Infusion of Milano Apoprotein Causes Rapid Regression of Atherosclerosis

Laurie Barclay, MD

November 04, 2003

Nov. 4, 2003 — Infusion of the Milano apoprotein A rapidly causes regression of atherosclerosis in patients with acute coronary syndromes (ACS), according to the results of a preliminary randomized trial published in the Nov. 5 issue of The Journal of the American Medical Association. This intravenous therapy targeting high-density lipoprotein cholesterol (HDL-C) may represent a new approach to the future treatment of atherosclerosis.

"Approximately 40 carriers with a naturally occurring variant of apolipoprotein A-I known as ApoA-I Milano...are characterized by very low levels of [HDL-C], apparent longevity, and much less atherosclerosis than expected for their HDL-C levels," write Steven E. Nissen, MD, from the Cleveland Clinic Foundation in Ohio, and colleagues.

Of 123 patients with ACS, aged 38 to 82 years, who were screened between November 2001 and March 2003 at 10 U.S. centers, 57 patients were randomized. Of 47 patients who completed the protocol, 11 received placebo, 21 received low-dose and 15 received high-dose recombinant ApoA-I Milano/phospholipid complexes (ETC-216) by intravenous infusion at weekly intervals for five doses.

Serial intravascular ultrasound measurements within two weeks of ACS and after treatment revealed that the mean percentage of atheroma volume decreased by 1.06% in the combined ETC-216 group compared with an increase of 0.14% in the placebo group. In the combined treatment groups, the absolute reduction in atheroma volume was a 4.2% decrease from baseline.

"This initial trial of an exogenously produced HDL mimetic demonstrated significant evidence of rapid regression of atherosclerosis," the authors write. "The potential utility of the new approach must be fully explored in a larger patient population with longer follow-up, assessing a variety of clinical end points, including morbidity and mortality."

Esperion Therapeutics funded this study. Several authors report various financial arrangements with several pharmaceutical companies.

In an accompanying editorial, Daniel J. Rader, MD, from the University of Pennsylvania School of Medicine in Philadelphia, discusses several study limitations, including small sample size, short treatment duration, unclear relationship of intravascular ultrasound findings to clinical benefit, and failure to compare infusion of normal ApoA-I with that of ApoA-I Milano.

"The results of this study are surprising to even the most optimistic supporters of the concept of targeting HDL as a therapy for atherosclerosis," he writes. "If this concept is confirmed in future studies, some day patients with acute coronary syndromes may receive 'acute induction therapy' with HDL-based therapies for rapid regression and stabilization of lesions, followed by long-term therapy to prevent the regrowth of these lesions. In this model, long-term HDL-based therapies will still be needed as a vital component of the preventive phase...."

Dr. Rader adds, "If the pace of these discoveries continues, the next two decades may be to HDL what the last two decades were to LDL: an era in which the development of new therapies may permit the unequivocal demonstration of the clinical benefit of targeting HDL to reduce the burden of atherosclerotic cardiovascular disease."

Dr. Rader reports financial arrangements with Esperion Therapeutics and other makers of lipid-lowering agents.

JAMA. 2003;290:2229-2300, 2322-2324

Reviewed by Gary D. Vogin, MD