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Cited by 462Amyloidosis: Diagnosis, Treatment, OutcomesAlzheimer's disease research and treatmentsAmyotrophic Lateral Sclerosis Research

Effects of Patisiran, an RNA Interference Therapeutic, on Cardiac Parameters in Patients With Hereditary Transthyretin-Mediated Amyloidosis: Analysis of the APOLLO Study

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Solomon, Scott D., Adams, David, Kristen, Arnt, Grogan, Martha, González-Duarte, Alejandra, Maurer, Mathew S., Merlini, Giampaolo, Damy, Thibaud +12 more·2019·Circulation
DOI 10.1161/circulationaha.118.035831PMC PMC12611557
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Abstract

Background: Hereditary transthyretin-mediated (hATTR) amyloidosis is a rapidly progressive, multisystem disease that presents with cardiomyopathy or polyneuropathy. The APOLLO study assessed the efficacy and tolerability of patisiran in patients with hATTR amyloidosis. The effects of patisiran on cardiac structure and function in a prespecified subpopulation of patients with evidence of cardiac amyloid involvement at baseline were assessed. Methods: APOLLO was an international, randomized, double-blind, placebo-controlled phase 3 trial in patients with hATTR amyloidosis. Patients were randomized 2:1 to receive 0.3 mg/kg patisiran or placebo via intravenous infusion once every 3 weeks for 18 months. The prespecified cardiac subpopulation comprised patients with a baseline left ventricular wall thickness ≥13 mm and no history of hypertension or aortic valve disease. Prespecified exploratory cardiac end points included mean left ventricular wall thickness, global longitudinal strain, and N -terminal prohormone of brain natriuretic peptide. Cardiac parameters in the overall APOLLO patient population were also evaluated. A composite end point of cardiac hospitalizations and all-cause mortality was assessed in a post hoc analysis. Results: In the cardiac subpopulation (n=126; 56% of total population), patisiran reduced mean left ventricular wall thickness (least-squares mean difference ± SEM: –0.9±0.4 mm, P =0.017), interventricular septal wall thickness, posterior wall thickness, and relative wall thickness at month 18 compared with placebo. Patisiran also led to increased end-diastolic volume (8.3±3.9 mL, P =0.036), decreased global longitudinal strain (–1.4±0.6%, P =0.015), and increased cardiac output (0.38±0.19 L/min, P =0.044) compared with placebo at month 18. Patisiran lowered N -terminal prohormone of brain natriuretic peptide at 9 and 18 months (at 18 months, ratio of fold-change patisiran/placebo 0.45, P <0.001). A consistent effect on N -terminal prohormone of brain natriuretic peptide at 18 months was observed in the overall APOLLO patient population (n=225). Median follow-up duration was 18.7 months. The exposure-adjusted rates of cardiac hospitalizations and all-cause death were 18.7 and 10.1 per 100 patient-years in the placebo and patisiran groups, respectively (Andersen–Gill hazard ratio, 0.54; 95% CI, 0.28–1.01). Conclusions: Patisiran decreased mean left ventricular wall thickness, global longitudinal strain, N -terminal prohormone of brain natriuretic peptide, and adverse cardiac outcomes compared with placebo at month 18, suggesting that patisiran may halt or reverse the progression of the cardiac manifestations of hATTR amyloidosis. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01960348.

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  • Current ATTR amyloidosis treatments are limited by the requirement for long-term administration to maintain TTR knockdown.

    “but are limited by the requirement for long-term administration to maintain TTR knockdown.”

    From CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis (2021) · cites this paper as [14]

    The Methods (Study Design and Treatment; page unavailable) report patisiran infusions every three weeks for 18 months, and the introductory passage describes its reduction of TTR protein. The paper does not establish that long-term administration is required to maintain TTR knockdown or characterize that requirement as a limitation of current ATTR treatments generally. (LLM, conf=0.82)

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Authors
Solomon, S. D., Adams, D., Kristen, A., Grogan, M., González-Duarte, A., Maurer, M. S., Merlini, G., Damy, T., Slama, M. S., Brannagan, T. H., Dispenzieri, A., Berk, J. L., Shah, A. M., Garg, P., Vaishnaw, A., Karsten, V., Chen, J., Gollob, J., Vest, J., & Suhr, O.
Affiliations
  • Brigham and Women's Hospital (US)
  • Université Paris-Sud (FR)
  • Heidelberg University (DE)
  • Mayo Clinic (US)
  • Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, Mexico (A.G.-D.).
  • Columbia University Irving Medical Center (US)
  • University of Pavia (IT)
  • Inserm (FR)
  • Columbia University (US)
  • Boston Medical Center (US)
  • Alnylam Pharmaceuticals (United States) (US)
  • Umeå University (SE)
ORCID
Venue
Circulation
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2019-01-22
Volume
139
Issue
4
Pages
431-443
ISSN
  • 0009-7322 (ISSN-L)
  • 1524-4539
DOI
10.1161/circulationaha.118.035831
PMC
PMC12611557
OpenAlex
W2912435333
Cited by
462
References
29
Citations by year
2026: 13 · 2025: 55 · 2024: 60 · 2023: 63 · 2022: 67 · 2021: 74 · 2020: 71 · 2019: 57 · 2018: 2
FWCI
22.26
Type
journal article
Language
en
Open access
Locations
  • Circulation (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
Funders
  • Alnylam Pharmaceuticals
  • National Heart, Lung, and Blood Institute (K24HL152008, R01HL135008)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Amyloidosis: Diagnosis, Treatment, Outcomes
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
Keywords
patisiran, hereditary transthyretin amyloidosis, cardiac amyloidosis, prealbumin, RNA interference, left ventricular wall thickness, global longitudinal strain, cardiac function, cardiac hospitalization, all-cause mortality, APOLLO trial, cardiomyopathy, end-diastolic volume
MeSH terms
RNAi Therapeutics, Adolescent, Adult, Aged, Aged, 80 and over, Double-Blind Method, Female, Humans, Male, Middle Aged, Cardiomyopathies, Patient Admission, Peptide Fragments, Prealbumin, Time Factors, Biomarkers, Ventricular Function, Left, Treatment Outcome, Natriuretic Peptide, Brain, Recovery of Function, Ventricular Remodeling, Amyloid Neuropathies, Familial, RNA, Small Interfering, Young Adult

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