CSL112, a plasma-derived apolipoprotein A-1 (Apo-A1), was found in a phase 2b trial to be well tolerated and safe among patients after acute myocardial infarction (MI). Infusion of the compound in combination with standard of care did not cause a clinically significant alteration in either liver or kidney function when compared with placebo.
The results were simultaneously published online in Circulation and presented by C. Michael Gibson, MD, of the Beth Israel Deaconess Medical Center, at the Scientific Sessions of the American Heart Association held November 12 to 16, 2016, in New Orleans, LA. John H. Alexander, MD, and Pierluigi Tricoci, MD, PhD, from Duke were also involved in the trial.
Apo-A1 is the primary functional component of high-density lipoprotein (HDL) and supports the rapid removal of cholesterol from plaque. Determining the safety of CSL112 is important for 2 reasons:
- A previous formulation of Apo-A1 was associated with a dose-related elevation in liver enzyme levels related to its phosphatidylcholine content.
- Other infusible agents with very high levels of sucrose have been associated with a potential risk of acute kidney injury.
CSL112 contains low concentrations of both of these excipients, said Gibson.
On infusion, CSL112 produces an immediate and robust increase in cholesterol efflux capacity, which is the ability of HDL to accept cholesterol from macrophages. As such, efflux is the first step of reverse cholesterol transport, a process by which HDL transports excess cholesterol to the liver for removal from the body, explained Gibson.
Gibson noted that an earlier study showed that a single 80 mg/kg infusion of reconstituted Apo-A1 led to a 50% reduction of fat in human femoral plaque and in the size of macrophages within 5 to 7 days. In addition, epidemiologic studies have demonstrated that an increase in cholesterol efflux improves cardiovascular outcomes, independent of traditional cardiovascular risk factors.
Because of the rapid manner in which CSL112 elevates cholesterol efflux capacity, the compound may reduce early recurrent cardiovascular events following acute coronary syndrome.
The current study included 1,258 patients randomly assigned to 4 weekly infusions of either CSL112 (2 g or 6 g) or placebo.
The co-primary safety end points were clinically significant changes in hepatic and renal function. In addition, a secondary exploratory end point was a composite of cardiovascular death, nonfatal MI, ischemic stroke, and hospitalization for unstable angina. All patients had safety follow up to day 112.
Hepatic safety was defined as an increase in the alanine transaminase level of more than 3 times the upper limit of normal or an increase in the total bilirubin level of more than 2 times the upper limit of normal.
Renal safety was defined as an increase in the serum creatinine level of more than 1.5 times baseline or a new requirement for renal replacement therapy.
No significant differences were observed in either safety end point for both doses of CSL112. However, Gibson noted that an adequately powered phase 3 trial will be needed to assess the efficacy of CSL112.
Source: Gibson CM, Korjian S, Tricoci P, et al. 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: American Heart Association Scientific Sessions 2016; November 12-16, 2016; New Orleans, LA. Abstract LBCT.03.