Death watch intensifies for HDL-based interventions.
WASHINGTON -- Is it finally time to give up on HDL cholesterol-based interventions to treat atherosclerotic disease?
The approach "is on life support," admitted Stephen J. Nicholls, MD, a long-time leader in the field who has reported results from a series of studies during the past 10 or so years that tested various approaches to juicing HDL cholesterol activity in patients, only to see each and every candidate intervention result in an inability to budge clinical outcomes.
"What we've seen is the progressive failure of HDL-targeted treatments over the course of a decade," Dr. Nicholls said during something of a postmortem that he delivered at the annual meeting of the American College of Cardiology.
The latest disappointment he reported was for CER-001, an engineered HDL mimetic agent. In a placebo-controlled international study, CARAT (CER-001 Atherosclerosis Regression ACS Trial), with 301 randomized patients and 272 completers, 10 weekly infusions of CER001 over the course of 9 weeks failed to produce discernible incremental regression of atherosclerotic plaque volume, compared with standard care measured by serial examination using intravascular ultrasound (IVUS), Dr. Nicholls reported. The absence of any detectable benefit "suggests that this is not a promising strategy," he said during his report at the meeting.
Enthusiasm for HDL cholesterol-based interventions dates to 2003, when an IVUS study of a first-generation HDL mimetic agent, ETC-216, showed an apparent ability to produce regression of coronary atheroma after five infusions over a 2-week period, compared with placebo-treated patients (JAMA. 2003 Nov 5;290:2292-300). But the successor compound to this agent, MDCO-216, flamed out in an IVUS study with 113 completing patients that Dr. Nicholls reported at the American Heart Association Scientific Sessions in November 2016.
Also lying dead on the trial trail during past years are several cholesterol ester transfer protein inhibitors --torcetrapib, dalcetrapib and evacetrapib--as well as other agents that Dr. Nicholls described in a recent review (Arch Med Sci. 2016 Oct 24; 12: 1302-7).
"HDL wouldn't be the first risk factor we've seen that is not a modifiable target. Homocysteine is a really good example" of another atherosclerotic disease risk that's proven immune to intervention, Dr. Nicholls said in an interview at the meeting. "Ultimately we'll come to a point when the enthusiasm [for potential HDL interventions] will wane, but we're not quite there yet."
One example of ongoing belief in HDL's future despite its dispiriting track record was voiced by Deepak L. Bhatt, MD, as a discussant on Dr. Nicholl's report: The neutral result with CER-001 reported at the meeting "shouldn't discourage further research in the field. I think research into HDL-modifying treatments should go on," said Dr. Bhatt, a professor of medicine at Harvard Medical School in Boston and a cardiologist at Brigham and Women's Hospital.
"There are other players in the HDL field" that remain viable, said Dr. Nicholls, most notably CSL112, plasma-derived apoAl--the primary functional part of HDL cholesterol --that's infused into patients to boost HDL activity. Results from a phase II study reported in November 2016 showed it increased cholesterol efflux (Circulation 2016 Nov. doi: 10.1161/ CIRCULATIONAHA.116.025687), and is now the subject of additional phase II testing.
"But with every negative trial, it will get harder and harder [to fund new HDL research], and we'll look for other targets," he said.
One promising alternative target is triglycerides. "HDL has received more attention than triglycerides over the past decade, but I think that will start to change as HDL can't deliver," predicted Dr. Nicholls, professor of cardiology at the South Australian Health & Medical Research Institute in Adelaide.
Understandably "financial support is the biggest issue. Do companies and investors still believe in the [HDL] dream?" Dr. Nicholls said that, objectively, looking at the HDL research record should definitely give investors pause before they sink money into new compounds for HDL intervention.
"If I was sitting at the drawing board now, would HDL be the risk factor I'd target? Probably not," he concluded.
Dr. Nicholls received research support from Cerenis, the company that is developing CER-001, and he has received honoraria and research support from several other companies. Dr. Bhatt has received research support from several drug companies.
BY MITCHEL L. ZOLER
On Twitter @mitchelzoler
Caption: Dr. Stephen J. Nicholls
Caption: Dr. Deepak L. Bhatt