Patisiran: Cardiac Results from the Global OLE Study

Patisiran: Cardiac Results from the Global OLE Study

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 Summary

Index

Global OLE – Post-hoc Analysis of Pooled Cardiac Population – Abbreviations – References

 Global OLE

Study Design

The Global OLE study (N=211) 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).1

Efficacy assessments included measures of polyneuropathy, quality of life, nutritional status, disability, and ambulation status.1

Baseline Characteristics

At enrollment, patients in the APOLLO-placebo group had higher levels of NT-proBNP and more severe polyneuropathy compared to patients in the APOLLO-patisiran and phase 2 OLE-patisiran groups. 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 characteristics are provided in Table 1.1

Table 1. Baseline Characteristics at Global OLE Enrollment.4

12-Month Results

Cardiac Results

From Global OLE enrollment to 12 months, NT‑proBNP concentrations were stable in both groups previously treated with patisiran. In the APOLLO-placebo group, NT‑proBNP levels increased (a sign of increased cardiac stress) during APOLLO, but decreased once patisiran treatment was initiated in the OLE (Table 2).2,5 The geometric mean fold change in NT‑proBNP at Global OLE 12 months relative to parent study baseline and Global OLE enrollment is presented in Table 3.5

Table 2. NT-proBNP at Parent Study Baseline, Global OLE Enrollment, and 12 Months.5

Table 3. Geometric Mean Fold Change in NT‑ProBNP at 12 Months.5

Mortality Results

In a post‑hoc analysis using data from the parent study baseline to the 12‑month OLE assessment, a higher frequency of cardiac deaths in the APOLLO-placebo group (6/49, 12%) was observed in comparison to the APOLLO-patisiran group (11/148, 7%) and phase 2 OLE-patisiran group (1/27, 4%). Cardiac deaths were defined as a subset of deaths adjudicated as being cardiovascular related and excluded the subcategory of fatal stroke. A summary of relevant exposure-adjusted mortality rates is presented in Table 4.5

Table 4. Integrated Exposure-Adjusted Mortality Rates in Patients with hATTR with Polyneuropathy Enrolled Across the Patisiran Development Program at 12 Months.5

5-Year Results

Mortality

Risk factors for mortality at the parent study baseline were evaluated. Univariate analyses identified associations between mortality and NT-proBNP, familial amyloid polyneuropathy stage, genotype, LV wall thickness, LV mass, NYHA classification, cardiac subpopulation, parent study treatment, NAC ATTR amyloidosis stage, NIS, and PND score. In both full and selection-based multivariate analysis, familial amyloid polyneuropathy stage and parent study treatment were associated with mortality (Table 5).1

Table 5. Multivariate Analysis of Risk Factors for Mortality.1

Safety

The rates of AEs and serious AEs were higher in the APOLLO-placebo than the APOLLO-patisiran and phase 2 OLE-patisiran groups. The types of AEs reported were similar to those observed in APOLLO, and the exposure-adjusted event rates were similar or lower than in APOLLO. Cardiac AEs, which were all reported as serious AEs, are summarized in Table 6.1

Table 6. Cardiac AEs.1

 Post-Hoc Analysis of Pooled Cardiac Population

Study Design

A post-hoc analysis of pooled data from the APOLLO-B OLE and the cardiac subpopulation of the Global OLE evaluated the long-term effects of patisiran on survival, hospitalizations, and cardiac parameters in patients with hATTR-PN and evidence of cardiac involvement or a diagnosis of ATTR-CM.3

Baseline Characteristics

Baseline demographics and disease characteristics are provided in Table 7.3

Table 7. Baseline Characteristics.3

Results

Survival and Hospitalization

In patients who received patisiran in the parent studies, the hazard for mortality and for hospitalizations decreased by 41.3% and 23.3%, respectively, relative to those who were randomized to placebo (Figure 1 and Figure 2).3

Figure 1. Probability of Survival Over Time.3

Figure 2. Probability of No Hospitalizations Over Time.3

NT-proBNP Levels

Patients randomized to patisiran had a stable geometric mean fold change in NT-proBNP from baseline throughout APOLLO. The rate of worsening of geometric mean fold change in NT-proBNP from baseline decreased in patients randomized to placebo when they were switched to patisiran at month 18 (Figure 3).3

Figure 3. Long-Term Stability of NT-proBNP with Patisiran in the APOLLO Trial.3

Left Ventricular Function

Better preservation of peak longitudinal strain was observed with patisiran when compared with placebo in the APOLLO study (Figure 4).3

Figure 4. Impact of Patisiran on Left Ventricular Function in the APOLLO Trial.3

 Abbreviations

AE = adverse event; ATTR = transthyretin amyloidosis; ATTR-CM = transthyretin amyloidosis with cardiomyopathy; CI = confidence interval; FAP = familial amyloid polyneuropathy; hATTR-PN = hereditary transthyretin amyloidosis; IQR = interquartile range; IV = intravenous; LV = left ventricular; NAC = National Amyloidosis Centre; NIS = Neuropathy Impairment Score; NT‑proBNP = N‑terminal pro-brain natriuretic peptide; NYHA = New York Heart Association; OLE = open-label extension; PND = polyneuropathy disability; SD = standard deviation; SEM = standard error of the mean; wtATTR = wild-type transthyretin amyloidosis.

Updated 27 February 2025

 References

1.  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. Published online January 13, 2025. doi:10.1001/jamaneurol.2024.4631

2.  Adams, Polydefkis, González-Duarte, et al. Long-term safety and efficacy of patisiran for hereditary transthyretin-mediated amyloidosis with polyneuropathy: 12-month results of an open-label extension study. Lancet Neurol. 2021;20(1):49-59. doi:10.1016/S1474-4422(20)30368-9

3.  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.

4.  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. Published online January 13, 2025. doi:10.1001/jamaneurol.2024.4631.

5.  Supplement to: Adams D, Polydefkis M, González-Duarte A, et al. Long-term safety and efficacy of patisiran for hereditary transthyretin-mediated amyloidosis with polyneuropathy: 12-month results of an open-label extension study. Lancet Neurol. 2021;20(1):49-59. doi:10.1016/S1474-4422(20)30368-9