Medical Policy
Policy Num: M5.001.015
Policy Name: Treatment of Hereditary Transthyretin-Mediated Amyloidosis in Adult Patients
Policy ID: [M5.001.015] [Ac / MA / M+ / P+] [5.01.30]
Last Review: May 10, 2024
Next Review: May 20, 2025
Related Policies: None
Population Reference No. | Populations | Interventions | Comparators | Outcomes |
1 | Individuals: · Who are adults with polyneuropathy of hereditary transthyretin-mediated amyloidosis | Interventions of interest are: · Patisiran | Comparators of interest are: · Standard of care | Relevant outcomes include: · Symptoms · Change in disease status · Functional outcomes · Quality of life · Treatment-related morbidity · Treatment-related mortality |
2 | Individuals: · Who are adults with polyneuropathy of hereditary transthyretin-mediated amyloidosis | Interventions of interest are: · Inotersen | Comparators of interest are: · Standard of care | Relevant outcomes include: · Symptoms · Change in disease status · Functional outcomes · Quality of life · Treatment-related morbidity · Treatment-related mortality |
3 | Individuals: · Who are adults with polyneuropathy of hereditary transthyretin-mediated amyloidosis | Interventions of interest are: · Vutrisiran | Comparators of interest are: · Standard of care | Relevant outcomes include: · Symptoms · Change in disease status · Functional outcomes · Quality of life · Treatment-related morbidity · Treatment-related mortality |
4 | Individuals: · Who are adults with cardiomyopathy of hereditary transthyretin-mediated amyloidosis | Interventions of interest are: · Tafamidis meglumine or tafamidis | Comparators of interest are: · Standard of care | Relevant outcomes include: · Symptoms · Change in disease status · Functional outcomes · Quality of life · Treatment-related morbidity · Treatment-related mortality |
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.
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 inotersen, the evidence includes 1 pivotal RCT. Relevant outcomes are symptoms, change in disease status, functional outcomes, QOL, treatment-related morbidity and treatment-related mortality. Data from the NEURO-TTR III trial demonstrated a statistically significant mean improvement in neurologic function and neuropathy-related QOL with inotersen at 15 months compared to placebo. There was no evidence of improvement in cardiac outcomes with inotersen treatment after 15 months compared to placebo. However, the trial was not powered to detect a difference in cardiac outcomes. Results of NEURO-TTR trial have limited generalizability because it included only 3 patients (1.7%) 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 include 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 regard 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 one 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 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. The evidence is sufficient to determine that the technology results in an improvement in the net health outcome.
Not applicable
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.
Patisiran, inotersen, and vutrisiran are considered medically necessary for individuals if they meet criteria 1 through 5:
Confirmatory diagnosis of hATTR by a genetic test OR tissue biopsy showing amyloid deposition.
Presence of clinical signs and symptoms of polyneuropathy characterized by any one of the following:
Baseline polyneuropathy disability (PND) IIIb or lower (see Table 1 in background section)
Baseline familial amyloid polyneuropathy (FAP) Stage 1 or 2 (see Table 1 in background section).
New York Heart Association (NYHA) class III or IV heart failure
Sensorimotor or autonomic neuropathy not related to hATTR amyloidosis (monoclonal gammopathy, autoimmune disease, etc.)
Prior liver transplantation.
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.
Incremental reauthorization of patisiran, inotersen, and vutrisiranare considered medically necessary for individuals if they meet criteria 1 through 2:
Continues to meet the initial treatment criteria cited above.
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, inotersen, and vutrisiran are considered investigational when the above criteria are not met.
Tafamidis and tafamidis meglumine are considered medically necessary for individuals if they meet criteria 1 through 5:
18 years of age or older.
Confirmatory diagnosis of hereditary or wild-type transthyretin-mediated amyloidosis by a genetic test OR tissue biopsy showing amyloid deposition.
Presence of clinical signs and symptoms of cardiac involvement by all of the following:
End-diastolic interventricular septal wall thickness exceeding 12 mm on echocardiography.
