"We know that inflammation is a significant component, in both atherosclerosis initiation and progression and perhaps even in the events leading to ACS, so to test a drug that focuses on one of these proinflammatory pathways makes a lot of sense," Tardif commented. VIA-2291 is a 5-lipoxygenase inhibitor, and it demonstrated significant and dose-related inhibition of leukotrienes in the study, "so we know we are hitting the target, and that's good. There are a lot of data pointing to leukotrienes as a significant player," he added.

If successful, Tardif said VIA-2291 would likely be given long term, as secondary prevention, in addition to statins, antihypertensives, and anticoagulants, to patients with ACS. Another phase 2 trial with the compound was also reported, in patients due to undergo carotid endarterectomy, but this did not meet its primary end point.

One of the chairs of the session on VIA-2291, Dr Douglas Mann (Baylor College of Medicine, Houston, TX), told heartwire: "For phase 2, the data are provocative and warrant further studies, [but] . . . there were some inconsistencies between the two trials [that] are concerning."

Dr Subodh Verma (University of Toronto, ON), who has a research interest in inflammation and heart disease but was not involved with these studies, told heartwire that "there are growing biological data to support the role of leukotrienes in human and experimental atherosclerosis, and . . . in my opinion, blockade of leukotriene production is a logical target for exploration."

However, it is early days, he cautioned: "Although the two papers reported at the AHA provide some preliminary biochemical efficacy end-point data [on VIA-2291], we need more conclusive surrogate data prior to embarking on large clinical trials."

In the ACS study, 191 patients who had recently had an MI or unstable angina were treated once daily with 25 mg, 50 mg, or 100 mg of VIA-2291 or placebo for 12 weeks. A further subset of around 90 patients continued in the trial for an additional 12 weeks of treatment at the same doses.

All the doses tested showed a significant effect on the primary end point—change from baseline in leukotriene B₄ production—compared with placebo (p<0.01). However, there was no effect of VIA-2291 on C-reactive protein (CRP) in those treated for 12 weeks, although CRP was significantly reduced in the subset of patients who continued to take the drug for 24 weeks, Tardif said.

"The drug was pretty well tolerated," he added. There was a small increase in liver-function-test (LFT) abnormalities, slight increases in lipases and amylases, and some drops in hemoglobin seen in those taking VIA-2291, but these were all completely asymptomatic, he noted.

"We've been talking a lot about the role of inflammation over the past 10 years," says Tardif, "but there really is not a drug that specifically targets inflammation or one of these specific inflammatory pathways. Now we have a drug that would be tested over and above all the other traditional drugs."

He is particularly excited about the results, given the findings from the landmark JUPITER study, also reported at the AHA meeting last week: "We saw from JUPITER that patients with systemic inflammation—as revealed by high C-reactive protein—seem to benefit even more from a statin," he noted, "and we know that statins do have anti-inflammatory effects, but it is difficult to dissociate their effects on cholesterol and lipids from their effects on inflammation. So there's a future for drugs that have specific anti-inflammatory effects without effects on other markers."

Also reported at the AHA meeting, by Dr Tilmann Brotz (VIA Pharmaceuticals, San Francisco), was a small trial with VIA-2291 in 50 patients scheduled for elective carotid endarterectomy (CEA), who were treated for 12 weeks with either 100 mg of the drug or placebo and then underwent the procedure.

There was no difference between the active and placebo groups in terms of the primary end point in this trial—percentage of reduction in macrophage inflammatory cells in plaque tissue—but VIA-2291 did meet some key secondary end points, including reduction of CRP (p<0.01).

Tardif told heartwire: "This was a small, mechanistic study that did not meet its primary end point, but I still think there are some interesting findings, such as the significant reduction in CRP with VIA-2291, which complements pretty well our study in patients with ACS."

A third phase 2 trial of VIA-2291 is still under way, measuring reductions in plaque inflammation as measured with fluorodeoxyglucose positron-emission tomography (FDG-PET) in patients with ACS. Results are expected next year.

Mann said: "There were some inconsistencies between the two trials. In the ACS trial, the CRP dropped late at 24 weeks, whereas in the endarterectomy trial the CRP fell fast. I queried the [investigators] about the discrepancy between the two studies, and they replied that [in the first study] patients were recovering from the ACS and that is why the inflammation was slow to drop.

"In the endarterectomy trial, the CRP dropped, but they did not show a direct effect on inflammation in plaque tissue. When you view both trials together, there is a suggestion that VIA-2201 is having an effect on inflammation using a very good surrogate marker (ie, CRP); however, it is not clear from the data presented that VIA-2201 is targeting inflammation in vulnerable plaques. Hopefully, the FDG-PET study will provide further insight on mechanisms of action."

Dr Rebecca Taub (VIA Pharmaceuticals, Princeton, NJ) told heartwire that no specific decisions have yet been made about exactly what form phase 3 trials of this compound will take or what specific doses will be tested.