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

Analysis of the APOLLO Study
Originally publishedhttps://doi.org/10.1161/CIRCULATIONAHA.118.035831Circulation. 2019;139:431–443

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.

Clinical Perspective

What Is New?

  • The phase 3 APOLLO study assessed the effect of patisiran, a novel RNA interference therapeutic that inhibits transthyretin synthesis, in patients with hereditary transthyretin-mediated amyloidosis.

  • The current analysis presents results for exploratory end points in a prespecified subpopulation of patients from the APOLLO study with evidence of cardiac amyloid involvement.

  • In this subpopulation, patisiran resulted in decreased mean left ventricular wall thickness, global longitudinal strain, and N-terminal prohormone of brain natriuretic peptide compared with placebo at month 18.

  • In a post hoc analysis, patisiran treatment lowered combined all-cause hospitalization and mortality compared with placebo at month 18.

What Are the Clinical Implications?

  • Hereditary transthyretin-mediated amyloidosis, an inherited, rapidly progressive, life-threatening disease with limited treatment options has a clinical presentation that includes both cardiomyopathy and polyneuropathy.

  • Results from this prespecified subgroup analysis of the phase 3 study suggest that patisiran may provide benefit to patients with the cardiac manifestations of hereditary transthyretin-mediated amyloidosis.

Introduction

Editorial, see p 444

Hereditary transthyretin-mediated (hATTR) amyloidosis is an inherited, rapidly progressive, life-threatening disease1–3 caused by mutation of the transthyretin (TTR) gene. Pathogenic mutations cause TTR protein to misfold and accumulate as amyloid fibrils, typically consisting of both mutant and wild-type (WT) TTR protein. The amyloid fibrils deposit in multiple tissues including the heart, nerves, gastrointestinal tract, and kidneys,1,4–6 resulting in a multisystem disease with a heterogeneous clinical presentation that includes cardiomyopathy and polyneuropathy.1,7,8

Patients with hATTR amyloidosis and cardiomyopathy typically experience progressive symptoms of heart failure and cardiac arrhythmias, with death typically occurring 2.5 to 5 years after diagnosis.2,3,9,10 Cardiac infiltration of the extracellular matrix by TTR amyloid fibrils leads to a progressive increase of ventricular wall thickness and a marked increase in chamber stiffness, resulting in impaired diastolic function. Systolic function is also impaired, typically reflected by abnormal longitudinal strain despite a normal ejection fraction, which is preserved until late stages of the disease.4,9–11 In patients with ATTR amyloidosis and light-chain (AL) cardiac amyloidosis, both longitudinal strain and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) have been shown to be independent predictors of survival.12–14

Patisiran is an RNAi therapeutic composed of a small interfering RNA formulated as a lipid nanoparticle that enables delivery to hepatocytes, the main site of TTR production. After intracellular release, the small interfering RNA blocks production of mutant and WT TTR protein by inducing cleavage of TTR messenger RNA.15 Patisiran has demonstrated dose-dependent reduction of TTR protein in healthy volunteers and patients with hATTR amyloidosis.15,16 The recently completed phase 3 APOLLO study assessed the efficacy and safety of patisiran in patients with hATTR amyloidosis. As described separately,17 the APOLLO study met its primary end point demonstrating improvements in neuropathy as well as polyneuropathy and all secondary end points, including quality of life, ambulatory function, and autonomic symptoms, with patisiran compared with placebo. Furthermore, the APOLLO study demonstrated an acceptable safety profile for patisiran. Here we present the effect of patisiran on cardiac structure and function in a prespecified subpopulation of APOLLO patients with evidence of cardiac involvement at study entry, as well as cardiac safety in the overall APOLLO patient population.

Methods

Because of the sensitive nature of the data collected for this study, the dataset will not be made available to other researchers. However, requests from qualified researchers for additional analyses may be sent to Alnylam Pharmaceuticals ().

Study Oversight

APOLLO (NCT01960348) was a multicenter, international, randomized, double-blind, placebo-controlled, phase 3 study of patisiran in patients with hATTR amyloidosis. The study was approved by the central and local institutional review boards or ethics committees and was conducted according to the International Conference on Harmonization for Good Clinical Practice, the World Health Organization Declaration of Helsinki, and the 1996 Health Insurance Portability and Accountability Act. All participants provided written informed consent. The full methodology of APOLLO is described in detail elsewhere.18

Study Participants

Eligible patients were 18 to 85 years of age, had a diagnosis of hATTR amyloidosis with a documented TTR mutation and symptomatic neuropathy, were ambulatory (with or without walking aids), had adequate liver function (aspartate transaminase and alanine transaminase levels ≤2.5 times the upper limit of normal), and adequate renal function (creatinine levels ≤2 times the upper limit of normal). Patients with previous liver transplant, type I diabetes mellitus, New York Heart Association (NYHA) classification >2, acute coronary syndrome within the past 3 months, uncontrolled cardiac arrhythmia, or unstable angina were excluded from the study. The use of tafamidis, diflunisal, doxycycline, tauroursodeoxycholic acid, or any investigational agent other than patisiran was prohibited during treatment with the study drug, and a wash-out period was mandated if these agents were used before screening. A cardiac subpopulation was prespecified in the statistical analysis plan and comprised patients with evidence of cardiac amyloid involvement, defined as a baseline left ventricular (LV) wall thickness ≥13 mm and no history of aortic valve disease or hypertension.