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.
Baseline NT-proBNP ≥ 600 pg/mL.
Does not have any of the following:
NYHA class IV heart failure.
Presence of light-chain amyloidosis.
History of liver or heart transplantation.
Implanted cardiac device.
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.
Incremental reauthorization for tafamidis and tafamidis meglumine are considered medically necessary for individuals if they meet criteria 1 through 2:
Continues to meet the initial treatment criteria cited above.
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.
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.
It is given as subcutaneous injection 284 mg once weekly.
Contraindicated if platelet count is less than 100 x 109 /L or if the individual has a history of acute glomerulonephritis caused by inotersen or if the individual has a history of a hypersensitivity reaction to inotersen.
Assess platelet count prior to treatment and monitored during treatment as inotersen causes reductions in platelet count that may result in sudden and unpredictable thrombocytopenia, which can be life-threatening.
Monitor alanine amino transferase, aspartate aminotransferase, and total bilirubin every 4 months during treatment and in case of symptoms of hepatic dysfunction.
Assess serum creatinine, estimated glomerular filtration rate (eGFR), urine protein to creatinine ratio (UPCR), and a urinalysis prior to starting treatment as inotersen can cause glomerulonephritis that may require immunosuppressive treatment and may result in dialysis dependent renal failure. During treatment, monitor serum creatinine, eGFR urinalysis, and UPCR every 2 weeks. Inotersen should not be given to patients who develop a UPCR of 1000 mg/g or higher, or eGFR below 45 mL/minute/1.73 m 2, pending further evaluation of the cause.
Inotersen is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the TEGSEDI REMS Program, because of risks of serious bleeding caused by severe thrombocytopenia and because of glomerulonephritis. Important requirements of REMS program include:
Prescribers must be certified within the program by enrolling and completing training.
Individuals must enroll in the program and comply with ongoing monitoring requirements.
Pharmacies must be certified with the program and must only dispense to patients who are authorized to receive inotersen.
It is given as subcutaneous injection.
25 mg once every 3 months (Quarterly)
Injection should be administered by a healthcare professional.
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).
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.
See the Codes table for details.
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.
FAP Stage | Clinical Description |
Stage 0 | No symptoms |
Stage 1 | Unimpaired ambulation |
Stage 2 | Assistance with ambulation required |
Stage 3 | Wheelchair-bound or bedridden |
PND Score | |
Stage 0 | No symptoms |
Stage I | Sensory disturbances but preserved walking capability |
Stage II | Impaired walking capacity but ability to walk without a stick or crutches |
Stage IIIA | Walking with the help of 1 stick or crutch |
Stage IIIIB | Walking with the help of 2 sticks or crutches |
Stage IV | Confined to a wheelchair or bedridden |
Adapted from Ando et al (2013)3,FAP: familial amyloid polyneuropathy; PND: polyneuropathy disability.
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 tests programs that offer no-cost, confidential genetic testing and genetic counseling services sponsored by the manufacturers of inotersen and patisiran. These are summarized in Table 2.
Program | Program Eligibility | Tests Offered | Detail |
AlnylamActTM | Patients 18 years and older with a suspected diagnosis or a confirmed family history of hATTR amyloidosis. | Invitae Cardiomyopathy Comprehensive Panel | Testing for ~50 genes associated with inherited cardiomyopathy conditions, including hATTR amyloidosis |
Invitae Comprehensive Neuropathies Panel | Testing for ~70 genes that cause dominant, recessive, and X-linked hereditary neuropathies, including hATTR amyloidosis | ||
Invitae Transthyretin Amyloidosis Test | Single-gene genetic testing for the TTR gene, which is associated with hATTR amyloidosis | ||
The hATTR CompassTM Program | Patients who are 18 years and older and who have a family history of or are experiencing symptoms of hATTR amyloidosis. | hATTR Amyloidosis Test | Single-gene test for TTR |
CardioNext | Up to 85-gene panel targeting patients with cardiomyopathies, including hATTR amyloidosis | ||
NeuropathySelect | 80-gene panel targeting patients with hereditary neuropathies, including hATTR amyloidosis (available at select centers) |
Adapted from AlnylamActTM and The hATTR CompassTM Program7,8,hATTR: hereditary transthyretin-mediated amyloidosis; TTR: transthyretin.
