PROPOSED Local Coverage Determination (LCD)

MolDX: Molecular Testing for Identification and Management of Hereditary Transthyretin Amyloidosis

DL39948

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MolDX: Molecular Testing for Identification and Management of Hereditary Transthyretin Amyloidosis
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Issue Description

This LCD outlines limited coverage for this service with specific details under Coverage Indications, Limitations and/or Medical Necessity.

Issue - Explanation of Change Between Proposed LCD and Final LCD

CMS National Coverage Policy

Title XVIII of the Social Security Act, §1862(a)(1)(A) allows coverage and payment for only those services that are considered to be reasonable and necessary.

42 CFR §410.32(a) Diagnostic x-ray tests, diagnostic laboratory tests, and other diagnostic tests: Conditions

CMS Internet-Only Manual, Pub. 100-02, Medicare Benefit Policy Manual, Chapter 15, §80 Requirements for Diagnostic X-Ray, Diagnostic Laboratory, and Other Diagnostic Tests, §80.1.1 Certification Changes

Coverage Guidance

Coverage Indications, Limitations, and/or Medical Necessity

This contractor will cover molecular diagnostic tests for use in the evaluation and management of beneficiaries suspected of having Hereditary Transthyretin Amyloidosis (hATTR) when all the following criteria are met:

  • The patient has a clinical diagnosis of ATTR; OR
    • Has cardiac features suggestive of ATTR-cardiomyopathy; AND
      • Is of African American descent; OR
      • Has a first-degree relative with an hATTR diagnosis; OR
      • Has at least one additional feature suggestive of hATTR according to expert consensus and society guidelines.
    • Has progressive sensorimotor and/or autonomic neuropathy; AND
      • Has a first-degree relative with an hATTR diagnosis; OR
      • Has at least one additional features suggestive of hATTR according to expert consensus and society guidelines.
  • The patient has been offered counseling regarding the test and potential results.
  • The results of the test will be used to aid in treatment decisions.
  • The test performed includes at least the minimum genetic content (genes or genetic variants) with definitive or well-established guidelines-based evidence required for clinical decision making for its intended use that can be reasonably detected by the test.
  • The test does not include additional genetic content that could be considered harmful to the patient.
  • A single variant may be tested if it is the only variant considered to be reasonable and necessary for a patient given that it is a known familial variant.
  • The test has successfully completed a technical assessment (TA) that ensures the test is reasonable and necessary as described above.
Summary of Evidence

Background

Transthyretin is a protein produced in the liver, choroid plexus, and retinal pigment epithelium and transports thyroid hormone thyroxine and the retinal-binding protein bound to retinol.1,2 In transthyretin amyloidosis (ATTR) the homotetrameric protein is destabilized, leading to monomers that misfold, aggregate and form amyloid fibrils. These fibrils are deposited in certain organs including the heart, eyes, digestive tract, nervous system, and kidneys.3 There are two types of ATTR: a sporadic, non-genetic form known as wild-type ATTR (wtATTR) and a hereditary form (hATTR, also referred to as the variant form ATTRv) caused by pathogenic variants in the TTR gene inherited in an autosomal dominant (AD) manner. In patients with wtATTR, amyloid fibrils are deposited almost entirely in the myocardium, resulting in ATTR cardiomyopathy (ATTR-CM).4,5 In contrast, hATTR may present as ATTR-CM, polyneuropathy (ATTR-PN), or a mixed phenotype of both through the deposition of the misfolded protein in both the cardiovascular and peripheral nervous systems.3,6 The true prevalence of wtATTR is unknown; however autopsy studies have suggested that it is higher than previously recognized with some studies showing that ~25% of individuals 80 or older have wild-type fibrils, regardless of symptoms.5,7-9 Historically, hATTR was thought to be endemic to certain regions including northern Portugal, northern Sweden and Japan with a prevalence of 1-10 per 10,000 individuals. However, to date the disorder has now been reported in multiple countries with an estimated global prevalence of 5000-40,000 individuals.9-11

