ACC.24 – Four weekly infusions of CSL112 (Apolipoprotein A-1) did not reduce the primary endpoint of CV death, MI or stroke at 90 days compared with placebo among AMI patients at high risk, as shown in the AEGIS-II trial

This summary is based on the presentation of Michael Gibson, MD (Boston, MA, US) at the ACC.24 Scientific Session -CSL 112 (Apolipoprotein A-I ) Infusions and Cardiovascular Outcomes in Patients With Acute Myocardial Infarction (ApoA-I Event ReducinG in Ischemic Syndromes II (AEGIS-II) Trial)

Introduction and methods

Higher levels of HDL-c are associated with lower CV events, but attempts in the past with novel therapies that raise HDL-c particle numbers have not reduced CV events and some even resulted in off target toxicity. A new rationale in the ‘HDL hypothesis’ was to improve HDL function instead of improving HDL-c particle numbers. Therefore, it was examined whether improving HDL function by infusing ApoA-1, the primary functional component of HDL, would improve outcomes.

HDL function is assessed by measuring the cholesterol efflux capacity from macrophages. Macrophages with radioactive cholesterol are added to the patient’s blood and the amount of radioactive cholesterol taken up by HDL is measured. Indeed, it has been shown that improved cholesterol efflux capacity (CEC) is associated with improved survival in patients after acute MI up to 6 years, with the benefit starting as early as 30 days.

CSL112 is human ApoA-1 purified from human plasma, and has the ability to increase cholesterol efflux by 4-fold compared to baseline.

The AEGIS-II trial was a phase 3, multicenter, double-blind, randomized, placebo-controlled, event-driven, parallel group trial in which 18,219 patients within 5 days of MI after angio were enrolled. Eligible patients were high-risk patients with multivessel disease and either drug treated diabetes or 2 or the following: ≥65 years, prior MI, PAD. Patients were randomized to 4 weekly infusions of 6 g CSL112 or placebo. The primary endpoint of time to first occurrence of CV death, MI or stroke was assessed at 90 days, and key secondary endpoints at 180 and 365 days.

Main results

• The primary endpoint occurred in 4.9% in the CSL 112 group vs. 5.2% in the placebo group (HR 0.93, 95%CI: 0.81-1.05, P=0.24).
• The key secondary endpoints at 180 days and 365 days showed similar results (HR 0.91, 95%CI: 0.81-1.01 and HR 0.93, 95%CI: 0.85-1.02, respectively).
• There were suggestions of reductions in MI types in the CSL 112 groups compared with placebo, especially for stent thrombosis.
• When looking at exploratory subgroups, patients with baseline LDL-c ≥ 100 mg/dL had a lower rate of the primary endpoint with CSL 112 compared to placebo at 90 days (HR 0.69, 95%CI: 0.53-0.90, P=0.007) with similar results at 180 and 365 days. No benefit of CSL 112 was observed in the subgroup of patients with baseline LDL-c < 100 mg/dL.
• In these patients with baseline hyperlipidemia (LDL-c ≥ 100 mg/dL), individual components of the primary endpoint (CV death, MI, or CV death/MI) were reduced in the CSL 112 group compared with the placebo group.
• Overall, the drug was well tolerated. There were 14 hypersensitive events in the CSL112 group vs. 4 in the placebo group.

Conclusion

In the AEGIS-II trial, four weekly infusions of CLS112 compared with placebo did not reduce the primary endpoint of CV death, MI or stroke through 90 days in patients after acute MI with multivessel disease and additional risk factors.

Gibson ended his presentation by stating that the benefit of ApoA-1 infusions in hyperlipidemic patients is biologically plausible, but the observation is hypothesis generating and requires prospective validation.

- Our reporting is based on the information provided at the ACC.24 Scientific Session -

The findings of this study were simultaneously published in N Eng J Med