Promising phase 2 results for anti-atherosclosis drug Reply

Initial phase 2 results for an anti-atherosclerotic agent that inhibits sPLA2 are encouraging, according to a new report and commentary published in the Lancet. In a dose-ranging study of 393 patients with stable coronary disease, the experimental drug A-002 (Anthera Pharmaceuticals) reduced sPLA2 by 87% and also caused reductions in LDL cholesterol and CRP levels.

An accompanying commentary by Marshall Corson notes that “the race is on” to develop this class of drugs, since “PLA2s may be uniquely situated at the interface of lipoproteins and macrophages, promoting plaque instability and clinical events by stimulating cell necrosis and apoptosis.” Nevertheless, adverse events were observed in a trial with one earlier agent, and other promising classes of anti-atherosclerotic drugs have fallen by the wayside. “These difficulties could increase the regulatory hurdles that need to be cleared for these, or other, novel antiatherosclerotic therapies,” Corson concludes.
Not everyone agrees the study should have been published in the Lancet. Harlan Krumholz told CardioBrief: “I was surprised to see a Phase II study in Lancet.” Nevertheless, he said, “the results are interesting and supportive of further development of this secretory phospholipase A2 inhibitor. As the authors state, the findings are potentially clinically relevant.”

The Lancet press release:
DRUG A-002 COULD BE EFFECTIVE ANTI-ATHEROSCLEROTIC AGENT

The secretory phospholipase A2 enzyme (sPL A2) inhibitor A-002 could be an effective anti-athersclerotic agent, concludes an Article in this week’s edition of The Lancet, written by Professor Robert S Rosenson, University of Michigan, USA, and colleagues.

Atherosclerosis is a disease of the arteries in which they become blocked and inflamed by a build-up of white blood cells and fatty (lipid) material within. Phospolipid molecules in the blood and vessel wall are broken down by sPLA2 , producing two potentially bioactive fats that can be involved in atheroscelroisis. There are ten separate groups in the family of sPLA2 enzymes, of which groups IIA, V, and X are highly expressed in atherosclerotic lesions in both humans and mice. Thus any potential treatment would need to target these three groups. The authors tested the effect of A-002, an sPLA2 enzyme inhibitor that targets these three groups, on sPLA2 and on plasma lipoproteins and inflammatory biomarkers in patients with coronary heart disease, specifically examining the effect on sPLA2 IIA. Groups V and X sPLA2 are more highly concentrated in the vessel wall, so these were not specifically analysed.

In this phase II randomised controlled trial, 393 patients from the USA and Ukraine were randomised to receive placebo (79), or one of four does of A-002: 50mg (79), 100mg (80), 250mg (78) or 500mg (77). All groups received their treatment twice daily for eight weeks. The researchers found that mean sPLA2 IIA concentration fell by 87% in the overall A-002 group, compared with a fall of only 5% in the placebo group. The reductions for A-002 patients were does dependent, ranging from 69% in the 50mg group to 96% in the 500mg group. Mean LDL (bad) cholesterol concentrations decreased by 8.0% in the overall A-002 treatment group, compared with 1.7% in the placebo group. C-reactive protein (an inflammatory marker) concentrations decreased by 56% in the overall A-002 treatment group, and by only 25% in the placebo group.

The authors say*: “Our study demonstrates that sPLA2 inhibition produces favorable changes in plasma lipids, oxidized LDL and inflammatory markers, and the magnitude of these changes was larger in statin-treated patients. Proof of concept for sPLA2 inhibition has been established in experimental animal studies. These studies have demonstrated that sPLA2 inhibition with varespladib reduced atherosclerosis progression and improved histopathological features associated with plaque stability. The clinical utility of sPLA will require a randomized, double-blind clinical trial that investigates the effects of sPLA2 inhibition on reducing atherosclerosis progression and cardiovascular events.”

The authors conclude: “The reductions in sPLA2 concentration suggest that A-002 might be an effective anti-atherosclerotic agent.”

In an accompanying Comment, Dr Marshall A Corson, University of Washington/Harborview Medical Center, Seattle, Washington, says that these enzymes are promising targets for therapeutic interventions. But he also cautions that recent attempts to develop selective anti-inflammatory or antioxidant therapies initially showed favourable effects on biomarkers and measures of efficacy, but were subsequently found to be adverse or neutral for cardiovascular disease events. He concludes: “[This difficulty] suggests that challenges might lie ahead for sPLA2 inhibitors. These difficulties could increase the regulatory hurdles that need to be cleared for these, or other, novel antiatherosclerotic therapies.”

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