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Impact of vutrisiran on exploratory cardiac parameters in hereditary transthyretin-mediated amyloidosis with polyneuropathy

Publication Details

European Journal of Heart Failure

February 2024

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Author(s)

Pablo Garcia-Pavia^{1 2 3}, Martha Grogan⁴, Parag Kale⁵, John L Berk⁶, Mathew S Maurer⁷, Isabel Conceição⁸, Marcelo Di Carli⁹, Scott D Solomon¹⁰, Chongshu Chen¹¹, Elena Yureneva¹¹, John Vest¹¹, Julian D Gillmore¹²

Affiliations

¹Department of Cardiology, Hospital Universitario Puerta de Hierro, Madrid, Spain; ²Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain;³Universidad Francisco de Vitoria (UFV), Pozuelo de Alarcon, Spain; ⁴Department of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA; ⁵Center for Advanced Heart and Lung Disease, Baylor University Medical Center, Dallas, TX, USA; ⁶Amyloidosis Center, Boston Medical Center, Boston University, Boston, MA, USA; ⁷Division of Cardiology, Department of Medicine, Center for Advanced Cardiac Care, Columbia University Irving Medical Center, New York, NY, USA; ⁸Centro Hospitalar Universitário Lisboa Norte, Hospital de Santa Maria and Faculdade de Medicina, Lisbon, Portugal; ⁹Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; ¹⁰Cardiovascular Division, Brigham and Women's Hospital, Boston, MA, USA; ¹¹Alnylam Pharmaceuticals, Cambridge, MA, USA; ¹²National Amyloidosis Centre, University College London, Royal Free Hospital, London, UK

Abstract

Aims:

HELIOS-A was a Phase 3, open-label study of vutrisiran, an RNA interference therapeutic, in patients with hereditary transthyretin (ATTRv) amyloidosis with polyneuropathy. This analysis evaluated vutrisiran's impact on exploratory cardiac endpoints in HELIOS-A patients.

Methods and Results:

Patients were randomized 3:1 to subcutaneous vutrisiran 25 mg every 3 months or intravenous patisiran 0.3 mg/kg every 3 weeks (reference group) for 18 months. Exploratory cardiac endpoints included change from baseline in N-terminal prohormone of brain-type natriuretic peptide (NT-proBNP) and echocardiographic parameters versus external placebo (APOLLO study). The modified intent-to-treat (mITT) population comprised randomized patients receiving any study drug (n = 122). A cardiac subpopulation with evidence of cardiac amyloid involvement (n = 40) was prespecified. 99mTc scintigraphy exploratory assessments in a planned vutrisiran-treated cohort at select sites were compared with baseline. At Month 18, vutrisiran demonstrated beneficial effects on NT-proBNP versus external placebo in the mITT and cardiac subpopulations (adjusted geometric mean fold change ratio [95% confidence interval] 0.480 [0.383–0.600], p = 9.606 × 10−10 and 0.491 [0.337–0.716], p = 0.0004, respectively). Benefits or trends towards benefit in echocardiographic parameters versus external placebo were observed for both populations. In 99mTc scintigraphy assessments, 32/47 (68.1%) and 31/48 (64.6%) patients exhibited reduced normalized left ventricular total uptake and heart-to-contralateral lung ratio, respectively. Perugini grade was reduced or unchanged versus baseline in 55/57 (96.5%) evaluable patients. No increase in cardiac adverse events was observed with vutrisiran versus external placebo.

Conclusions:

Vutrisiran demonstrated evidence of potential benefit on cardiac manifestations in patients with ATTRv amyloidosis with polyneuropathy, with an acceptable safety profile.