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Transthyretin-mediated amyloidosis (ATTR) is a rare, under-recognized, progressively debilitating, fatal disease caused by the aggregation and extracellular deposition of amyloid transthyretin (TTR) fibrils in multiple organs and tissues throughout the body. TTR is predominantly synthesized by the liver and normally circulates as a homotetramer, while misfolded monomers aggregate to form amyloid fibrils. One strategy to treat ATTR amyloidosis is to reduce the amount of TTR produced by the liver using drugs that directly target the TTR mRNA or gene. This narrative review focuses on how TTR gene silencing tools act to reduce TTR production, describing strategies for improved targeted delivery of these agents to hepatocytes where TTR is preferentially expressed. Antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs), termed RNA silencers, cause selective degradation of TTR mRNA, while a TTR gene editing tool reduces TTR expression by introducing nonsense mutations into the TTR gene. Two strategies to facilitate tissue-specific delivery of these nucleic acid-based drugs employ endogenous receptors expressed by hepatocytes. Lipid nanoparticles (LNPs) that recruit apolipoprotein E support low-density lipoprotein receptor-mediated uptake of unconjugated siRNA and are now used for CRISPR gene editing tools. Additionally, conjugating N-acetylgalactosamine (GalNAc) moieties to ASOs or siRNAs facilitates receptor-mediated uptake by the asialoglycoprotein receptor. In summary, ATTR is a progressive disease with various clinical manifestations due to TTR aggregation, deposition, and amyloid formation. Receptor-targeted ligands (eg, GalNAc) and nanoparticle encapsulation (eg, LNPs) are technologies to deliver ASOs, siRNAs, and gene editing tools to hepatocytes, the primary location of TTR synthesis., (© 2022 The Authors. Journal of the Peripheral Nervous System published by Wiley Periodicals LLC on behalf of Peripheral Nerve Society.)

Introduction: Initial clinical manifestations of transthyretin amyloidosis (ATTR) are not well understood, making timely diagnosis challenging. Methods: Patients aged ≥68 years newly diagnosed with ATTR were identified using Medicare Research Identifiable Files. Symptom manifestation and healthcare utilization were measured during 3 years pre-diagnosis; demographics and comorbidity index during 1-year pre-diagnosis. Controls (ATTR-free) were matched 1:1 to patients with ATTR based on age, sex and region; same index date and enrollment as match. Results: We identified 552 matched ATTR-control pairs: mean age 78.3 (standard deviation 6.3) and 64.5% male. Among patients with ATTR (vs controls), cardiovascular conditions (92.9 vs 75.9%) and hospitalization (54.0 vs 35.5%) were frequent during 3 years pre-diagnosis. Conclusion: Patients with ATTR have multiple symptoms and hospitalizations pre-diagnosis, recognition of which may facilitate earlier diagnosis and treatment.

Background: Patients with transthyretin amyloid cardiomyopathy (ATTR-CM) experience infiltrative cardiomyopathy and heart failure symptoms requiring costly hospitalizations. The Transthyretin Amyloidosis Cardiomyopathy Clinical Trial (ATTR-ACT) demonstrated the efficacy of tafamidis on the frequency of cardiovascular (CV)-related hospitalizations in patients with ATTR-CM., Purpose: As length of stay can affect the total hospitalization burden, our study aimed to better understand the impact of tafamidis on the number of CV-related hospital days avoided in the management of ATTR-CM patients., Methods: Data from ATTR-ACT were used to calculate the total burden of CV-related hospitalization (days) by treatment arm in this post hoc analysis., Results: In the total trial population, patients receiving tafamidis had significantly fewer CV-related hospitalizations per year (relative risk reduction [RRR] 0.68; 0.4750 vs. 0.7025, p < 0.0001) and a shorter mean length of stay per CV-related hospitalization event (8.6250 vs. 9.5625 days) than patients receiving placebo. Taken together, tafamidis prevented 2.62 CV-related hospitalization days per patient per year. A subgroup analysis showed that with earlier treatment initiation of tafamidis, the annual number of CV-related hospitalizations was significantly lowered by 52% compared with placebo (RRR 0.48; 0.3378 vs. 0.7091, p < 0.0001). With 1.14 fewer days per hospitalization, tafamidis reduced the annual number of CV-related hospitalization days by 3.96 days per New York Heart Association class I/II patient., Conclusions: In patients with ATTR-CM, tafamidis was associated with a lower rate of CV-related hospitalizations and shorter length of hospital stay. Timely diagnosis and treatment with tafamidis could further decrease the total number of CV-related hospitalization days per year., Gov Identifier: NCT01994889., (© 2022. The Author(s).)

