NEW ORLEANS (FRONTLINE MEDICAL NEWS) – The future doesn’t look bright at the moment for use of agents that mimic HDL cholesterol to reverse coronary disease, based on disappointing results of the randomized, phase II MILANO-PILOT trial.

Among 120 patients with recent acute coronary syndrome, a mimetic known as MDCO-216 was no better than placebo at reducing coronary plaque measured by intravascular ultrasound (IVUS), according to data presented at the American Heart Association scientific sessions.

The median reduction in percent atheroma volume, the trial’s primary endpoint, was 0.5% with the mimetic and 0.8% with placebo, reported Stephen J. Nicholls, MD, of the South Australian Health and Medical Research Institute, University of Adelaide (Australia). Findings were similar for secondary outcomes assessing other measures of disease regression.

These data bring to an end a story that began in the 1980s, with discovery that a family in a town in northern Italy had a naturally occurring apolipoprotein A-I variant that mimics the actions of HDL cholesterol, subsequently named ApoA-IMilano. Despite having low levels of HDL, family members have a reduced risk of coronary disease.

In a small randomized trial, patients with acute coronary syndrome given an early recombinant form of this apolipoprotein saw a reduction in IVUS-measured coronary atherosclerosis ( JAMA. 2003;290:2292-300 ). This prompted development of the refined recombinant form, MDCO-216, tested in the new trial.

“MDCO-216 did not produce a significant effect on coronary disease progression as measured by IVUS,” said Dr. Nicholls, who discussed the findings in a video interview . “These results occurred on a background of contemporary therapy in the post-ACS setting, which in 2016 is very effective for many patients.”

“The findings from this pilot study do not provide the evidence required to proceed with further development,” he concluded.

Hope hinges on wild type

“This trial was extremely well done, world-class investigators carried out this trial, it was three times the size of the previous IVUS trial, and I think it is convincingly negative,” said discussant Daniel J. Rader, MD, associate director of the Institute for Translational Medicine and Therapeutics and director of the Preventive Cardiovascular Program at Penn Medicine, Philadelphia. “The sponsor has elected to stop the development of this product, and I think we can probably write the obituary for ApoA-IMilano, even though it was never studied in cardiovascular outcomes.”

However, he cautioned against extrapolating the trial’s findings to other similar products that use wild-type ApoA-I instead of ApoA-IMilano. An important structural difference between the two appears to translate to differences in clearance from the body and in impacts on lipid metabolism, giving reason to think the wild type may be efficacious when the variant is not.

“At the end of the day, my message is that this has been a wild ride with ApoA-IMilano, and it’s sad to see that, at least when it comes to coronary atherosclerosis, this trial does not support that ApoA-IMilano has an effect,” Dr. Rader concluded. “But I do think we need to see through the other products with wild-type ApoA-I given the marked difference in structure before we can conclude that this general approach of infusing a reconstituted ApoA-I particle is not going to work.”

Trial details

Patients from 22 centers globally were randomized in MILANO-PILOT. All patients had experienced acute coronary syndrome in the past 14 days and had maximum stenosis of 20%-50% of a target vessel on coronary angiography.

After undergoing IVUS, they were randomized evenly to double-blind treatment with five weekly intravenous infusions of MDCO-216 or placebo, each combined with statin therapy.

Results showed – as expected based on past experience – that HDL cholesterol levels increased by 8.0% with placebo and decreased by 7.8% with MDCO-216 (P less than .001), Dr. Nicholls reported. Apolipoprotein A-I levels increased by 5.6% in the former and decreased by 5.3% in the latter (P less than .001). Changes in a variety of other lipid measures did not differ significantly between groups.

“These study patients were extraordinarily well treated. We achieved LDL cholesterol levels in both treatment groups that were less than 70 mg/dL,” he pointed out.

In addition to the lack of difference in the reduction in percent atheroma volume, there was also no significant difference between MDCO-216 and placebo in the secondary endpoints of median change in total atheroma volume, either in the entire vessel length imaged (–4.7 vs. –6.9 mm3) or in the most diseased 10-mm segment (–2.4 vs. –2.4 mm3).

The percentage of patients having any degree of disease regression was 55.8% with MDCO-216 and 67.2% with placebo, another nonsignificant difference.

“The majority of patients in this study demonstrated some degree of regression, and I believe that really highlights the impact of contemporary treatment guidelines have on coronary atherosclerosis in the early post-ACS setting in the contemporary era,” Dr. Nicholls maintained.

Exploratory analyses did not indicate any clear differential impact of MDCO-216 versus placebo according to whether patients had already been taking statins at baseline.

MDCO-216 was generally safe and well tolerated. “We saw no differences between the groups in terms of a range of biochemical adverse events, serious adverse events, and infusion site reactions,” reported Dr. Nicholls, who disclosed that he received a research grant from The Medicines Company, which sponsored the trial.