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Publications

Journal Article Ahead of print 1 citation

PubMed: 42742182 DOI: 10.1038/s41591-026-04670-6

Eplontersen with and without background transthyretin stabilizers in transthyretin amyloid cardiomyopathy: secondary analysis of a phase 3, randomized controlled trial.

Nat Med

Authors: Pablo García-Pavía, Francesco Cappelli, Margot K Davis, Marianna Fontana, Julian D Gillmore, Mazen Hanna, Ahmad Masri, Laura Obici, Scott D Solomon, Brett W Sperry, Nobuhiro Tahara, Márcia Waddington-Cruz, Kurt Boman, Sarah A M Cuddy, Philippe Debonnaire, Nowell M Fine, Piotr Podolec, Ali Yilmaz, Tom Conrad, Qingqing Yang, Brian L Claggett, Jersey Chen, Sotirios Tsimikas, Mathew S Maurer

Affiliations

  • Department of Cardiology, Hospital Universitario Puerta de Hierro Majadahonda, IDIPHIM, CIBERCV, and Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
  • Tuscan Regional Amyloidosis Center, Department of Clinical and Experimental Medicine, Careggi University Hospital, Florence, Italy.
  • Division of Cardiology, University of British Columbia, Vancouver, BC, Canada.
  • National Amyloidosis Centre, Division of Medicine, University College London, Royal Free Hospital, London, United Kingdom.
  • Amyloidosis Center, Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH, USA.
  • Division of Cardiovascular Medicine, Oregon Health and Sciences University, Portland, OR, USA.
  • Amyloidosis Research and Treatment Centre, IRCCS Fondazione Policlinico San Matteo, Pavia, Italy.
  • Cardiovascular Division, Brigham and Women's Hospital, Boston, MA, USA.
  • Saint Luke's Mid America Heart Institute, Kansas City, MO, USA.
  • Division of Cardiovascular Medicine, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.
  • Centro de Paramiloidose Antônio Rodrigues de Mello (CEPARM), Amyloidosis Center, University Hospital, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil; Amyloidosis Center, Complexo Hospitalar Américas- Samaritano-Vitória, Barra da Tijuca, Rio de Janeiro, Brazil.
  • Research Unit, Skellefteå County Hospital, Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.
  • Amyloidosis Program, Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • Cardiology Department, AZ Sint-Jan Brugge, Bruges, Belgium.
  • Libin Cardiovascular Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
  • Department of Cardiac and Vascular Diseases, Jagiellonian University Medical College, John Paul II Hospital, Krakow, Poland.
  • Division of Cardiovascular Imaging, Department of Cardiology I, University Hospital Münster, Münster, Germany.
  • Late-Stage Development, Cardiovascular, Renal, and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, MD, USA.
  • Ionis Pharmaceuticals Inc, Carlsbad, CA, USA.
  • Columbia University Irving Medical Center, New York, NY, USA.

Abstract

Transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) therapies include both TTR gene silencers and TTR stabilizers. The role of TTR gene silencers added to background TTR stabilizer therapy is unknown, and the effects of silencer treatment in the absence of stabilizer use is unclear. In the CARDIO-TTRansform study, 1,432 patients, (n=135 [9.4%] female and n=1297 [90.6%] male), with ATTR-CM were randomized (1:1) and treated with the antisense oligonucleotide eplontersen (45 mg every 4 weeks) targeting TTR or with placebo for up to 140 weeks. Fifty-seven percent of patients were taking TTR stabilizers at baseline. In the overall study, treatment with eplontersen did not significantly reduce the primary composite endpoint. Here, in a prespecified analysis, we show that the primary endpoint (a composite of cardiovascular mortality and recurrent cardiovascular events) was modified by baseline stabilizer use (P interaction = 0.017). Benefit was seen in those patients not on stabilizers at baseline (RR 0.71, 95% CI, 0.54-0.93, P = 0.012), whereas no benefit seen in those on stabilizers at baseline (RR 1.14, 95% CI, 0.85-1.53, P = 0.39). The safety profile of eplontersen was favorable, irrespective of baseline stabilizer use. Treatment with eplontersen versus placebo demonstrated a clinically meaningful benefit among patients not receiving background stabilizers but provided no additional clinical benefit in those on background stabilizer therapy. These findings of a strong treatment effect modification may offer insight for therapeutic decision-making in clinical practice. ClinicalTrials.gov registration: NCT04136171.

MeSH

Genes, Molecular Biology, Prealbumin, Therapeutics, Amyloid, Cardiomyopathies, Transthyretin Amyloid Cardiomyopathy