Study Design and Treatment

Patients were enrolled between December 2013 and January 2016 at 44 sites in 19 countries. Patients were randomly assigned 2:1 (as previously described18) to receive 0.3 mg/kg patisiran or placebo via intravenous infusion once every 3 weeks for 18 months. To mitigate against infusion-related reactions, patients received premedication (dexamethasone 10 mg, paracetamol/acetaminophen 500 mg, and H1 [diphenhydramine 50 mg] and H2 [ranitidine 50 mg] blockers, or equivalent) before infusion. Because TTR is a transporter of retinol-binding protein,19 patients received oral supplements of vitamin A at the recommended daily allowance to prevent deficiency. Both patisiran and placebo groups received premedication and vitamin A supplements.

Cardiac Measures and Safety Assessments

Assessment of cardiac structure and function via 2-dimensional echocardiography, as well as biomarkers of cardiac stress and injury including NT-proBNP and troponin I, were exploratory end points in the APOLLO study. Measurements of cardiac parameters were conducted at baseline, month 9, and month 18. Echocardiography was used to assess cardiac structure and function; parameters prespecified in the statistical analysis plan included mean LV wall thickness, LV mass, longitudinal strain, and ejection fraction. Cardiac output, left atrial size, LV end-diastolic volume (LVEDV), and LV end-systolic volume were also analyzed. Echocardiograms were obtained at the study sites according to a prespecified protocol and underwent blinded assessment in a cardiac imaging core laboratory. Myocardial strain was assessed with speckle tracking using vendor-independent software (TOMTEC). Reproducibility of echocardiographic measures and myocardial strain has been previously reported.20,21 Analysis of NT-proBNP and troponin I was also prespecified in the statistical analysis plan, and biomarkers were analyzed at a central laboratory using chemiluminescence assays (Roche Diagnostic Cobas for NT-proBNP, Siemens Centaur XP for troponin I). Creatinine levels were measured at baseline in a central laboratory, and the estimated glomerular filtration rate was calculated from creatinine levels using the Modification of Diet in Renal Disease study formula.22 Adverse events (AEs) were coded according to the Medical Dictionary for Regulatory Activities. Cardiac AEs were AEs that mapped within the cardiac disorders system organ class. Cardiac arrhythmia AEs were AEs that mapped within the cardiac arrhythmias Medical Dictionary for Regulatory Activities high-level group term. Cardiac failure AEs were AEs that mapped within the cardiac failure standardized Medical Dictionary for Regulatory Activities query: narrow search. A blinded, independent clinical end point adjudication committee determined whether deaths were of a cardiovascular (CV) or non-CV origin according to a prespecified charter; hospitalizations were not adjudicated.

Statistical Analysis

The primary population for efficacy and safety analyses was the modified intention-to-treat (mITT) population (all randomized patients who received ≥1 dose of the study drug). The cardiac parameters were analyzed in the prespecified cardiac subpopulation using the mixed-effects model repeated measures method. The model included change from baseline as the outcome variable, baseline value as a covariate, and fixed-effect terms including treatment arm, visit (month 9 or 18), and treatment-by-visit interaction. The primary comparison was the difference in the least-squares means between the patisiran and placebo groups at 18 months. The normally distributed assumption for the response variable in the mixed-effects model repeated measures model was examined using normal Q-Q plots. For echocardiographic parameters, there was no indication of a violation of the distributional assumption. For NT-proBNP, normality assumption was apparently violated; therefore, a logarithmic transformation was applied to normalize the data before fitting the mixed-effects model repeated measures model. The adjusted geometric mean fold change and the ratio of the fold change (patisiran/placebo) from baseline were calculated along with the corresponding 95% CIs. The proportions of patients achieving the following clinically meaningful threshold values were also estimated for evaluable patients who had both baseline and month 18 assessments: mean LV wall thickness change (increase or decrease) of >2 mm,12 longitudinal strain absolute change (increase or decrease) of >2%,12 and NT-proBNP values >3000 ng/L or change from baseline (increase or decrease) ≥30% and ≥300 ng/L in patients with baseline NT-proBNP ≥650 ng/L.23,24

