Primary Results From Apollo-B, A Phase 3 Study Of Patisiran In Patients With Transthyretin-Mediated Amyloidosis With Cardiomyopathy

Introduction Transthyretin-mediated (ATTR) amyloidosis is a progressive, multisystem, fatal disease. Treatment options for patients with ATTR amyloidosis with cardiomyopathy are currently limited, with only the TTR stabilizer tafamidis approved for this population. 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 is being investigated in the ongoing APOLLO-B study (NCT03997383). Hypothesis Reduction of TTR protein levels by patisiran provides benefit in patients with ATTR amyloidosis with cardiomyopathy. Methods Patients were 18–85 yrs old with evidence of cardiac amyloidosis by echocardiography, and either ATTR amyloid by tissue biopsy or fulfilling nonbiopsy diagnostic criteria for ATTR amyloidosis with cardiomyopathy. Medical history of heart failure (HF) due to ATTR amyloidosis with ≥1 prior hospitalization for HF or current clinical evidence of HF was also 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. Secondary endpoints to M12 included the effect of patisiran vs placebo on health status and quality of life (KCCQ-OS score), and death and hospitalization outcomes. 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 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) 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 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 cardiomyopathy, with consistency across clinically important subgroups. The efficacy and safety of patisiran continues to be studied in the APOLLO-B open-label extension.