Diagnosing heart failure with preserved ejection fraction in cardiac amyloidosis or diagnosing cardiac amyloidosis in heart failure with preserved ejection fraction?

Abstract

This article refers to 'Value of the HFA-PEFF and H 2 FPEF scores in patients with heart failure and preserved ejection fraction caused by cardiac amyloidosis' by D. Tomasoni et al., published in this issue on pages 2374-2386.Heart failure (HF) with preserved ejection fraction (HFpEF) is increasingly common and projected to be the dominant form of HF in the future. 1 Cardiac amyloidosis (CA), caused by immunoglobulin light-chain (AL) amyloidosis or transthyretin (ATTR) amyloidosis are under-recognized causes of cardiomyopathy and HF. In particular, wild-type (wt) ATTR amyloidosis is increasingly recognized as a common cause of HFpEF. 2

The myeloperoxidase inhibitor mitiperstat (AZD4831) does not prolong the QT interval at expected therapeutic doses

“…In the ongoing phase 2b dose-finding study (ENDEAVOR [NCT04986202], in which 2.5 and 5 mg doses are being tested), mitiperstat 5 mg once daily is the highest dose under evaluation. 14 Results from this study will be used to guide phase 3 dose selection. In the previous phase 2a study (SATELLITE), mitiperstat 5 mg once daily reduced myeloperoxidase specific activity by approximately 50% versus the baseline and approximately 70% versus placebo after 90 days.…”

“…According to current guidance from the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), “high clinical exposure” is the C max at steady state, achieved when the maximum therapeutic dose is administered in the presence of the intrinsic or extrinsic factor that has the largest effect on increasing the C max 15 . The expected therapeutic dose of mitiperstat is no higher than 5 mg once daily, administered as oral tablets, and this is the highest dose being tested in the ongoing phase 2b dose‐finding study (ENDEAVOR; NCT04986202) 14 . The “high clinical exposure” scenario for this dose at steady state, as defined in the ICH E14/S7B guidance questions and answers document (FDA 2022) is 0.093 μmol/L.…”

“…15 The expected therapeutic dose of mitiperstat is no higher than 5 mg once daily, administered as oral tablets, and this is the highest dose being tested in the ongoing phase 2b dose-finding study (ENDEAVOR; NCT04986202). 14 The "high clinical exposure" scenario for this dose at steady state, as defined in the ICH E14/S7B guidance questions and answers document (FDA 2022) is 0.093 μmol/L. This scenario considers the impact of renal impairment on mitiperstat exposure.…”

“…13 The highest expected therapeutic dose of mitiperstat is 5 mg once daily, and this is the highest dose being tested in the ongoing phase 2b dose-finding study in patients with HFpEF/HFmrEF (ENDEAVOR, NCT04986202). 14 Major regulatory bodies worldwide have published guidelines requiring assessment of the risk of QT interval prolongation by new drugs with systemic bioavailability. Concentration-QT (C-QT) modeling is currently accepted as the primary method for analysis of this risk.…”

“…Daily oral doses of mitiperstat 2.5 mg for 10 days followed by 5 mg for 80 days reduced myeloperoxidase specific activity by more than 50% from the baseline and by 75% versus placebo, with few treatment‐related adverse events 13 . The highest expected therapeutic dose of mitiperstat is 5 mg once daily, and this is the highest dose being tested in the ongoing phase 2b dose‐finding study in patients with HFpEF/HFmrEF (ENDEAVOR, NCT04986202) 14 …”