Patisiran: APOLLO-B Study

Patisiran: APOLLO-B Study

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 Summary

Index

Study Design – Patient Demographics & Baseline Characteristics – 6-MWT – KCCQ-OS – Secondary Composite Endpoints – Pharmacodynamic Endpoint – Exploratory Endpoints – Safety Results – Abbreviations – References

 Study Design

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) vs. placebo (n=179) in patients with ATTR-CM, including both hATTR and wtATTR. Randomization was stratified by baseline tafamidis (yes vs. no), genotype (hATTR vs. wtATTR), and NYHA Class I or II and age < 75 years vs. all other. 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 The inclusion and exclusion criteria for APOLLO‑B are presented in Table 1.1,2

Table 1. APOLLO-B Inclusion and Exclusion Criteria.1,2

 Patient Demographics & Baseline Characteristics

Baseline characteristics were comparable between the patisiran and placebo arms, as shown in Table 2.1

Table 2. Baseline Patient Demographics and Clinical Characteristics.1

 6-MWT

Patisiran demonstrated a statistically significant difference compared with placebo in the primary endpoint of change from baseline in 6‑MWT at 12 months, as seen in Figure 1. The HL estimate of median difference was 14.69 m (95% CI: 0.69, 28.69; p=0.02).1 The decline in 6‑MWT observed in the patisiran arm was similar to the typical age-related decline seen in healthy adults.3–6

Figure 1. Change from Baseline in 6-MWT at 12 Months.1,a

A prespecified sensitivity analysis was conducted using MMRM to confirm the primary endpoint results for change from baseline in 6‑MWT at 12 months for patisiran compared with placebo, which resulted in a LS mean difference of 18.15 m (95% CI: 2.48, 33.82).2

In a post-hoc analysis, a greater proportion of patients treated with patisiran achieved an improvement in 6‑MWT distance at 12 months compared with placebo across specific thresholds assessed (Figure 2). At 12 months, 32% of patients in the patisiran arm improved by at least 15 m versus 21% of patients in the placebo arm (p<0.05); and 24% of patients in the patisiran arm improved by at least 30 m compared with 14% of patients in the placebo arm (p<0.01).7

Figure 2. Proportion of Patients with Specified Threshold Levels of Change in 6-MWT.7

 KCCQ-OS

Patisiran demonstrated a statistically significant difference in the first secondary endpoint of change from baseline in patient-reported health status and quality of life as measured by the KCCQ‑OS score at 12 months compared with placebo (patisiran, 0.3 vs. placebo, -3.4) with a LS mean difference of 3.7 (95% CI: 0.2, 7.2; p=0.04). A consistent treatment effect was observed across all KCCQ domains (Figure 3).1,7

Figure 3. LS Mean Difference in Change from Baseline in KCCQ‑OS Domains and Clinical Summary Score at 12 Months.7

In a post-hoc analysis, a greater proportion of patients treated with patisiran had an improvement in the KCCQ‑OS score at 12 months compared with placebo across a range of thresholds assessed (Figure 4). At 12 months, 34% of patients in the patisiran arm improved from baseline by at least 5 points versus 24% of patients in the placebo arm (p<0.05).7

Figure 4. Proportion of Patients by Threshold of Change from Baseline in KCCQ‑OS Score at 12 Months.7

 Secondary Composite Endpoints

Secondary endpoints were evaluated in a hierarchical manner. There was a non-significant result for 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 compared with placebo with a win ratio (patisiran vs. placebo) of 1.27 (95% CI: 0.99, 1.61).1 Deaths, hospitalizations, and urgent HF visits due to COVID‑19 were excluded from the analysis. Patients who underwent heart transplantation and/or ventricular assist device placement after randomization were handled in the same manner as death in this efficacy analysis.1

Because of the non-significant result with the second secondary endpoint, no formal statistical testing was performed on two additional composite endpoints. These secondary endpoints included2:

         Composite of all-cause mortality and frequency of all-cause hospitalizations and urgent HF visits in patients not on tafamidis at baseline, which resulted in a HR of 0.997 (95% CI: 0.62, 1.60)

         Composite of all-cause mortality and frequency of all-cause hospitalizations and urgent HF visits in the overall study population, which resulted in a HR of 0.88 (95% CI: 0.58, 1.34).

