AEGIS-II Misses Primary Endpoint, Suggests Potential for CSL112 in Hyperlipidemia

C. Michael Gibson, MD
Credit: American College of Cardiology

Use of CSL112, a 6 mg infusion of apolipoprotein A-I (ApoA-1), was not associated with a reduction in major adverse cardiovascular events in the AEGIS-II trial, according to data presented at the American College of Cardiology (ACC 2024) Annual Scientific Session.

A phase 3 trial aimed at assessing the effects of cholesterol efflux on cardiovascular risk, results demonstrate use was not associated with a reduction in the primary endpoint at 90 days. Still, investigators called attention to additional analyses suggesting use could provide a reduction in events after the 90-day endpoint, with data indicating an apparent reduction at 6 months and beyond.

“This was not the beginning or the end, this is the end of the beginning. This is the first trial to really look at this. This was human ApoA-I that made your good cholesterol go to great cholesterol, with 4 times better function,” explained lead investigator C. Michael Gibson, MD, a professor of medicine at Harvard Medical School and chief executive officer of the BAIM Institute for Clinical Research, in an interview with HCPLive at ACC.24.

A component of HDL cholesterol, previous data suggest ApoA-I contributes to the stabilization of coronary plaque and could, thereby, reduce cardiovascular events. An investigational agent developed by CSL Behring, CSL112 is extracted from human plasma and use of a single infusion was associated with reductions of up to 50% in LDL cholesterol in arterial plaque in previous trials.^2,3

An international, multicenter, randomized, double-blind, placebo-controlled trial, the AEGIS-II trial was conducted at 886 sites across 49 countries, with the first patient dosed in 2018. A total of 18,231 patients with a recent acute myocardial infarction, multi-vessel coronary artery disease, and additional cardiovascular risk factors in a 1:1 ratio to 4 weekly infusions of 6 grams of CSL 112 or placebo therapy, with the first infusion occurring within 5 days of first contact for acute myocardial infarction. Of note, 7 patients were excluded due to concerns related to data quality from 1 site.¹

Overall, 9112 patients were randomized to CSL112 and 9107 were randomized to placebo. According to investigators, these groups were well balanced. The entire study cohort had a mean age of 65.5 years and 74.1% were men. Investigators pointed out 99.4% of patients attended the 90-day follow-up visit and 98.9% attended the 365-day follow-up visit, with no differences between groups in reasons for not completing the study.¹

The trial’s primary efficacy outcome was the time to first occurrence of a composite of cardiovascular death, myocardial infarction, or stroke from randomization through 90 days, with investigator assessing this in an intention-to-treat analysis. The trial’s secondary outcomes of interest included total number of hospitalizations for coronary, cerebral, or peripheral ischemia from the time of randomization through 90 days as well as time to first occurrence of the primary outcome through 180 days and through 365 days.¹

Upon analysis, results indicated there was no significant difference between the CSL112 and placebo groups at 90 days, with a primary outcome event occurring among 4.8% receiving CSL112 and 5.2% of those receiving placebo (Hazard Ratio [HR], 0.93; 95% Confidence Interval [CI], 0.81 to 1.05; P= .24). Further analysis suggested such an event occurred among 6.9% and 7.6% of the CSL112 and placebo groups, respectively, at 180 days of follow-up (HR, 0.91; 95% CI, 0.81 to 1.01). At 365 days of follow-up, a primary outcome event was observed among 9.8% of the CSL group and 10.5% of the placebo group (HR, 0.93; 95% CI, 0.85 to 1.02).¹

“We declare that the trial did not reach its primary endpoint. But we're going to show a lot of data that, essentially, says it may be worth rethinking this and maybe there's another trial on this,” said trial investigator Robert Harrington, MD, the Stephen and Suzanne Weiss Dean of Weill Cornell Medicine and Provost for Medical Affairs of Cornell University, in an interview with HCPLive.

In his presentation at ACC.24, Gibson presented data examining the effect of CSL112 stratified by baseline LDL-C level. In this analysis, patients with an LDL-C level of 100 mg/dL or greater on statin therapy saw a greater effect from use of CSL112 than those with baseline levels less than 100 mg/dL. In those with elevated baseline LDL-C, results pointed to statistically significant reductions for risk of the primary composite endpoint relative to placebo at 90 days ([3.4% vs 4.9%] HR, 0.69; 95% CI, 0.53 to 0.90; P = .007), 180 days ([5.3% vs 7.3%] HR, 0.71; 95% CI, 0.57 to 0.88; P= .002), and 365 days ([7.8% vs 9.9%] HR, 0.78; 95% CI, 0.65 to 0.93; P= .006). Further analysis of individual components of the composite endpoint supported these findings.¹

"So, there was actually did see a signal of reduction in cardiovascular death and myocardial infarction," explained Serge Korjian, MD, of Harvard Medical School, in an interview with HCPLive. "Specifically, at 180 days it was statistically significant as well. Obviously, all secondary endpoints are exploratory at this point, but there is clearly evidence that this is biologically plausible according to the mechanism of action and the drug."

References:

1. ^{Gibson C, Duffy D, Korjian S, et al. CSL112 (Apolipoprotein A-I) Infusions And Cardiovascular Outcomes In Patients With Acute Myocardial Infarction (ApoA-I Event Reducing In Ischemic Syndromes II (AEGIS-II) Trial): Primary Trial Results. Presented at: American College of Cardiology (ACC.24) Annual Scientific Session. April 6 – 8, 2024. Atlanta, GA.}
2. ^{American College of Cardiology. No Reduction in 90-Day Deaths, Heart Attacks With Human Apo/A1, A Building Block of HDL Cholesterol. April 6, 2024. Accessed April 6, 2024.}
3. ^{CSL Behring. CSL announces top-line results from the phase 3 AEGIS-II trial evaluating the efficacy and safety of CSL112 (Apolipoprotein A-I [human]). PR Newswire: press release distribution, targeting, monitoring and marketing. February 11, 2024. Accessed April 6, 2024. https://www.prnewswire.com/news-releases/csl-announces-top-line-results-from-the-phase-3-aegis-ii-trial-evaluating-the-efficacy-and-safety-of-csl112-apolipoprotein-a-i-human-302059156.html.}