Amyloid transthyretin (ATTR) amyloidosis is a clinically heterogeneous and fatal disease that results from deposition of insoluble amyloid fibrils in various organs and tissues, causing progressive loss of function. The objective of this review is to increase awareness and diagnosis of ATTR amyloidosis by improving recognition of its overlapping conditions, misdiagnosis, and multiorgan presentation. Cardiac manifestations include heart failure, atrial fibrillation, intolerance to previously prescribed antihypertensives, sinus node dysfunction, and atrioventricular block, resulting in the need for permanent pacing. Neurologic manifestations include progressive sensorimotor neuropathy (e.g., pain, weakness) and autonomic dysfunction (e.g., erectile dysfunction, chronic diarrhea, orthostatic hypotension). Non-cardiac red flags often precede the diagnosis of ATTR amyloidosis and include musculoskeletal manifestations (e.g., carpal tunnel syndrome, lumbar spinal stenosis, spontaneous rupture of the distal tendon biceps, shoulder and knee surgery). Awareness and recognition of the constellation of symptoms, including cardiac, neurologic, and musculoskeletal manifestations, will help with early diagnosis of ATTR amyloidosis and faster access to therapies, thereby slowing the progression of this debilitating disease., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Background: Hereditary transthyretin-mediated amyloidosis, also known as ATTRv amyloidosis (v for variant), is a rare, autosomal dominant, fatal disease, in which systemic amyloid progressively impairs multiple organs, leading to disability and death. The recent approval of disease-modifying therapies offers the hope of stabilization or eventual reversal of disease progression, and yet highlights a lack of disease-management guidance. A multidisciplinary panel of expert clinicians from France and the US came to consensus on monitoring the disease and identifying progression through a clinical opinion questionnaire, a roundtable meeting, and multiple rounds of feedback., Monitoring Disease and Progression: A multidisciplinary team should monitor ATTRv amyloidosis disease course by assessing potential target organs at baseline and during follow-up for signs and symptoms of somatic and autonomic neuropathy, cardiac dysfunction and restrictive cardiomyopathy, and other manifestations. Variability in penetrance, symptoms, and course of ATTRv amyloidosis requires that all patients, regardless of variant status, undergo regular and standardized assessment in all these categories. Progression in ATTRv amyloidosis may be indicated by: worsening of several existing quantifiable symptoms or signs; the appearance of a new symptom; or the worsening of a single symptom that results in a meaningful functional impairment., Conclusions: We suggest that a multisystem approach to monitoring the signs and symptoms of ATTRv amyloidosis best captures the course of the disease. We hope this work will help form the basis of further, consensus-based guidance for the treatment of ATTRv amyloidosis., (© 2021. The Author(s).)

Aims: Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressive, fatal disorder that remains underdiagnosed. The Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) was the first large clinical trial to include both wild-type (ATTRwt) and hereditary (ATTRv) patients. A description of the natural history of ATTR-CM, utilizing data from placebo-treated patients in ATTR-ACT, will provide a greater understanding of presentation and progression of ATTR-CM and may aid in disease awareness, earlier diagnosis and treatment monitoring., Methods and Results: Changes in clinical endpoints (mortality, cardiovascular [CV]-related hospitalizations, 6-min walk test [6MWT] distance and Kansas City Cardiomyopathy Questionnaire Overall Summary [KCCQ-OS] score) from baseline to Month 30 in the 177 patients (134 ATTRwt, 43 ATTRv) who received placebo in ATTR-ACT were assessed. ATTRwt patients tended to have less severe disease at baseline. Over the duration of ATTR-ACT, there were 76 (42.9%) all-cause deaths, and 107 (60.5%) patients had a CV-related hospitalization. There was a lower proportion of all-cause deaths in ATTRwt (49, 36.6%) than ATTRv (27, 62.8%). There was a similar, steady decline in mean (SD) 6MWT distance from baseline to Month 30 in ATTRwt (93.9 [93.7] m) and ATTRv (89.1 [107.2] m) patients. The decline in mean (SD) KCCQ-OS score was less severe in ATTRwt (13.8 [20.7]) than ATTRv (21.0 [26.4]) patients., Conclusions: Patients with ATTR-CM experience a severe, progressive disease. In ATTR-ACT, placebo-treated patients with ATTRv, compared with ATTRwt, had more severe disease at baseline, and their disease progressed more rapidly as shown by mortality, hospitalizations and quality of life over time., (© 2021 Pfizer Inc. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aim: Delayed diagnosis of transthyretin amyloid cardiomyopathy (ATTR-CM) represents a missed opportunity for intervention. This study estimates the health benefits of timely diagnosis and treatment with tafamidis. Methods: A disease simulation model was developed to predict health outcomes under scenarios of timely and delayed diagnosis and treatment. Efficacy and quality of life (QoL) profiles were derived from the pivotal tafamidis trial and diagnostic delay durations from the literature. Results: Timely diagnosis and treatment were predicted to extend mean life expectancy by 5.46 and 7.76 years, relative to delayed diagnosis, for wild-type and hereditary ATTR-CM, respectively. Corresponding QALY gains were 4.50 and 6.22. Conclusion: Timely diagnosis and treatment with tafamidis are predicted to significantly improve survival and QoL for ATTR-CM patients.

