Abstract Body (Do not enter title and authors here): Major adverse cardiovascular (CV) events (MACE) occur in a substantioal percentage of individuals following acute coronary syndromes (ACS), primarily driven by residual vascular inflammation. Anti-inflammatory drugs have improved CV outcomes but their use is limited by significant side-effects. Low-dose interleukin 2 (IL2) increases regulatory T (Treg) cells, which are powerful endogenous regulators of the immune response, and could provide a new, targeted anti-inflammatory strategy in high-risk ACS patients. In IVORY, we hypothesised that treatment with low-dose IL2 would reduce arterial inflammation measured by ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography/computed tomography (PET/CT), compared to placebo. In IVORY FINALE we hypothesised that low dose IL2 could reduce MACE compared to placebo at follow up (up to 5 years.)

IVORY was a double-blind, placebo-controlled, Phase IIb trial randomising ACS patients with high-sensitivity CRP levels ≧ 2mg/L to receive either 1.5×10⁶IU IL2 or placebo (1:1). Dosing consisted of a daily induction (5 days) and a weekly maintenance phase (7 weeks). ¹⁸F-FDG-PET/CT imaging of the ascending aorta and carotid arteries was performed before and after treatment. The primary outcome was the difference in the mean maximum target-to-background ratio (TBRmax) in the index vessel on follow-up imaging between the groups.

60 patients (IL2:placebo, n=31:29) completed the trial. Arterial inflammation in the index vessel was lower at the end of treatment in the IL2 group than in placebo (TBRmax = -0.171[-7.7%], 95% CI -0.308 to -0.034, p=0.015)[Fig1]. In more inflamed areas with a mean TBRmax ≧ 2 (active slices), the difference between the groups was greater (-0.185 [-8.3%], P=0.009, 95% CI -0.323 to -0.0478). Overall, the additive treatment effect of low-dose IL2 was greater at higher baseline inflammation [Fig 2]. Low-dose IL2 significantly increased circulating Tregs compared to placebo (p<0.001) [Fig 3]. There was no difference between the groups for changes in effector T cells. It was well-tolerated in ACS. At a median follow-up of 2.5 years, a trend towards lower MACE in the IL2 group (number of events [n]=0), compared to placebo (n= 7; 2 deaths, 2 non-fatal MIs, 3 unplanned revascularisations) was seen.

In summary, in high-risk ACS, immunomodulation with low-dose IL2 produces a safe and significant reduction in arterial inflammation, compared to placebo. Larger trials are needed to confirm its impact on CV outcomes.