It is estimated that the neuropathy-predominant form of hATTR affects at least 10,000 people worldwide,9, and roughly 3,000-3,500 people in the United States (U.S.).10, Due to under-diagnosis and a lack of population-based data, these numbers may underestimate the actual prevalence.11,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.9,10, 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%.12, However, phenotypic penetrance resulting in overt clinical cardiac disease depends on age and varies widely from 7% to 80%.13, 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.
Variant | Median Age at Symptoms Onset (Yr) | Median Age at Diagnosis (YrP) | Median age at Death (Yr) |
T60A | 60.2 | 64.5 | 67.6 |
V30M | 64.3 | 67.8 | 74.7 |
V122I | 63.7 | 69.3 | 72.9 |
S77Y | 55.8 | 60.1 | 65.8 |
Other | 53.1 | 56.7 | 62.1 |
Adapted from Swiecicki et al, 201514,
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. 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.
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.
Inotersen 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.
In August 2018, patisiran (OnpattroTM, Alnylam Pharmaceuticals, Inc.) was approved by the FDA for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults.
In October 2018, inotersen (TegsediTM, Ionis Pharmaceuticals, Inc.) was approved by the FDA for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults.
In June 2022, vutrisiran (AmvuttraTM, Alnylam Pharmaceuticals, Inc.) 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.
This evidence review was created in December 2018 with a search of the PubMed database. The most recent literature update was performed through Sep 21, 2023.
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
The purpose of patisiran, inotersen, and vutrisiran 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.
The relevant population of interest are individuals with polyneuropathy of hATTR.
The therapies being considered are patisiran, inotersen, and vutrisiran.
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.
The general outcomes of interest are related to assessing the impact of disease on sensorimotor, autonomic and cardiovascular manifestation and summarized in Table 4.
Outcome | Objective | Description | MCID |
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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.
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.
Studies with duplicative or overlapping populations were excluded.
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 (see 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 also 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<0.0001). 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.
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.
Study; Trial | Countries | Sites | Dates | Participants | Interventions | |
Adams et al. (2018); APOLLO, NCT01960348)27, | Multiple countries | 14 | 2013-2016 |
| n=148 patisiran 0.3 mg/kg IV Q3W for 18 months Cardiac subpopulation n=90 | n=77 placebo IV Q3W for 18 months Cardiac subpopulation n=36 |
Adams et al, (2021); (NCT02510261) 30,Interim results at 12-months | Multiple countries | 56 | 2015-2017 |
| n=211 patisiran (APOLLO placebo=49; APOLLO n=137; phase 2 OLE=25) 0.3 mg/kg IV Q3W | None |
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.
