Vutrisiran in Transthyretin Amyloidosis: A Pooled Safety Analysis of HELIOS-A and HELIOS-B.

Background: Vutrisiran is an RNA interference therapeutic that has demonstrated efficacy for the treatment of patients with transthyretin amyloidosis (ATTR) with polyneuropathy and cardiomyopathy in the phase 3 HELIOS-A and HELIOS-B studies, respectively. During the initial randomized treatment periods of these studies, vutrisiran was well tolerated and had an acceptable safety profile.

Objectives: This pooled safety analysis aimed to evaluate the safety of vutrisiran in a large population of patients with hereditary ATTR and wild-type ATTR who received treatment for up to 58 months in HELIOS-A and HELIOS-B.

Transthyretin amyloid cardiomyopathy: natural history and treatment response assessed by cardiovascular magnetic resonance.

Background And Aims: Cardiovascular magnetic resonance (CMR) and extracellular volume (ECV) mapping can measure amyloid burden in vivo. This study sought to assess the natural history of transthyretin amyloid cardiomyopathy (ATTR-CM) in terms of amyloid deposition burden (ECV) over time, changes in cardiac amyloid load following treatment with patisiran, and the association between change in ECV and mortality.

Methods: All 189 patients (untreated = 119, patisiran = 70) underwent assessment with CMR at baseline, 160 patients (untreated = 94, patisiran = 66) had a 1-year follow-up CMR and 75 patients (untreated = 42, patisiran = 33) had a 2-year follow-up CMR, of whom 36 patients (untreated = 17, patisiran = 29) had follow-up CMR at both timepoints.

Uncertain Clinical Relevance of Serial Bone Scintigraphy Findings in Treated Transthyretin Amyloid Cardiomyopathy.

Background: Technetium-99m-labeled 3,3-diphosphono-1,2-propanodicarboxylic acid (Tc-DPD) scintigraphy is a critical part of the validated nonbiopsy diagnostic algorithm for transthyretin amyloid cardiomyopathy (ATTR-CM). With the advent of novel disease-modifying therapies for ATTR-CM, there is intense interest in establishing the utility of DPD scans as an indicator of treatment response.

Objectives: The authors conducted a retrospective multimodality imaging study to determine the utility of Tc-DPD to track treatment response in ATTR-CM.

Skin Biopsy as a Diagnostic Tool for ATTRv Amyloid Neuropathy in the UK.

Objective: Gene silencing therapy for ATTRv has revolutionised treatment. In minimally symptomatic, early neuropathic disease, skin biopsy can aid in the diagnosis of ATTRv-PN, assessing both amyloid deposition and IENFD. Our aim was to study the value of performing skin biopsies in the diagnosis of ATTRv-PN in UK patients and to assess the influence of this on accessing gene silencing treatment.

Revised renal stratification and progression models for predicting long-term renal outcomes in immunoglobulin light chain amyloidosis.

Renal prognosis in light-chain amyloidosis (AL) is determined by categorizing patients into three renal stages at diagnosis and assessing Renal Response or Renal Progression following chemotherapy after 6 months. We evaluated, in a test (N=1935) cohort of patients with renal AL amyloidosis who were followed for a median of 95 months, a modified 4-stage model where Renal Stage 2 was sub-categorized according to preserved (2A) or reduced (2B) estimated Glomerular Filtration Rate (eGFR). A hybrid model for evaluation of Renal Progression was also introduced, using an eGFR cut-off of 30ml/min/1.

Long-term efficacy of tafamidis in patients with transthyretin amyloid cardiomyopathy by National Amyloidosis Centre stage.

Aims: Tafamidis is an approved treatment for patients with transthyretin amyloid cardiomyopathy (ATTR-CM) based on the 30-month Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT). This post-hoc analysis evaluated outcomes in ATTR-ACT and its long-term extension study (LTE) by baseline National Amyloidosis Centre (NAC) stage.

Methods And Results: Patients received either the approved dose of tafamidis 80 mg or placebo in ATTR-ACT and tafamidis in the LTE.

Design and Mechanistic Analysis of a Potent Bivalent Inhibitor of Transthyretin Amyloid Fibrillogenesis.

Transthyretin amyloidosis (ATTR) is a systemic disease that primarily affects the heart and the peripheral nervous system. Despite available therapeutic options, advanced ATTR amyloidosis still presents unmet medical needs. We have therefore focused on the design of bivalent small molecules starting from our prototype palindromic ligand mds84, whose binding by transthyretin (TTR) greatly improves stability of the native structure by overcoming the negative cooperativity which is typical of monovalent stabilizers.

