AZ drug for hard-to-treat heart failure has mixed results in trial

AstraZeneca has reported the first phase 2 results with a drug for heart failure with preserved ejection fraction (HFpEF), showing it worked as expected but wasn’t able to provide any clinical benefit to patients. 

Daily doses of AZD4831 were able to reduce the activity of myeloperoxidase (MPO), an enzyme linked to tissue and blood vessel damage due to inflammation and scar tissues formation (fibrosis) in models of cardiovascular disease, by 69% after 30 days in the phase 2a SATELLITE study.

However, the MPO inhibitor was no different to placebo on clinical measures associated with heart failure – including the change from baseline in coronary flow velocity reserve (CFVR) and six-minute walk distance (6MWD) – although that’s not wholly surprising in an early-stage trial in heart failure.

It also missed the mark in two exploratory outcome measures – the change from baseline in NT-pro BNP – a peptide released from the walls of the heart when it is overloaded – and the KCCQ scale used to measures patients’ perception of their health status, including heart failure symptoms.

The drugmaker is sticking with the drug, saying that there were trends in favour of AZD4831 with numerical increases in exercise capacity – measured using the 6MWD – and wellness based on the KCCQ score.

It also points to preliminary results suggesting that biomarkers associated with increased morbidity and mortality in patients with HFpEF were partially reversed by the drug.

HFpEF is associated with high hospitalisation rates, poor quality of life and increased mortality and accounts for around half of all heart failure cases. It has become something of an epidemic as it is often seen in elderly patients and so is tracking the ageing of the global population.

Unfortunately while strides forward have been made in improving survival in heart failure with reduced ejection fraction (HFrEF) – including with AstraZeneca’s SGLT2 inhibitor Farxiga/Forxiga (dapagliflozin) – just one pharmacological therapy has so far been approved for HFpEF.

Novartis’ Entresto (sacubitril/valsartan) was cleared by the FDA for this type of heart failure in February, although its label says that the drug’s benefits are more evident in patients with reduced ejection fraction – the volume of blood discharged by the heart as it pumps.

AZ is testing Farxiga for HFpEF as well, as are its main rivals Eli Lilly and Boehringer Ingelheim with their SGLT2 drug Jardiance (empagliflozin), with results due in the next year or so.

The disease is thought to be highly heterogeneous, so can result from impairments in a range of parameters including diastolic integrity, the function of the vasculature and kidneys, and even the oxygen carrying capacity of the blood.

Microvascular inflammation has also been proposed as an underlying mechanism of disease, which promoted AZ to investigate AZD4831 in this type of heart failure.

Lead investigator Professor Carolyn Lam of National Heart Centre Singapore said the results “show the potential of MPO inhibition with AZD4831” in HFpEF.

AZ is also testing AZD4831 in non-alcoholic fatty liver disease, chronic kidney disease and coronary artery disease, which are also thought to be driven by inflammation and fibrosis.

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