Study | LSM Difference(mNIS+7) | LSM Difference (Secondary Outcomes) | PND Score (Disease Progression), n (%) | LSM Difference (QOL) | Safety n (%) |
Adams et al. (2018); APOLLO27, | |||||
N | 235 | 235 | 203 | 235 | 235 |
Patisiran | -6.0±1.7 | NIS-W: 0.1±1.3 R-ODS: 0.0±0.6 10-MWTa: 0.08±0.02 mBMIb: -3.7±9.6 COMPASS-31: -5.3±1.3 | Improved: 12 (8) No Change: 96 (65) Worsened: 30 (20) Missing: 10 (7)c | Norfolk QOL:-6.7±1.8 EQ-5D-5L: 0.3±0.2 EQ-5D-VAS: -7.1±2.3 | Any AE: 97% Any SAE: 36% AE Rx discontinuation: 5% AE trial withdrawal: 5% |
Placebo | 28.0±2.6 | NIS-W: 17.9±2.0 R-ODS: -8.9±0.9 10-MWTa: -0.24±0.04 mBMIb: -119.4±14.5 COMPASS-31: 2.2±1.9 | Improved: 0 No Change: 23 (30) Worsened: 32 (42) Missing: 22 (29)c | Norfolk QOL: 14.4±2.7 EQ-5D-5L: -0.17±0.02 EQ-5D-VAS: 2.4±1.6 | Any AE: 97% Any SAE: 40% AE Rx discontinuation: 14% AE trial withdrawal: 12% |
Diff (±SE) | -34±3.0 | NIS-W: 17.9±2.3 R-ODS: 9.0±1.0 10-MWTa: 0.31±0.04 mBMIb: 115.7±16.9 COMPASS-31: -7.5±2.2 | Not reported | Norfolk QOL: -21.1 EQ-5D-5L: 0.2 EQ-5D-VAS: 9.5 | NA |
P Value | <0.001 | All p values: <0.001 | Not reported | All p values: <0.001 | NA |
Adams et al, (2021)30, | Change in mean mNIS+7 (95% CI) | Norfolk QOL-DN | Safety (Serious adverse events) | ||
APOLLO-patisiran | -4.0 (-7.7 to -0.3)d | -3.9 (-8.1 to 0.3) | 48/137 (35%) | ||
Phase 2 OLE | -4.7 (-11.9 to 2.4)d | Not reported | 6/25 (24%) | ||
APOLLO-placebo | -1.4 (-6.2 to 3.5)d | -4·5 (-9.6 to 0.7) | 28/49 (57%) |
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 eventa meter/secondsb kilogram/meter2 x albumin (gram/deciliter)c Missing includes all deaths prior to 18-month visitd 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.
Study | Populationa | Interventionb | Comparatorc | Outcomesd | Follow-Upe |
Adams et al. (2018); APOLLO27, | 4. Study population not representative of intended use. | 1, 2. (36 months follow-up is insufficient to establish long-term harms) |
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.
Inotersen
One pivotal RCT of inotersen (NEURO-TTR) with 172 adults with hATTR amyloidosis with polyneuropathy received either inotersen or placebo (see Table 8).32, Although the treatment arms were well balanced at baseline, notable imbalances included more severe sensorimotor and autonomic neuropathy and a higher proportion of patients with cardiac symptoms in the inotersen group compared to placebo. Other publications reporting the post-hoc analysis of NEURO-TTR were not reviewed.33,34,
Results are summarized in Table 9. The trial met its primary end point of least squares mean (LSM) change from baseline to 18 months in mNIS+7 significantly favored inotersen compared with placebo. However, the mNIS+7 used in this trial was substantially different from the mNIS+7 used in the APOLLO trial. Unlike the mNIS+7 used in the APOLLO trial in which the maximum possible score was 304 points with 5 domains (motor strength, reflexes, quantitative score testing, nerve conduction testing and postural blood pressure), mNIS+7 used in the NEURO-TTR trial had a maximum possible score of 346.6 points with 6 domains (motor strength, reflexes, sensation, quantitative score testing, nerve conduction testing and heart rate response to deep breathing). Detailed analysis of QOL outcomes reported that inotersen treatment also improved neuropathy-related QOL as shown by improvements in mean scores, as well as the proportion of patients reporting improved scores after 15 months of treatment with inotersen compared to those on placebo.35, However, neither the mNIS+7 nor the Norfolk-QOL-DN had a validated threshold of what magnitude of improvement or worsening is clinically relevant. Cardiac endpoints (data not shown) did not differ statistically between the inotersen group and the placebo group after 15 months of intervention; however, the trial was not powered to detect differences in cardiac outcomes.
Cardiac outcomes (global longitudinal strain or other echocardiographic measures, including ejection fraction, posterior wall thickness, and left ventricular mass) were assessed in a cardiac subpopulation that included patients with intraventricular septum thickness ≥ 1.3 cm. There was no evidence of improvement in cardiac outcomes with inotersen treatment after 15 months compared to placebo.
