AstraZeneca’s investigational MPO inhibitor AZD4831 shows promise in patients with heart failure and a preserved ejection fraction

Results from the Phase IIa SATELLITE trial demonstrated that AZD4831, a myeloperoxidase (MPO) inhibitor, achieved pre-specified target engagement in patients with heart failure with preserved ejection fraction (HFpEF), supporting the further development of this novel therapy.¹

In HFpEF, microvascular inflammation is proposed as an underlying mechanism of disease.² AZD4831 represents a unique class of MPO inhibitors, which have been shown to reduce inflammation and fibrosis, and improve microvascular function in preclinical models.³

Findings from a planned interim analysis of the SATELLITE trial showed a 69% (95% CI: 36.3, 85.0) reduction in MPO activity in the AZD4831 group from baseline to day 30.¹ AZD4831 was generally well tolerated, with no new clinically significant safety findings.¹ The trial was stopped early based on data confirming target engagement and satisfactory safety profile.¹

There were no statistically significant differences seen between the AZD4831 and placebo groups in change from baseline in coronary flow velocity reserve (CFVR) and 6-minute walk distance (6MWD), both secondary endpoints, or in change from baseline in N-terminal pro B-type natriuretic peptide (NT-proBNP) and Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ-OSS), two exploratory endpoints. There were however, numerical increases in exercise capacity (6MWD) and wellness (KCCQ-OSS) scores in patients treated with AZD4831.¹

Professor Carolyn Lam, Senior Consultant, National Heart Centre Singapore and SATELLITE study lead investigator, said: “Heart failure with preserved ejection fraction is associated with high hospitalisation rates, poor quality of life and increased mortality, yet it remains an area of significant unmet need, with limited treatment options. The SATELLITE trial findings shared today show the potential of MPO inhibition with AZD4831 to help address this important need.”

Regina Fritsche Danielson, Senior Vice President and Head of Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, said: “These new data from the SATELLITE trial support the further development of AZD4831 as a first-in-class molecule in the treatment of heart failure with preserved ejection fraction. We are also investigating the potential of this exciting therapy in other life-threatening conditions which are driven by inflammatory responses, such as non-alcoholic fatty liver disease, chronic kidney disease and coronary artery disease.”

Additionally, in an ad hoc exploratory analysis of molecular signatures using data from the SATELLITE trial, proteomic abnormalities associated with increased morbidity and mortality in patients with HFpEF were partially reversed by AZD4831 treatment. These results support that MPO is causally involved in the inflammatory pathophysiology, and also underpin the value of further investigation of MPO inhibition in HFpEF.⁴

Results from both analyses were presented today at the Heart Failure 2021 online congress.^1,4

Heart failure (HF) and heart failure with preserved ejection fraction (HFpEF)

HF is a chronic disease where half of patients will die within five years of diagnosis.⁵ HFpEF occurs when the heart is unable to fill with blood sufficiently, due to increased stiffness of the muscle in the left ventricle and its inability to relax. HFpEF represents about half of all HF cases,⁶ and is highly prevalent in patients with hypertension, diabetes, obesity, metabolic syndrome or chronic kidney disease.⁷ HF remains as fatal as some of the most common cancers in both men (prostate and bladder cancers) and women (breast cancer).⁸ Chronic HF is the leading cause of hospitalisation for those over the age of 65 and represents a significant clinical and economic burden.⁹

SATELLITE

SATELLITE is a Phase IIa randomised, double-blind, placebo-controlled, parallel group, multicentre study to assess the target engagement, safety and tolerability of AZD4831 in patients with HFpEF. Patients aged 45–85 were randomized 2:1 to receive either once-daily AZD4831 five milligrams (mg), escalated from 2.5mg on day 10, or placebo for 90 days. Of the 41 randomised patients (AZD4831, n=27; placebo, n=14), 31 completed 90 days’ treatment (AZD4831, n= 23; placebo, n=8).^1,10 The trial was initially paused due to the COVID-19 pandemic and consequently stopped early based on available data.¹

AZD4831

AZD4831 is an investigational, first-in-class myeloperoxidase (MPO) inhibitor for patients diagnosed with HFpEF, to increase survival, reduce hospitalisation and improve quality of life. The molecule was developed in-house at AstraZeneca.

