Key Points:
- While inflammation is critical to the pathogenesis of atherosclerosis, few available anti-inflammatory treatments have been tested in ACS.
- In IVORY FINALE, low-dose interleukin 2 (IL-2) was compared to placebo in ACS. The primary endpoint was change in arterial inflammation, as measured by PET scan. Safety and tolerability were also assessed.
- In the primary analysis, IL-2 resulted in a significant reduction in arterial inflammation in the index vessel on PET. Over a median of 2.6 years of follow-up, IL-2 also decreased MACE compared to placebo.
Inflammation is essential to the pathogenesis and progression of atherosclerosis, and it becomes even more important in the setting of acute myocardial infarction. However, existing standard-of-care therapies for myocardial infarction do not primarily address underlying vascular and systemic inflammation. Prior studies have demonstrated a reduction in cardiovascular events with anti-inflammatory therapies such as colchicine and canakinumab, but the implementation of these therapies is limited by both side effects and cost. Low-dose therapy with interleukin 2, which potentiates regulatory T cell production, has previously been shown to be beneficial in autoimmune disorders. In a breaking presentation at the 2024 ESC Congress today, Dr. Rouchelle Sriranjan and her team presented their study: “Low-dose interleukin-2 for the reduction of vascular inflammation in acute coronary syndromes (IVORY) and clinical outcomes and follow-up (IVORY FINALE).”
The IVORY study (NCT06427694) was a randomized, double-blinded trial examining the safety and efficacy of low-dose interleukin 2 (IL-2) vs placebo after acute coronary syndrome. Participants were required to have a current admission for acute coronary syndrome and evidence of residual inflammation (defined as an hsCRP >2mg/L). Women enrolled in the study were required to be postmenopausal, perimenopausal with a negative pregnancy test, or unable to conceive due to surgical sterilization. Key exclusions were cardiogenic shock, cardiac arrest, history of transplant or recurrent seizures, and active infection. The primary efficacy outcome in IVORY was change in vascular inflammation as measured by the mean TBRmax in the index coronary vessel by PET scan. In IVORY FINALE, the primary outcome was MACE at one, two, and five years after initial dosing.
A total of 63 patients were 1:1 randomized to either IL-2 or placebo. A baseline PET scan was performed, followed by five days of a daily induction period with IL-2 or placebo, then followed by a seven week maintenance period of weekly dosing and a subsequent repeat PET. The mean age was 56 with 16% women; 55% of individuals had a STEMI, and the median hsCRP was 9ml/L. 100% of individuals were on dual antiplatelet therapy with either clopidogrel or ticagrelor, and 99% were on statin therapy. Of the 63 randomized individuals, one individual was ultimately withdrawn from the IL-2 arm due to a rash, and two individuals were withdrawn from the placebo arm for liver enzyme elevation and COVID-19 infection, respectively. IL-2 was reasonably well tolerated, with no serious adverse events, and only one adverse event (rash) resulting in treatment interruption. The most common mild or moderate reactions to IL-2 were site reactions (91% vs 16% placebo) or bruising (56% vs 81% in placebo). There was a significant reduction in arterial inflammation in the index vessel (-0.171 +/- 0.068 units of TBRmax) in the treatment group compared to placebo. There was also a significant reduction in MACE at a median follow-up of 2.6 years (log-rank p 0.03).
When discussing the clinical implications of the study at the ESC Congress, Dr. Sriranjan stated: “Low-dose IL-2 significantly reduces arterial inflammation when compared to placebo in ACS patients on optimal medical therapy…with a trend towards a reduction in MACE….larger clinical trials are needed to determine the effect of IL-2 on clinical outcomes.”
