In the current phase 2 study, a total of 57 ACS patients were randomized to placebo or one of two doses of ETC-216 (15 mg/kg or 45 mg/kg). IVUS was performed to assess changes in atheroma within two weeks of initial ACS diagnosis and again after the last ETC-216 infusion.

The researchers report that the change in percent atheroma from baselinethe primary efficacy end point of the studywas significantly different at follow-up for patients who received ETC-216, whereas the change in the placebo group was not statistically significant. The secondary efficacy end points, mean change in total atheroma volume and mean change from baseline in maximum atheroma thickness, also showed the active treatment groups to have achieved statistically significant changes over the course of the treatments, whereas changes in the placebo-treated patients were not significant. No differences were seen between the different doses of ETC-216, suggesting "that ETC-216 is capable of enhancing reverse cholesterol transport at both dosage levels," the authors write.

Nissen et al also analyzed their findings according to disease severity and report that, not surprisingly, the effect of ETC-216 occurred predominantly in the most severely diseased 10-mm subsegments, but that no effect was seen in the least severely diseased subsegments.

Two patients, both in the high-dose ETC-216 group, withdrew from the trial because of adverse effects "deemed possibly drug-related," but Nissen told heartwire that he doesn't believe the agent was responsible and thinks the drug is actually very safe.

He acknowledged that the mode of drug administration is cumbersome: "That's the downside," he said, "but given the lethality of coronary disease, we don't think [weekly infusions] are such an odious thing to do."

In an editorial accompanying the study, Dr Daniel J Rader (University of Pennsylvania School of Medicine, Philadelphia) notes that ways of up-regulating the gene expression of ApoA-1 have remained elusive for two decades, and as such, Nissen et al's study "represents the first clinical trial of the administration of ApoA-1 Milano, and indeed any form of ApoA-1, in humans with regard to effects on atherosclerosis."2 Their results, Rader adds, "are surprising to even the most optimistic supporters of the concept of targeting HDL as a therapy for atherosclerosis."

A critical issue, as yet unanswered, is whether ApoA-1 Milano actually has biological properties that make it more effective than wild-type ApoA-1. Rader points out that there is little economic incentive for developing an approach to simulate wild-type ApoA-1, since this concept is already in the public domain. "From a scientific standpoint, it remains an unanswered question as to whether ApoA-1 Milano has unique properties that result in greater antiatherogenic potential than normal ApoA-1."

Future studies are "planned" and, as Rader observes, will need to address whether short-term changes in atheroma burden seen on IVUS actually translate into clinical benefit in the long term.

Nissen is optimistic. "In the past, therapies that have slowed the progression of atherosclerosis have proven to reduce morbidity and mortality; there's a very tight linkage between improvements in plaque growth and improvements in clinical outcomes. Unless this is completely different from anything we've ever tested, it's going to reduce morbidity and mortality," he told heartwire.

Rader, too, seems cautiously sanguine about therapies that target HDL, the ApoA-1 Milano strategy among them. "If the pace of these discoveries continues, the next two decades may be to HDL what the past 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."