 Pharmacodynamic Endpoint

Serum TTR reduction at 12 months was assessed as a pharmacodynamic endpoint of the APOLLO‑B study. Patients treated with patisiran achieved a mean (SD) percent serum TTR reduction of 86.8 (13.6).1

The mean (SD) percent reduction in serum TTR in the patisiran arm was 83.7 (16.3) for patients receiving tafamidis at baseline and 87.9 (12.3) for patients not receiving tafamidis at baseline. Patients with hATTR and patients with wtATTR achieved a mean (SD) percent TTR reduction of 85.2 (12.7) and 87.2 (13.9), respectively.1

 Exploratory Endpoints

Cardiac Biomarkers

The change from baseline in NT-proBNP at 12 months was assessed as an exploratory endpoint. At 12 months, the adjusted geometric mean factor change from baseline in NT-proBNP was 1.11 (95% CI: 1.04, 1.19) in the patisiran arm and 1.38 (95% CI: 1.29, 1.48) in the placebo arm. The ratio of adjusted geometric mean factor change (patisiran/placebo) was 0.80 (95% CI: 0.73, 0.89).1

The change from baseline in troponin I at 12 months was also assessed as an exploratory endpoint. At 12 months, the adjusted geometric mean factor change from baseline in troponin I was 1.13 (95% CI: 1.07, 1.20) in the patisiran arm and 1.30 (95% CI: 1.22, 1.38) in the placebo arm. The ratio of adjusted geometric mean factor change (patisiran/placebo) was 0.87 (95% CI: 0.80, 0.95).1

The changes from baseline in NT-proBNP and troponin I at 12 months are summarized in Table 3.1

Table 3. Changes from Baseline in NT‑proBNP and Troponin I at 12 Months.1

Echocardiographic Parameters

Echocardiographic parameters were assessed as exploratory endpoints to evaluate the change from baseline in LV structure and function at 12 months. The change from baseline in LV mass at 12 months was -1.00 g (95% CI: -7.31, 5.32) in the patisiran arm and 8.45 g (95% CI: 2.02, 14.89) in the placebo arm, resulting in a between-group LS mean difference of -9.45 g (95% CI: ‑18.48, -0.42).1

The change from baseline in LV global longitudinal strain at 12 months was 0.36 percentage points (95% CI: 0.01, 0.71) in the patisiran arm and 0.90 percentage points (95% CI: 0.55, 1.26) in the placebo arm, resulting in a between-group LS mean difference of -0.54 percentage points (95% CI: ‑1.04, ‑0.05).1

The change in LV stroke volume was 0.48 mL (95% CI, ‑1.19, 2.15) in the patisiran arm and ‑2.52 mL (95% CI, ‑4.21, ‑0.82) in the placebo arm, with a between-group LS mean difference of 3.00 mL (95% CI: 0.61, 5.38).1

Technetium Scintigraphy

Overall, 40 patients in the patisiran arm and 37 patients in the placebo arm were evaluated with scintigraphy at baseline, and 37 patients in the patisiran arm and 28 patients in the placebo arm were evaluated at 12 months.8

Of the 37 evaluable patients in the patisiran arm, all had either reduced or stable Perugini grade compared to baseline at 12 months; 14 patients (37.8%) showed a reduction of ≥1 Perugini grade, including 3 patients (8.1%) who showed a reduction of ≥2 Perugini grades from baseline at 12 months. Of the 28 evaluable patients in the placebo arm, none had a reduced Perugini grade compared to baseline at 12 months; 1 patient (3.6%) showed an increase in Perugini grade.8

 Safety Results

During the 12‑month treatment period, AEs were reported in 91% of patients in the patisiran arm and 94% of patients in the placebo arm (Table 4). The majority of AEs were mild or moderate in severity, and the frequency of serious and severe AEs was similar between the two arms. AEs that were reported in ≥5% of patients in the patisiran arm and seen ≥3% more frequently with patisiran than with placebo were IRRs, arthralgia, and muscle spasms. Serious AEs reported in ≥2% of patients in either arm were cardiac failure, atrial fibrillation, complete atrioventricular block, amyloidosis, and syncope. In the safety analysis, 5 deaths (3%) occurred in the patisiran arm and 8 deaths (4%) occurred in the placebo arm. No clinically relevant changes in laboratory measures, vital signs, or electrocardiograms were observed in either treatment arm during the study.1

