Inotersen therapy of transthyretin amyloid cardiomyopathy

Abstract

Background: Cardiomyopathy is a major cause of death in patients with systemic transthyretin amyloidosis. Long term effect of therapy designed to inhibit hepatic production of the amyloid precursor has not been established in cardiomyopathy. The purpose of this study was to evaluate the long term safety and efficacy of transthyretin specific antisense oligonucleotide therapy, inotersen, in transthyretin cardiomyopathy. Methods: Patients with hereditary or wildtype transthyretin cardiomyopathy (NYHA I-III) with an LV wall thickness ! 1.3 cm and clinical evidence of congestive heart failure were eligible for this single centre, open label protocol. Safety and cardiac structural and functional parameters were prospectively studied. Results: As of October 2018, 33 subjects have entered the study. Twenty have completed 1 year, 16 have completed 2 years, and 14 have completed three years. At the 2 year time point, mean LV mass decreased by 8.4% as measured by MRI, and exercise tolerance increased by 20.2 metres as measured by 6 minute walk test. Further positive indicators were noted at 3 years, with LV mass decreasing by 11.4% and 6MWT increasing by 16.2 metres. Conclusion: Long term treatment of amyloid cardiomyopathy with inotersen is safe and effective in inhibiting progression and potentially reversing amyloid burden.

Transthyretin amyloidosis with cardiomyopathy after domino liver transplantation: Results of a cross-sectional study

“…However, given that a myocardial radiotracer uptake grade 1 or higher is 99% sensitive for detecting ATTR-CM, it does not seem justified to perform an invasive procedure such as an endomyocardial biopsy in our Val30Met DLT recipients since they all had grade 0 uptake. 16 In this regard, the measurement of extracellular volume by cardiac magnetic resonance may correlate with early ATTR deposition in patients with hereditary ATTR amyloidosis and symptoms of peripheral neuropathy but without criteria for ATTR-CM. 24…”

“…14 Recently, gene silencers, such as patisiran and inotersen, have shown improved outcomes in patients with ATTR-CM. 15,16 Given the lack of information regarding the development of ATTR-CM in recipients of DLT, the purpose of our study was to perform a systematic cardiac evaluation of DLT recipients at a specific time point during routine follow-up of these patients to establish the presence and characteristics of ATTR-CM in these patients.…”

Transthyretin amyloid cardiomyopathy: An uncharted territory awaiting discovery

“…These are able to directly interfere with TTR synthesis via the liver, resulting in a considerable drop in circulating levels of TTR protein (approaching 80%) [2] . These drugs are promising disease-modifying approaches that have been demonstrated to promote clinical amelioration of and beneficial changes in infiltrated cardiac muscle [ 27 , 28 ]. The choice amongst different therapeutic approaches does not rely only on the assessment of drug safety and efficacy in different patient populations, such as those with cardiac and/or neuropathic involvement, but also on approval by regulatory authorities and the possibility of reimbursement.…”

<p>Diagnosis and Screening of Patients with Hereditary Transthyretin Amyloidosis (hATTR): Current Strategies and Guidelines</p>

“…While not a primary end point of these trials, imaging and functional data suggest that these drugs may also stabilize or reverse hereditary ATTR cardiomyopathy. 12,13 Patisiran is administered intravenously every 3 weeks with pretreatment with steroids and Benadryl to offset drug reactions. 10 Second generation formulations of inotersen and patisiran are currently being studied prospectively in hereditary and wild-type ATTR cardiomyopathy.…”