Patrice Wendling

November 16, 2016

NEW ORLEANS, LA — One late-breaking clinical trial presented at the American Heart Association 2016 Scientific Sessions has crushed initial enthusiasm for recombinant apolipoprotein A-1 (apoA-1) Milano, while another,  ApoA-1 Event Reducing in Ischemic Syndromes-1 (AEGIS-1), righted hopes for the reconstituted human apoA-1 CSL112 (CSL Behring) after a rocky start with an earlier formulation. 

Final data from the MILANO-PILOT study[1] were unable to confirm a 2003 study showing weekly infusions of apoA-1 Milano, an HDL mimetic, produced significant regression of coronary atherosclerosis by intravascular ultrasound (IVUS) in ACS patients.

Dr Stephen Nicholls

In the current study, the median change in the primary end point of percent atheroma volume was -0.5% after five infusions of MDCO-216 (the Medicines Company), as the agent is known, and -0.8% with placebo (P=0.10), study cochair Dr Stephen Nicholls (University of South Wales, Sydney, Australia) reported.

Discussant Dr Daniel Rader (University of Pennsylvania, Philadelphia) said he penned an effusive editorial about the 2003 data at the time, so "It's appropriate I'm up here basically delivering its obituary."

The Medicines Company has recently announced it is discontinuing development of MDCO-216, but Rader said there are still wild-type apoA-1 products in development that differ in structure and function from apoA-1 Milano.

"Of course, we have no idea whether they're going to be beneficial, but I would suggest that the failure of apoA-1 Milano in this IVUS study should not necessarily kill off all further attempts to develop wild-type apoA-1 and test ultimately its ability to reduce cardiovascular events."

Commenting to heartwire from Medscape, past AHA president Dr Robert Eckel (University of Colorado School of Medicine, Denver) said, "I would say apoA-1 Milano is over there and reconstituted normal wild-type apoA-1 is here, and I think the studies should continue.

"If I were a patient or referring a patient for such a study I would have to show that this is simple, the amount of commitment you are making into this scientific investigation is minimal, and harm at this point has not been demonstrated."

AEGIS-1 Trial

The phase 2b dose-ranging AEGIS-1 trial, also published online in Circulation[2], met its primary end point (safety) for CSL112, a human apoA-1 reconstituted with phosphatidylcholine and stabilized with sucrose.

An earlier version, CSL111, showed evidence of reducing the size of coronary atheroma but at high doses caused an increase in liver enzymes. Acute kidney injury also has been seen with other infusible agents with very high levels of sucrose.

Dr C Michael Gibson

CSL112 contains low concentrations of both of these excipients and is designed to increase cholesterol-efflux capacity, the first step in reverse cholesterol transport, study cochair Dr C Michael Gibson (Beth Israel Deaconess Medical Center, Boston, MA) said. By enhancing cholesterol-efflux capacity, it is thought CSL112 may stabilize additional lesions at risk of rupture, thereby reducing the rate of recurrent events after an MI.

The trialists randomly assigned 1258 ACS patients to four consecutive weekly infusions of CSL112 at low (2-g) or high (6-g) doses or placebo in addition to standard medical care.

The co–primary end points were occurrence of a hepatic safety event (an increase in alanine aminotransferase (ALT) >3 times the upper limit of normal [ULN] or a change in total bilirubin >2 times the ULN) or a renal safety event (a rise in serum creatinine >1.5 times the baseline value or new need for renal-replacement therapy). Mild renal impairment was present in 680 of the 1258 patients.

There were no hepatic safety events with placebo vs four events with low-dose CSL112 (P=0.12) and two events with high-dose CSL112 (P=0.50), which was within the protocol-defined noninferiority margin of 4%.

One renal safety event occurred in the placebo group vs none with low-dose CSL112 (P=0.50) and three with high-dose CSL112 (P=0.62), which was within the noninferiority margin of 5%.

In prespecified exploratory analysis, the harder composite major adverse cardiovascular event end point of CV death, nonfatal MI, and stroke occurred through day 112 in 4.3% of controls vs 4.5% of low-dose CSL112 patients (hazard ratio [HR] 0.60, 95% CI 0.26–1.37) and 6.6% of high-dose CSL112 patients (HR 0.66, 95% CI 0.30–1.46 vs placebo).

CSL112 also increased, in a dose-dependent fashion, total cholesterol-efflux capacity and ABCA1-dependent cholesterol-efflux capacity, which focuses specifically on efflux as it relates to plaque, and raised apoA-1 and HDL-cholesterol levels, Gibson said.

Discussant Dr Philip Barter (University of New South Wales, Sydney, Australia) said, "What this study has shown is that within the limits of this study [CSL112] it is safe."

He added that the low number of participants and events makes it impossible to draw any meaningful conclusions regarding clinical-event outcomes and urged the sponsors to support a much larger, adequately powered trial.

The results support continued planning for phase 3, and further data are being collected from an ongoing phase 2 study in MI patients with moderate renal impairment, study sponsor CSL Behring said in a release.

Eckel told heartwire , "I think the data Gibson presented today are encouraging and relate to an unanswered question: Can we get [apo]A1 reconstituted with phospholipid and be able to infuse it successfully without it being overly expensive?"

MILANO-PILOT was sponsored by the Medicines Company. Nicholls reports consulting for AstraZeneca, Amgen, Anthera, Boehringer Ingelheim, CSL Behring, Eli Lilly, Esperion, Merck, Takeda, Roche, Kowa, LipoScience, Novartis, and Sanofi-Regeneron and conducting clinical trials with Amgen, Anthera, AstraZeneca, Eli Lilly, Novartis, Cerenis, the Medicines Company, Resverlogix, InfraReDx, Roche, Sanofi-Regeneron, and LipoScience. AEGIS-1 was sponsored by CSL Behring. Gibson reports consulting for Amarin Pharma, Research Institute, Cardiovascular Research Foundation, CSL Behring, Eli Lilly, Gilead, Novo Nordisk, Pfizer, Pharma Mar, Roche Diagnostics, St Francis Hospital, St Jude Medical, the Medicines Company, and WebMD and had research funding from Angel Medical, Bayer, CSL, Ikaria, Janssen Pharmaceuticals, Johnson & Johnson, Portola Pharmaceuticals, Stealth Peptides, and St Jude Medical. Disclosures for the coauthors are listed in the article.

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