Inotersen was approved with a black box warning because it can cause sudden and unpredictable thrombocytopenia that can be life-threatening. Platelet counts below 100 x 109/L occurred in 25% of inotersen-treated patients compared with 2% of patients on placebo. Platelet counts below 75 x 109/L occurred in 14% of inotersen-treated patients, compared to no patients on placebo. In the NEURO-TTR trial and its extension study, 39% of inotersen-treated patients with a baseline platelet count below 200 x109/L had a nadir platelet count below 75 x 109/L, compared to 6% of patients with baseline platelet counts 200 x109/L or higher. Three inotersen -treated patients (3 %) had sudden severe thrombocytopenia (platelet count below 25 x 109/L), which can have potentially fatal bleeding complications, including spontaneous intracranial or intrapulmonary hemorrhage. One patient in a clinical trial experienced a fatal intracranial hemorrhage.
Data from an OLE study of the NEURO-TTR trial suggests a sustained delay of progression of polyneuropathy and maintenance of QOL.36, The interim findings of this study are based on analysis of data at the cutoff date of May 31, 2018. Study participants received median inotersen exposure of 591 days (range 1-1429 days). Interim results report continued efficacy after 2 years with no additional safety concerns or signs of increased toxicity for up to 5 years’ cumulative inotersen exposure. Routine platelet and renal monitoring to manage the risk of severe thrombocytopenia and glomerulonephritis appear to be effective. However, the published results are based on an interim analysis, and continued observation and reporting are needed to assess whether the clinical benefits and safety are maintained to the end of the 5-year global OLE. 36,
The purpose of the study limitations tables (Table 10) 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 NEURO-TTR trial is related to the generalizability of its results to the U.S. population. Only 3 patients (1.7%) included had the Val122Ile variant, which is the most common variant observed in the U.S. This was due to the trial inclusion criterion of polyneuropathy-predominant hATTR. Secondly, while the open-labeled extension phase of the study has reported outcomes for data up to 52 months, long safety data is inadequate as these drugs are intended for chronic use. And lastly, treatment discontinuations occurred more frequently among inotersen patients compared to placebo (22.3% vs. 13.3%). Inotersen patients discontinued most due to adverse events while placebo patients discontinued most due to voluntary withdrawal and disease progression (n=3, 5% each). No major gaps were identified in study design and conduct.
Study; Trial | Countries | Sites | Dates | Participants | Interventions | |
Active | Comparator | |||||
Benson et al. (2018); NEURO-TTR (NCT01737398)32, | Multiple countries | 14 | 2013-2017 |
| Inotersen weekly 300 mg subcutaneous injections (n=112) | Placebo subcutaneous injections (n=60) |
Brannagan et al. (2020); NCT0217500436, | Multiple countries | 22 | Not reported |
| Inotersen-inotersen (n=85) Placebo-inotersen (n=50) Overall n= 135 (300 mg inotersen weekly subcutaneous injections) | None |
FAP: familial amyloid polyneuropathy; hATTR: hereditary transthyretin-mediated; IV: intravenous; kg: kilogram; mNIS+7: Modified Neuropathy Impairment Score; NIS: Neuropathy Impairment Score; QOL: quality of life; PND: polyneuropathy disability; Q3W: every 3 weeks; TTR: transthyretin.
