Patisiran: Hospitalization and Mortality

Patisiran: Hospitalization and Mortality

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 Summary

 Index

APOLLO-B – APOLLO – Global OLE – Pooled Analyses – Abbreviations – References

 APOLLO-B

APOLLO-B was a multicenter, randomized (1:1), double-blind, placebo-controlled, phase 3 study designed to evaluate the efficacy and safety of IV patisiran 0.3 mg/kg every 3 weeks (n=181) versus placebo (n=179) in patients with ATTR-CM, including both hATTR and wtATTR. The primary endpoint was the change from baseline in the 6-MWT at 12 months. After the 12-month double-blind treatment period, all eligible patients received patisiran in an open-label extension period.1

Patient Demographics and Baseline Characteristics

The baseline demographic and clinical characteristics were generally balanced between the patisiran and placebo arms and representative of the global population of patients with ATTR-CM. Across both groups of patients, the median age was 76 years, majority were men, and 25% received tafamidis at baseline. Approximately 80% of patients in each group had wtATTR. Among the patients with hATTR, there were 16 different pathogenic TTR variants. Most patients were NYHA class II (patisiran 86%, placebo 84%) and ATTR amyloidosis Stage 1 (patisiran 69%, placebo 67%).1

Secondary Composite Endpoints over 12 Months

The secondary composite endpoint of all-cause mortality, frequency of CV events (CV hospitalizations and urgent HF visits) and change from baseline in 6-MWT over 12 months resulted in a win ratio of 1.27 (95% CI: 0.99, 1.61) and did not significantly differ between patisiran and placebo.1 Table 1 includes a summary of the secondary composite endpoints over 12 months.6

Table 1. Secondary Composite Outcome Endpoints over 12 Months.6

Mortality Over 12 Months

In the overall population of the APOLLO-B study, 4 deaths (2.2%) occurred in the patisiran group and 10 deaths (5.6%) occurred in the placebo group. The estimated HR (patisiran-to-placebo) was 0.36 (95% CI, 0.11 to 1.14). Two patients (1.1%) from the placebo group received heart transplants, which were counted as deaths in the efficacy analysis. Data for a patient who died from COVID-19 (1 patient [0.56%] in the patisiran group) were censored at the date of death, and this death was not included as an event in the efficacy analysis.1

 APOLLO

APOLLO was a multicenter, international, randomized (2:1), double-blind, placebo-controlled, phase 3 study designed to assess the efficacy and safety of IV patisiran 0.3 mg/kg every 3 weeks (n=148) versus placebo (n=77) in patients with hATTR-PN. The primary endpoint was the change from baseline in the mNIS+7 at 18 months.2

Patient Demographics and Baseline Characteristics

The baseline demographics and clinical characteristics were generally well-balanced between the patisiran and placebo arms. Across both groups, the median age was 62 years, 74% of patients were male, and 72% were white/Caucasian. The median time to diagnosis in the patisiran group was 1.3 years and 1.4 years in the placebo group. Most patients in both groups were in FAP stage 1 (patisiran, 45%, placebo 48%) or FAP stage 2 (patisiran 55%, placebo 51%). There was a similar distribution between groups by NYHA class: NYHA class I (patisiran 47%, placebo 52%) and NYHA class II (patisiran 52%, placebo 47%).2

Post-Hoc Analyses of Hospitalization and Mortality

Post-hoc analyses of the APOLLO study were conducted in the mITT population (N=225) to assess the composite of all-cause hospitalization and/or all-cause mortality and the composite of cardiac hospitalization and/or all-cause mortality. The mITT population was defined as all randomized patients who received ≥1 dose of study drug. All-cause hospitalization and mortality were defined as any hospitalization or death associated with a SAE that occurred within 28 days of the last dose of study drug (placebo or patisiran). Cardiac hospitalizations were defined as any SAE coded to cardiac disorders that led to hospitalization or prolongation of an existing hospitalization. For these events of interest, the exposure-adjusted event rates were estimated for patients treated with either placebo or patisiran.3

The exposure-adjusted rates of the composite of all-cause hospitalization and/or death were 71.8 and 34.7 per 100 patient-years in the placebo and patisiran groups, respectively. The rates of the composite of cardiac hospitalizations and all-cause death were 18.7 and 10.1 per 100 patient-years in the placebo and patisiran groups, respectively. Patisiran was associated with an approximate reduction of 50% for all-cause hospitalization and mortality and an approximate reduction of 45% for cardiac hospitalization and all-cause mortality (Figure 1).3

Figure 1. Composite Rates of Hospitalization and Mortality Events Per Patient from Baseline to Month 18.3

 Global OLE

The Global OLE study was a multicenter, international study designed to evaluate the long-term safety and efficacy of IV patisiran in patients with hATTR-PN. Patients with hATTR-PN who completed the patisiran Phase 2 OLE study or phase 3 APOLLO study and met eligibility criteria were able to start or continue IV patisiran 0.3 mg/kg every 3 weeks for up to 5 years. The study enrolled 25 patients from the patisiran Phase 2 OLE study (Phase 2 OLE-patisiran group), 137 patients from the APOLLO-patisiran arm (APOLLO-patisiran group), and 49 patients from the APOLLO-placebo arm (APOLLO-placebo group).4

Patient Demographics and Baseline Characteristics

At Global OLE enrollment, patients in the APOLLO-placebo group had higher levels of NT-proBNP and more severe polyneuropathy than patients in the APOLLO-patisiran and Phase 2 OLE‑patisiran groups. Across the study populations, the mean age was 61.3 years, and 73.9% of patients were male. There was a higher proportion of patients in the Phase 2 OLE-patisiran group with the V30M genotype compared with the APOLLO-placebo and APOLLO‑patisiran groups. Additional baseline disease characteristics are presented in Table 2.4,7