Transthyretin amyloid cardiomyopathy (ATTR-CM) is a life-threatening condition with a heterogeneous clinical presentation. The recent availability of treatment for ATTR-CM has stimulated increased awareness of the disease and patient identification. Stratification of patients with ATTR-CM is critical for optimal management and treatment; however, monitoring disease progression is challenging and currently lacks best-practice guidance. In this report, experts with experience in treating amyloidosis and ATTR-CM developed consensus recommendations for monitoring the course of patients with ATTR-CM and proposed meaningful thresholds and frequency for specific parameters. A set of 11 measurable features across three separate domains were evaluated: (i) clinical and functional endpoints, (ii) biomarkers and laboratory markers, and (iii) imaging and electrocardiographic parameters. Experts recommended that one marker from each of the three domains provides the minimum requirements for assessing disease progression. Assessment of cardiac disease status should be part of a multiparametric evaluation in which progression, stability or improvement of other involved systems in transthyretin amyloidosis should also be considered. Additional data from placebo arms of clinical trials and future studies assessing ATTR-CM will help to elucidate, refine and define these and other measurements., (© 2021 European Society of Cardiology.)

Background: The global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causing the ongoing coronavirus disease 2019 (COVID-19) pandemic has raised serious concern for patients with chronic disease. A correlation has been identified between the severity of COVID-19 and a patient's preexisting comorbidities. Although COVID-19 primarily involves the respiratory system, dysfunction in multiple organ systems is common, particularly in the cardiovascular, gastrointestinal, immune, renal, and nervous systems. Patients with amyloid transthyretin (ATTR) amyloidosis represent a population particularly vulnerable to COVID-19 morbidity due to the multisystem nature of ATTR amyloidosis., Main Body: ATTR amyloidosis is a clinically heterogeneous progressive disease, resulting from the accumulation of amyloid fibrils in various organs and tissues. Amyloid deposition causes multisystem clinical manifestations, including cardiomyopathy and polyneuropathy, along with gastrointestinal symptoms and renal dysfunction. Given the potential for exacerbation of organ dysfunction, physicians note possible unique challenges in the management of patients with ATTR amyloidosis who develop multiorgan complications from COVID-19. While the interplay between COVID-19 and ATTR amyloidosis is still being evaluated, physicians should consider that the heightened susceptibility of patients with ATTR amyloidosis to multiorgan complications might increase their risk for poor outcomes with COVID-19., Conclusion: Patients with ATTR amyloidosis are suspected to have a higher risk of morbidity and mortality due to age and underlying ATTR amyloidosis-related organ dysfunction. While further research is needed to characterize this risk and management implications, ATTR amyloidosis patients might require specialized management if they develop COVID-19. The risks of delaying diagnosis or interrupting treatment for patients with ATTR amyloidosis should be balanced with the risk of exposure in the health care setting. Both physicians and patients must adapt to a new construct for care during and possibly after the pandemic to ensure optimal health for patients with ATTR amyloidosis, minimizing treatment interruptions.

