Apolipoprotein A1 Infusions After Acute MI Disappoint in Phase III Trial

ATLANTA — Plasma-derived human apolipoprotein A1 (CSL112) infusions failed to improve outcomes for acute myocardial infarction (MI) patients with multivessel coronary artery disease and other cardiovascular risk factors, the large international AEGIS-II study showed.

The primary endpoint — MI, stroke, or cardiovascular death through 90 days — was not significantly different between the group randomized to four weekly infusions of investigational CSL112 atop guideline-recommended therapy and those who received placebo shots (4.8% vs 5.2%; HR 0.93, 95% CI 0.81-1.05, P=0.24), reported C. Michael Gibson, MD, of Beth Israel Deaconess Medical Center in Boston, at the American College of Cardiology (ACC) annual meeting here.

Nor were there significant differences in that composite outcome at 6 months (6.9% vs 7.6%) or 1 year (9.8% vs 10.5%), according to findings published simultaneously in the New England Journal of Medicine (NEJM).

While the acute MI component of the primary endpoint and exploratory analyses of patients with baseline LDL cholesterol levels of 100 mg/dL or above hinted at potential benefit in the treatment arm, said Gibson, whether that’s enough for research with CSL112 to continue is uncertain.

The data are “hot off the press,” he told MedPage Today at a press conference. “We have not yet begun to explore the data deeply, so we really need to do that before we determine what the path forward might be. We are wrestling, looking at all the learnings from this study.”

Prior research has shown higher HDL cholesterol to be associated with lower cardiac event rates, yet therapies raising HDL have not proven successful. With that in mind, the AEGIS-II investigators sought to answer whether improving HDL function by enhancing cholesterol efflux capacity via apolipoprotein A1 — the primary functional component of HDL — could protect against atherosclerotic disease.

‘Sigh of Disappointment’

“I think it would be safe to say that the preventive cardiology and lipidology community all around the globe let out a great sigh of disappointment with the release of these results,” said ACC discussant Pamela Morris, MD, of the Medical University of South Carolina in Charleston.

“We are very good now at development of new drugs for diabetes; we are getting better and better at hypertension; we have antiplatelet therapies that are beneficial; we are getting very good at lowering LDL cholesterol, and yet despite all that, patients continue to have recurrent events, so targeting residual risk — which this study is about — is the Holy Grail,” she said. “So this type of trial makes perfect sense.”

Morris too expressed enthusiasm about the results of the hypothesis-generating exploratory analysis, which showed a lower 90-day rate of MI, stroke, or cardiovascular death for patients with a baseline LDL of 100 mg/dL or above in the CSL112 arm (3.4% vs 4.9% in the placebo arm, P=0.041), a difference that widened at 6 months (5.3% vs 7.4%) and 1 year (7.8% vs 9.9%) while remaining significant.

“This really seemed to be an agent that would have some hope of success,” Morris said. “So while we are disappointed by the main findings, we are excited about some of the exploratory analyses.”

In an editorial accompanying the NEJM paper, Christie Ballantyne, MD, and Vijay Nambi, MD, PhD, both of Baylor College of Medicine in Houston, also offered mixed opinions of AEGIS-II.

The duo called it a “well-conducted trial that involved a high-risk population, had adequate power, and used a drug that has been shown to promote robust cholesterol efflux capacity.” But they raised several issues, including the lack of data on baseline or post-treatment cholesterol efflux capacity values and how they correlate with outcomes; that the HDL increase in the study was different than in AEGIS I; and whether decreased cholesterol efflux capacity should have been an inclusion criterion.

Ballantyne and Nambi also questioned whether increasing the cholesterol efflux capacity would have been tied to a 90-day reduction in adverse cardiovascular outcomes given that many early post-acute MI events may be linked with stent thrombosis, which may not be impacted by cholesterol efflux.

“Most lipid-altering therapies start showing benefits at approximately 12 months or later, whereas antiplatelet therapies show benefit within the first 90 days,” they wrote. “One wonders whether 4 weeks of increased cholesterol efflux capacity and reverse cholesterol transport are sufficient to address years of plaque development.”

Trial Details

AEGIS II took place from 2018 to 2022 in 49 countries and had a total of 18,219 patients for its intention-to-treat analysis. The mean age in the full population was around 65 years, about three-fourths were men, and roughly 85% were white. A little over a third were in central and eastern Europe.

A little over half of the participants had ST-elevation MI, and about 97% underwent coronary angiography for the index MI. Medications in use at randomization were aspirin, a P2Y12 inhibitor or other antiplatelet agent, or a statin or high-intensity statin therapy. The median total cholesterol was about 160 mg/dL, with median HDL and LDL coming in at 84 mg/dL and 39 mg/dL, respectively.

Patients were randomly assigned to either four weekly infusions of 6 g of CSL112 or matching placebo. The first infusion was given within 5 days after the first medical contact for the acute MI. Around 8% of patients in both groups quit the trial.

Although adverse events (AEs) between the two groups were similar, Gibson noted that a higher number of hypersensitivity AEs were reported in the CSL112 group (14 vs 4). However, fewer patients in the CSL112 group had acute kidney injuries versus placebo (6.3% vs 7.2%), with such AEs defined as increases in creatinine of ≥0.3 mg/dL from baseline during the active treatment period.

A trial limitation was the low representation of women and ethnic minorities.

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