24 Month Open Label Study of the Tolerability and Efficacy of Inotersen in TTR Amyloid Cardiomyopathy Patients

This is an open-label, single center study of 50 patients with cardiac amyloidosis due to wild-type or mutant TTR. Eligible patients will have evidence of cardiac amyloidosis due to transthyretin. The diagnosis will be made by biopsy of the heart or other affected organ with appropriate staining techniques confirming that the amyloid deposits are derived from transthyretin. Alternatively, recent imaging data have shown that a strongly positive nuclear scan using technetium pyrophosphate in the absence of evidence of a plasma cell dyscrasia and in the presence of a typical echocardiographic or cardiac magnetic resonance appearance of cardiac amyloidosis is indicative of TTR amyloidosis and that a biopsy is not needed. This will be acceptable for study entry. As inotersen has been associated with kidney toxicity in a small number of patients, all subjects in the study will be required to have a glomerular filtration rate greater than 45. Once study criteria have been met, and baseline imaging including echocardiography and (where feasible) cardiac magnetic resonance imaging have been performed, all patients will receive inotersen in a weekly 300 mg dosing. Subsequent visits will occur at 6 weeks, and 3, 6, 12, 18 and 24 months. Every 2 weeks, blood will be monitored for renal function and platelet count and urine will be tested by dipstick for proteinuria. Should kidney function be noted to be deteriorating or should proteinuria be found, a more intense renal workup will be performed in order to detect or rule out potential kidney toxicity. At each visit, in addition to standard laboratory work and pregnancy testing if applicable, (complete blood count, comprehensive metabolic panel, thyroid function tests, and urinalysis), Vitamin A level will be drawn (as TTR is a transport protein for Vitamin A) and TTR (prealbumin) level will be drawn to determine degree of suppression. Disease progression will be measured by serial cardiac biomarkers, 6-minute walk, cardiopulmonary stress testing, advanced "strain" echocardiography and cardiac MRI. Patients will be compared to data derived from a historical control group and from data in the literature to determine whether inotersen slows or stops disease progression.