Post hoc analyses of recurrent hospitalization and death events were conducted to assess the composite end points of 1) any hospitalization and/or all-cause death and 2) cardiac hospitalization and/or all-cause death. Any hospitalization or death event associated with a serious adverse event (SAE) that occurred within 28 days of last dose of study drug was included in the analysis. Cardiac hospitalizations were SAEs that coded to the cardiac disorders system organ class that led to hospitalization or prolongation of existing hospitalization. For both composite end points, the exposure-adjusted event rates were estimated by treatment arm. A nonparametric mean cumulative function method was used to estimate the average number of events expected per patient at a certain time point. In addition, negative binomial regression and Andersen–Gill models were applied to analyze the recurrent-events data. Overall, type I error was not controlled for the exploratory end points. Differences in baseline characteristics were tested using t tests for log-transformed continuous variables, including years since hATTR amyloidosis diagnosis, estimated glomerular filtration rate, NT-proBNP, Wilcoxon rank-sum test for age that deviated from normal distribution, and Fisher’s exact tests for all categorical variables. Further details of the statistical analyses used in APOLLO are described elsewhere.18

Results

Patient Population

Among the 225 total patients enrolled in APOLLO, 126 (56%) fulfilled criteria to be included in the prespecified cardiac subpopulation. Among the cardiac subpopulation, 36 of 126 patients (28.6%) received placebo and 90 of 126 patients (71.4%) received patisiran. Ninety-nine patients did not meet the prespecified criteria for the cardiac subpopulation and are referred to as “all other patients.” Among these other patients, 55.6% also had a mean LV wall thickness ≥13 mm but were excluded from the cardiac subpopulation primarily because of a history of hypertension. Baseline demographic and disease characteristics and baseline echocardiographic parameters, for both the cardiac subpopulation and all other patients, are shown in Tables 1 and 2, respectively.

Among the cardiac subpopulation, the median age of patients was 61 years (interquartile range [IQR], 54–67), and 78% were male (Table 1). The median time from diagnosis was 1.4 years (IQR, 0.0–21.0), and 73% of patients were non-Val30Met genotype. A higher proportion of patients receiving placebo were Asian (50.0% versus 25.6% in the patisiran arm); otherwise there were no differences in demographic characteristics between treatment groups.

Table 1. Baseline Demographics and Disease Characteristics

CharacteristicCardiac SubpopulationAll Other Patients (n=99)*
Placebo (n=36)Patisiran (n=90)Overall (n=126)
Age, y
 Median, IQR62 (57.0–72.0)60 (54.0–66.0)61 (54.0–67.0)65 (51.0–71.0)
 ≥75 y, n (%)5 (13.9)5 (5.6)10 (7.9)8 (8.1)
Male sex, n (%)30 (83.3)68 (75.6)98 (77.8)69 (69.7)
Race, n (%)
 Asian18 (50.0)23 (25.6)41 (32.5)11 (11.1)
 Black1 (2.8)2 (2.2)3 (2.4)2 (2.0)
 White16 (44.4)63 (70.0)79 (62.7)84 (84.9)
Region, n (%)
 North America7 (19.4)21 (23.3)28 (22.2)19 (19.2)
 Western Europe12 (33.3)31 (34.4)43 (34.1)55 (55.6)
 Rest of the world17 (47.2)38 (42.2)55 (43.7)25 (25.3)
  Asia15 (41.7)20 (22.2)35 (27.8)9 (9.1)
  Central and South America2 (5.6)11 (12.2)13 (10.3)6 (6.1)
  Eastern Europe07 (7.8)7 (5.6)10 (10.1)
Median, IQR, time since hATTR diagnosis, y1.2 (0.1–8.8)1.7 (0.0–21.0)1.4 (0.0–21.0)1.4 (0.0–17.2)
TTR genotype, n (%)
 non-Val30Met§24 (66.7)68 (75.6)92 (73.0)37 (37.4)
 Val30Met12 (33.3)22 (24.4)34 (27.0)62 (62.6)
FAP stage, n (%)
 113 (36.1)42 (46.7)55 (43.7)49 (49.5)
 223 (63.9)48 (53.3)71 (56.3)49 (49.5)
 30001 (1.0)
NIS score, n (%)
 <5012 (33.3)40 (44.4)52 (41.3)45 (45.5)
 ≥5024 (66.7)50 (55.6)74 (58.7)54 (54.5)
Previous TTR stabilizer use, n (%)17 (47.2)46 (51.1)63 (50.0)56 (56.6)
eGFR, mL/min per 1.73 m2
 Median, IQR97.8 (85.1–135.3)114.4 (83.6–138.0)109.3 (83.6–137.6)97.2 (75.6–123.3)
  <60, n (%)1 (2.8)10 (11.1)11 (8.7)10 (10.1)
Cardiac implanted devices, n (%)9 (25.0)13 (14.4)22 (17.5)18 (18.2)
 Pacemaker9 (25.5)11 (12.2)20 (15.9)18 (18.2)
 Defibrillator02 (2.2)2 (1.6)0
Medical history, n (%)
 Hypertension00062 (62.6)
 Supraventricular arrhythmias6 (16.7)17 (18.9)23 (18.3)15 (15.2)
  Atrial fibrillation3 (8.3)11 (12.2)14 (11.1)7 (7.1)
 Diabetes mellitus03 (3.3)3 (2.4)3 (3.0)
 Aortic valve disease0003 (3.0)
Baseline treatment, n (%)
 β-blockers2 (5.6)3 (3.3)5 (4.0)27 (27.3)
 ACE inhibitors01 (1.1)1 (0.8)18 (18.2)
 ARBs01 (1.1)1 (0.8)13 (13.1)
 Furosemide7 (19.4)12 (13.3)19 (15.1)9 (9.1)
 Spironolactone2 (5.6)6 (6.7)8 (6.3)3 (3.0)
 Hydrochlorothiazide1 (2.8)1 (1.1)2 (1.6)8 (8.1)
 Torasemide03 (3.3)3 (2.4)3 (3.0)
NYHA class, n (%)
 I16 (44.4)34 (37.8)50 (39.7)60 (61.9)
 II20 (55.6)56 (62.2)76 (60.3)37 (38.1)
NT-proBNP, pg/mL
 Median, IQR845.7 (373.2–1581.7)756.4 (285.4–2432.4)837.2 (292.4–2354.1)314.3 (157.6–776.4)
 Geometric mean (CV %)711.1 (190.8)726.9 (220.3)722.5 (210.1)360.7 (230.2)