Diagnosis

Symptoms of patients with ATTR-CM include those commonly seen in heart failure including fatigue, exercise intolerance, palpitations, conduction abnormalities, and arrhythmias.4,5 Other early indicator disease characteristics include elevated troponin or N-terminal pro-brain natriuretic peptide levels, an intolerance of angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or beta-blockers, carpel tunnel syndrome (CTS), lumbar spinal stenosis, and biceps tendon rupture.4,12,13 The age of onset of wtATTR-CM is generally above the age of 60, whereas that of hATTR-CM varies from 30-80 years old depending on the TTR variant. The median survival after diagnosis is ~3.5 and ~2.5 years respectively for wtATTR-CM and hATTR-CM.4 The clinical presentation of patients with hATTR-PN is also variable with no specific signs or symptoms uniquely associated with the disease. However, a number of “red flags” have been identified that should raise suspicion.14 Karam et al. reported that the most important features suggestive of hATTR are the rate of neuropathy progression and comorbidities such as gastrointestinal dysmotility, heart failure with preserved ejection fraction, autonomic failure and CTS.15 For example, although common in the general population, CTS in patients with hATTR is more often bilateral, more prone to recurrence and more refractory to treatment. A family or personal history of idiopathic neuropathy that does not respond to treatments for other neuropathies or is rapidly progressing is also suggestive for hATTR.

Due to the variability of clinical presentation and overlap with other disorders, misdiagnoses are common. Studies have suggested that 32-74% of patients with hATTR have received at least one misdiagnosis with 18% receiving multiple misdiagnoses.3 For example, the resulting heart failure in ATTR-CM may be attributed to other more common disorders such as hypertrophic cardiomyopathy, aortic stenosis and hypertensive heart disease.5 The peripheral neuropathy is often mistaken for other neurologic conditions such as chronic inflammatory demyelinating polyneuropathy, diabetic neuropathy or motor neuropathy.3,15 Historically, a diagnosis of hATTR was made through identification of amyloid deposits through biopsy followed by confirmatory gene sequencing. This often requires assessment of multiple tissue sites and interpretation of pathology can be variable with a reported sensitivity of 60-80% depending on the tissue type.16,17 Therefore, a negative biopsy does not definitively exclude a diagnosis and further testing, including additional biopsies, are necessary. Cardiac technetium (99mTc)-based tracer scintigraphy scanning may also be utilized if available. A positive grade 2 or 3 myocardial uptake of radiotracer and the absence of a clonal plasma cell process has shown a positive predictive value of 100% for ATTR-CM.18 However, detection of a pathogenic variant in the TTR gene is definitive for hereditary disease.

To date, nearly 150 different pathogenic variants in TTR have been associated with hATTR. Penetrance is variable and is highest in endemic regions due to founder mutations.3,9 However, the penetrance increases with age reaching nearly 100% by the ninth decade regardless of the variant.19-21 The p.Val50Met (legacy p.Val30Met) variant was the first discovered and is the most common word wide. It leads to a variable clinical presentation ranging from asymptomatic to systemic disease with both early (age <50 years) and late (age ≥50 years) onset forms.9,11,22 The early onset disease is highly penetrant and presents as ATTR-PN with sensorimotor symptoms beginning in the lower extremities with relatively mild autonomic symptoms whereas late onset typically presents with peripheral rather than autonomic neuropathy, is more likely to occur in males, and penetrance increases with age. In the United States, the most common pathogenic variant associated with hATTR is p.Val142Ile (legacy p.Val122Ile).11,23 In contrast to p.Val50Met, the clinical presentation is almost exclusively cardiac. Population studies suggest it is present in 3.4% of individuals of African descent with a disease penetrance of ~40% and has been reported in 10% of African Americans older than 65 with severe congestive heart failure.23-25 Given the increased availability of effective therapies, gene sequencing performed earlier in the diagnostic strategy confirms an hATTR diagnosis and facilitates optimal treatment choices. This strategy is endorsed by multiple societies, associations, and disease experts.4,26-28

Therapeutic strategies

Historically, liver transplantation was the only available treatment for hATTR. Since transthyretin is primarily produced in the liver, a transplant stops the production of mutant protein, decreasing amyloid formation and inhibits disease progression.29,30 However, studies have suggested that outcomes are less favorable for patients with alterations other than p.Val50Met and those with late onset or more advanced disease.30,31 Also, transplantation eliminates the production of abnormal but not wild-type transthyretin, so further deposition of wild-type transthyretin continues after transplantation. In addition, production of abnormal protein from the ocular and central nervous systems continues and cardiovascular complications post-transplant are more common than in patients undergoing transplant for end stage liver disease.30 Today, available treatments target different aspects of the production of amyloid deposits that when administered early in the course of disease slow it’s progression.

