Adrenomedullin
AM, ADM, adrenomedullin(1-52), bio-ADM (biologically active adrenomedullin)
Adrenomedullin is a 52-residue vasodilator peptide isolated in 1993 from human phaeochromocytoma tissue, structurally related to CGRP and amylin. It is a key regulator of endothelial barrier integrity, and blood concentrations rise markedly in sepsis and heart failure. It is now better established as a biomarker and antibody target than as a therapy in its own right.
Mechanism
The ADM gene encodes preproadrenomedullin, processed to adrenomedullin and to proadrenomedullin N-terminal 20 peptide (PAMP), both C-terminally amidated. Adrenomedullin signals through calcitonin receptor-like receptor (CLR) paired with RAMP2 to form the AM1 receptor and with RAMP3 to form AM2; the same CLR paired with RAMP1 is the CGRP receptor, so RAMP identity alone determines whether the complex responds to adrenomedullin or CGRP. Signalling is predominantly Gs-coupled, raising cyclic AMP and activating protein kinase A, with additional PI3K/Akt-dependent activation of endothelial nitric oxide synthase.
The function that dominates current clinical interest is stabilisation of the endothelial barrier. Adrenomedullin acting from the luminal side of the endothelium strengthens junctional integrity through cyclic AMP-dependent cortical actin reorganisation, reducing vascular leak; acting from the interstitial side it causes vasodilatation and hypotension. This compartment-dependent duality is the rationale for the unusual therapeutic strategy of a non-neutralising antibody that binds adrenomedullin and retains it in the circulation rather than blocking it, thereby shifting the peptide towards its barrier-protective role.
What the research shows
AdrenOSS-2 randomised 301 patients with early septic shock and elevated adrenomedullin to a single infusion of adrecizumab, a non-neutralising anti-adrenomedullin antibody now called enibarcimab, at 2 or 4 mg/kg or placebo, given at a median of 8.5 hours after vasopressor start. It was well tolerated, with one infusion interruption, no haemodynamic destabilisation, no difference in serious adverse event rates and no difference in 90-day mortality. The efficacy endpoint, change in the Sepsis Support Index, did not differ significantly (difference 0.72, CI -1.93 to 0.49, p=0.24). Twenty-eight-day mortality was 23.9 per cent with the antibody versus 27.7 per cent with placebo, hazard ratio 0.84 (95 per cent CI 0.53 to 1.31, log-rank p=0.44). Among secondary endpoints, delta SOFA favoured the antibody by 0.76 points (95 per cent CI 0.18 to 1.35, p=0.007). The authors' own conclusion was that further randomised trials are required to confirm efficacy and safety.
Subsequent post-hoc analyses reported that a subgroup defined by high bio-adrenomedullin and low circulating dipeptidyl peptidase 3 showed a fall in 28-day mortality from 24 to 8 per cent. That is a striking number and it is also exactly the kind of biomarker-defined post-hoc finding that fails on prospective testing more often than not. Enibarcimab has US Fast Track designation and a pivotal trial is planned; until that reports, the honest position is that adrenomedullin-directed therapy is unproven. Separately, bio-ADM has become a reasonably well-validated prognostic biomarker for congestion and vascular dysfunction in sepsis and acute heart failure, which is a different and more secure claim.
Evidence assessment
Limited evidence
Downgraded from mixed on audit. The single randomised human trial, in 301 patients, had safety and tolerability as its primary endpoints, which it met in the sense of showing no harm. Its efficacy endpoint, the Sepsis Support Index, was not significant, and 28-day mortality did not differ. The only positive efficacy claims are a secondary SOFA measure and a post-hoc biomarker subgroup. No efficacy has been demonstrated in humans.
Tiers are applied consistently across the library and re-checked when new trials read out. Read the grading method.
Key studies
Adrenomedullin: a novel hypotensive peptide isolated from human pheochromocytoma Preclinical only
Original isolation of adrenomedullin from human phaeochromocytoma tissue, identifying a potent hypotensive peptide structurally related to CGRP.
Safety and tolerability of non-neutralizing adrenomedullin antibody adrecizumab (HAM8101) in septic shock patients: the AdrenOSS-2 phase 2a biomarker-guided trial Preclinical only
Primary endpoints were safety and tolerability, which showed no signal of harm. The efficacy endpoint (Sepsis Support Index) was not significant (p=0.24) and 28-day mortality did not differ (23.9 versus 27.7 per cent, HR 0.84, 95% CI 0.53-1.31, p=0.44). Delta SOFA favoured treatment by 0.76 points (p=0.007), a secondary endpoint.
Effects of enrichment strategies on outcome of adrecizumab treatment in septic shock: Post-hoc analyses of the phase II AdrenOSS-2 trial Preclinical only
In a subgroup with high bio-adrenomedullin and low circulating DPP3, 28-day mortality was reported to fall from 24 to 8 per cent. Post-hoc and hypothesis-generating only; not a prespecified analysis.
Safety
Adrenomedullin infusion produces dose-dependent hypotension, flushing and reflex tachycardia, which is the principal barrier to giving the peptide itself. The antibody approach was well tolerated in 301 septic shock patients, with grade 3 or higher treatment-emergent adverse events in 70.5 per cent of the antibody group and 71.1 per cent of the placebo group, one infusion interruption and no haemodynamic destabilisation. That is a single trial in a critically ill population and says nothing about other settings or repeated dosing.
Regulatory status
| Jurisdiction | Status |
|---|---|
| United Kingdom | No UK marketing authorisation for adrenomedullin or any adrenomedullin-directed antibody. The peptide is unlicensed with no lawful supply route for human consumption. |
| United States | No FDA-approved adrenomedullin product. Enibarcimab (formerly adrecizumab) holds FDA Fast Track designation for septic shock but is investigational; Fast Track designation is a review-process designation and is not an approval or evidence of efficacy. The peptide is a research reagent, not for human use. |
| WADA (sport) | Not individually named on the Prohibited List. Prohibited at all times under section S0 as a non-approved substance; its vascular effects could also attract scrutiny under the growth factor provisions of section S2. |
Questions
Because enibarcimab does not neutralise adrenomedullin. It binds the peptide and holds it in the bloodstream, where adrenomedullin strengthens the endothelial barrier, and away from the interstitium, where it causes hypotension. The aim is redistribution, not blockade.
No. AdrenOSS-2 was primarily a safety trial and it showed the antibody was safe. Its efficacy endpoint was not significant and 28-day mortality did not differ. The dramatic subgroup result came from post-hoc analysis and needs prospective confirmation before it means anything.