ACE indicates angiotensin converting enzyme; ARB, angiotensin receptor blocker; CV, coefficient of variation; eGFR, estimated glomerular filtration rate; FAP, familial amyloid neuropathy; hATTR, hereditary transthyretin-mediated amyloidosis; IQR, interquartile range; NIS, neuropathy impairment score; NT-proBNP, N-terminal prohormone of brain natriuretic peptide; NYHA, New York Heart Association; and TTR, transthyretin.

*Includes patients with <13 mm mean left ventricular wall thickness or ≥13 mm mean left ventricular wall thickness and history of hypertension or aortic valve disease.

†Statistically significant difference between patisiran and placebo in cardiac subpopulation (P>0.05).

‡North America: United States, Canada; Europe: Germany, Spain, France, United Kingdom, Italy, The Netherlands, Portugal, Sweden; Rest of the world: Asia: Japan, Korea, Taiwan; Central and South America: Mexico, Argentina, Brazil; Eastern Europe: Bulgaria, Cyprus, Turkey.

§Represents 31 different TTR mutations; listed in Table I in the online-only Data Supplement.

¶Statistically significant difference between cardiac subpopulation and all other patients (P<0.001).

At baseline, the majority (60%) of patients in the cardiac subpopulation were classified as NYHA class II, with the remainder (40%) classified as NYHA class I. Echocardiographic features in the cardiac subpopulation were notable for increased LV wall thickness (median [IQR], 16.4 [14.8–18.3] mm), reduction in global longitudinal strain (median [IQR], –15.1% [–17.5 to –12.6]), and preserved LV ejection fraction (mean±SD 61±10.0%) (Table 2). The median NT-proBNP level was 837 pg/mL (IQR, 292–2354). Within the cardiac subpopulation, treatment groups were generally balanced with respect to cardiac measures.

Table 2. Baseline Echocardiographic Parameters

Parameters*Cardiac SubpopulationAll Other Patients (n=99)
Placebo (n=36)Patisiran (n=90)Overall (n=126)
Left ventricular ejection fraction
 Mean (SD), %62.2 (8.6)60.0 (9.9)60.6 (9.6)63.9 (10.1)
 ≤40%, n (%)0 (0.0)4 (4.5)4 (3.2)4 (4.3)
 >40%, n (%)36 (100.0)84 (95.5)120 (96.8)88 (95.7)
Left ventricular mass, g243.7 (206.2–341.0)270.9 (216.0–322.8)264.9 (213.6–322.8)209.7 (153.3–286.4)
Left ventricular wall thickness, mm16.2 (14.9–17.9)16.4 (14.8–18.6)16.4 (14.8–18.3)14.6 (11.6–16.7)
Intraventricular septum thickness, mm16.4 (15.0–18.3)16.7 (15.5–18.9)16.5 (15.4–18.7)14.7 (11.8–16.7)
Posterior wall thickness, mm16.1 (14.3–17.8)16.3 (14.3–18.0)16.3 (14.3–18.0)14.3 (11.2–16.8)
Left ventricular relative wall thickness, mm0.8 (0.7–0.9)0.8 (0.7–1.0)0.8 (0.7–0.9)0.7 (0.6–0.8)
Global longitudinal strain, %–15.5 (–18.0 to –12.8)–15.1 (–17.2 to –12.6)–15.1 (–17.5 to –12.6)–17.3 (–19.5 to –15.6)
Cardiac output, L/min3.5 (3.2–4.3)3.5 (3.0–4.2)3.5 (3.1–4.2)4.1 (3.6–5.0)
Left ventricular end-diastolic volume, mL81.2 (68.7–102.2)81.4 (69.0–100.7)81.2 (69.0–101.3)89.9 (74.6–104.0)
Left ventricular end-systolic volume, mL29.6 (14.6–72.7)30.1 (14.0–116.7)30.1 (23.5–43.1)30.2 (25.1–38.8)

