siRNA targeting TTR improves functional capacity in ATTR cardiac amyloidosis

Introduction and methods

Background

Transthyretin-mediated (ATTR) amyloidosis is a progressive, debilitating, and fatal disease caused by the accumulation of amyloid fibrils composed of misfolded TTR protein in the heart, nerves, and other organs [1-3]. In the heart, the disease manifests as cardiomyopathy [4-6].

Patisiran, an RNA interference therapeutic agent that inhibits the production of TTR in the liver, received US and European market approval for the treatment of hereditary (variant) ATTR amyloidosis in patients with polyneuropathy based on the results of the phase 3 APOLLO trial [7,8]. This study also suggested patisiran can halt or reverse the progression of ATTR cardiac amyloidosis [9].

Aim of the study

The authors examined the efficacy and safety of patisiran in patients with variant or wild-type ATTR cardiac amyloidosis.

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Methods

The APOLLO-B (A Study to Evaluate Patisiran in Participants With Transthyretin Amyloidosis With Cardiomyopathy) trial is an ongoing, international, double-blind, placebo-controlled, phase 3 RCT in which 360 patients with variant or wild-type ATTR cardiac amyloidosis were randomized to patisiran 0.3 mg/kg (maximum dose: 30 mg) intravenously or placebo once every 3 weeks for 12 months. Thereafter, patients were eligible to be enrolled in the open-label extension period.

Key exclusion criteria were, among others, NYHA class III HF symptoms plus ATTR amyloidosis stage 3, or NYHA class IV HF symptoms. Treatment with tafamidis at baseline was permitted (used by 25% of the patients in each group).

Outcomes

The primary endpoint was the change from baseline to 12 months in functional capacity, as measured by the 6-minute walk distance (6MWD).

The first secondary endpoint was the change from baseline to 12 months in health status and quality of life, as measured by the KCCQ-OS score. The second secondary endpoint was a composite outcome of all-cause mortality, CV events, or change in the 6MWD from baseline to 12 months. The third secondary endpoint was a composite outcome of all-cause mortality, all-cause hospitalization, or urgent HF visits over 12 months.

Exploratory endpoints included changes in NT-proBNP and troponin I levels and echocardiographic measures of cardiac structure and function.

Safety was evaluated by assessments of adverse events, clinical laboratory variables, and vital signs.

Main results

Efficacy

• At 12 months, patients treated with patisiran (n=181) showed a smaller decline from baseline in the 6MWD than placebo-treated patients (n=179). The median 6MWD change was −8.15 m (95%CI: −16.42 to 1.50) and −21.35 m (95%CI: −34.05 to −7.52), respectively (Hodges–Lehmann estimate of median difference: 14.69 m; 95%CI: 0.69–28.69; P=0.02).
• In the placebo group, the KCCQ-OS score decreased from baseline (least-squares (LS) mean change: −3.4 points; 95%CI: −5.9 to −0.9), whereas it increased slightly in the patisiran group (LS mean change: 0.3 points; 95%CI: −2.2 to 2.8) (LS mean difference: 3.7 points; 95%CI: 0.2–7.2; P=0.04).
• The second secondary endpoint (composite all-cause mortality, CV events, and change in 6MWD) was not significantly different between the patisiran and placebo groups (win ratio over 12 months: 1.27; 95%CI: 0.99–1.61), and neither was the third secondary endpoint (composite of all-cause mortality, all-cause hospitalization, and urgent HF visits) (estimated HR: 0.88; 95%CI: 0.58–1.34).
• During the 12-month study period, 4 deaths (2.2%) occurred in the patisiran group and 10 (5.6%) in the placebo group (estimated HR: 0.36; 95%CI: 0.11–1.14).
• As for the exploratory endpoints, the median change in the NT-proBNP level from baseline to 12 months was 131 pg/mL (IQR: −280 to 817) in the patisiran group and 518 pg/mL (IQR: 51–1544) in the placebo group (ratio of adjusted geometric mean factor increase: 0.80; 95%CI: 0.73–0.89). The median change in the troponin I level was 3.8 pg/mL (IQR: −7.1 to 19.9) and 14.5 pg/mL (IQR: 0.0–32.2), respectively (ratio of adjusted geometric mean factor increase: 0.87; 95%CI: 0.80–0.95).
• Echocardiographic analyses showed changes in cardiac structure and function in favor of patisiran.

Safety

• The frequency of adverse events was similar for the patisiran and placebo groups (91% vs. 94%), and most of these events were mild or moderate in severity.
• The incidences of serious adverse events and severe (treatment-emergent) adverse events were also similar in the 2 groups.
• Infusion-related reactions, arthralgia, and muscle spasms were observed more frequently among patients in the patisiran group compared with those in the placebo group.

Conclusion

References

Find this article online at N Engl J Med.