https://doi.org/10.1007/s00392-024-02526-y
1Toulouse University Hospital Department of Cardiology Toulouse, Frankreich; 2Hôpital Bichat Claude Bernard ervice de Cardiologie, Unité de Rythmologie Paris, Deutschland; 3French Referral Center for Cardiac Amyloidosis GRC Amyloid Research Institute and Department of Cardiology Créteil, Frankreich; 4Hôpital Pontchaillou Service de Cardiologie Rennes, Frankreich; 5Alnylam Pharmaceuticals Research & Development Cambridge, MA, USA; 6Alnylam Pharmaceuticals Medical Affairs Paris, Frankreich; 7Université Paris Sud, APHP Centre national de référence des neuropathies amyloïdes familiales (NNERF) Le Kremlin Bicêtre Cedex, Frankreich
Introduction:
Transthyretin-mediated (ATTR) amyloidosis is a progressive, fatal disease in which the most serious manifestations are polyneuropathy and cardiomyopathy. Patients with hereditary ATTR (ATTRv; v for variant) amyloidosis commonly develop a mixed phenotype, and patients with wild-type ATTR amyloidosis predominantly have cardiomyopathy, although polyneuropathy may coexist. Patisiran, an RNAi therapeutic that rapidly knocks down TTR, has shown long-term benefit on measures of polyneuropathy in the APOLLO open-label extension (OLE) study in patients with ATTRv amyloidosis.
Purpose:
To evaluate the long-term benefit of patisiran on survival, hospitalisations and cardiac parameters in a pooled cohort of patients with ATTR amyloidosis and evidence of cardiac involvement, across the patisiran clinical programme (Phase [Ph] 2 launched in 2012).
Methods:
Post hoc analysis of pooled data from cardiac subpopulations of patients with ATTRv amyloidosis and polyneuropathy from 5-year Global OLE (NCT02510261; Ph 2 OLE [NCT01961921] and Ph 3 APOLLO [NCT01960348]; patients with baseline left ventricular [LV] wall thickness ≥13 mm; absence of history of aortic valve disease or hypertension), and Ph 3 APOLLO-B (NCT03997383; patients with wild-type or ATTRv cardiac amyloidosis). Patients received patisiran or placebo every 3 weeks for 18 months in APOLLO and 12 months in APOLLO-B; all patients received patisiran thereafter. Analyses included Kaplan-Meier estimates and Cox regression of survival and all-cause hospitalisations, and summary statistics of cardiac biomarkers and echocardiographic parameters by initial treatment arm.
Results:
Pooled analysis included 496 patients (initial arm placebo, n=214; initial arm patisiran, n=282). Compared with placebo, patients initially receiving patisiran had better long-term survival and fewer hospitalisations (hazard ratio [95% confidence interval] over 84 months for all-cause mortality and all-cause hospitalisations: 0.59 [0.37–0.93] [Figure 1] and 0.77 [0.60–0.99], respectively). At baseline, NT-proBNP and troponin I levels, peak longitudinal strain and LV wall thickness were comparable between patisiran vs placebo-treated patients. Placebo-treated patients showed worsening of all these parameters whilst on placebo; the rates of worsening decreased once the patients initiated patisiran. In contrast, patients who initially received patisiran demonstrated relative stability over 84 months in the Global OLE and significant benefit compared with those initially treated with placebo.
Conclusion:
Long-term benefit of patisiran in patients with cardiomyopathy was observed on survival, hospitalisations, cardiac biomarkers and echocardiographic parameters. Outcomes were significantly more favourable for those initially randomised to patisiran than placebo, highlighting the impact of initiating treatment early in the course of disease.