Adrecizumab: an investigational agent for the biomarker-guided treatment of sepsis

ABSTRACT

Introduction: Sepsis is a major health problem with a high incidence and mortality. ADM, a free-circulating peptide mainly expressed and secreted by vascular endothelial cells, shows vasodilatory properties and causes hypotension when present in higher concentrations during sepsis.

Areas covered: Adrecizumab (ADZ) (HAM 8101) is a humanized targeted therapy directed against the N-terminus of adrenomedullin (ADM). ADZ inhibits excessive circulating sepsis-induced ADM and stimulates protective effects on the endothelial barrier, and decreases interstitial vasodilatory effects. ADZ demonstrated a promising safety profile in healthy subjects in phase I studies. According to these results, a phase II proof of concept study enrolling 300 septic patients is currently in course (NCT03085758).

Expert opinion: ADZ is the first humanized antibody directed against ADM. The main interest of ADZ is its potential use as a ‘biomarker-guided therapy’ in septic patients with high circulating ADM. ADZ is increasingly seen as a potential adjunct therapy to restore endothelial function in septic shock. A positive pivotal phase III trial is indeed needed to convince the intensive care community to prescribe ADZ in septic shock patients. Further, it would be of interest to see whether ADZ might also benefit other critical diseases such as cardiogenic shock where endothelial dysfunction has also been described.

KEYWORDS:

• Adrecizumab
• adrenomedullin
• antibody
• biomarker guided-therapy
• sepsis

Box 1. Drug summary

Article highlights

• Adrenomedullin, a free-circulating 52 amino-acid peptide mainly expressed and secreted by vascular endothelial cells causing vasodilation and hypotension during sepsis.

• No molecular targeted therapy demonstrated efficacy during sepsis management, highlighting the great unmet need for novel adjuvant therapies.

• Adrecizumab (HAM 8101) is a humanized antibody directed against the N-terminus of Adrenomedullin.

• ADZ stimulates Adrenomedullin’s protective effects of the endothelial barrier, and decreases interstitial vasodilatory effects. The drug demonstrated a promising safety profile in healthy subjects in phase I studies. In addition, in the first sepsis human phase II study, biotherapy by ADZ was associated with benefits.

This box summarizes key points contained in the article.

Declaration of interest

A Mebazaa reports personal fees from Orion, Servier, Otsuka, Philips, Sanofi, Adrenomed, Epygon and Fire 1 and grants and personal fees from 4TEEN4 Pharmaceuticals GmbH, Abbott, and Sphingotec. B Deniau was invited to meetings in Hennigsdorf by 4TEEN4 Pharmaceuticals GmbH. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.