Dr. C. Michael Gibson
Credit: American College of Cardiology

The use of CSL112, a 6 mg infusion of apolipoprotein AI (ApoA-1), was associated with the major adverse cardiovascular effects in the AEGIS-II trial, according to data published in the American College of Cardiology (ACC 2024) Annual Report. Scientific sessions were not associated with a reduction in events.

In a phase 3 trial aimed at evaluating the impact of cholesterol efflux on cardiovascular risk, results showed that use was not associated with a reduction in the primary endpoint at 90 days. Still, the researchers cautioned against additional analyzes that suggest use may reduce events beyond the 90-day endpoint, with data showing clear reductions after 6 months.

“Although we did not meet our primary endpoint, our data support the hypothesis that HDL cholesterol plays a role in reducing subsequent coronary plaque rupture events, such as heart attacks, by enhancing cholesterol efflux. ” said lead researcher C. Michael Gibson, a professor of medicine. He holds a PhD from Harvard Medical School and is CEO of the BAIM Clinical Research Institute.²

Previous data suggest that ApoA-I, a component of HDL cholesterol, may contribute to the stabilization of coronary artery plaques, thereby reducing cardiovascular events. CSL112, an investigational drug developed by CSL Behring, is extracted from human plasma and has been shown in previous trials to reduce LDL cholesterol in arterial plaques by up to 50% after a single infusion.³

The AEGIS-II study, an international, multicenter, randomized, double-blind, placebo-controlled trial, was conducted at 886 sites in 49 countries, with the first patients being administered in 2018. A total of 18,231 patients with recent acute myocardial infarction were included. multivessel coronary artery disease, and additional cardiovascular risk factors in a 1:1 ratio of 6 grams of CSL 112 or placebo therapy four times per week. However, the first injection is performed within 5 days of the first contact with acute myocardial infarction. Of note, seven of his patients were excluded due to concerns related to data quality from one institution.¹

Overall, 9,112 patients were randomized to CSL112 and 9,107 to placebo. The groups were well balanced, the researchers said. The mean age of the entire study cohort was 65.5 years, and 74.1% were male. The researchers noted that 99.4% of patients participated in the 90-day follow-up and 98.9% participated in the 365-day follow-up, but there were no differences between groups in reasons for not completing the study. .¹

The trial’s primary efficacy outcome was time to first occurrence of a composite of cardiovascular death, myocardial infarction, or stroke from randomization to 90 days, which researchers assessed with an intention-to-treat analysis. did. Secondary outcomes of interest for this trial include the total number of hospitalizations for coronary, cerebral, or peripheral ischemia from the time of randomization up to 90 days and 180 and 365 days until the first primary outcome. It included the time.¹

Analysis showed that there was no significant difference between the CSL112 and placebo groups at 90 days, with 4.8% of the CSL112 group and 5.2% of the placebo group experiencing the primary outcome event (hazard ratio) [HR]0.93; 95% confidence interval [CI]0.81 to 1.05. P= .24). Further analysis suggested that at 180 days of follow-up, such events occurred in 6.9% and 7.6% of the CSL112 and placebo groups, respectively (HR, 0.91; 95% CI, 0.81 to 1.01). At 365 days of follow-up, the primary outcome event was observed in 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 this trial did not meet its primary endpoint. However, we essentially intend to present a number of data showing that it may be worth reconsidering this.” And perhaps there will be another trial on this,” said trial investigator Robert Harrington, MD, and Dean of the Weill Cornell Medical College Stephen and Suzanne Weiss.Cornell University Medical Dean in an interview HCP Live.

In his presentation at ACC.24, Gibson presented data examining the effects of CSL112 stratified by baseline LDL-C levels. In this analysis, patients on statin therapy with LDL-C levels ≥100 mg/dL saw a greater benefit from the use of CSL112 than patients with baseline levels <100 mg/dL. . Results showed that patients with elevated baseline LDL-C had a statistically significant reduction in the risk of the primary composite endpoint compared 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 the individual components of the composite endpoint supported these findings.¹

“Overall, our findings are consistent with ApoA-I having a role in stabilizing heart blockages and reducing the risk of blockages rupturing beyond 90 days and causing a heart attack.” added Gibson. “By administering ApoA-1 to remove cholesterol from the body and then treating patients with cholesterol-lowering drugs to keep LDL cholesterol levels low, we may see long-lasting reductions in deaths and heart attacks.” “It’s possible,” Gibson said. He said.²

References:

1. ^{Gibson C, Duffy D, Cojan S, et al. CSL112 (apolipoprotein AI) infusion and cardiovascular outcomes in patients with acute myocardial infarction (ApoA-I Event Reduction in Ischemic Syndrome II (AEGIS-II) trial): primary trial results. Presentation location: American College of Cardiology (ACC.24) Annual Scientific Sessions. April 6-8, 2024, Atlanta, Georgia.}
2. ^{American College of Cardiology. No reduction in 90-day deaths and heart attacks due to human Apo/A1, a component of HDL cholesterol. April 6, 2024. Accessed April 6, 2024.}
3. ^{CSL Bering. CSL Announces Topline Results from Phase 3 AEGIS-II Study Evaluating Efficacy and Safety of CSL112 (Apolipoprotein AI) [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 -csl112-apolipoprotein-ai-human-302059156 Validity and safety of .html.}