Safety and efficacy of a TTR specific antisense oligonucleotide in patients with transthyretin amyloid cardiomyopathy.

Objectives: Cardiomyopathy is a major cause of death in both the hereditary form of transthyretin (TTR) amyloidosis and the sporadic late-age-onset transthyretin amyloidosis (ATTR wild-type (ATTR)). Clinically disease progression from time of diagnosis to death is usually quoted as 5- to 15-years. In prior studies, significant progression of cardiac parameters in patients with moderate to severe cardiomyopathy has been noted within a 12-month time span.

Methods: The present study was designed to prospectively monitor changes in cardiac parameters, both structural and functional, in patients with ATTR cardiomyopathy while treated with a TTR specific antisense oligonucleotide (ASO; IONIS-TTR) designed to lower blood levels of the amyloid fibril precursor protein. To date 22 patients have been admitted to the study, 15 have completed 12 months on the drug and are the subject of this report.

Results: Eight patients with hereditary ATTR amyloidosis and 7 patients with wild-type ATTR amyloidosis with moderate to severely advanced restrictive cardiomyopathy showed stabilization of disease as measured by left ventricular wall thickness, left ventricular mass (LVM), 6-min walk test (6MWT), and echocardiographic global systolic strain. IONIS-TTR was well tolerated by all 15 subjects and showed a good safety profile.

Conclusions: ASO treatment of patients with moderate to advanced ATTR cardiomyopathy shows indication of stabilization of disease progression and may therefore contribute to enhanced life expectancy.