Background: Transthyretin amyloidosis (also known as ATTR amyloidosis) is a systemic, life-threatening disease characterized by transthyretin (TTR) fibril deposition in organs and tissue. A definitive diagnosis of ATTR amyloidosis is often a challenge, in large part because of its heterogeneous presentation. Although ATTR amyloidosis was previously considered untreatable, disease-modifying therapies for the treatment of this disease have recently become available. This article aims to raise awareness of the initial symptoms of ATTR amyloidosis among general practitioners to facilitate identification of a patient with suspicious signs and symptoms., Methods: These consensus recommendations for the suspicion and diagnosis of ATTR amyloidosis were developed through a series of development and review cycles by an international working group comprising key amyloidosis specialists. This working group met to discuss the barriers to early and accurate diagnosis of ATTR amyloidosis and develop a consensus recommendation through a thorough search of the literature performed using PubMed Central., Results: The cardiac and peripheral nervous systems are most frequently involved in ATTR amyloidosis; however, many patients often also experience gastrointestinal and other systemic manifestations. Given the multisystemic nature of symptoms, ATTR amyloidosis is often misdiagnosed as a more common disorder, leading to significant delays in the initiation of treatment. Although histologic evaluation has been the gold standard to confirm ATTR amyloidosis, a range of tools are available that can facilitate early and accurate diagnosis. Of importance, genetic testing should be considered early in the evaluation of a patient with unexplained peripheral neuropathy., Conclusions: A diagnostic algorithm based on initial red flag symptoms and manifestations of cardiac or neurologic involvement will facilitate identification by the general practitioner of a patient with clinically suspicious symptoms, enabling subsequent referral of the patient to a multidisciplinary specialized medical center.

Cardiomyopathy is a manifestation of transthyretin amyloidosis (ATTR), which is an underrecognized systemic disease whereby the transthyretin protein misfolds to form fibrils that deposit in various tissues and organs. ATTR amyloidosis is debilitating and associated with poor life expectancy, especially in those with cardiac dysfunction, but a variety of treatment options have recently become available. Considered a rare disease, ATTR amyloidosis may be more prevalent than thought, particularly in older persons. Diagnosis is often delayed because of a lack of disease awareness and the heterogeneity of symptoms at presentation. Given the recent availability of effective treatments, early recognition and diagnosis are especially critical because treatment is likely more effective earlier in the disease course. The Amyloidosis Research Consortium recently convened a group of experts in ATTR amyloidosis who, through an iterative process, agreed on best practices for suspicion, diagnosis, and characterization of disease. This review describes these consensus recommendations for ATTR associated with cardiomyopathy as a resource to aid cardiologists and others in the recognition and diagnosis of ATTR associated with cardiomyopathy. Included in this review is an overview of red flag signs and symptoms and a recommended diagnostic approach, including testing for monoclonal protein, scintigraphy, or biopsy and, if ATTR associated with cardiomyopathy is identified, TTR genotyping.

Background: Transthyretin (TTR) amyloidosis is an underdiagnosed disease caused by destabilization of TTR due to pathogenic mutations or aging. Both pathogenic and protective mutations illuminate mechanisms of disease and potential interventions. AG10 is a selective, oral TTR stabilizer under development for transthyretin amyloidosis cardiomyopathy (ATTR-CM) that mimics a protective TTR mutation., Objectives: This randomized, double-blind, placebo-controlled study evaluated safety, tolerability, pharmacokinetics, and pharmacodynamics of AG10 in ATTR-CM patients with symptomatic, chronic heart failure., Methods: ATTR-CM, New York Heart Association functional class II to III subjects (n = 49, mutant or wild-type) were randomized 1:1:1 to AG10 400 mg, AG10 800 mg, or placebo twice daily for 28 days. Safety and tolerability were assessed by clinical and laboratory criteria. AG10 plasma levels were measured. TTR stability was assessed by changes in serum TTR, and 2 established ex vivo assays (fluorescent probe exclusion and Western blot)., Results: AG10 treatment was well-tolerated, achieved target plasma concentrations and demonstrated near-complete stabilization of TTR. TTR stabilization was more complete and less variable at the higher dose with stabilization by fluorescent probe exclusion of 92 ± 10% (mean ± SD) at trough and 96 ± 9% at peak (both p < 10 -12 vs. placebo). Average serum TTR increased by 36 ± 21% and 51 ± 38% at 400 and 800 mg, respectively (both p < 0.0001 vs. placebo). Baseline serum TTR in treated subjects was below normal in 80% of mutant and 33% of wild-type subjects. AG10 treatment restored serum TTR to the normal range in all subjects., Conclusions: AG10 has the potential to be a safe and effective treatment for patients with ATTR-CM. A phase 3 trial is ongoing. (Study of AG10 in Amyloid Cardiomyopathy; NCT03458130)., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)