29. Klaassen SHC, Tromp J, Nienhuis HLA, et al. Frequency of and Prognostic Significance of Cardiac Involvement at Presentation in Hereditary Transthyretin-Derived Amyloidosis and the Value of N-Terminal Pro-B-Type Natriuretic Peptide. Am J Cardiol. Jan 01 2018; 121(1): 107-112. PMID 29153245
30. Adams D, Polydefkis M, González-Duarte A, et al. Long-term safety and efficacy of patisiran for hereditary transthyretin-mediated amyloidosis with polyneuropathy: 12-month results of an open-label extension study. Lancet Neurol. Jan 2021; 20(1): 49-59. PMID 33212063
31. Schmidt HH, Wixner J, Planté-Bordeneuve V, et al. Patisiran treatment in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy after liver transplantation. Am J Transplant. Jun 2022; 22(6): 1646-1657. PMID 35213769
32. Adams D, Tournev IL, Taylor MS, et al. Efficacy and safety of vutrisiran for patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy: a randomized clinical trial. Amyloid. Mar 2023; 30(1): 1-9. PMID 35875890
33. Coelho T, Marques W, Dasgupta NR, et al. Eplontersen for Hereditary Transthyretin Amyloidosis With Polyneuropathy. JAMA. Oct 17 2023; 330(15): 1448-1458. PMID 37768671
34. Prescribing Information for Wainua (eplontersen) injection, for subcutaneous use. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/217388s000lbl.pdf. Accessed on January 15, 2024.
35. Burns DJP, Arora J, Okunade O, et al. International Consortium for Health Outcomes Measurement (ICHOM): Standardized Patient-Centered Outcomes Measurement Set for Heart Failure Patients. JACC Heart Fail. Mar 2020; 8(3): 212-222. PMID 31838032
36. Zannad F, Garcia AA, Anker SD, et al. Clinical outcome endpoints in heart failure trials: a European Society of Cardiology Heart Failure Association consensus document. Eur J Heart Fail. Oct 2013; 15(10): 1082-94. PMID 23787718
37. Psotka MA, Abraham WT, Fiuzat M, et al. Functional and Symptomatic Clinical Trial Endpoints: The HFC-ARC Scientific Expert Panel. JACC Heart Fail. Dec 2022; 10(12): 889-901. PMID 36456063
38. Psotka MA, von Maltzahn R, Anatchkova M, et al. Patient-Reported Outcomes in Chronic Heart Failure: Applicability for Regulatory Approval. JACC Heart Fail. Oct 2016; 4(10): 791-804. PMID 27395351
39. Spertus JA, Jones PG, Sandhu AT, et al. Interpreting the Kansas City Cardiomyopathy Questionnaire in Clinical Trials and Clinical Care: JACC State-of-the-Art Review. J Am Coll Cardiol. Nov 17 2020; 76(20): 2379-2390. PMID 33183512
40. Gonzalez-Saenz de Tejada M, Bilbao A, Ansola L, et al. Responsiveness and minimal clinically important difference of the Minnesota living with heart failure questionnaire. Health Qual Life Outcomes. Feb 14 2019; 17(1): 36. PMID 30764842
41. Lewis EF, Claggett BL, McMurray JJV, et al. Health-Related Quality of Life Outcomes in PARADIGM-HF. Circ Heart Fail. Aug 2017; 10(8). PMID 28784687
42. Nassif ME, Windsor SL, Tang F, et al. Dapagliflozin Effects on Biomarkers, Symptoms, and Functional Status in Patients With Heart Failure With Reduced Ejection Fraction: The DEFINE-HF Trial. Circulation. Oct 29 2019; 140(18): 1463-1476. PMID 31524498
43. Fuentes-Abolafio IJ, Stubbs B, Pérez-Belmonte LM, et al. Physical functional performance and prognosis in patients with heart failure: a systematic review and meta-analysis. BMC Cardiovasc Disord. Dec 09 2020; 20(1): 512. PMID 33297975
44. ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories. ATS statement: guidelines for the six-minute walk test. Am J Respir Crit Care Med. Jul 01 2002; 166(1): 111-7. PMID 12091180
45. Forman DE, Fleg JL, Kitzman DW, et al. 6-min walk test provides prognostic utility comparable to cardiopulmonary exercise testing in ambulatory outpatients with systolic heart failure. J Am Coll Cardiol. Dec 25 2012; 60(25): 2653-61. PMID 23177293
46. Maurer MS, Schwartz JH, Gundapaneni B, et al. Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy. N Engl J Med. Sep 13 2018; 379(11): 1007-1016. PMID 30145929
47. Prescribing Information for Vyndaqel (tafamidis meglumine) capsules, for oral administration and Vyndamex (tafamidis) capsules, for oral administration. Available at https://labeling.pfizer.com/ShowLabeling.aspx?format=PDF&id=11685. Accessed on January 15, 2024.
48. Damy T, Garcia-Pavia P, Hanna M, et al. Efficacy and safety of tafamidis doses in the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) and long-term extension study. Eur J Heart Fail. Feb 2021; 23(2): 277-285. PMID 33070419
49. Adams D, Suhr OB, Hund E, et al. First European consensus for diagnosis, management, and treatment of transthyretin familial amyloid polyneuropathy. Curr Opin Neurol. Feb 2016; 29 Suppl 1(Suppl 1): S14-26. PMID 26734952
50. Patisiran for treating hereditary transthyretin amyloidosis. Highly specialized technologies guidance. Published: 14 August 2019. Available at www.nice.org.uk/guidance/hst10. Accessed on January 16, 2024.
51. Vutrisiran for treating hereditary transthyretin related amyloidosis. Technology appraisal guidance Published: 15 February 2023. Available at www.nice.org.uk/guidance/ta868. Accessed on January 18, 2024.
52. Tafamidis for treating transthyretin amyloidosis with cardiomyopathy. Technology appraisal guidance [TA984]. Published: 19 June 202. Available at https://www.nice.org.uk/guidance/ta984/resources/tafamidis-for-treating-transthyretin-amyloidosis-with-cardiomyopathy-pdf-82615910400709. Accessed on October 17, 2024.

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