In the early 1990s, it was reported that patients with a p.Thr139Met (legacy p.Thr119Met) variant in a compound heterozygous state with p.Val50Met had no or mild symptoms of disease.32 Functional studies demonstrated that this amino acid change increased the kinetic stability of the tetramer, slowing dissociation and suppressing disease.33,34 Further studies established that the dissociation was the first and slowest step of the aggregation cascade and that small molecules that bind to and stabilize the tetramer would have a similar effect.35-37 These studies led to the identification of tafamidis (trade name: Vyndaqel®) a small molecule that binds selectively to unoccupied thyroxine-binding sites and kinetically stabilizes the tetramer.38,39 Based on clinical trial outcomes, tafamidis was approved for use in stage 1 patients with ATTR-PN in Europe, Japan, and Mexico.40-42 More recently in the US, clinical trial outcomes showed patients that were prescribed tafamidis had a decrease in all-cause mortality, rates of cardiovascular hospitalizations, and reduced functional capacity43 and in 2019 tafamidis became the first FDA-approved medication for use in ATTR-CM as a TTR stabilizer. The non-steroidal anti-inflammatory drug (NSAID) diflunisal is also a strong stabilizer and has shown to be effective.44 However, NSAIDs are relatively contraindicated in patients with heart failure and therefore it is not an optimal choice for patients with cardiac manifestations. Gillmore et al. recently reported results of the ATTRibute-CM trial in which patients that received acoramidis, a novel TTR stabilizer, had significantly better outcomes in mortality, morbidity and function than the placebo group.45

A more recent therapeutic strategy is RNA interference (RNAi), a process by which small interfering RNAs (siRNAs) or antisense oligonucleotides (ASOs) mediate the cleavage of target mRNA resulting in a robust decrease in the expression of the gene of interest thereby preventing the production of protein.46,47 There are currently four FDA-approved RNAi therapies targeting hepatic messenger RNA (mRNA) available for patients with hATTR. The Neuro-TTR Trial demonstrated that inotersen (trade name: TegsediTM), an antisense oligonucleotide (ASO) that targets the 3’ untranslated region (UTR) of TTR, was shown to improve the course of neurologic disease and quality of life in patients with hATTR when administered as a weekly subcutaneous injection.48 However, there were some safety concerns around thrombocytopenia and glomerulonephritis requiring additional monitoring after FDA approval. In a similar study published simultaneously, data from the landmark APOLLO trial showed that intravenous administration every three weeks of patisiran (trade name: Onpattro), an siRNA also targeting the 3’ UTR, reduced the mean serum levels of TTR by ~80% and significantly improved neuropathy with all study endpoints better than placebo regardless of age of onset, stage of the disease or TTR variant.49 Vutrisiran (trade name: Amvuttra) is a second-generation form of patisiran with an enhanced stabilizing chemistry administered every three months subcutaneously approved by the FDA in 2022.50 The most recent therapy to receive FDA approval in 2023, eplontersen (trade name: WainuaTM), is a second-generation version of inotersen with an enhanced delivery method that increases the potency of the molecules by 20 to 30-fold allowing for lower effective doses.51 Studies on newly emerging therapies such as gene editing, amyloid disruption, and aggregation inhibition as well as the results of combination therapies are also underway.52,53

Analysis of Evidence (Rationale for Determination)

Transthyretin amyloidosis (ATTR) is a historically under-recognized cause of cardiomyopathy and neuropathy. The hereditary form is a systemic disease presenting as either cardiac disease, peripheral neuropathy, or a mix of both. It is progressive and associated with a poor prognosis, therefore early disease identification and timely therapeutic intervention are key to improving outcomes for patients. Several different therapeutic options are available and underscore the need for diagnosis as early as possible.