Study | mNIS+7 | Norfolk-QOL-DN | PND Score (Disease Progression) | ||
Benson et al. (2018); NEURO-TTR32, | Mean change from baseline (95% CI) | % Improvementa (95% CI) | Mean change from baseline (95% CI) | % Improvementa (95% CI) | n (%) |
N | 172 | 172 | 172 | 172 | 138 |
Inotersen | 5.8 (1.6 to 10.0) | 36.5% | 1.0 (-3.2 to -5.2) | 50.0% | Improved: 9 (8) No Change: 56 (50) Worsened: 21 (19) Missing: 26 (23) |
Placebo | 25.5 (20.2 to 30.8) | 19.2% | 12.7 (7.4 to 17.9) | 26.9% | Improved: 2 (3) No Change: 37 (62) Worsened: 13 (22) Missing: 8 (13) |
Diff <0.001 | -19.7 (-26.4 to -13.0) | 17.2% (2.4 to 32.1) | -11.7 (-18.3 to -5.1) | 23.1% (7.0 to 39.2) | Not reported |
Brannagan et al. (2020)36, | Mean change (SE) from OLE baseline to week 104 | Relative to the NEURO-TTR baseline, mNIS + 7 improved (<0-point change) | Mean (SE) changefrom OLE baseline to week 104 | Relative to the NEURO-TTR baseline, NORFOLK-DN improved (<0-point change) | Severe TEAE |
Inotersen-Inotersen | 11.18 (3.347) | 37% at 92 weeks 30% at 118 weeks 24% at 170 weeks | 5.22 (3.321) | 51% at 92 weeks 44% at 118 weeks 46% at 170 weeks | 34 (40.0%) |
Placebo-Inotersen | 5.08 (4.159) | 28% at 26 weeks 47% at 52 weeks 47% at 104 weeks | 2.26 (3.997) | 46% at 26 weeks 53% at 52 weeks 42% at 104 weeks | 10 (20.0%) |
CI: confidence interval; mNIS+7: Modified Neuropathy Impairment Score; PND: polyneuropathy disability; QOL-DN: Quality of Life - Diabetic Neuropathy; SE: standard error; TEAE: treatment-emergent adverse effects. a Improvement defined as no increase from baseline
Study | Populationa | Interventionb | Comparatorc | Outcomesd | Follow-Upe |
Benson et al. (2018); NEURO-TTR32, | 4. Study population not representative of intended use. | 1, 2. (52 months follow-up is insufficient to establish long-term harms) |
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. 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.
The evidence includes one pivotal multicenter, randomized, open labeled trial, HELIOS-A37,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.
Study: Trial | Countries | Sites | Dates | Participants | Interventions | |
Active | Comparator | |||||
HELIOS-A (NCT03759379)37, | Multiple Countries | 57 | 2019-2020 | Inclusion Criteria
Primary endpoint
|
|
|
hATTR: hereditary transthyretin-mediated; Q3W: every 3 weeks
Study | mNIS+7a | Norfolk-QOL-DNa | 10-MWTb | mBMIc |
HELIOS-A37, | ||||
Vutrisiran (N=122), LS mean change from baseline to month 9 (SEM) | -2.2 (1.4) | -3.3 (1.7) | 0 (0.02) | 7.6 (7.9) |
Placebod(N=77), LS mean change from baseline to month 9 (SEM) | 14.8 (2.0) | 12.9 (2.2) | -0.13 (0.03) | -60.2 (10.1) |
Difference in LS Mean Difference (95% CI) | -17.0 (-21.8, -12.2) | -16.2 (-21.7, -10.8) | 0.13 (0.07, 0.19) | 67.8 (43.0, 92.6) |
p value | .001 | .001 | .001 | .001 |
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 meana A lower number indicates less impairment/fewer symptomsb A higher number indicates less disability/less impairmentc 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.
Study | Populationa | Interventionb | Comparatorc | Outcomesd | Follow-Upe |
HELIOS-A37, | 1, 2. (9 months follow-up is insufficient to establish long-term benefits and harms) |
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.
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. 1, 2 & 3 Policy Statement | [X] MedicallyNecessary | [ ] Investigational |
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.
The relevant population of interest are individuals with cardiomyopathy of hATTR.
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.
Management approaches include the use of pharmacotherapy.
The International Consortium for Health Outcomes Measurement has identified 3 domains of outcomes for a standard outcome set for patients with heart failure.38,
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.39, 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.40, 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.41,42,43,44,45,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.40, 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.46,47, CPET is more comprehensive than the 6MWT, as it integrates ventilatory measurements and evaluates contributions from noncardiac disease processes to dyspnea and functional limitation.48, 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.40,
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.
