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.

Real‐world versus trial patients with transthyretin amyloid cardiomyopathy

“…Therefore, the possibility, as highlighted by the present report, of diagnosing ATTR‐AC in patients mostly with few symptoms may represent a striking opportunity in order to offer tafamidis treatment to a greater number of subjects expected to benefit from it, altering significantly the course of their disease. Medications that silence TTR production have also shown some preliminary positive results, but their investigation so far has been limited to ATTRv‐AC patients of younger age and with milder disease as compared to the ATTR‐ACT and RW ones analysed here . Interestingly, the pre‐defined proportion of ATTRv/ATTRwt‐AC of ATTR‐ACT was replicated by chance in our RW population, in which ATTRv‐AC was mostly related to Ile68Leu, Val122Ile and Val30Met late‐onset mutations.…”

Emerging therapies in transthyretin amyloidosis – a new wave of hope after years of stagnancy?

“…Patients were previously classified as NYHA class I (40%) and NYHA class II (60%), whilst patients with higher classes were excluded. The exploratory endpoints comprised echocardiographic parameters, as well as cardiac biomarkers NT‐proBNP and troponin I. Patisiran induced an average reduction in left ventricular wall thickness of −0.9 mm ( P = 0.017) compared to baseline, along with reductions in interventricular septal thickness and left ventricular mass . In consideration of the mostly unchanged values for patients receiving placebo, these results indicate that patisiran may lead to the reversal of structural changes in the myocardium, typically evoked by amyloid deposition.…”

“…If pharmaceuticals are not discussed in this section, no valid clinical data are available at this point to the best of our knowledge. A summary of all trials taken into consideration can be found in Table (polyneuropathy) and Table (cardiomyopathy) …”

“…Patisiran was primarily studied in the APOLLO trial ( n = 225) described above . In a recent publication, Solomon and colleagues analysed the data for exploratory endpoints in a pre‐specified cardiac subpopulation ( n = 126), including ATTRv patients with left ventricular wall thickness ≥13 mm and no history of aortic valve disease or hypertension . Patients were previously classified as NYHA class I (40%) and NYHA class II (60%), whilst patients with higher classes were excluded.…”

Localized RNA interference therapy to eliminate residual lung cancer after incomplete microwave ablation

“…The APOLLO phase 3 trial proved that patisiran was beneficial to patients with hereditary transthyretin amyloidosis. The approval of patisiran may finally lead to the development of RNAi drugs . Nanoparticle‐mediated siRNA treatment is expected to be an alternative to chemotherapy for lung cancers.…”