Identification of causative variants in TTR is definitive for disease, however multi-gene panels that contain genes in addition to TTR may be considered reasonable and necessary to rule out or confirm other hereditary disorders with overlapping clinical features. For example, when presented with males of known African descent over the age of sixty with signs and symptoms of diastolic dysfunction confirmed by echocardiography, hATTR should be considered and genetic testing should be performed. In addition, due to the potential of unexpected results or the identification of variants of uncertain significance, pre- and post-test counseling should be provided.

Given the clinical overlap with other disorders, availability of treatment options and published society recommendations and guidelines, this contractor finds that molecular tests that aid in identifying patients with hATTR are reasonable and necessary. This contractor will continue to monitor the evidence and coverage may be re-evaluated following any substantial new evidentiary developments or guideline changes.

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Bibliography
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  2. Sanguinetti C, Minniti M, Susini V, et al. The journey of human transthyretin: synthesis, structure stability, and catabolism. Biomedicines. 2022;10(8):1906. doi:10.3390/biomedicines10081906
  3. Adams D, Koike H, Slama M, Coelho T. Hereditary transthyretin amyloidosis: a model of medical progress for a fatal disease. Nat Rev Neurol. 2019;15(7):387-404. doi:10.1038/s41582-019-0210-4
  4. Maurer MS, Bokhari S, Damy T, et al. Expert consensus recommendations for the suspicion and diagnosis of transthyretin cardiac amyloidosis. Circ Heart Fail. 2019;12(9):e006075. doi:10.1161/CIRCHEARTFAILURE.119.006075
  5. Ruberg FL, Grogan M, Hanna M, Kelly JW, Maurer MS. Transthyretin amyloid cardiomyopathy: JACC state-of-the-art review. J Am Coll Cardiol. Jun 11 2019;73(22):2872-2891. doi:10.1016/j.jacc.2019.04.003
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  7. Tanskanen M, Peuralinna T, Polvikoski T, et al. Senile systemic amyloidosis affects 25% of the very aged and associates with genetic variation in alpha2-macroglobulin and tau: a population-based autopsy study. Ann Med. 2008;40(3):232-239. doi:10.1080/07853890701842988
  8. Pinney JH, Whelan CJ, Petrie A, et al. Senile systemic amyloidosis: clinical features at presentation and outcome. J Am Heart Assoc. 2013;2(2):e000098. doi:10.1161/JAHA.113.000098
  9. Obi CA, Mostertz WC, Griffin JM, Judge DP. ATTR Epidemiology, genetics, and prognostic factors. Methodist Debakey Cardiovasc J. 2022;18(2):17-26. doi:10.14797/mdcvj.1066
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  11. Gentile L, Coelho T, Dispenzieri A, et al. A 15-year consolidated overview of data in over 6000 patients from the Transthyretin Amyloidosis Outcomes Survey (THAOS). Orphanet J Rare Dis. 2023;18(1):350. doi:10.1186/s13023-023-02962-5
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  13. Westermark P, Westermark GT, Suhr OB, Berg S. Transthyretin-derived amyloidosis: probably a common cause of lumbar spinal stenosis. Ups J Med Sci. 2014;119(3):223-228. doi:10.3109/03009734.2014.895786
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  16. Paulsson Rokke H, Sadat Gousheh N, Westermark P, et al. Abdominal fat pad biopsies exhibit good diagnostic accuracy in patients with suspected transthyretin amyloidosis. Orphanet J Rare Dis. 2020;15(1):278. doi:10.1186/s13023-020-01565-8
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  19. Hellman U, Alarcon F, Lundgren HE, Suhr OB, Bonaiti-Pellie C, Plante-Bordeneuve V. Heterogeneity of penetrance in familial amyloid polyneuropathy, ATTR Val30Met, in the Swedish population. Amyloid. 2008;15(3):181-186. doi:10.1080/13506120802193720