Table 2. Select Baseline Characteristics at Global OLE Enrollment.7

Mortality

5-Year Results

Post-hoc analyses of survival were conducted based on AE data and assessed using Kaplan-Meier analysis. Exposure-adjusted mortality rates were calculated as the total number of deaths per 100 patient-years and only included deaths following the first dose of patisiran.4

During the Global OLE, death was reported in 41 (19.4%) patients. None of the deaths were considered related to patisiran by the investigators. Survival rates were higher among patients who received patisiran in their parent studies compared with those who received placebo in the parent study and switched to patisiran upon entering the Global OLE. The exposure-adjusted mortality rate per 100 patient-years was 12.8 (95% CI, 8.2-19.8) in the APOLLO-placebo group, 3.3 (95% CI, 2.3-4.9) in the APOLLO-patisiran group, 1.7 (95% CI, 0.5-5.2) in the Phase 2 OLE-patisiran group, and 4.4 (95% CI, 3.3-5.8) in the overall Global OLE population.4

Risk factors for mortality at parent study baseline were evaluated and univariate analyses identified associations between mortality and select baseline characteristics. Post-hoc multivariate Cox proportional hazards analyses were conducted using factors that were significant in the univariate model. In both full and selection-based multivariate analyses, FAP stage and parent study treatment were associated with mortality (Table 3).4

Table 3. Multivariate Analyses of Risk Factors for Mortality in the Global OLE.4

 Pooled Analyses

Post-hoc analyses of a pooled cardiac population of patients across patisiran clinical studies were conducted to evaluate the long-term effect of patisiran on survival, hospitalizations, and cardiac parameters. The pooled cardiac population consisted of patients with hATTR-PN from the Global OLE that had a baseline LV wall thickness ≥13 mm and an absence of history of aortic valve disease or hypertension, in addition to all patients with ATTR-CM from the APOLLO-B OLE.5

Survival and Hospitalization

The probabilities of survival and all-cause hospitalizations by initial treatment arm are shown in Figures 2 and 3, respectively.5

Figure 2. Survival by Initial Treatment Arm in the Pooled Cardiac Populations.5

Figure 3. Hospitalizations by Initial Treatment Arm in the Pooled Cardiac Populations.5

Abbreviations

6-MWT = 6-minute walk test; AE = adverse event; ATTR = transthyretin amyloidosis; ATTR-CM = transthyretin amyloidosis with cardiomyopathy; CI = confidence interval; CV = cardiovascular; FAP = familial amyloid polyneuropathy; hATTR = hereditary transthyretin amyloidosis; hATTR-PN = hereditary transthyretin amyloidosis with polyneuropathy; HF = heart failure; HR = hazard ratio; IV = intravenous; LV = left ventricular; mITT = modified intent-to-treat; mNIS+7 = modified Neuropathy Impairment Score +7;  NAC = National Amyloidosis Centre; NC = not calculable; NIS = Neuropathy Impairment Score; Norfolk QOL-DN = Norfolk Quality of Life-Diabetic Neuropathy; NT-proBNP = N-terminal pro-brain natriuretic peptide; NYHA = New York Heart Association; OLE = open-label extension; PND = polyneuropathy disability; RR = rate ratio; SAE = serious adverse event; SD = standard deviation; TTR = transthyretin; wtATTR = wild‑type transthyretin amyloidosis.

Updated 29 September 2025

References

1.  Maurer MS, Kale P, Fontana M, et al. Patisiran treatment in patients with transthyretin cardiac amyloidosis. N Engl J Med. 2023;389(17):1553-1565. doi:10.1056/NEJMoa2300757

2.  Adams D, Gonzalez-Duarte A, O’Riordan WD, et al. Patisiran, an RNAi therapeutic, for hereditary transthyretin amyloidosis. N Engl J Med. 2018;379(1):11-21. doi:10.1056/NEJMoa1716153

3.  Solomon SD, Adams D, Kristen A, et al. Effects of patisiran, an RNA interference therapeutic, on cardiac parameters in patients with hereditary transthyretin-mediated amyloidosis: an analysis of the APOLLO study. Circulation. 2019;(suppl):1-9. doi:10.1161/CIRCULATIONAHA.118.035831

4.  Adams D, Wixner J, Polydefkis M, et al. Five-year results with patisiran for hereditary transthyretin amyloidosis with polyneuropathy: A randomized clinical trial with open-label extension. JAMA Neurol. 2025. doi:10.1001/jamaneurol.2024.4631

5.  Lairez O, Algalarrondo V, Damy T, et al. Long-term effects of patisiran on survival and cardiac parameters in patients with transthyretin-mediated cardiac amyloidosis: Post hoc analysis of APOLLO-B and cardiac subpopulation of APOLLO OLE. Presented at: European Society of Cardiology (ESC) Congress; August 30 - September 2, 2024; London, UK.

6.  Supplement to: Maurer MS, Kale P, Fontana M, et al. Patisiran treatment in patients with transthyretin cardiac amyloidosis. N Engl J Med. 2023;389(17):1553-1565. doi:10.1056/NEJMoa2300757

7.  Supplement to: Adams D, Wixner J, Polydefkis M, et al. Five-year results with patisiran for hereditary transthyretin amyloidosis with polyneuropathy: A randomized clinical trial with open-label extension. JAMA Neurol. 2025. doi:10.1001/jamaneurol.2024.4631.