The novel biased apelin receptor agonist, MM07, is a potent vasodilator in human forearm and hand vein – First in human study

A Brame, J Maguire, B Yang, J Cheriyan, I Wilkinson, A Davenport. University of Cambridge, Cambridge, UK

Apelin1 has an emerging role in the human cardiovascular system. It is the most potent inotrope discovered to date2. Apelin causes nitric oxide dependent arterial vasodilatation in forearm blood flow studies in volunteers and coronary vasodilatation with increased cardiac output in heart failure patients, suggesting apelin agonists would be of therapeutic benefit in this condition. To date, there have been no studies investigating the properties of novel synthetic apelin agonist in man

A limitation of many agonists acting at GPCR’s is that, after signalling via G-proteins to produce a physiological action, the target receptor is internalised via the β-arrestin pathway, limiting the beneficial physiological effect. We hypothesize that a ‘biased’ agonist which preferentially activates G-protein mediated downstream signalling pathways rather than β-arrestin, will reduce desensitisation and produce a more robust response, continued vasodilatation and beneficial inotropy – this is a new therapeutic approach.

Using computational chemistry we have designed and identified the first ‘biased’ apelin agonist, MM07 and shown that it has comparable activity to the native peptide in G-protein mediated pathways in vitro but ~1000 fold lower β-arrestin internalisation activity.

Our aim was to test whether MM07 produces vasodilatation compared with endogenous (Pyr1)apelin-13 when infused in the human forearm and hand vein in vivo. Forearm blood flow was measured simultaneously in both arms using venous occlusion plethysmography. A pilot study was carried out to determine the effective doses of each apelin peptide, these were subsequently infused randomly in three incremental doses with a washout period in between the peptides (n= 12). The Aellig vein technique was used to compare MM07 and apelin in 9 healthy volunteers.

Graphs showing increase in forearm blood flow (A) and dilatation in human hand vein (B) expressed as % noradrenaline reversal, in response to MM07 (green) compared with (Pyr1)apelin-13 (blue) and control (black)

MM07 caused rapid and significant peripheral arterial dilatation in the human forearm. The magnitude of the response was significantly greater than the endogenous peptide. Crucially, there was no evidence of desensitization when repeated infusions were given. In the human hand vein, MM07 significantly reversed an established noradrenaline preconstriction.

MM07 is a potent vasodilator and inotrope and may be a more effective agonist for investigating the apelin system, which we believe to be an important modulator in cardiovascular disease.

(1) Pitkin SL, et al (2010), Pharmacol Rev, 62,331-342.

(2) Maguire JJ et al (2009), Hyperten, 54:598-604