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  21. Saporta MA, Zaros C, Cruz MW, et al. Penetrance estimation of TTR familial amyloid polyneuropathy (type I) in Brazilian families. Eur J Neurol. 2009;16(3):337-41. doi:10.1111/j.1468-1331.2008.02429.x
  22. Manganelli F, Fabrizi GM, Luigetti M, Mandich P, Mazzeo A, Pareyson D. Hereditary transthyretin amyloidosis overview. Neurol Sci. 2022;43(Suppl 2):595-604. doi:10.1007/s10072-020-04889-2
  23. Buxbaum JN, Ruberg FL. Transthyretin V122I (pV142I)* cardiac amyloidosis: an age-dependent autosomal dominant cardiomyopathy too common to be overlooked as a cause of significant heart disease in elderly African Americans. Genet Med. 2017;19(7):733-742. doi:10.1038/gim.2016.200
  24. Kaniper S, Lynch D, Owens SM, et al. Non-cardiac amyloidosis findings are not increased in African American carriers of TTR V142I with heart failure and/or arrhythmia. J Pers Med. 2024;14(3):271. doi:10.3390/jpm14030271
  25. Madhani A, Sabogal N, Massillon D, et al. Clinical penetrance of the transthyretin V122I variant in older black patients with heart failure: the SCAN-MP (Screening for Cardiac Amyloidosis With Nuclear Imaging in Minority Populations) study. J Am Heart Assoc. 2023;12(15):e028973. doi:10.1161/JAHA.122.028973
  26. Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Joint Committee on clinical practice guidelines. J Am Coll Cardiol. 2022;79(17):e263-e421. doi:10.1016/j.jacc.2021.12.012
  27. Wilde AAM, Semsarian C, Marquez MF, et al. European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) expert consensus statement on the state of genetic testing for cardiac diseases. Heart Rhythm. 2022;19(7):e1-e60. doi:10.1016/j.hrthm.2022.03.1225
  28. Adams D, Ando Y, Beirao JM, et al. Expert consensus recommendations to improve diagnosis of ATTR amyloidosis with polyneuropathy. J Neurol. 2021;268(6):2109-2122. doi:10.1007/s00415-019-09688-0
  29. Carvalho A, Rocha A, Lobato L. Liver transplantation in transthyretin amyloidosis: issues and challenges. Liver Transpl. 2015;21(3):282-292. doi:10.1002/lt.24058
  30. Ericzon BG, Wilczek HE, Larsson M, et al. Liver transplantation for hereditary transthyretin amyloidosis: after 20 years still the best therapeutic alternative? Transplantation. 2015;99(9):1847-1854. doi:10.1097/TP.0000000000000574
  31. Algalarrondo V, Antonini T, Theaudin M, et al. Cause of death analysis and temporal trends in survival after liver transplantation for transthyretin familial amyloid polyneuropathy. Amyloid. 2018;25(4):253-260. doi:10.1080/13506129.2018.1550061
  32. Coelho T, Chorao R, Sousa A, Alves I, Torres MF, Saraiva, MJ. Compound heterozygotes of transthyretin Met30 and transthyretin Met119 are protected from the devestating effects of familial amyloid polyneuropathy. Neuromuscular Disorders. 1996;6:27. doi:doi.org/10.1016/0960-8966(96)88826-2
  33. Hammarstrom P, Schneider F, Kelly JW. Trans-suppression of misfolding in an amyloid disease. Science. 2001;293(5539):2459-2462. doi:10.1126/science.1062245
  34. Hammarstrom P, Wiseman RL, Powers ET, Kelly JW. Prevention of transthyretin amyloid disease by changing protein misfolding energetics. Science. 2003;299(5607):713-716. doi:10.1126/science.1079589
  35. Connelly S, Choi S, Johnson SM, Kelly JW, Wilson IA. Structure-based design of kinetic stabilizers that ameliorate the transthyretin amyloidoses. Curr Opin Struct Biol. 2010;20(1):54-62. doi:10.1016/j.sbi.2009.12.009
  36. Foss TR, Wiseman RL, Kelly JW. The pathway by which the tetrameric protein transthyretin dissociates. Biochemistry. 2005;44(47):15525-15533. doi:10.1021/bi051608t
