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Atopaxar and its effects on markers of platelet activation and inflammation: results from the LANCELOT CAD program

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Abstract

Atopaxar is a reversible protease activated receptor (PAR)-1 thrombin receptor antagonist that interferes with platelet signaling. The effects of PAR-1 antagonists on biomarkers remain unknown. The primary objective was to assess the effects of atopaxar on biomarkers of inflammation and platelet activation. The LANCELOT-CAD trial randomized 720 subjects to atopaxar (50, 100, or 200 mg daily) or matching placebo for 24 weeks. Biomarkers were assessed at serial time points. A linear mixed model to account for repeated measures was used to evaluate the change in biomarker concentration from randomization across time to week 24. Least square means were determined from the linear mixed models. The concentration of sCD40L decreased on average over time by −553 (95 % CI −677, −429) ng/L in the combined atopaxar group versus −30.3 (−249 to 189) ng/L fall in the placebo arm (P < 0.001) and a dose-dependent trend was seen across treatment groups (P < 0.001 for trend). In contrast, Lp-PLA2 mass rose on average over time by 12.6 (95 % CI 10.0, 15.3) ng/ml in the combined atopaxar group as compared with 2.6 (95 % CI −2.1, 7.3) ng/ml in the placebo arm (P < 0.001). Similarly, the concentration of IL-18 rose by 17.5 (95 % CI 12.4, 22.6) pg/ml in the atopaxar group versus a −1.2 (95 % CI −10.2, 7.8) pg/ml fall in the placebo group (P < 0.001). The effects of atopaxar on Lp-PLA2 and IL-18 appeared to be dose-dependent (P < 0.001 for trend) and were observed in J-LANCELOT. Atopaxar did not have a significant effect on other inflammatory markers. In conclusion, atopaxar appeared to decrease sCD40L, but did not demonstrate an anti-inflammatory effect in patients with stable CAD. Although atopaxar increased the concentration of Lp-PLA2 and IL-18, the clinical relevance of these findings remains unknown and warrants further investigation and validation.

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Acknowledgments

The LANCELOT program and biomarker analyses were funded by Eisai Incorporated.

Conflict of interest

Dr. O’Donoghue has received research grants from Eisai, GlaxoSmithKline and Astra Zeneca. Dr. Bhatt discloses the following relationships - Advisory Board: Medscape Cardiology; Board of Directors: Boston VA Research Institute, Society of Chest Pain Centers; Chair: American Heart Association Get With The Guidelines Science Subcommittee; Honoraria: American College of Cardiology (Editor, Clinical Trials, Cardiosource), Duke Clinical Research Institute (clinical trial steering committees), Slack Publications (Chief Medical Editor, Cardiology Today Intervention), WebMD (CME steering committees); Research Grants: Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Sanofi Aventis, The Medicines Company; Unfunded Research: PLx Pharma, Takeda. Dr Flather has received honoraria for his participation at meetings related to the development of atopaxar and also receives research grants and honoraria for speaker meetings and advisory boards from sanofi aventis, Bristol Myers Squibb, Eli Lilly, Daiichi Sankyo, Novartis and GlaxoSmithKline. Dr. Goto has received research grants from sanofi aventis, Eisai, Otsuka; honoraria from sanofi aventis, Eisai, Otsuka; consulting fees from Merck and Eisai. Dr. Angiolillo reports honoraria for lectures from Bristol Myers Squibb, sanofi aventis, Eli Lilly, Daiichi Sankyo, Abbott Vascular, and Astra Zeneca; consulting fees from Bristol-Myers Squibb, sanofi aventis, Eli Lilly, Daiichi Sankyo, The Medicines Company, Portola, Novartis, Medicure, Accumetrics, Arena Pharmaceuticals, Merck, Abbott Vascular, and Astra Zeneca; and research grants from GlaxoSmithKline, Otsuka, Boston Scientific, Eli Lilly, Daiichi Sankyo, The Medicines Company, Portola, Accumetrics, Schering-Plough, Astra Zeneca, Eisai, Evolva, and Johnson and Johnson. Dr. Goodman has received research grant support and/or speaking/consulting/advisory board honoraria from Eisai, sanofi-aventis, Bristol Myers Squibb, Eli Lilly, Daiichi Sankyo, Astra Zeneca, and Merck. Dr Zeymer has received honoraria for his participation at meetings related to the development of atopaxar; research grants and honoraria for speaker meetings and advisory boards from sanofi aventis, Bristol Myers Squibb, Eli Lilly, Daiichi Sankyo and Astra Zeneca; consulting fees for Eli Lilly, Astra Zeneca and sanofi aventis. Dr. Aylward has received grants from Eisai, Merck and Astra Zeneca; speaking fees and/or honoraria from Astra Zeneca, sanofi Aventis, Boehringer Ingelheim, Merck; consulting fees for Astra Zeneca, Pfizer and Boehringer Ingelheim. Dr. Montalescot has received grants, consulting fees and/or lecture fees from Abott Vascular, BMS, Boston Scientific, Centocor, Eli Lilly, INSERM, ITC Edison, Medtronic, Pfizer, sanofi Aventis, Stago, Astra Zeneca, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Eisai, Eli Lilly, Menarini, Novartis, Portola, The Medicines Company, Accumetrics, Cordis, GSK, Menarini, Merck. Dr. Ziecina is an employee of Eisai. Fang Ren has no disclosures. Dr Wiviott has received grants from Eli Lilly, Daiichi Sankyo, Schering Plough; consulting fees from Bristol Myers Squibb, sanofi aventis, Astra Zeneca, ARENA, Medco.