Early Increase in Serum Transthyretin by Acoramidis Independently Predicts Improved Survival in TTR Amyloid Cardiomyopathy.

Background: Acoramidis is a novel, high-affinity stabilizer that achieves ≥90% transthyretin (TTR) stabilization. The phase 3 study, ATTRibute-CM (Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy), met its primary hierarchical efficacy endpoint with mortality, morbidity, and functional components at 30 months. Stabilization of TTR (prealbumin) by acoramidis results in an immediate and sustained rise in serum transthyretin (sTTR) levels, but the association between this pharmacodynamic effect and all-cause mortality (ACM) has not been elucidated.

Early cardiovascular autonomic failure in ATTRv predicts poor prognosis and may respond to disease-modifying therapy.

Background: Hereditary transthyretin amyloidosis (ATTRv) is a life-threatening, but treatable disease presenting with autonomic dysfunction. This study investigates the progression of autonomic failure, response to treatment, and the impact of autonomic failure in ATTRv.

Methods: Clinical features and autonomic function test (AFT) results were evaluated in 126 patients (40 had treatment) and 12 asymptomatic TTR variant carriers.

Clinical Phenotype and Prognostic Significance of Frailty in Transthyretin Cardiac Amyloidosis.

Background: The prevalence and clinical impact of frailty in transthyretin cardiac amyloidosis (ATTR-CA) remains poorly characterized.

Objectives: This study aimed to evaluate the prevalence, clinical determinants, and prognostic significance of frailty in a large cohort of patients with ATTR-CA.

Methods: Frailty was assessed in 880 patients with ATTR-CA (median age 80 years [Q1-Q3: 75-84 years], 719 [81.

Rationale and Design of ANTHOLOGY: An ATTR Amyloidosis Real-World Evidence Program Aiming to Address Gaps in Amyloidosis Care.

Introduction: Patients with amyloid transthyretin (ATTR) amyloidosis typically experience rapid disease progression, poor treatment outcomes, irreversible loss of health-related quality of life (HRQoL), and premature mortality. Early diagnosis is vital. However, diagnostic delays and misdiagnosis are common due to under-recognition of early signs and symptoms.

Impact of Heart Failure Severity on Vutrisiran Efficacy in Transthyretin Amyloidosis With Cardiomyopathy.

Background: Vutrisiran reduced the risk of all-cause mortality (ACM) and recurrent cardiovascular (CV) events in patients with transthyretin amyloidosis with cardiomyopathy (ATTR-CM) in HELIOS-B (A Study to Evaluate Vutrisiran in Patients With Transthyretin Amyloidosis With Cardiomyopathy; NCT04153149).

Objectives: This study sought to assess the effect of vutrisiran in HELIOS-B patients with different heart failure severities.

Methods: HELIOS-B randomized patients with ATTR-CM with NYHA functional class I-III (functional class IV or functional class III with National Amyloidosis Centre [NAC] stage 3 were excluded) 1:1 to vutrisiran 25 mg or placebo every 3 months for up to 36 months.

Impact of Vutrisiran on Functional Capacity and Quality of Life in Transthyretin Amyloidosis With Cardiomyopathy.

Background: Transthyretin amyloidosis with cardiomyopathy (ATTR-CM) progressively impairs functional capacity, health status, and quality of life (QOL). In HELIOS-B (A Study to Evaluate Vutrisiran in Patients With Transthyretin Amyloidosis With Cardiomyopathy), vutrisiran reduced all-cause mortality and recurrent cardiovascular events compared with placebo in patients with ATTR-CM.

Objectives: This study aims to further analyze the efficacy of vutrisiran on functional capacity, health status, and QOL.

Efficacy of Acoramidis on All-Cause Mortality and Cardiovascular Hospitalization in Transthyretin Amyloid Cardiomyopathy.

Background: Transthyretin amyloid cardiomyopathy (ATTR-CM) is an underdiagnosed chronic disease associated with progressive heart failure that results in impaired quality of life, repeated hospitalizations, and premature death. Acoramidis is a selective, oral transthyretin stabilizer recently approved by the U.S.

The evolving spectrum of kidney amyloidosis: advances in diagnosis, typing and treatment.