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) (see Table 14). 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.49,
The results of the trial are summarized in Table 15. 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.50,
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. 50, Data from an OLE study of the ATR-ACT suggests durability of treatment effect up to a follow-up of 51 months. 51,
Study; Trial | Countries | Sites | Dates | Participants | Interventions | |
ATR-ACT (NCT01994889)52,49, | Multiple countries | 80 | 2013-2015 | Inclusion
Exclusion
| n=264 Tafamidis 20 mg (n=88) or 80 mg (n=176) once daily for 30 months | n=177 matching placebo |
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
Study | Pooled Tafamidis | Placebo |
ATR-ACT52, | n=264 | n=177 |
Primary Analysis | ||
Number (%) alivea at month 30 | 186 (70.5) | 101 (57.1) |
Mean number of cardiovascular-related hospitalizations during 30 months (per patient per year) among those alive at month 30 | 0.297 | 0.455 |
P value | .0006 | |
Secondary Analysis | n=264 | n=177 |
Total (%) number with cardiovascular-related hospitalizations | 138 (52.3) | 107 (60.5) |
Cardiovascular-related Hospitalizations per yearb | 0.48 | 0.70 |
Pooled tafamidis vs placebo treatment difference (relative risk ratio)b | 0.68 | |
P value | <.0001 | |
6 MWT (meters) | ||
Baseline mean (SD) | 351 (±121) | 353 (±126) |
Change from baseline to month 30, LS mean (SE) | -55 (±5) | -131 (±10) |
Treatment difference from placebo LS mean (95% CI) | 76 (58 to 94) | |
KCCQ-OS | ||
Baseline mean (SD) | 67 (±21) | 66 (±22) |
Change from baseline to month 30, LS mean (SE) | -7 (±1) | -21 (±2) |
Treatment difference from placebo LS mean (95% CI) | 14 (9,18) |
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 factors6MWT: 6-minute walk test; KCCQ-OS: Kansas City Cardiomyopathy Questionnaire-Overall Summary; SD: standard deviation; LS: least squares; SE: standard error; CI: confidence interval
No notable limitations in study relevance or study design and conduct were noted.
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.
Population Reference No. 4 Policy Statement | [X] MedicallyNecessary | [ ] Investigational |
The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.
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 the European Network (2016) for transthyretin-mediated amyloidosis-familial amyloid polyneuropathy were published prior to the approval of patisiran and inotersen and, therefore, do not include any recommendation for either of the drugs.53, 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.
On May 22, 2019 the National Institute for Health and Care Excellence (NICE) issued highly specialized technologies guidance on inotersen for treating hereditary transthyretin amyloidosis. Inotersen is recommended, within its marketing authorization, as an option for treating stage 1 and stage 2 polyneuropathy in adults with hereditary transthyretin amyloidosis. It is recommended only if the company provides inotersen according to the commercial arrangement.54,
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.55,
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.56,
On May 125, 2021 the NICE issued technology appraisal guidance on tafamidis for treating hereditary transthyretin amyloidosis with cardiomyopathy. Tafamidis is not recommended, within its marketing authorization, for treating wild-type or hereditary transthyretin amyloidosis with cardiomyopathy in adults. The guidance concluded the following: "The committee recognized that ATTR-CM is a debilitating and progressive condition which has a substantial effect on a person's quality of life. It noted that awareness of ATTR-CM was improving but getting a definitive diagnosis was complicated and can take a long time. Without validated and objective measures for assessing ATTR-CM, identifying people who need treatment and those who are benefiting from treatment will continue to be a challenge. It acknowledged that tafamidis was more effective than placebo in the outcomes assessed in the ATTR-ACT pivotal trial. It remarked that there was considerable uncertainty about the modelling of stopping tafamidis and if treatment effects continue after this. It also remarked that there was a high degree of uncertainty about whether introducing tafamidis would reduce diagnosis delays and result in any additional benefits or cost savings that could be attributed to tafamidis. All this considered, the committee's most plausible range of incremental cost-effectiveness ratios (ICERs) was substantially above the range that NICE usually considers an acceptable use of NHS resources. So, the committee did not recommend using tafamidis in the NHS for treating ATTR-CM."57,
The ICER (2018) published a Report on comparative effectiveness and value of inotersen and patisiran for hereditary transthyretin-mediated amyloidosis.11,Differences in the primary outcome measures and trial population (e.g., race, geographic region, disease severity) precluded a direct comparison of the Phase III APOLLO; (patisiran) and NEURO-TTR (inotersen) trials. 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 and the NEURO-TTR trial to be of fair quality based on baseline differences in autonomic and sensorimotor neuropathy severity between treatment groups.