Values indicate median (interquartile range) unless otherwise indicated.

*Based on t test, all parameters are statistically significantly different when comparing cardiac subpopulation versus all other patients. No significant difference was found between the patisiran and placebo groups in the cardiac subpopulation (P<0.05).

†Includes patients with <13 mm mean left ventricular wall thickness or ≥13 mm mean left ventricular wall thickness and history of hypertension or aortic valve disease.

Compared with all other patients, a higher proportion of patients in the cardiac subpopulation were NYHA class II (60.3% versus 38.1%) and were non-Val30Met genotype (73.0% versus 37.4%). Genotypes more commonly found in the cardiac subpopulation, compared with all other patients, included Ala97Ser, Thr60Ala, and Ser50Arg (Table I in the online-only Data Supplement). Compared with all other patients, in the cardiac subpopulation there were signs of greater cardiac dysfunction at baseline, including greater abnormalities in cardiac structure and function and higher NT-proBNP levels (Tables 1 and 2).

Effects of Patisiran on Cardiac Parameters in the Cardiac Subpopulation

In the cardiac subpopulation, a reduction in mean LV wall thickness (least-squares mean difference±SEM, –0.9±0.4 mm; P=0.017) was observed with patisiran compared with placebo, and corresponding reductions were also seen in interventricular septal wall thickness, posterior wall thickness, and relative wall thickness. In patisiran-treated patients compared with placebo, global longitudinal strain was decreased (–1.4%±0.6%, P=0.015), cardiac output was increased (0.38±0.19 L/min, P=0.044), and LVEDV was increased (8.31±3.91 mL, P=0.036) (Figure 1A). The treatment effect of patisiran on these echocardiographic parameters was observed across all change thresholds at 18 months (Figure 1B). For LV mass, a reduction compared with baseline was observed in the patisiran arm (mean change, –15.1 g; 95% CI, –25.8 to –4.4), and a trend toward reduction relative to placebo was also observed. LV end-systolic volume decreased less in patients receiving patisiran than those receiving placebo, although the difference was not statistically significant (2.66±2.11 mL, P=0.211). There were no differences in LV ejection fraction or left atrial volume between the treatment groups (Table II in the online-only Data Supplement). A greater proportion of patients in the patisiran group had a reduction from baseline in mean LV wall thickness >2 mm compared with placebo (29.1% versus 4.0%) and an absolute decrease (indicating improvement in function) from baseline in global longitudinal strain of >2% compared with placebo (21.3% versus 8.0%), whereas a smaller proportion of patients in the patisiran group had an absolute increase (indicating worsening in function) from baseline in global longitudinal strain of >2% at 18 months (25.3% versus 44.0% in the placebo arm) (Figure 2).

Figure 1.

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.

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.

Patisiran reduced NT-proBNP compared with placebo at 9 months (ratio of fold change patisiran/placebo, 0.63; 95% CI, 0.50–0.80) and 18 months (ratio of fold change patisiran/placebo, 0.45; 95% CI, 0.34–0.59; P=7.7×10–8), corresponding to a 55% reduction relative to placebo (Figure 3A). The effect of patisiran (decrease in NT-proBNP compared with placebo) was observed across all change thresholds at both 9 and 18 months (Figure 3B). In the patisiran group, 31.6% of evaluable patients had a decrease (change from baseline) of NT-proBNP ≥30% and ≥300 pg/mL at month 18, whereas no placebo patients had a decrease in NT-proBNP of this magnitude. Conversely, at month 18, a lower proportion of evaluable patients in the patisiran group compared with placebo had an increase (change from baseline) in NT-proBNP ≥30% and ≥300 pg/mL (21.1% versus 58.3%) (Figure 3C). The majority of troponin I values (90.2%) were reported as <0.1 μg/L, which is also the limit of detection for the troponin I assay used in the study. Accordingly, the troponin I data prohibited an accurate assessment of patisiran treatment effect on troponin I. Patisiran treatment also impacted 10-meter walk test (10-MWT) gait speed in the cardiac subpopulation, with an increase compared with placebo of 0.161 m/s (95% CI, 0.076–0.246) at 9 months and 0.354 m/s (95% CI, 0.242–0.466) at 18 months.

