ApoA-I infusion is safe for the liver and kidney and increases cholesterol efflux capacity
The Safety and Tolerability of CSL112, a Reconstituted, Infusible, Human ApoA-I, After Acute Myocardial Infarction - The ApoA-I Event Reduction in Ischemic Syndromes I (AEGIS-I Trial)Presented at the AHA Scientific Sessions 2016 by: C. Michael Gibson, M.D., Beth Israel Deaconess Medical Center, Boston, MA, VS
An infusible formulation of human apoA-I, CSL112, was shown to increase cholesterol efflux capacity in a dose-dependent fashion, while it was well-tolerated without significantly affecting liver or kidney function.
CSL112 is a plasma-derived apolipoprotein A-I. ApoA-I is the primary functional component of HDL and supports the rapid removal of cholesterol from plaque. Thus, CSL112 was designed to rapidly remove cholesterol from the arteries and stabilize lesions at risk of rupture.
Upon infusion, CSL112 produces an immediate and robust increase in cholesterol efflux capacity. Efflux is the first step of reverse cholesterol transport, the process by which HDL transports excess cholesterol to the liver for removal from the body. It is postulated that CSL112 may reduce early recurrent CV events following ACS.
A single 80 mg/kg infusion of reconstituted ApoA-I has been demonstrated to reduce the size of human femoral plaque lipid and macrophage content over 50% in 5-7 days. An earlier formulation of apoA-I was associated with a dose-related elevation in transaminases related to its phosphatidylcholine content. A potential risk for acute kidney injury has been observed with other infusible agents that contain very high levels of sucrose. CSL112 contains low concentrations of both of these excipients. It is therefore hypothesised that infusion of apoA-I (CSL112) in addition to standard of care in post MI subjects does not cause a clinically significant alteration in either liver or kidney function when compared to placebo.
AEGIS-I (Apo-I Event Reduction in Ischemic Syndromes-I) was a multicenter, placebo-controlled, dose-ranging, randomised phase 2b trial that evaluated the safety profile of CSL112 and characterised its pharmacokinetic/pharmacodynamic properties among patients with recent heart attack (spontaneous Type 1 MI within 7 days). 1,258 patients were randomised to either 2 grams of CSL112, 6g CSL112 or placebo via weekly infusion for four consecutive doses.
The co-primary safety endpoints were the incidence of either hepatotoxicity or renal toxicity through the end of the active treatment period (study day 29). No statistically significant differences were seen in the hepatic safety endpoint with either dose, as compared with placebo (2g: 1.0% vs. 0.0%, P=0.12, 6g: 0.5% vs. 0.0%, P=0.50), nor in the renal endpoint (2g: 0.0% vs. 0.2%, P=0.50, 6g: 0.7% vs. 0.2%, P=0.62).
A major secondary endpoint was the time-to-first occurrence of cardiovascular death, heart attack, ischemic stroke, or hospitalisation for unstable angina from the beginning of the first infusion until the last treated subject had completed study day 112. When considering data through day 112, the low dose showed no difference in the risk of MACE as compared with placebo (HR: 1.12, 95%CI: 0.58-2.16), nor did the high dose of CSL112 (HR: 0.81, 95%CI: 0.40-1.64). When considering all data until the end of the study, HR: 1.18 (95%CI: 0.67-2.05) was seen with the low-dose and HR: 1.02 (95%CI: 0.57-1.80) with the high-dose.
Fold elevation in total cholesterol efflux capacity was higher after an infusion of CSL112 2g (1.87) and CSL112 6g (2.45), as compared with an infusion with placebo (0.94). ABCA1-dependent cholesterol efflux was also higher after the low dose (3.67) and the high dose (4.30), as compared with after placebo (0.82). ApoA-I was increased 1.29-fold with the low dose, and 2.06-fold with the high dose, as compared with 0.96-fold with placebo. HDL-c showed 1.09-fold, 1.27-fold and 0.97-fold changes after infusion.
Thus, infusion of CSL112 following MI and contrast was well tolerated and does not significantly alter liver or kidney function. CSL112 elevates cholesterol efflux capacity in a dose dependent fashion. Assessment of the efficacy of CSL112 will require further evaluation in an adequately powered phase 3 trial.
- Our reporting is based on the information provided during the AHA congress –