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HDL mimetic fails to demonstrate benefit on coronary atherosclerosis in ACS
NEW ORLEANS — Infusion of an investigational cholesterol efflux promoter failed to produce a significant effect on coronary disease progression measured by IVUS in the MILANO-PILOT study, leading to discontinuation of the clinical development program for the therapy.
In the days leading up to the American Heart Association Scientific Sessions, The Medicines Company announced in a press release that data from the proof-of-concept MILANO-PILOT study did not demonstrate an effect on intracoronary atherosclerotic plaque sufficient to warrant further development of the cholesterol efflux promoter (MDCO-216).
“Favorable effects of HDL infusions in several prior imaging studies provided support for targeting HDL to favorably impact coronary atherosclerosis. However, the failure to demonstrate benefit with MDCO-216 in the setting of contemporary medical therapy will raise further skepticism that targeting HDL will prove protective,” Stephen J. Nicholls, MD, PhD, from South Australian Health and Medical Research Institute, Adelaide, Australia, said here.
The phase 2, double blind, placebo-controlled trial included 120 patients (mean age, 62 years; three-quarters men) with recent ACS who were randomly assigned to receive five 20-mg/kg weekly infusions of MDCO-216 or placebo. IVUS examination of a single coronary artery (maximum stenosis, 20% to 50%) was also performed at baseline and within the same artery 1 week after the final infusion, according to the study details. The study was conducted at 22 sites in five countries.
A total of 113 patients had follow-up on IVUS of the originally imaged target vessel, according to the researchers.
The primary endpoint was median change in percent atheroma volume. Nicholls reported that this outcome was greater with placebo than MDCO-216 (–0.8% vs. –0.5%; P = .1).
A secondary endpoint was of total atheroma volume in the entire vessel length yielded a median change in volume that was greater in the placebo group (–6.9 mm3 vs. –4.7 mm3; P = .77). When the researchers assessed median change in total atheroma volume in the most diseased 10-mm segment, the finding was –2.4% in both groups (P = .53).
Nicholls noted that, as expected, HDL levels increased after infusion in the placebo group and decreased after infusion of MDCO-216.
The investigational therapy was well tolerated in both groups. Data presented here showed similar adverse clinical events and safety findings, with the exception of a higher rate of adverse events of special interest, including acute renal failure, infusion reaction, thromboembolic events, noninfectious hepatitis and liver abnormalities requiring investigation, with MDCO-216 (15.5% vs. 4.7%; P = .05).
According to Nicholls, “these results occurred on a background of contemporary therapy in the post-ACS setting.” Forty-four percent of patients in both groups were using high-intensity statins at baseline.
Nicholls concluded that “the findings from this pilot study do not provide the evidence required to proceed with further development.”
Clinical evaluation continues on HDL mimetics that differ in composition to MDCO-216 and also a CETP inhibitor, he said. However, “unless one of these new agents demonstrates clinical benefits, the HDL modulation story may soon end.”
MDCO-216 is a complex of dimeric recombinant apolipoprotein A-I Milano and a phospholipid that was under development to improve CV outcomes by reducing plaque burden in patients with atherosclerotic disease. MDCO-216 mimics pre-beta HDL and induces cholesterol efflux.
Apolipoprotein A-I Milano is a naturally occurring mutated variant. The first discovery of patients with this mutation was identified over 4 decades ago in a small city in Italy.
“Thus began the myth of apolipoprotein A-I Milano ... [and the] concept that this might be an interesting therapeutic,” Daniel J. Rader, MD, Seymour Gray professor of molecular medicine at Perelman School of Medicine, University of Pennsylvania, said during a discussion of the trial. “The story of apolipoprotein A-I Milano is unfortunately coming to a conclusion.” – by Katie Kalvaitis
Reference:
Nicholls SJ, et al. LBCT.03 – Insights from New Therapeutic Trials for Lipids. Presented at: American Heart Association Scientific Sessions; Nov. 12-16, 2016; New Orleans.
Disclosure: Nicholls reports receiving research grants from Amgen, Anthera, AstraZeneca, Cerenis, Eli Lilly, InfraRedX, Novartis, Resverlogix, Sanofi/Regeneron and The Medicines Company and consulting and/or serving on advisory boards for Amgen, AstraZeneca, Boehringer Ingelheim, CSL Behring, Eli Lilly, Merck, Pfizer, Roche, Sanofi/Regeneron and Takeda. Rader reports financial ties with Eli Lilly, Merck and Pfizer.
Perspective
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The data are conclusive at this stage of development of Apo-A1 Milano. The unanswered question I have is why do patients with Apo-A1 Milano have less CHD, if in fact reconstitution of Apo-A1 Milano in patients with ACS has no impact on the plaque? There are probably long-term effects of Apo-A1 Milano on events that are not captured in ACS, where Apo-A1 Milano infused in the patients has no benefit. I think ACS is different from long-term effects of these HDL molecules. This is an area that requires further investigation, and if I were a company, I would discontinue the manufacture and institution of this therapy for patients with ACS.