Figure 3.

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.

Effects of Patisiran on Cardiac Parameters in All Other Patients and the mITT Population

In the 44% of patients who did not fulfill the prespecified cardiac criteria (all other patients), no significant impact on echocardiographic parameters was observed with patisiran compared with placebo (data not shown). However, NT-proBNP was reduced relative to placebo in all other patients (51% reduction with patisiran treatment relative to placebo), which was similar to the effect seen in the cardiac subpopulation (Table III in the online-only Data Supplement). Furthermore, in all other patients, 10-MWT gait speed increased by 0.283 m/s (95% CI, 0.156–0.409) in the patisiran group compared with the placebo group at 18 months.

Analyses were also performed in the mITT population (all patients enrolled in APOLLO irrespective of cardiac status). Results for assessments of echocardiographic parameters were directionally similar to those observed in the cardiac subpopulation (Table IV in the online-only Data Supplement). NT-proBNP was reduced relative to placebo in the mITT population and in all prespecified subgroups (Figure I in the online-only Data Supplement). The effect on NT-proBNP was also seen regardless of baseline NT-proBNP level. In all NT-proBNP baseline categories, NT-proBNP levels decreased or were stable in the patisiran group and nearly doubled in the placebo group (Figure II in the online-only Data Supplement). In the mITT population, regardless of treatment group, survival was worse in patients with baseline NT-proBNP levels >3000 ng/L compared with patients with levels ≤3000 ng/L (hazard ratio, 19.3; 95% CI, 5.9–62.8) (Figure III in the online-only Data Supplement).

Cardiac Safety

The overall safety profile of patisiran has been described previously.17 In addition, a detailed evaluation of cardiac events was performed in the mITT population (Table 3). The proportions of patients with cardiac AEs, cardiac SAEs, and cardiac failure AEs were similar in the patisiran and placebo groups. The rate of cardiac arrhythmia AEs was lower in the patisiran group compared with placebo (18.9% versus 28.6%).

Table 3. Summary of Cardiac Events

VariablePlacebo* (n=77)Patisiran* (n=148)
Total duration of exposure, y96.1218.9
Cardiac adverse events, n (%)28 (36.4)42 (28.4)
Cardiac serious adverse events, n (%)10 (13.0)20 (13.5)
Cardiac arrhythmia high-level group term adverse events, n (%)22 (28.6)28 (18.9)
Supraventricular arrhythmias high-level term13 (16.9)15 (10.1)
Cardiac conduction disorders high-level term7 (9.1)10 (6.8)
Ventricular arrhythmias and cardiac arrest high-level term6 (7.8)4 (2.7)
Rate and rhythm disorders high-level term05 (3.4)
Torsades des pointes standard MedDRA query adverse events, n (%)14 (18.2)8 (5.4)
Cardiac failure standard MedDRA query adverse events, n (%)8 (10.4)14 (9.5)
Deaths, n (%)6 (7.8)7 (4.7)
Rate of death per 100 patient-years (95% CI)6.2 (2.5–12.7)3.2 (1.4–6.2)
Patients with all-cause hospitalization, n (%)30 (39.0)50 (33.8)
All-cause hospitalization per 100 patient-years (95% CI)69.7 (54.3–87.7)32.9 (25.9–41.1)
Patients with any hospitalization and/or death,§ n (%)31 (40.3)51 (34.5)
Hospitalization and/or death per 100 patient-years (95% CI)71.8 (56.1–90.1)34.7 (27.5–43.1)
Patients with cardiac hospitalizations, n (%)10 (13.0)18 (12.2)
Cardiac hospitalizations per 100 patient-years (95% CI)15.6 (9.0–24.9)8.2 (5.0–12.6)
Patients with cardiac hospitalization and/or death, n (%)12 (15.6)20 (13.5)
Cardiac hospitalization and/or death per 100 patient-years (95% CI)18.7 (11.4–28.8)10.1 (6.4–14.9)

MedDRA indicates Medical Dictionary for Regulatory Activities.

*Summary of cardiac events in the modified intention-to-treat population.

†Cardiac arrhythmia adverse events were those that mapped within the cardiac arrhythmias MedDRA high-level group term that included high-level terms of conduction disorders, rate and rhythm disorders, supraventricular and ventricular arrhythmias, and cardiac arrests.

‡The torsades de pointes standard MedDRA query is a search for events that may be associated with torsades de pointes. It does not mean that these are confirmed events of torsades de pointes. No events of torsades de pointes have been reported.

The analysis of hospitalization and death events was conducted post hoc based on reported adverse events. Any hospitalization or death event associated with a serious adverse event that occurred within 28 days of last dose of the study drug was included in the analysis. Serious adverse events within the MedDRA cardiac disorders system organ class that led to hospitalization or prolongation of hospitalization were classified as cardiac hospitalization. Cardiac hospitalizations were not adjudicated by an independent end point committee.

