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Novel apolipoprotein A-I infusion therapy feasible, well tolerated after acute MI
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NEW ORLEANS — Four weekly infusions of a novel apolipoprotein A-I therapy did not result in significant changes in liver or kidney function and were well tolerated in patients with acute MI, according to results of the phase 2b AEGIS-I study.
In addition, apolipoprotein A-I (apoA-I) infusion with CSL112 (CSL Behring) was associated with increases in apoA-I and ex vivo cholesterol efflux.
Results of the phase 2b safety and proof-of-mechanism clinical study were presented by C. Michael Gibson, MD, PhD, from the cardiovascular division of the department of medicine at Beth Israel Deaconess Medical Center and Harvard Medical School, during the American Heart Association Scientific Sessions and simultaneously published in Circulation.
The multicenter, randomized, double blind, placebo-controlled, dose-ranging trial enrolled 1,258 patients with acute MI. All patients were stratified based on renal function and then randomly assigned in a 1:1:1 ratio to receive four consecutive weekly infusions of CSL112 (2 g apoA-I/dose), high-dose CSL112 (6 mg apoA-I/dose) or placebo. Ninety-one percent of patients received all four infusions.
The study met both of its two co-primary safety endpoints: occurrence of a hepatic safety event, defined as an alanine transaminase increase more than three times the upper limit of normal or total bilirubin increase more than two times the upper limit of normal, and occurrence of a renal safety event, defined as a serum creatinine increase more than 1.5 times the baseline value or need for renal replacement therapy.
Hepatic impairment was reported in 0% of the placebo group, 1% of the CSL112 2-dose group (P vs. placebo = .12) and 0.5% of the CSL112 6-g dose group (P vs. placebo = .5). Renal impairment was reported in 0.2% of the placebo group, 0% of the CSL112 2-g dose group (P vs. placebo = .5) and 0.7% of the CSL112 6-g dose group (P vs. placebo = .62).
In other results, cholesterol efflux capacity was increased by 1.87-fold with the 2-g dose and 2.45-fold with the 6-g dose.
Immediately following infusion of CSL112, the researchers observed marked increases in cholesterol efflux capacity.
“In particular, ABCA1-dependent efflux, a pathway especially relevant to cholesterol-laden cells in plaque, was elevated [more than threefold] after infusion of CSL112. It is noteworthy that the elevation in the ABCA1-dependent efflux capacity was greater than the elevation of apoA-I, thus suggesting that infusion elevates not just the quantity but also the functionality of the apoA-I pool. Indeed, the ABCA1-dependent cholesterol efflux capacity/apoA-I ratios were elevated with both doses of CSL112 compared with placebo,” the researchers wrote in Circulation.
Risk for a composite of MACE (CV death, nonfatal MI, ischemic stroke, hospitalization for unstable angina) at 1 year was a secondary endpoint of the trial, and this outcome was similar between the groups.
“Assessment of the efficacy of CSL112 will require further evaluation in an adequately powered phase 3 trial,” Gibson said during a press conference.
Philip Barter, MD, PhD, from the University of Sydney, Australia, also stressed the importance of larger-scale analysis during a discussion of the trial results.
“Now is the time to go ahead and test what is the real hypothesis,” Barter said. “On the basis of this trial, I would urge ... support [of] a much larger trial to see whether safety and tolerability can also be accompanied by a reduction in cholesterol efflux.” – by Dave Quaile
References:
Gibson CM, et al. LBCT.03 – Insights from New Therapeutic Trials for Lipids. Presented at: American Heart Association Scientific Sessions; Nov. 12-16, 2016; New Orleans.
Gibson CM, et al. Circulation. 2016;doi:10.1161/CIRCULATIONAHA.116.025687.
Disclosure: Barter reports receiving research support from Pfizer; honoraria from Amgen, AstraZeneca, Kowa Pharmaceuticals, Merck, Pfizer and Sanofi; and consulting and/or serving on advisory boards for Amgen, AstraZeneca, CSL Behring, Dezima, Lilly, Merck, Pfizer and Sanofi. Gibson reports financial ties to various pharmaceutical and device companies.
Perspective
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Salim S. Virani, MD, PhD, FACC, FAHA
This trial showed that infusion of CSL112 was safe and well-tolerated in patients post MI. Although not powered to show a difference in CV outcomes, the overall major adverse CV events were comparable except for a higher CV mortality in the 6 g dose when compared with placebo. This increase could be a chance finding related to multiple testing. There was no clustering of deaths in proximity to CSL112 infusion. Nevertheless, this will need to be closely studied in future large-scale phase 3 studies of CSL112.
Infusion of CSL112 was also associated with an increase in apoA-1 and importantly, an increase in cholesterol efflux capacity. This increase in cholesterol efflux capacity seemed to be out of proportion to the apoA-1 increase and could signify an increase not just in the quantity but also the function of the apoA-1. Recent studies have shown low cholesterol efflux capacity to be better associated with major adverse CV events than HDL levels.
Although this trial did show safety and an increase in apoA-1 along with improvement in cholesterol efflux capacity with CSL-112, these are still early results. With the results of recent Mendelian randomization studies along with disappointing results of several HDL-related therapeutics (three of the four cholesteryl ester transfer protein inhibitors and apoA-1 Milano), the question remains whether modulation of HDL is a viable mechanism to further improve CV events in the contemporary era with very aggressive medical management of patients after ACS.
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