Mixed Results For ApoA-1 Therapies

–It’s still not time to write the obituary for all HDL therapies.

There was good news and bad news for a category of experimental drugs that attempt to mimic the putative beneficial effect of HDL at the American Heart Association meeting in New Orleans. Thirteen years after setting the field on fire with a promising pilot study, ApoA-1 Milano failed to spark even a flame of enthusiasm. But early positive findings for a different ApoA-1 agent suggested that the flame may not yet be entirely extinguished.

ApoA-1 Milano

Back in 2003 a study in JAMA by Nissen et al found that the naturally occurring variant of the ApoA-1 HDL apolipoprotein, called ApoA-1 Milano, caused a significant regression of atherosclerosis, as measured by IVUS, in a small group of ACS patients. Now, after surviving for 13 years in developmental limbo at 3 separate companies, a new and larger study has failed to confirm the positive findings of the earlier trial. The Medicines Company, which bought the rights to the drug in 2009, said it will not continue to develop the drug.

Investigators, led by Stephen Nicholls and Steve Nissen, performed IVUS imaging on 113 ACS patients who had been randomized to MDCO-216 or placebo. There was no difference in percent atheroma volume or other measures of atheroma progression or regression.

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

Nicholls held out hope that HDL-based drugs may prove to be beneficial, but unless one of the current trials involving other HDL mimetics or the one remaining trial with a CETP inhibitor is positive. “the HDL modulation story may soon end.”

The trial discussant, Daniel Rader (University of Pennsylvania), said that the negative results were “convincing.” “I think we can probably write the obituary for ApoA-1 Milano,” he said. But he made the case that wild-type ApoA-1 was sufficiently different from ApoA-1 Milano to leave room for hope that another ApoA-1 formulation would have a better effect.


A different approach to ApoA-1 therapy is CSL 112, a plasma-derived ApoA-1 product under early development. It is a reformulated version of an earlier compound that was discontinued because it caused liver complications.

Michael Gibson, the study presenter, reported on more than 1,200 ACS patients who received placebo or one of two doses of the drug. He said that CSL 112 was “well tolerated” and did not significantly alter liver or kidney function. Measurements of cholesterol efflux capacity indicated that the drug appeared to work as intended in a dose dependent fashion.

There were only 74 major adverse cardiac events in the trial. This was too small a number to reach any conclusion, Gibson reported, since the trial was not designed to assess cardiovascular outcomes. But there were fewer events in the active treatment arms.

Trial discussant Phillip Barter said that “this is much more important trial than is immediately apparent.” He said that the earlier version had produced early evidence of efficacy but had been stopped because of the liver complications. The new formulation may allow a fair test of the HDL hypothesis, he said.

“This trial has introduced a degree of comfort and I say it now is time to go ahead and test this for outcomes,” said Barter. “On the basis of this trial I would urge the sponsors to support a much larger trial that is powered adequately to see whether the safety and tolerability can also be accompanied by a reduction in cardiovascular events.”

Speak Your Mind