Design and rationale of FLAVOUR: A phase IIa efficacy study of the 5-lipoxygenase activating protein antagonist AZD5718 in patients with recent myocardial infarction

Eva Prescott; John Pernow; Antti Saraste; Axel Åkerblom; Oskar Angerås; David Erlinge; Erik L Grove; Marja Hedman; Lisette O Jensen; Sara Svedlund; Magnus Kjaer; Maria Lagerström-Fermér; Li-Ming Gan

doi:10.1016/j.conctc.2020.100629

Design and rationale of FLAVOUR: A phase IIa efficacy study of the 5-lipoxygenase activating protein antagonist AZD5718 in patients with recent myocardial infarction

Contemp Clin Trials Commun. 2020 Jul 30:19:100629. doi: 10.1016/j.conctc.2020.100629. eCollection 2020 Sep.

Authors

Eva Prescott¹, John Pernow², Antti Saraste³, Axel Åkerblom⁴, Oskar Angerås⁵, David Erlinge⁶, Erik L Grove^{7

8}, Marja Hedman⁹, Lisette O Jensen¹⁰, Sara Svedlund¹¹, Magnus Kjaer¹², Maria Lagerström-Fermér¹³, Li-Ming Gan^{5

13}

Affiliations

¹ Department of Cardiology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark.
² Division of Cardiology, Department of Medicine, Karolinska Institute, Heart and Vascular Theme, Karolinska University Hospital, Stockholm, Sweden.
³ University of Turku and Heart Centre, Turku University Hospital, Turku, Finland.
⁴ Department of Medical Sciences - Cardiology, and Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden.
⁵ Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, and Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden.
⁶ Cardiology, Department of Clinical Sciences, Lund University and Skåne University Hospital, Lund, Sweden.
⁷ Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark.
⁸ Department of Cardiology, Aarhus University Hospital, Aarhus, Denmark.
⁹ Department of Cardiothoracic Surgery, Heart Center, Kuopio University Hospital, Kuopio, Finland.
¹⁰ Department of Cardiology, Odense University Hospital, Odense, Denmark.
¹¹ Department of Clinical Physiology, Sahlgrenska University Hospital, and Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
¹² Early Biometrics and Statistical Innovation, Data Science & AI, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
¹³ Research and Early Development, Cardiovascular, Renal and Metabolic, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.

Abstract

Patients with coronary artery disease remain at increased risk of recurrent life-threatening cardiovascular events even after adequate guideline-based treatment of conventional risk factors, including blood lipid levels. Inflammation is a critical pathway in the pathogenesis of atherosclerosis and is independently associated with risk of recurrent cardiovascular events. Leukotrienes are potent pro-inflammatory and vasoactive mediators synthesized by leukocytes in atherosclerotic lesions. AZD5718 is a novel antagonist of 5-lipoxygenase activating protein that suppresses leukotriene biosynthesis. FLAVOUR is a phase IIa efficacy and safety study of AZD5718 in patients with myocardial infarction 1-4 weeks before randomization. Stenosis of the left anterior descending coronary artery after percutaneous intervention must be <50%, and Thrombolysis In Myocardial Infarction flow grade must be ≥ 2. Enrolled participants receive standard care plus oral AZD5718 200 mg, 50 mg, or placebo once daily for up to 12 weeks (extended from 4 weeks by protocol amendment). The planned sample size is 100 participants randomized to 12 weeks' treatment. Change in urine leukotriene E₄ levels is the primary efficacy outcome. FLAVOUR also aims to evaluate whether AZD5718 can improve coronary microvascular function, as measured by transthoracic colour Doppler-assisted coronary flow velocity reserve. Centrally pretrained study sonographers use standardized protocols and equipment. Additional outcomes include assessment of comprehensive echocardiographic parameters (including coronary flow, global strain, early diastolic strain rate and left ventricular ejection fraction), arterial stiffness, biomarkers, health-related quality of life, and safety. Specific anti-inflammatory therapies may represent novel promising treatments to reduce residual risk in patients with coronary artery disease. By combining primary pharmacodynamic and secondary cardiovascular surrogate efficacy outcomes, FLAVOUR aims to investigate the mechanistic basis and potential benefits of AZD5718 treatment in patients with coronary artery disease.

Keywords: 5-Lipoxygenase activating protein; Coronary flow reserve; Coronary flow velocity reserve; Echocardiography; Leukotrienes; Myocardial infarction.