CSL112, a reconstituted, infusible, plasma-derived apolipoprotein A-I: safety and tolerability profiles and implications for management in patients with myocardial infarction

ABSTRACT

Introduction: The risk of major adverse cardiac events (MACE) remains elevated soon after a coronary event. High-density lipoprotein (HDL) cholesterol has been proposed as a target to reduce cardiovascular endpoints, but there is growing recognition that increasing the function of HDL may be more important than merely increasing its concentration. CSL112 is a reconstituted, infusible human plasma-derived apolipoprotein A-I (apoA-I) that increases cholesterol efflux capacity – an ex vivo measure of the ability of HDL to accept cholesterol from macrophages.

Areas covered: This article reviews the pharmacology of CSL112 and its current clinical development status.

Expert opinion: Clinical trials provide clear evidence that LDL cholesterol is involved in the mechanism of atherogenesis, but data for the protective role of HDL cholesterol remains inconclusive. The AEGIS-I trial suggests that the CSL112 elevates the quantity and the functionality of the apoA-I pool. The number of MACE in the AEGIS-I trial was low, but the study was not powered for efficacy. In aggregate, the favorable safety results of the AEGIS-I study encouraged the initiation of a large-scale phase 3 outcomes trial. Any benefit of CSL112, if proven on a large scale, must be weighed against the costs of the compound.

KEYWORDS:

• CSL112
• HDL
• apoA-I
• High-density lipoprotein
• myocardial infarction
• major adverse cardiac events
• MACE
• AEGIS-I trial

Box 1. Drug summary.

Declaration of interest

D. Capodanno has received payments for consulting fees or honorarium from Bayer and AstraZeneca. R. Mehran has received consulting fees from Abbott Vascular, Abiomed, Boston Scientific, Bristol-Myers Squibb, Cardiovascular Systems, Elixir, Medscape, Shanghai BraccoSine Pharmaceutical, The Medicines Company and executive committee fees from Janssen Pharmaceuticals, Osprey Medical. R. Mehran also declares that her institution receives funding from AstraZeneca, Bayer, Beth Israel Deaconess, Bristol-Myers Squibb, Cardiokinetix, Claret Medical, CSL Behring, Eli Lilly/DSI, Medtronic, Novartis Pharmaceuticals, OrbusNeich, Spectranetics, and Watermark Research Partners. C.M. Gibson has received honoraria from Bayes, Janssen Pharmaceuticals, Johnson and Johnson Corporation, Portola Pharmaceuticals. Dr. Gibson also receives Research Grant Support and Consulting funds from CSL Behring. DJ. Angiolillo has received payments for: () Consulting fees or honorarium from Amgen, Aralez, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol-Myers Squibb, Chiesi, Daiichi-Sankyo, Eli Lilly, Haemonetics, Janssen, Merck, PLx Pharma, Pfizer, Sanofi, and The Medicines Company; (b) Participation in review activities from CeloNova and St. Jude Medical. Institutional payments for grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi-Sankyo, Eisai, Eli-Lilly, Gilead, Janssen, Matsutani Chemical Industry Co., Merck, Novartis, Osprey Medical, and Renal Guard Solutions; in addition, DJ. Angiolillo has received funding from the Scott R. MacKenzie Foundation and the NIH/NCATS Clinical and Translational Science Award to the University of Florida UL1 TR000064 and NIH/NHGRI U01 HG007269, outside the submitted work. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

This paper was not funded