Exploratory Analyses From Apollo-B, A Phase 3 Study Of Patisiran In Patients With Attr Amyloidosis With Cardiomyopathy

Introduction Transthyretin-mediated (ATTR) amyloidosis is a progressive and fatal disease caused by TTR amyloid accumulation in organs and tissues. Patients with hereditary or wild-type ATTR amyloidosis frequently develop cardiomyopathy, as demonstrated by cardiac biomarkers and imaging. Patisiran, an IV RNAi therapeutic that inhibits synthesis of wt and variant TTR, is approved for the treatment of hATTR amyloidosis with polyneuropathy. Hypothesis Patisiran can benefit a range of disease-relevant measures in patients with ATTR amyloidosis with cardiomyopathy. Methods Patients were 18–85 yrs old with evidence of cardiac amyloidosis by echocardiography, either ATTR amyloid deposition on tissue biopsy or fulfilling nonbiopsy diagnostic criteria for ATTR amyloidosis with cardiomyopathy, and with prior hospitalization for heart failure due to ATTR amyloidosis or clinical evidence of heart failure. Patients were randomized (1:1) to receive patisiran IV 0.3 mg/kg or placebo Q3W for 12 months. The primary endpoint was change from baseline in 6-MWT at Month 12 (M12) with patisiran vs placebo. Exploratory parameters at M12 included changes in cardiac biomarkers, echocardiographic parameters of cardiac structure and function, and Tc scintigraphy parameters. Results APOLLO-B enrolled 360 patients (patisiran, n=181; placebo, n=179): median age (range) age, 76.0 (41, 85) yrs; male, 89%; wtATTR, 80%; on tafamidis at baseline, 25%. Patisiran showed a significant benefit compared with placebo in the 6-MWT (median [95% CI] change from baseline: patisiran, -8.15 [-16.42, 1.50]; placebo, -21.35 [-34.05, -7.52]; Hodges-Lehmann estimate of median difference: 14.69 [0.69, 28.69]; p=0.0162). Patisiran demonstrated favorable trends in change from baseline of NT-proBNP (adjusted geometric mean fold change ratio [95% CI]: 0.8 [0.73, 0.89]; nominal p=1.825 × 10–5) and troponin I (LS mean [SEM] difference: -29.9 [20.7]; nominal p=0.1491) at M12 vs placebo. Patisiran also demonstrated a trend towards benefit in change from baseline of most evaluated echocardiographic parameters at M12 vs placebo. Patisiran-treated patients who were evaluable for scintigraphy (n=37) experienced a reduction (37.8%) or no change (62.2%) in Perugini grade at M12 compared with baseline (3 [8.1%] patisiran patients reduced from baseline by ≥2 Perugini grades). Among evaluable placebo patients (n=28) at M12, none experienced a reduction from baseline in Perugini grade, and 1 (3.6%) increased in grade. Patisiran demonstrated an acceptable safety profile; AEs were mostly mild or moderate in severity, and there were no no cardiac safety concerns. Conclusions Exploratory analyses after 12 months provide further evidence for the potential benefit of patisiran treatment on cardiac biomarkers and manifestations of cardiac amyloid involvement in patients with ATTR amyloidosis. The long-term impact of patisiran on these measures will be assessed in the ongoing APOLLO-B open-label extension (NCT03997383).