Patisiran Treatment in Patients with Transthyretin Cardiac Amyloidosis

Abstract

Background: Transthyretin amyloidosis, also called ATTR amyloidosis, is associated with accumulation of ATTR amyloid deposits in the heart and commonly manifests as progressive cardiomyopathy. Patisiran, an RNA interference therapeutic agent, inhibits the production of hepatic transthyretin.

Methods: In this phase 3, double-blind, randomized trial, we assigned patients with hereditary, also known as variant, or wild-type ATTR cardiac amyloidosis, in a 1:1 ratio, to receive patisiran (0.3 mg per kilogram of body weight) or placebo once every 3 weeks for 12 months. A hierarchical procedure was used to test the primary and three secondary end points. The primary end point was the change from baseline in the distance covered on the 6-minute walk test at 12 months. The first secondary end point was the change from baseline to month 12 in the Kansas City Cardiomyopathy Questionnaire-Overall Summary (KCCQ-OS) score (with higher scores indicating better health status). The second secondary end point was a composite of death from any cause, cardiovascular events, and change from baseline in the 6-minute walk test distance over 12 months. The third secondary end point was a composite of death from any cause, hospitalizations for any cause, and urgent heart failure visits over 12 months.

Results: A total of 360 patients were randomly assigned to receive patisiran (181 patients) or placebo (179 patients). At month 12, the decline in the 6-minute walk distance was lower in the patisiran group than in the placebo group (Hodges-Lehmann estimate of median difference, 14.69 m; 95% confidence interval [CI], 0.69 to 28.69; P = 0.02); the KCCQ-OS score increased in the patisiran group and declined in the placebo group (least-squares mean difference, 3.7 points; 95% CI, 0.2 to 7.2; P = 0.04). Significant benefits were not observed for the second secondary end point. Infusion-related reactions, arthralgia, and muscle spasms occurred more often among patients in the patisiran group than among those in the placebo group.

Conclusions: In this trial, administration of patisiran over a period of 12 months resulted in preserved functional capacity in patients with ATTR cardiac amyloidosis. (Funded by Alnylam Pharmaceuticals; APOLLO-B ClinicalTrials.gov number, NCT03997383.).

Figure 1.. Changes over Time between the Patisiran Group and the Placebo Group.

Panel A shows the median change from baseline in the distance covered on the 6-minute walk test (primary end point) with 95% confidence intervals. A farther distance walked indicates better function. At baseline, the median distance covered on the 6-minute walk test was 358.00 m (interquartile range, 295.00 to 420.00) in the patisiran group and 367.74 m (interquartile range, 300.00 to 444.25) in the placebo group. Missing assessments owing to deaths not caused by coronavirus disease 2019 [Covid-19] or owing to the inability to walk because of progression of transthyretin amyloidosis (also known as ATTR amyloidosis) disease were imputed as −115 meters (the worst 10th percentile change observed across all patients in the double-blind period). Other missing data (e.g., assessments obtained after a serious adverse event due to Covid-19, which were counted as missing) were multiply imputed assuming that data were missing at random (see the statistical analysis plan, available with the protocol, for details). Missing data were imputed 100 times to create 100 complete data sets. All data sets were analyzed with the use of the stratified Wilcoxon rank-sum test and the stratified Hodges–Lehmann (H–L) estimate, and the results were combined according to Rubin’s rules. The 6-minute walk test assessments were conducted in all patients at baseline; 6% and 8% of patients in the patisiran and placebo groups, respectively, had missing assessments at month 12. Panel B shows the leastsquares mean change from baseline in the Kansas City Cardiomyopathy Questionnaire–Overall Summary (KCCQ-OS) score (secondary end point), analyzed with the use of a mixed model with repeated measures. Lower values indicate worse quality of life. The KCCQ-OS assessments were conducted in all patients at baseline; 5% and 6% of patients in the patisiran and placebo groups, respectively, had missing assessments at month 12. Panel C shows the mean percentage change from baseline in serum transthyretin levels (measured with the use of a proprietary enzyme-linked immunosorbent assay [ELISA]). At baseline, the mean (±SD) serum transthyretin level was 235.32±68.05 mg per liter in the patisiran group and 244.77±73.17 mg per liter in the placebo group. At month 12, the mean serum transthyretin level was 30.93±33.60 mg per liter in the patisiran group and 229.40±77.15 mg per liter in the placebo group. Transthyretin levels were measured in all patients at baseline; 13% and 8% of patients in the patisiran and placebo groups, respectively, had missing measurements at month 12. The widths of the confidence intervals have not been adjusted for multiplicity and may not be used in place of hypothesis testing. I bars indicate confidence intervals.

Figure 2.. Change in Cardiac Biomarker Levels (Exploratory End Points).

Panel A shows the adjusted geometric mean factor change from baseline to month 12 in the N-terminal pro–B-type natriuretic peptide (NT-proBNP) level, a cardiac biomarker, with higher values indicating a greater level of cardiac stress. All patients had an NT-proBNP measurement obtained at baseline; assessments were missing for 8% of patients in both the patisiran and placebo groups at month 12. Panel B shows the adjusted geometric mean factor change from baseline in the high-sensitivity troponin I level, a measure of myocardial wall injury, with higher values indicating a greater level of myocardial injury. Troponin I measurements were missing for 4% of patients in the patisiran group and 3% of patients in the placebo group at baseline; at month 12, measurements were missing for 9% and 10% of patients in the patisiran and placebo groups, respectively. The number of patients assessed at each time point is shown for both biomarkers. The median levels of each cardiac biomarker measured at baseline and 12 months and the change from baseline to month 12 are also shown. I bars indicate confidence intervals. The widths of the confidence intervals have not been adjusted for multiplicity and may not be used in place of hypothesis testing. IQR denotes interquartile range.