Effects of Patisiran, an RNA Interference Therapeutic, on Cardiac Parameters in Patients With Hereditary Transthyretin-Mediated Amyloidosis

Abstract

Background: Hereditary transthyretin-mediated (hATTR) amyloidosis is a rapidly progressive, multisystem disease that presents with cardiomyopathy or polyneuropathy. The APOLLO study assessed the efficacy and tolerability of patisiran in patients with hATTR amyloidosis. The effects of patisiran on cardiac structure and function in a prespecified subpopulation of patients with evidence of cardiac amyloid involvement at baseline were assessed.

Methods: APOLLO was an international, randomized, double-blind, placebo-controlled phase 3 trial in patients with hATTR amyloidosis. Patients were randomized 2:1 to receive 0.3 mg/kg patisiran or placebo via intravenous infusion once every 3 weeks for 18 months. The prespecified cardiac subpopulation comprised patients with a baseline left ventricular wall thickness ≥13 mm and no history of hypertension or aortic valve disease. Prespecified exploratory cardiac end points included mean left ventricular wall thickness, global longitudinal strain, and N-terminal prohormone of brain natriuretic peptide. Cardiac parameters in the overall APOLLO patient population were also evaluated. A composite end point of cardiac hospitalizations and all-cause mortality was assessed in a post hoc analysis.

Results: In the cardiac subpopulation (n=126; 56% of total population), patisiran reduced mean left ventricular wall thickness (least-squares mean difference ± SEM: -0.9±0.4 mm, P=0.017), interventricular septal wall thickness, posterior wall thickness, and relative wall thickness at month 18 compared with placebo. Patisiran also led to increased end-diastolic volume (8.3±3.9 mL, P=0.036), decreased global longitudinal strain (-1.4±0.6%, P=0.015), and increased cardiac output (0.38±0.19 L/min, P=0.044) compared with placebo at month 18. Patisiran lowered N-terminal prohormone of brain natriuretic peptide at 9 and 18 months (at 18 months, ratio of fold-change patisiran/placebo 0.45, P<0.001). A consistent effect on N-terminal prohormone of brain natriuretic peptide at 18 months was observed in the overall APOLLO patient population (n=225). Median follow-up duration was 18.7 months. The exposure-adjusted rates of cardiac hospitalizations and all-cause death were 18.7 and 10.1 per 100 patient-years in the placebo and patisiran groups, respectively (Andersen-Gill hazard ratio, 0.54; 95% CI, 0.28-1.01).

Conclusions: Patisiran decreased mean left ventricular wall thickness, global longitudinal strain, N-terminal prohormone of brain natriuretic peptide, and adverse cardiac outcomes compared with placebo at month 18, suggesting that patisiran may halt or reverse the progression of the cardiac manifestations of hATTR amyloidosis.

Clinical trial registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01960348.

Keywords: APOLLO; RNA interference; cardiac amyloidosis; cardiomyopathy; hATTR amyloidosis; patisiran.

Figure 1.. Change in echocardiographic parameters at 18 months.

A, Change in echocardiographic parameters in placebo and patisiran groups (cardiac subpopulation). B, Cumulative distribution plots of mean LV wall thickness, global longitudinal strain, end-diastolic volume, and cardiac output at 18 months in placebo and patisiran groups (cardiac subpopulation). LS indicates least-squares; and LV, left ventricular.

Figure 2.. Threshold analysis of LV wall thickness and global longitudinal strain.

A, Change in mean LV wall thickness at clinically relevant threshold at 18 months (cardiac subpopulation). B, Change in global longitudinal strain at clinically relevant threshold at 18 months (cardiac subpopulation). LV indicates left ventricular.

Figure 3.. Change in NT-proBNP.

A, NT-proBNP at 9 and 18 months in placebo and patisiran groups (cardiac subpopulation). B, Cumulative distribution plots of NT-proBNP at 9 and 18 months in placebo and patisiran groups (cardiac subpopulation). C, Change in NT-proBNP at clinically relevant threshold (cardiac subpopulation). NT-proBNP indicates N-terminal prohormone of brain-type natriuretic peptide.

Figure 4.. Analysis of composite end points of hospitalization and death events, with plots of mean cumulative function showing the average number of events per patient from baseline to month 18.

A, Composite rate of all-cause hospitalization and mortality. B, Composite rate of cardiac hospitalization and all-cause mortality. For all-cause hospitalization/mortality: negative binomial regression RR, 0.49 (95% CI, 0.30–0.79); Andersen–Gill HR, 0.48 (95% CI, 0.34–0.69). For cardiac hospitalization/mortality: negative binomial regression RR, 0.54 (95% CI, 0.25–1.16); Andersen–Gill HR, 0.54 (95% CI, 0.28–1.01). HR indicates hazard ratio; and RR, rate ratio.