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Authors and Affiliations

  1. Cardiovascular Division and TIMI Study Group, Brigham and Women’s Hospital, 350 Longwood Avenue, 1st floor, Boston, MA, 02115, USA

    Michelle L. O’Donoghue, Fang Ren & Stephen D. Wiviott

  2. VA Boston Healthcare System and TIMI Study Group, Brigham and Women’s Hospital, Boston, MA, USA

    Deepak L. Bhatt

  3. Clinical Trials and Evaluation Unit, Royal Brompton Hospital, London, UK

    Marcus D. Flather

  4. Department of Medicine (Cardiology), Tokai University School of Medicine, Kanagawa, Japan

    Shinya Goto

  5. University of Florida College of Medicine, Jacksonville, FL, USA

    Dominick J. Angiolillo

  6. Division of Cardiology, St. Michael’s Hospital, University of Toronto, Toronto, ON, Canada

    Shaun G. Goodman

  7. Herzzentrum Ludwigshafen, Ludwigshafen, Germany

    Uwe Zeymer

  8. Department of Cardiovascular Medicine, Flinders Cardiovascular Centre, Adelaide, SA, Australia

    Philip E. Aylward

  9. Institut de Cardiologie, Pitié-Salpêtrière University Hospital, Paris, France

    Gilles Montalescot

  10. Eisai Ltd, Frontier Product Creation Unit, European Knowledge Centre, Hatfield, UK

    Rafal Ziecina

  11. Department of Clinical Pharmacology, Tokai University School of Medicine, Kanagawa, Japan

    Hiroyuki Kobayashi

Authors
  1. Michelle L. O’Donoghue
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  2. Deepak L. Bhatt
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  3. Marcus D. Flather
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  4. Shinya Goto
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  5. Dominick J. Angiolillo
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  6. Shaun G. Goodman
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  7. Uwe Zeymer
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  8. Philip E. Aylward
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  9. Gilles Montalescot
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  10. Rafal Ziecina
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  11. Hiroyuki Kobayashi
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  12. Fang Ren
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  13. Stephen D. Wiviott
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Corresponding author

Correspondence to Michelle L. O’Donoghue.

Additional information

This study was conducted on behalf of the LANCELOT Investigators.

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O’Donoghue, M.L., Bhatt, D.L., Flather, M.D. et al. Atopaxar and its effects on markers of platelet activation and inflammation: results from the LANCELOT CAD program. J Thromb Thrombolysis 34, 36–43 (2012). https://doi.org/10.1007/s11239-012-0750-6

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  • DOI: https://doi.org/10.1007/s11239-012-0750-6

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