Risk Factors for Mortality in Patients with Hereditary Transthyretin-Mediated Amyloidosis: An Analysis of APOLLO and Global Open Label Extension Studies

Abstract

Hereditary transthyretin-mediated (hATTR) amyloidosis is a rapidly progressive, fatal disease caused by transthyretin gene mutations resulting in amyloid deposition in multiple organs and tissues. Heterogenous clinical manifestations occur and most patients (pts) develop a mixed phenotype of polyneuropathy and cardiomyopathy. Patisiran, an RNAi therapeutic, was investigated in APOLLO (NCT01960348), the largest study in pts with hATTR amyloidosis with polyneuropathy; 56% of pts qualified for the pre-defined cardiac subpopulation. At 18 months, patisiran halted or reversed neuropathy and had a favorable benefit:risk profile. 99% of eligible pts enrolled into the Global OLE study (NCT02510261). Survival data from APOLLO and the Global OLE were retrospectively analyzed for potential baseline mortality risk factors in pts with hATTR amyloidosis. Univariate and multivariate Cox proportional hazards regression analyses were used to compare the hazard ratios for baseline factors including: genotype (non-V30M vs V30M), FAP stage (1, 2, 3), NT-proBNP (>3000ng/L vs ≤ 3000ng/L), age of disease onset ( The analysis indicated higher risk of mortality in pts with non-V30M, NT-proBNP level >3000ng/L and advanced neuropathy (FAP 2/3) (Table 1); this was consistent with literature. APOLLO pts were evaluated for the presence of all three risk factors at baseline which revealed an imbalance (11.5% of patisiran pts at risk vs 5.2% placebo). In these pts with the identified mortality risk, the exposure-adjusted all-cause mortality rate (per 100 person-year) was 30.4 in patisiran and 57.8 in placebo; exposure-adjusted cardiac mortality rates were comparable 30.4 vs 28.9, respectively. In the entire population, exposure-adjusted all-cause mortality rates were lower in patisiran (3.2) vs placebo (6.2) and compared to natural history studies (NHS) (6.8-19). In the Global OLE, exposure-adjusted mortality rates remain lower (4.8) than in NHS.Patients at highest risk for mortality were those with non-V30M, severe neuropathy, and elevated NT-proBNP underscoring the importance of early diagnosis. Although a greater number of high-risk pts were in the patisiran arm, overall exposure-adjusted mortality rates were lower than in placebo supporting patisiran clinical benefit.