AZD4831 inhibits MPO, known to cause the formation of hypochlorous acid and other free radicals that interfere with microvascular function (the tiny artery blood vessels in the heart).¹¹ In addition, MPO has been shown to be involved in the biology of atherosclerotic plaques and development of coronary artery disease,¹¹ considered one of the more important comorbidities driving HFpEF. AZD4831 is currently being investigated in Phase II trials in HFpEF and in preclinical development for chronic kidney disease and nonalcoholic steatohepatitis.

AstraZeneca in CVRM

Cardiovascular, Renal and Metabolism (CVRM), part of BioPharmaceuticals, forms one of AstraZeneca’s three therapy areas and is a key growth driver for the Company. By following the science to understand more clearly the underlying links between the heart, kidneys and pancreas, AstraZeneca is investing in a portfolio of medicines for organ protection and to improve outcomes by slowing disease progression, reducing risks and tackling co-morbidities. The Company’s ambition is to modify or halt the natural course of CVRM diseases and potentially regenerate organs and restore function, by continuing to deliver transformative science that improves treatment practices and cardiovascular health for millions of patients worldwide.

AstraZeneca
AstraZeneca (LSE/STO/Nasdaq: AZN) is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialisation of prescription medicines in Oncology and BioPharmaceuticals, including Cardiovascular, Renal & Metabolism, and Respiratory & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 100 countries, and its innovative medicines are used by millions of patients worldwide. Please visit astrazeneca.com and follow the Company on Twitter @AstraZeneca.

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References

1. Lam CSP, Voors AA, Shah SJ et al. Myeloperoxidase inhibitor AZD4831 target engagement and safety in a phase 2a study in patients with heart failure with preserved ejection fraction (SATELLITE). Abstract presented at Heart Failure 2021.
2. Hage C, Michaëlsson E, Kull Myeloperoxidase and related biomarkers are suggestive footprints of endothelial microvascular inflammation in HFpEF patients. ESC Heart Fail 2020 Aug;7(4):1534-1546. doi: 10.1002/ehf2.12700. Epub 2020 May 19.
3. Nelander K, Lagerstrom-Fermer M, Amilon C, et al. Early Clinical Experience With AZD4831, A Novel Myeloperoxidase Inhibitor, Developed for Patients With Heart Failure With Preserved Ejection Fraction. Clin Transl Sci. 2021 May;14(3):812-819.
4. Michaëlsson E, Hage C, Lund LH et al. Myeloperoxidase inhibition reverses the inflammatory proteomic pattern in heart failure with preserved ejection fraction. Abstract presented at Heart Failure 2021.
5. Mozaffarian D et al. Heart Disease and Stroke Statistics-2016 Update: A Report From the American Heart Association. Circulation 2016; 133(4):e38-360.
6. Dunlay, S., Roger, V. & Redfield, M. Epidemiology of heart failure with preserved ejection fraction. Nat Rev Cardiol 14, 591–602 (2017).
7. Oktay AS and Shah Diagnosis and Management of Heart Failure with Preserved Ejection Fraction: 10 Key Lessons. Curr Cardiol Rev.2015 Feb; 11(1): 42–52.
8. Mamas MA et al. Do patients have worse outcomes in heart failure than in cancer? A primary care-based cohort study with 10-year follow-up in Scotland. Eur J Heart Fail 2017; 19(9):1095–104.
9. Azad N, Lemay G. Management of chronic heart failure in the older population. J Geriatr Cardiol 2014; 11(4):329–37.
10. gov. Safety and Tolerability Study of AZD4831 in patients with heart failure. (SATELLITE). Available at: https://clinicaltrials.gov/ct2/show/NCT03756285. Last accessed June 2021.
11. Gan L‐M, Lagerström‐Fermér M, Ericsson H, et al. Safety, tolerability, pharmacokinetics and effect on serum uric acid of the myeloperoxidase inhibitor AZD4831 in a randomized, placebo‐controlled, phase I study in healthy volunteers. Br J Clin Pharmacol. 2019;85:762–770.