Fontana, Marianna

Abstract Introduction Transthyretin amyloid cardiomyopathy (ATTR-CM) is a chronic condition associated with progressive heart failure, resulting from extracellular deposition of misfolded transthyretin (TTR) protein as amyloid fibrils in the myocardium. Currently, there are few disease-modifying treatments. NNC6019–0001 is a humanized monoclonal antibody designed to deplete amyloid via antibody-mediated phagocytosis by targeting a unique epitope that is exposed only on misfolded monomeric and aggregated forms of TTR. In a phase 1, open-label, 3-month dose escalation trial, NNC6019–0001 was well tolerated at all doses tested (up to and including 30 mg/kg).1 The maximum tolerated dose was not reached. Exploratory cardiac endpoints were stable or indicated a possible benefit. Purpose To evaluate the effect of NNC6019–0001 30 mg/kg and 100 mg/kg on cardiac functional endpoints and predictive biomarkers in patients with ATTR-CM, and to assess pharmacokinetics, safety and tolerability, to establish the optimal dose for a phase 3 trial. Methods This is a randomized, double-blind, placebo-controlled trial recruiting 99 patients with hereditary or wild-type ATTR-CM (Figure). Inclusion criteria are New York Heart Association (NYHA) class II or III heart failure, left ventricle wall thickening (LVWT) ≥12 mm, N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels ≥650 pg/mL in sinus rhythm and >1000 pg/mL in atrial fibrillation, and a 6-minute walk test (6MWT) distance of 150–450 m. Patients will be randomly assigned to receive intravenous NNC6019–0001 30 mg/kg or 100 mg/kg or placebo, each in addition to standard of care, every 4 weeks for 52 weeks, followed by a 12-week follow-up. In a sentinel dosing phase, three patients per arm will receive the study drug or placebo, in combination with 24-hour inpatient cardiac monitoring and 7 days of continuous cardiac (tele-) monitoring. The primary endpoints are change from baseline to week 52 in 6MWT and in NT-proBNP levels. Secondary endpoints include cardiac measures: extracellular volume on cardiac magnetic resonance imaging, global longitudinal strain, troponin T levels, hospitalization due to cardiovascular events, and urgent visits due to heart failure. Quality of life will be assessed using the Kansas City Cardiomyopathy Questionnaire (KCCQ). All-cause mortality, pharmacokinetics and treatment-emergent adverse events will also be assessed. Results The trial will start mid-2022 with global recruitment. Conclusion Disease-modifying treatments are needed for patients with ATTR-CM, where treatment is often limited to managing symptoms and best supportive care; the first disease-modifying therapies recently became available. This phase 2 trial will be used to determine the appropriate dose for the phase 3 trial of NNC6019–0001, a novel antibody therapy designed to deplete amyloid in patients with ATTR-CM. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): This trial was funded by Novo Nordisk A/S. Medical writing support was provided by Johanna Scheinost PhD, PharmaGenesis Oxford Central, Oxford, UK, with funding from Novo Nordisk A/S.

Abstract Cardiac amyloidosis is a serious and progressive infiltrative disease that is caused by the deposition of amyloid fibrils at the cardiac level. It can be due to rare genetic variants in the hereditary forms or as a consequence of acquired conditions. Thanks to advances in imaging techniques and the possibility of achieving a non-invasive diagnosis, we now know that cardiac amyloidosis is a more frequent disease than traditionally considered. In this position paper the Working Group on Myocardial and Pericardial Disease proposes an invasive and non-invasive definition of cardiac amyloidosis, addresses clinical scenarios and situations to suspect the condition and proposes a diagnostic algorithm to aid diagnosis. Furthermore, we also review how to monitor and treat cardiac amyloidosis, in an attempt to bridge the gap between the latest advances in the field and clinical practice.

Abstract Cardiac amyloidosis is a serious and progressive infiltrative disease that is caused by the deposition of amyloid fibrils at the cardiac level. It can be due to rare genetic variants in the hereditary forms or as a consequence of acquired conditions. Thanks to advances in imaging techniques and the possibility of achieving a non-invasive diagnosis, we now know that cardiac amyloidosis is a more frequent disease than traditionally considered. In this position paper the Working Group on Myocardial and Pericardial Disease proposes an invasive and non-invasive definition of cardiac amyloidosis, addresses clinical scenarios and situations to suspect the condition and proposes a diagnostic algorithm to aid diagnosis. Furthermore, we also review how to monitor and treat cardiac amyloidosis, in an attempt to bridge the gap between the latest advances in the field and clinical practice.

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.