Table 4. Adverse Events in APOLLO-B at 12 Months.1

Cardiac Safety Summary

Table 5 below summarizes the cardiac safety findings from APOLLO‑B, providing the number of events identified within Standardized MedDRA Queries.9

Table 5. APOLLO-B Cardiac Safety Summary at 12 Months.9

 Abbreviations

6‑MWT = 6-minute walk test; ACEI = angiotensin-converting enzyme inhibitor; AE = adverse event; ARB = angiotensin‑receptor blocker; ARNI = angiotensin receptor–neprilysin inhibitor; ATTR = transthyretin amyloidosis; ATTR-CM = transthyretin amyloidosis with cardiomyopathy; CI = confidence interval; CV = cardiovascular; eGFR = estimated glomerular filtration rate; hATTR = hereditary transthyretin amyloidosis; HF = heart failure; HIV = human immunodeficiency virus; HL = Hodges‑Lehmann; HR = hazard ratio; IQR = interquartile range; IRR = infusion-related reaction; IV = intravenous; KCCQ‑OS = Kansas City Cardiomyopathy Questionnaire-Overall Summary; LS = least squares; LV = left ventricular; m = meter; mBMI = modified body mass index; MMRM = mixed model repeated measures; NT‑proBNP = N-terminal pro-brain natriuretic peptide; NYHA = New York Heart Association; PND = polyneuropathy disability; QT = QT interval; ROW = rest of world; SAE = serious adverse event; SD = standard deviation; SE = standard error; SEM = standard error of the mean; SGLT2 = sodium‑glucose cotransporter‑2; SMQ = Standardized MedDRA (Medical Dictionary for Regulatory Activities) Query; TTR = transthyretin; wtATTR = wild-type transthyretin amyloidosis.

Updated 29 July 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.  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

3.  Maurer MS, Fontana M, Berk JL, et al. Primary results from APOLLO-B, a phase 3 study of patisiran in patients with transthyretin-mediated amyloidosis with cardiomyopathy. Presented at: Heart Failure Society of America (HFSA) Annual Scientific Meeting; September 30-October 2, 2022; Washington, DC, USA.

4.  Enright PL, Sherrill DL. Reference equations for the six-minute walk in healthy adults. Am J Respir Crit Care Med. 1998;158(5 Part 1):1384-1387. doi:10.1164/ajrccm.158.5.9710086

5.  Troosters T, Gosselink R, Decramer M. Six minute walking distance in healthy elderly subjects. Eur Respir J. 1999;14(2):270-274. doi:10.1034/j.1399-3003.1999.14b06.x

6.  Camarri B, Eastwood PR, Cecins NM, Thompson PJ, Jenkins S. Six minute walk distance in healthy subjects aged 55-75 years. Respir Med. 2006;100(4):658-665. doi:10.1016/j.rmed.2005.08.003

7.  Berk JL, Lairez O, Schwartzmann P, et al. Benefits of patisiran on functional capacity in ATTR cardiac amyloidosis: Post hoc analysis of APOLLO-B. JACC Adv. 2025;4(8):101876. doi:10.1016/j.jacadv.2025.101876

8.  Kale P, Maurer MS, Fontana M, et al. Exploratory analyses from APOLLO-B, a phase 3 study of patisiran in patients with ATTR amyloidosis with cardiomyopathy. Presented at: Heart Failure Society of America (HFSA) Annual Scientific Meeting; September 30-October 3, 2022; Washington, DC, USA.

9.  Maurer MS, Fontana M, Berk JL, et al. Primary results from APOLLO-B, a phase 3 study of patisiran in patients with transthyretin-mediated amyloidosis with cardiomyopathy. Presented at: International Symposium on Amyloidosis (ISA) Annual Meeting; September 4-8, 2022; Heidelberg, Germany.