Synthetic HDL reduces atheroma burden, phase 2 trial shows

Shelley Wood

November 05, 2003

Chicago, IL - A pilot trial testing recombinant apolipoprotein (Apo) A-1 Milano, an HDL mimetic that appears to confer heightened protection against cardiovascular disease (CVD), has found that weekly infusions of the agent over five weeks produced significant regression of coronary atherosclerosis in ACS patients[1]. Researchers say their initial skepticism over the agent, known as ETC-216, has been completely dispelled by the magnitude of changes seen in the vessels of patients who received it.

Lead investigator Dr Steven E Nissen (Cleveland Clinic, OH) has briefly discussed his initial doubtsthen amazementover recombinant ApoA-1 Milano with heartwire in the past and was even more forthcoming now that the full results are being published in the November 5, 2003 issue of the Journal of the American Medical Association.

Who would believe that with five weeks of therapy we could actually remove significant quantities of plaque from the coronaries?

"I really didn't think it was likely to work. CVD is a chronic disease; people take decades to develop atherosclerosiswho would believe that with five weeks of therapy we could actually remove significant quantities of plaque from the coronaries? It's so far out that I'm sure there were people who thought we shouldn't even be testing it," Nissen said. "When I got the data back, I couldn't believe it. It's just astonishing and a real paradigm switch. Everything up to now has been about lowering LDL, and we've got good drugs for doing that, but we haven't had good drugs for HDL and we haven't been able to turn HDL into a therapeutic target. Well, now we can."

The company developing the agent, Esperion Therapeutics Inc, released preliminary results from the study earlier this year, as reported by heartwire . The idea for ETC-216 sprang from the observation that 40 people living in a small village in northern Italy who carry a variant of ApoA-1 (known as ApoA-1 Milano) have very low levels of HDL-C (17 on average) but paradoxically low rates of cardiovascular disease and normal life expectancy, a finding attributed to their particular ApoA-1 variant and potentially its ability to enhance lipid transport out of coronary plaques.

The magic of Italy

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.

Change from baseline in placebo- and ETC-216-treated patients



Combined ETC-216 groups

Mean change in atheroma volume (%) +0.14 -1.06
Mean change in total atheroma volume (mm3) -2.9 -14.1
Mean change in maximum atheroma thickness (mm -0.008 -0.042


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."

Surprising the optimistic supporters

In an editorial accompanying the study[2], 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." 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."


Media buzz over ApoA-1 Milano

The alluring backstory that paved the way for Nissen et al's findingsnamely, the lucky Italian villagers with the super-HDLproved irresistible to media outlets around the globe. Countless newspapers and websites carried the Associated Press (AP) story, which quoted Nissen describing the concept behind ETC-216 as "liquid Drano for the coronary arteries."

Medical experts interviewed by mainstream reporters for the most part echoed the surprise and optimism voiced by Nissen and Rader in the JAMA paper and editorial.

Professor Sir Charles George, medical director of the British Heart Foundation, told BBC News Online that the "ApoA-l Milano variant is of considerable interest, since some people with it seem to be protected from coronary heart disease. The small study shows that this modification could have positive effects in treating patients."

Both the AP and the New York Times quoted Dr Bryan Brewer, chief of the molecular disease branch at the National Heart, Lung, and Blood Institute. "This is clearly on the level of a breakthrough that will have far-reaching implications," Brewer told the AP. To the Times, Brewer added, ""We're clearly at the beginning of the field, but it's extremely encouraging."

Gina Kolata of the Times spoke to Dr Prediman K Shah (Cedars Sinai Medical Center, Los Angeles, CA), who pioneered the early animal studies using ApoA-1 Milano, as reported by heartwire . According to the Times, even Shah was surprised by how quickly plaque accumulation was reversed in mice. "Holy moly, to our big surprise, within 48 hours what these mice showed," he exclaimed. "The cholesterol content of the plaques had dropped by almost 50%. Almost 50% of the lipid was gone. And the inflammation had dropped. The plaques had regressed."

Dr Alan R Tall (Columbia University) told the Times that the study's small size was a limitation. "It's not a watertight case by any means, but I basically believe it," he said. "I think it's exciting." reported that the treatment had "made a big difference" to John Pierce, a 51-year-old who presumably participated in Nissen et al's study. "I feel like my old self again," Pierce is quoted on "There's no pain in the chest, there's no tightness in the chest, there's no shortness of breath."

Wall Street Journal reporter Ron Winslow noted that drug companies have been searching for HDL-targeted therapies for more than a decade. Pfizer, Japan Tobacco Inc, and Avant Immunotherapeutics Inc "are among the companies that have trials of other HDL drugs under way in people," Winslow reports.



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