In summarizing the clinical evidence, the ICER Report noted, “In considering the current evidence for inotersen and patisiran, the limitations of inotersen and patisiran 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, they also noted, “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 these medications.”
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+”). For inotersen, they concluded there is moderate certainty of a comparable, small, or substantial net health benefit relative to best supportive care, with a high certainty of at least a comparable net health benefit, and therefore rated the clinical evidence for inotersen to be comparable or better (C+).
Not applicable.
There is no national coverage determination or local coverage determination.
Some currently unpublished trials that might influence this review are listed in Table 14.
NCT No. | Trial Name | Planned Enrollment | Completion Date |
Patisiran | |||
Ongoing | |||
NCT03997383a | APOLLO-B: A Phase 3, Randomized, Double-blind, Placebo-controlled Multicenter Study to Evaluate the Efficacy and Safety of Patisiran in Patients With Transthyretin Amyloidosis With Cardiomyopathy (ATTR Amyloidosis With Cardiomyopathy) | 360 | Jun 2025 |
NCT04561518a | ConTTRibute: A Global Observational Study of Patients With Transthyretin (TTR)-Mediated Amyloidosis (ATTR Amyloidosis) | 1500 | Sep 2030 |
NCT05873868 | Myocardial Effects in Patients With hATTR With Polyneuropathy Treated With Patisiran (MyocardON-TTR) | 20 | July 2024 |
Inotersen | |||
Ongoing | |||
NCT04843020 | ION-682884 in Patients With TTR Amyloid Cardiomyopathy | 17 | Dec 2025 |
NCT04270058a | TEGSEDI Pregnancy Surveillance Program | 20 | Nov 2030 |
NCT04850105a | A Non-interventional Cohort Safety Study of Patients With hATTR-PN | 240 | Mar 2036 |
Vutrisiran | |||
Ongoing | HELIOS-B: A Study to Evaluate Vutrisiran in Patients With Transthyretin Amyloidosis With Cardiomyopathy | 655 | Feb 2024 |
Unpublished | |||
NCT03702829a | 24 Month Open Label Study of the Tolerability and Efficacy of Inotersen in TTR Amyloid Cardiomyopathy Patients | 50 | Mar 2022 |
NCT04201418a | A Phase 4 Multicenter Observational Study to Evaluate the Effectiveness of Patisiran in Patients With Polyneuropathy of Hereditary Transthyretin-Mediated (ATTRv) Amyloidosis With a V122I or T60A Mutation | 67 | May 2022 |
NCT: national clinical trial.a Denotes industry-sponsored or cosponsored trial.
Codes | Number | Description |
---|---|---|
CPT | No code | |
HCPCS | J0222 | Injection, patisiran, 0.1 mg |
J0225 | Injection, vutrisiran, 1 mg | |
J3490 | Unclassified drugs (There is no specific code for Inotersen; tafamidis and tafamidis meglumine. The unlisted code would be used.) | |
ICD10 PCS | ICD-10-PCS codes are only used for inpatient services | |
ICD10 CM | E85.1-E85.9 | Amyloidosis code range |
Type of Service | Pharmacy | |
Place of Service | Outpatient |
Date | Action | Description |
---|---|---|
5/10/2024 | Policy Review | Policy presented at the Utilization Management MA Committee |
2/15/2024 | Policy created | New Policy |