§For any hospitalization/death analysis: negative binomial regression rate ratio, 0.49 (95% CI, 0.30–0.79); Andersen–Gill hazard ratio, 0.48 (95% CI, 0.34–0.69).

¶For cardiac hospitalization/death analysis: negative binomial regression rate ratio, 0.54 (95% CI, 0.25–1.16); Andersen–Gill hazard ratio, 0.54 (95% CI, 0.28–1.01).

Median survival follow-up duration on the study was 18.7 months. In the mITT population, there were 7 (4.7%) deaths in the patisiran group (all adjudicated as CV in nature) and 6 (7.8%) deaths in the placebo group (3 adjudicated as CV in nature, 2 non-CV, and 1 unknown origin). All deaths were considered unlikely or not related to the study drug by the investigators (Table V in the online-only Data Supplement). The exposure-adjusted death rate per 100 patient-years was 6.2 (95% CI, 2.5–12.7) in the placebo group and 3.2 (95% CI, 1.4–6.2) in the patisiran group. In a post hoc analysis of the safety data, the rates of any hospitalization and/or all-cause death were 71.8 and 34.7 per 100 patient-years in the placebo and patisiran groups, respectively, whereas the rates of cardiac hospitalizations and/or all-cause death were 18.7 and 10.1 per 100 patient-years in the placebo and patisiran groups, respectively (Table 3). This approximates a reduction in event rate of ≈50% for all-cause hospitalization and mortality and ≈45% for cardiac hospitalization and all-cause mortality (Figure 4).

Figure 4.

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.

In the cardiac subpopulation, the proportion of patients with cardiac AEs (32.2% versus 36.1%) and cardiac SAEs (14.4% versus 11.1%) was comparable across the patisiran and placebo groups, respectively. The proportion of patients with cardiac arrhythmia AEs was higher in the placebo group (30.6%) than the patisiran group (18.9%). The proportion of patients with cardiac failure AEs was higher in the patisiran group (11.1%) compared with the placebo group (5.6%). This difference may be because of baseline imbalances in the cardiac subpopulation with respect to cardiac history and NYHA status. There were 5 (5.6%) deaths in the patisiran group (all CV in nature) and 4 (11.1%) deaths in the placebo group (1 CV, 2 non-CV, and 1 unknown origin).

Discussion

In this prespecified analysis of patients with evidence of cardiac involvement because of hATTR amyloidosis, treatment with patisiran for ≤18 months resulted in improvement relative to placebo in important measures of cardiac structure and function. These included a reduction in ventricular wall thickness and a decrease (improvement) in global longitudinal strain. In addition, patisiran treatment led to a reduction in NT-proBNP as early as 9 months after initiating treatment. These findings collectively suggest that patisiran may provide benefit to patients with cardiac manifestations of hATTR amyloidosis.

The prespecified cardiac subpopulation was intended to allow for more sensitive and specific detection of patisiran treatment effects on cardiac parameters, which might be difficult to discern in the overall population. In this subpopulation, treatment with patisiran compared with placebo improved important measures of cardiac structure and function. LV wall thickening caused by myocardial infiltration of TTR amyloid is associated with impaired myocardial function, with increases of 1 mm (the approximate difference observed between patisiran and placebo groups) being associated with worsening of global longitudinal strain.12 The change in wall thickness observed in the present study was also associated with an increase in LVEDV. Given that ventricular capacitance, reflected by LVEDV, is central to the pathophysiology of diastolic dysfunction in hATTR amyloidosis, this change in cavity volume may reflect decreased myocardial infiltration and potentially a reduction in preexisting amyloid deposits.

Global longitudinal strain, a sensitive measure of systolic function, is known to increase (indicating worse function) in amyloid heart disease,12,25 often in the setting of a normal ejection fraction. The magnitude of difference in global longitudinal strain observed between patisiran and placebo groups has been shown to independently predict survival in patients with ATTR and AL amyloidosis,12 providing further support for the potential clinical significance of the observed treatment effect.

In addition, a treatment effect of patisiran on NT-proBNP was observed. NT-proBNP is a potent marker of the severity of heart failure and is prognostic of outcome in patients with heart failure of various etiologies,26,27 including amyloidosis.28,29 It was modestly elevated in the cardiac subpopulation at baseline, with a median value in the range that would be considered diagnostic for heart failure. Reduction in NT-proBNP with patisiran was apparent based on both mean values and the proportion of patients achieving established treatment response thresholds. It is important to note that the relative reduction with patisiran was apparent as early as 9 months, despite there being no discernible improvement in echocardiographic measures at this time point. This finding suggests that NT-proBNP may be an earlier indicator of the effect of patisiran on cardiac function than echocardiography and that circulating forms of TTR may have a cardiotoxic effect beyond amyloid deposition in the heart.