  37. Johnson SM, Wiseman RL, Sekijima Y, Green NS, Adamski-Werner SL, Kelly JW. Native state kinetic stabilization as a strategy to ameliorate protein misfolding diseases: a focus on the transthyretin amyloidoses. Acc Chem Res. 2005;38(12):911-921. doi:10.1021/ar020073i
  38. Bulawa CE, Connelly S, Devit M, et al. Tafamidis, a potent and selective transthyretin kinetic stabilizer that inhibits the amyloid cascade. Proc Natl Acad Sci U S A. 2012;109(24):9629-9634. doi:10.1073/pnas.1121005109
  39. Johnson SM, Connelly S, Fearns C, Powers ET, Kelly JW. The transthyretin amyloidoses: from delineating the molecular mechanism of aggregation linked to pathology to a regulatory-agency-approved drug. J Mol Biol. 2012;421(2-3):185-203. doi:10.1016/j.jmb.2011.12.060
  40. Coelho T, Maia LF, da Silva AM, et al. Long-term effects of tafamidis for the treatment of transthyretin familial amyloid polyneuropathy. J Neurol. 2013;260(11):2802-2814. doi:10.1007/s00415-013-7051-7
  41. Coelho T, Maia LF, Martins da Silva A, et al. Tafamidis for transthyretin familial amyloid polyneuropathy: a randomized, controlled trial. Neurology. 2012;79(8):785-792. doi:10.1212/WNL.0b013e3182661eb1
  42. Merlini G, Plante-Bordeneuve V, Judge DP, et al. Effects of tafamidis on transthyretin stabilization and clinical outcomes in patients with non-Val30Met transthyretin amyloidosis. J Cardiovasc Transl Res. 2013;6(6):1011-1020. doi:10.1007/s12265-013-9512-x
  43. Maurer MS, Schwartz JH, Gundapaneni B, et al. Tafamidis treatment for patients with transthyretin amyloid cardiomyopathy. N Engl J Med. 2018;379(11):1007-1016. doi:10.1056/NEJMoa1805689
  44. Berk JL, Suhr OB, Obici L, et al. Repurposing diflunisal for familial amyloid polyneuropathy: a randomized clinical trial. JAMA. 2013;310(24):2658-2667. doi:10.1001/jama.2013.283815
  45. Gillmore JD, Judge DP, Cappelli F, et al. Efficacy and safety of acoramidis in transthyretin amyloid cardiomyopathy. N Engl J Med. 2024;390(2):132-142. doi:10.1056/NEJMoa2305434
  46. Bennett CF, Swayze EE. RNA targeting therapeutics: molecular mechanisms of antisense oligonucleotides as a therapeutic platform. Annu Rev Pharmacol Toxicol. 2010;50:259-293. doi:10.1146/annurev.pharmtox.010909.105654
  47. Watts JK, Corey DR. Silencing disease genes in the laboratory and the clinic. J Pathol. 2012;226(2):365-379. doi:10.1002/path.2993
  48. Benson MD, Waddington-Cruz M, Berk JL, et al. Inotersen treatment for patients with hereditary transthyretin amyloidosis. N Engl J Med. 2018;379(1):22-31. doi:10.1056/NEJMoa1716793
  49. Adams D, Gonzalez-Duarte A, O'Riordan WD, et al. Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis. N Engl J Med. 2018;379(1):11-21. doi:10.1056/NEJMoa1716153
  50. 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. 2023;30(1):1-9. doi:10.1080/13506129.2022.2091985
  51. Coelho T, Waddington Cruz M, Chao CC, et al. Characteristics of patients with hereditary transthyretin amyloidosis-polyneuropathy (ATTRv-PN) in NEURO-TTRansform, an open-label phase 3 study of eplontersen. Neurol Ther. 2023;12(1):267-287. doi:10.1007/s40120-022-00414-z
  52. Wu D, Chen W. Molecular mechanisms and emerging therapies in wild-type transthyretin amyloid cardiomyopathy. Heart Fail Rev. 2024;29(2):511-521. doi:10.1007/s10741-023-10380-9
  53. Qarni TN, Jones FJS, Drachman B, et al. Treatment characteristics of patients with hereditary transthyretin amyloidosis: a cohort study. Orphanet J Rare Dis. 2024;19(1):191. doi:10.1186/s13023-024-03198-7
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Bibliography
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Keywords

  • Hereditary Transthyretin Amyloidosis
  • hATTR

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