Kidney amyloidosis encompasses a spectrum of heterogeneous conditions in which damage is caused by the deposition of various misfolded proteins that aggregate into fibrils. The main form of renal amyloidosis in the Western countries is immunoglobulin light chain (AL) amyloidosis, which is usually secondary to a plasma cell clone or less frequently a B cell clone, while rarer causes include AA amyloidosis, ALECT2 and hereditary amyloidoses. The main renal manifestations include nephrotic syndrome and kidney dysfunction with modest or absent proteinuria.

Worsening of Heart Failure in Outpatients With Transthyretin Amyloidosis and Cardiomyopathy in the APOLLO-B Trial.

Background: Outpatient worsening heart failure (HF), defined by initiation or intensification of diuretics, is adversely prognostic for patients with either reduced or preserved ejection fraction.

Objectives: This study sought to investigate the prognostic value of outpatient worsening HF in transthyretin amyloidosis with cardiomyopathy and the effect of patisiran treatment.

Methods: Post hoc analyses of the APOLLO-B trial (NCT03997383) evaluated the associations between outpatient worsening HF (defined by oral diuretic initiation or intensification), measures of disease progression, and a composite endpoint of all-cause mortality and cardiovascular (CV) events.

Clinical Phenotype and Prognosis of Asymptomatic Patients With Transthyretin Cardiac Amyloid Infiltration.

Importance: Patients with transthyretin (ATTR) cardiac amyloid infiltration are increasingly diagnosed at earlier disease stages with no heart failure (HF) symptoms and a wide range of cardiac amyloid infiltration.

Objective: To characterize the clinical phenotype and natural history of asymptomatic patients with ATTR cardiac amyloid infiltration.

Design, Setting, And Participants: This cohort study analyzed data of all patients at 12 international centers for amyloidosis from January 1, 2008, through December 31, 2023.

Diagnosis and management of monoclonal gammopathy of renal significance: A British Society for Haematology good practice paper.

This guideline provides consensus opinion on the investigations required for people presenting with suspected monoclonal gammopathy of renal significance to both nephrology and haematology physicians. The guideline discusses the principles of treating a patient with MGRS and provides recommendations for both supportive management and haematological therapy. It details the recommended on-going monitoring required for both specialty areas.

Oxidative conversion of transthyretin in formalin-fixed clinical amyloid samples results in the formation of the His90Asp and His90Asn variants.

Background: Proteomics is routinely used to type clinical amyloid deposits, and offers additional benefit of identifying genetic variants, which can be diagnostically useful. Reviewing the proteomics data for ATTR patients attending our Centre revealed an unusually large number of samples containing a rare pathogenic H90D TTR variant alongside the more common H90N variant.

Methods: These findings raised questions to their source.

Outpatient Worsening Heart Failure in Patients With Transthyretin Amyloidosis With Cardiomyopathy in the HELIOS-B Trial.

Background: Transthyretin amyloidosis with cardiomyopathy (ATTR-CM) is a fatal disease, caused by misfolded transthyretin depositing as amyloid fibrils in the heart. Because disease progression is common, practical and sensitive methods are needed to monitor patients and optimize treatment decisions. Outpatient worsening heart failure (HF) (oral loop diuretic intensification or initiation) is simple to assess and has been shown to be prognostic of mortality in patients with ATTR-CM.

Long-Term Efficacy and Safety of Acoramidis in ATTR-CM: Initial Report From the Open-Label Extension of the ATTRibute-CM Trial.

Background: In the phase 3 randomized controlled study ATTRibute-CM (Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy), acoramidis, a transthyretin stabilizer, demonstrated significant efficacy on the primary end point. Participants with transthyretin amyloid cardiomyopathy who completed ATTRibute-CM were invited to enroll in an open-label extension study (OLE). We report the efficacy and safety data of acoramidis in participants who completed ATTRibute-CM and enrolled in the ongoing OLE.

CRISPR-Cas9 Gene Editing with Nexiguran Ziclumeran for ATTR Cardiomyopathy.

Background: Transthyretin amyloidosis with cardiomyopathy (ATTR-CM) is a progressive, often fatal disease. Nexiguran ziclumeran (nex-z) is an investigational therapy based on CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats and associated Cas9 endonuclease) targeting the gene encoding transthyretin ().

Methods: In this phase 1, open-label trial, we administered a single intravenous infusion of nex-z to patients with ATTR-CM.