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Hot, cool, cold: The future of phospholipase A₂ as a therapeutic target for CHD

Issue: July 2014

BySeth S. Martin, MD, MHS, FACC, FAHA, FASPC

ByBrian Houston, MD

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Brian Houston

Seth S. Martin

After three runs down the track at the 2014 Winter Olympics in Sochi, Russia, the US bobsled team of Elana Meyers and Lauryn Williams had the gold medal in their sights. Leading by 0.11 seconds over the Canadian team, a clean fourth run would guarantee a place on top of the podium. But after nicking the wall on the second turn, and scraping the side a few more times, the US team would settle for silver, having been beaten by a mere tenth of a second. Meyers would say afterward: “Anytime you’re that close and you can taste it and you don’t come down with a result, it hurts a little bit.”

If phospholipase A₂ inhibitors could talk, they might express a similar sentiment.

Results from the first large outcomes trial of lipoprotein-associated phospholipase A₂ (Lp-PLA₂) inhibition were presented before a packed room in the main tent at the American College of Cardiology Scientific Sessions in March. The STABILITY trial was a randomized, placebo-controlled, double blind, prospective, event-driven evaluation of the Lp-PLA₂ inhibitor darapladib (GlaxoSmithKline) in patients with CHD. Despite certain lines of promising epidemiologic, basic science and IVUS data, to the disappointment of many, the trial did not meet its primary endpoint.

Considering the controversial motto of the 2014 Winter Olympics, Hot. Cool. Yours, is the PLA₂ journey Hot. Cool. Cold?

Hot

Early work established the pro-inflammatory role of PLA₂ enzymes, and interest in the enzymes as a potential therapeutic target increased when pathologic studies placed them “at the scene of the crime.” Secretory PLA₂ was demonstrated in atherosclerotic lesions and myocardial regions that had sustained ischemic injury. Lp-PLA₂ was found to be highly expressed in apoptotic macrophages in high-risk human coronary lesions. Moreover, in swine, darapladib reduced coronary artery lesion development and progression.

Epidemiologic studies turned up the heat after demonstration that higher levels of secretory PLA₂ (particularly the IIA group) were associated with CV risk in asymptomatic individuals and patients with CHD. Similarly, an analysis of 32 prospective studies concluded that Lp-PLA₂ activity and mass are associated, in a continuous dose-dependent fashion, with CHD risk. This increase in risk was similar in magnitude to non-HDL cholesterol or systolic BP.

Cool

The view of the A2 phospholipases as a suitable therapeutic target was not quite uniform. There was a theoretical concern that inhibition of the Lp-PLA₂ might lead to an increase in platelet activation, and adenoviral transfer of Lp-PLA₂ in apolipoprotein E-deficient mice actually reduced the atherosclerotic burden.

Nevertheless, clinical study of the secretory PLA₂ inhibitor varespladib (Anthera Pharmaceuticals) was initiated in the VISTA-16 randomized clinical trial. In this double blind, multinational trial, 5,145 patients were randomly assigned in a 1:1 fashion to varespladib 500 mg or placebo daily within 96 hours of presentation with ACS. Disappointingly, the trial was stopped prematurely for futility and possible harm.

Earlier, in 2008, the IBIS-2 study investigated treatment with darapladib (160 mg daily for 12 months) vs. placebo in 220 patients with ACS or chronic CHD. Co-primary endpoints included coronary atheroma deformability on IVUS palpography and serum levels of high-sensitivity C-reactive protein.

Neither outcome differed significantly between the darapladib or placebo arms. However, there remained a string of hope to latch on to: A secondary outcome showed a reduction in the average size of plaque necrotic core size as determined by IVUS virtual histology. Whether this favorable change in the characteristic of the plaque would translate into improved clinical outcomes necessitated large outcome trials.

Cold

At ACC 2014, we were disappointed to learn that darapladib missed its primary endpoint in a well-done study of patients with stable CHD. The STABILITY trial enrolled 15,828 patients with chronic CHD (defined as prior MI, revascularization or multivessel coronary disease on angiography) who were randomly assigned darapladib or placebo for an anticipated median treatment duration of 2.75 years. The primary endpoint was a combination of major coronary and stroke events.

The median age of the participants was 65 years, 19% were women, 59% had a prior MI and 75% had a prior revascularization. Patients were followed for longer than expected, a median of nearly 4 years, in this event-driven trial. In general, patients were well treated, with 90% on aspirin, 96% on statin therapy, 79% on a beta-blocker and 80% on an ACE inhibitor or angiotensin receptor blocker at the trial close.

The primary endpoint occurred in 9.7% of patients (769 events) assigned daily darapladib vs. 10.4% of patients assigned placebo (819 events). The researchers calculated an HR of 0.94 (95% CI, 0.85-1.03). Of note, compared with placebo, there was an encouraging 10% relative reduction in major coronary events (HR=0.9; 95% CI, 0.82-1).

Interaction analyses of 35 prespecified subgroups showed evidence of effect modification by smoking status (P=.04). Smokers had a 23% reduction in events (HR=0.77; 95% CI, 0.62-0.96), whereas the signal was null in non-smokers. Prior studies showed that smokers tend to have higher Lp-PLA₂ levels than nonsmokers. We look forward to the seeing an analysis of the levels of Lp-PLA₂ activity and mass in STABILITY. One wonders how the trial levels match up with levels from prior epidemiologic analyses, and whether there is a signal for greater treatment response in patients with high baseline Lp-PLA₂ levels.

Unfortunately, it was recently announced that a second phase 3 study of darapladib also failed to meet its primary endpoint. The SOLID-TIMI 52 trial enrolled 13,000 patients within 30 days of an ACS and randomly assigned them to darapladib or placebo. On May 13, the company announced that there was no significant reduction in major coronary events. Detailed analyses of the trial results will follow, but, at this time, the word is that regulatory approval for darapladib will not be pursued.

The future

One wonders if we are witnessing the Olympic fall of PLA₂ or if the suggested CHD benefit from STABILITY is cause for continued optimism. As endorsed by the 2013 ACC/American Heart Association guidelines, preventing both MI and stroke is the name of the game. Indeed, statins currently stand alone at the top of the podium in preventing both of these important atherosclerotic disease endpoints with Olympic gold medal efficacy. STABILITY showed us that statins and other established risk-reducing agents can be very effectively implemented. However, we clearly need more risk-reducing therapies for our patients and the stakes are high. For those in the game, we can only hope there are more gold medals to go around.

Disclosure: The authors report no relevant financial disclosures.