Substantial disease progression was observed in the placebo group, with increasing NT-proBNP levels and worsening global longitudinal strain along with decreasing cardiac output and LVEDV, although wall thickness was relatively stable. There are limited natural history data available for patients with hATTR amyloidosis with cardiomyopathy; however, increasing NT-proBNP and decreasing LVEDV have been observed in an independent cohort of patients with hATTR amyloidosis over 18 months.11 Our findings, including improvements in LV wall thickness and NT-proBNP relative to baseline, suggest that patisiran may impede cardiac disease progression and possibly reflect clearance of amyloid deposits from the myocardium.

Patisiran treatment also resulted in an improvement in functional status relative to the placebo group as measured by 10-MWT gait speed. Although an improvement in 10-MWT gait speed was also seen in all other patients, the effect seen in the cardiac subpopulation was greater. Both peripheral neuropathy and cardiomyopathy can compromise ambulatory ability; as such, it is possible that the effect of patisiran on gait speed was the result of its impact on both aspects of the disease.

It is probable that cardiac amyloid involvement was present outside of the predefined cardiac subpopulation. Indeed, evidence of potential cardiac amyloid involvement was seen in most patients in the study; 80% had LV wall thickness >13 mm and 79% had abnormal NT-proBNP levels. Accordingly, the treatment effect was also assessed in all other patients who did not meet criteria for the prespecified cardiac subpopulation, to further understand the impact of patisiran on cardiac parameters in patients with less overt (wall thickness <13 mm) or less specific (wall thickness ≥13 mm with confounding medical history) cardiac manifestations. Among these patients, there were no discernible differences between treatment arms in the effect on echocardiographic parameters over 18 months. As expected, abnormalities in baseline echocardiographic parameters were less pronounced in these patients compared with the cardiac subpopulation, and confounding effects of hypertension on parameters including wall thickness were present. Consequently, echocardiographic assessment may have lacked the sensitivity to discern a treatment effect in these patients. By contrast, the treatment effect of patisiran on NT-proBNP observed in these patients likely reflects the higher sensitivity of the biomarker assay compared with echocardiography. These findings suggest that most patients with hATTR amyloidosis may have cardiac involvement, and that NT-proBNP could be used as a biomarker to assess response to treatment. Given that patisiran’s treatment effect relative to placebo increased over time on both echocardiographic parameters and NT-proBNP, it is possible that further improvement could be achieved with a longer treatment duration. In the mITT population, a patisiran treatment effect on NT-proBNP was observed regardless of baseline disease severity, suggesting that patisiran may benefit patients with hATTR amyloidosis regardless of disease stage, and that early intervention may provide benefit in this rapidly progressive disease.

Patisiran had an acceptable safety profile based on an in-depth analysis of cardiac events in both the mITT population and cardiac subpopulation. It is important to note that a post hoc analysis of safety data showed that rates of all-cause death and cardiac hospitalization were decreased in the patisiran group compared with the placebo group.

Some limitations of this analysis should be noted. The cardiac subpopulation was defined by LV wall thickness, a measure that increases the likelihood of, but does not definitively establish, cardiac amyloid involvement. Similarly, the lack of this degree of ventricular wall thickness does not rule out cardiac involvement. A further limitation is the exploratory nature of the reported cardiac assessments, where overall type I error was not controlled. Nevertheless, the consistency of the biomarker findings, in concert with the observed effect on multiple echocardiographic parameters and the clinical end point of 10-MWT gait speed, suggests a patisiran treatment effect on cardiac disease manifestations. It should also be noted that the study did not include patients with NYHA class III or IV at baseline and that the majority of patients had preserved ejection fraction. Although this study was not designed or powered to investigate the effect of patisiran on clinical outcomes such as death or CV hospitalization, the safety data suggest promising trends in the reduction in cardiac hospitalizations and all-cause mortality.

Conclusions

In conclusion, treatment with the RNAi therapeutic patisiran resulted in improvement in several important measures of cardiac structure and function over 18 months, including reduction in LV wall thickness and NT-proBNP compared with both baseline and placebo, and relative improvement in global longitudinal strain compared with placebo. These findings suggest that patisiran may halt or possibly reverse the progression of hATTR amyloid heart disease.

Acknowledgments

Alnylam Pharmaceuticals thanks all patients and their families as well as all investigators involved in this APOLLO study subgroup analysis.

Footnotes

Sources of Funding, see page 442

https://www.ahajournals.org/journal/circ

The online-only Data Supplement, podcast, and transcript are available with this article at https://www.ahajournals.org/doi/suppl/10.1161/CIRCULATIONAHA.118.035831.

Scott D. Solomon, MD, Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115. Email

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