Introduction: Transthyretin-mediated (ATTR) amyloidosis is a progressive, multisystem, fatal disease. Patisiran, an IV RNAi therapeutic, is approved for the treatment of hereditary ATTR amyloidosis with polyneuropathy. The safety and efficacy of patisiran in patients with wild-type or hereditary ATTR amyloidosis with cardiomyopathy (CM) is being investigated in the ongoing APOLLO-B study.
Methods: Patients were 18–85 yrs old with evidence of cardiac amyloidosis by echocardiography, and ATTR amyloid by tissue biopsy or fulfilling nonbiopsy diagnostic criteria for ATTR amyloidosis with CM. Medical history of heart failure (HF) due to ATTR amyloidosis with ≥1 prior hospitalization or current clinical evidence of HF was required. Patients were randomized 1:1 to 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.
Results: APOLLO-B enrolled 360 patients (patisiran, n=181; placebo, n=179): median age (range), 76.0 (41, 85) yrs; male, 89%; wtATTR, 80%. Baseline characteristics were consistent between patients on tafamidis at baseline (91/360 [25%]) and those who were not. Patisiran achieved a rapid and sustained reduction in serum TTR, irrespective of baseline tafamidis treatment. At M12, patisiran showed a significant benefit vs placebo in 6-MWT (median [95% CI] change from baseline: patisiran, -8.15 [-16.42, 1.50]; placebo, -21.35 [-34.05, -7.52]; HL estimate of median difference: 14.69 [0.69, 28.69]; p=0.0162) and KCCQ-OS (LS mean [SEM] change from baseline: patisiran, 0.300 [1.263]; placebo, -3.408 [1.277]; LS mean [SEM] difference: 3.709 [1.796]; p=0.0397). Consistent benefits with patisiran in 6-MWT and KCCQ-OS were observed across predefined patient subgroups. Time to first event of all-cause hospitalization, urgent HF visit, or death directionally favored patisiran vs placebo (HR [95% CI], 0.839 [0.557, 1.263]), as did all-cause mortality (HR [95% CI], 0.355 [0.110, 1.138]), but all composite outcomes endpoints did not achieve statistical significance over 12 months. Patisiran was well tolerated; most AEs were mild or moderate in severity, and there were no cardiac safety concerns.
Conclusions: Benefits at 12 months were observed with patisiran vs placebo in functional capacity, and health status and quality of life, in patients with ATTR amyloidosis with CM. The efficacy and safety of patisiran continues to be studied in the APOLLO-B open-label extension.