Long-term Treatment with Inotersen for Amyloid Transthyretin Amyloidosis Cardiomyopathy

Abstract

Introduction Amyloid transthyretin (TTR) amyloidosis cardiomyopathy (ATTR-CM) is a progressive and fatal disease manifested by a build-up of TTR in the heart. ATTR-CM may be caused by mutations in TTR (hereditary ATTR [hATTR]) or deposition of normal TTR in older individuals (wild-type ATTR [wtATTR]). Natural history data show a progressive decline in cardiac functional and structural parameters specifically reduction in 6-minute walk test (6MWT) distance and increased left ventricular mass (LVM). Inotersen, an antisense oligonucleotide inhibitor of TTR production, has demonstrated safety and efficacy in the NEURO-TTR study involving patients with hATTR, including patients with extensive cardiac disease. We previously reported the efficacy and safety of inotersen in patients with hATTR-CM and wtATTR-CM after 1 year of treatment. Hypothesis Longer-term treatment with inotersen stabilizes and/or improves CM in patients with hATTR-CM and wtATTR-CM. Methods Patients with biopsy proven hATTR-CM or wtATTR-CM, interventricular septum [IVS] thickness ≥1.3 cm[A1] [A2] on echo, and evidence of congestive heart failure [CHF]) received 300 mg inotersen by subcutaneous injection weekly in a single center, open-label, investigator initiated study. Safety monitoring included complete blood count and assessment of renal function. Assessments included plasma TTR levels, 6MWT distance, and echo and cardiac MRI measurements of cardiac structure. Results As of January 2018, 15 of 25 patients enrolled in this study completed 2 years of inotersen treatment; 8 patients had hATTR-CM (mean age at entry, 63 years) and 7 patients had wtATTR-CM (mean age at entry, 74 years). Five patients completed 3 years of treatment (hATTR-CM, n=4; wtATTR-CM, n=1). Inotersen was well-tolerated. No drug-related serious adverse events (AEs) occurred and there were no severe thrombocytopenia or renal AEs. TTR suppression ranged from 42% to 93%; maximal mean TTR suppression was 77%. An additional 1-year of follow-up demonstrated continued improvement in 6MWT distances and reduction in LVM from previously reported results. Improvement from baseline in 6MWT distance was 41 meters at 2 years compared with 29 meters at 1 year. An 8.5% reduction in LVM was observed at 2 years compared with a 0.54% reduction observed at 1 year. Interventricular septal thickness decreased or remained stable in most patients and left ventricular ejection fraction increased or remained stable in most patients. Conclusions Long-term treatment with inotersen was well-tolerated and resulted in improvement or stabilization in cardiac function and structure in patients with hATTR-CM and wtATTR-CM. Sustained and substantially reduced serum TTR levels were demonstrated, depleting the substrate for amyloid production. Additionally, improvement in 6MWT distances and decreased LVM suggest possible improvement in cardiac function. [A1] [A2]