NT-proBNP Levels in Patients with Hereditary Transthyretin-mediated Amyloidosis Treated in the Phase 3 APOLLO Study Based on Diuretic Use

Abstract

Hereditary transthyretin-mediated (hATTR) amyloidosis is a rare, multisystem, rapidly progressive, life-threatening disease caused by a mutation in the TTR gene, resulting in deposition of amyloid fibrils in multiple organs. Heterogeneous clinical presentation includes neuropathy and cardiomyopathy, resulting in significant morbidity and mortality. NT-proBNP, a marker of cardiac function, has been shown to be an independent predictor of survival in patients (pts) with hATTR amyloidosis. Patisiran, an investigational RNAi therapeutic, significantly reduced NT-proBNP compared with placebo (pbo) in pts with hATTR amyloidosis in the Phase 3 APOLLO study. Evaluate in a post-hoc analysis whether the patisiran treatment effect on NT-proBNP in APOLLO was impacted by concomitant diuretic use. APOLLO was a Phase 3, randomized (2:1), double-blind, pbo-controlled study of patisiran in patients with hATTR amyloidosis with polyneuropathy (NCT01960348). NT-proBNP was measured in a central laboratory at baseline, months 9 and 18 (or at early withdrawal). Of the 225 randomized pts, 94 (42%) were receiving concomitant diuretics at baseline or at any time during the study. A higher proportion pts in the pbo group (n=37, 48%) were receiving diuretics than in the patisiran group (n=57, 39%). Within the patisiran group, NT-proBNP was significantly lowered compared with pbo at month 18 in both pts receiving diuretics (43% relative reduction) and pts not receiving diuretics (58% relative reduction). In a pre-specified subpopulation of pts with echocardiographic evidence of cardiac involvement at study entry (n=126), patisiran significantly lowered NT-proBNP compared with pbo at month 18 and NT-proBNP lowering was similar in those receiving diuretics (56% relative reduction) and not receiving diuretics (55% relative reduction). Improvement in NT-proBNP occurred regardless of concomitant diuretic use. This finding, together with additional echocardiographic data showing impact of patisiran on cardiac structure and function, indicate that patisiran improved the underlying cardiomyopathy relative to placebo in patients with hATTR amyloidosis.