A study suggests that use of a investigational drug, DG-031, that inhibits a specific protein in patients with genetic variants that increase the risk for myocardial infarction, reduced the levels of inflammatory markers associated with risk of myocardial infarction.

In 2003, through a population-based, genome-wide study involving hundreds of myocardial infarction patients and their family members in Iceland, deCODE Genetics, a biopharmaceutical company, discovered variations in the gene encoding FLAP, or 5-lipoxygenase activating protein, that double the risk of the disease.

Hakon Hakonarson, of deCODE Genetics, Reykjavik, Iceland and colleagues conducted a study to determine the effect of an inhibitor of FLAP on levels of biomarkers associated with myocardial infarction risk.

The branch of the leukotriene pathway linked to risk of myocardial infarction, through the activity of FLAP, leads to the production of leukotriene B4, which is a potent mediator of arterial inflammation.

The researchers' previously published findings indicate that myocardial infarction patients, both those with and without the at-risk variants of the FLAP gene, produce more leukotriene B4 than do controls.
This suggests that the up-regulation of the leukotriene pathway contributes to risk of the disease, both through genetic and environmental factors, primarily by promoting inflammation in atherosclerotic plaques and increasing their propensity to rupture.
By inhibiting the function of FLAP and thereby down-regulating the activity of the leukotriene pathway, the risk of myocardial infarction may be decreased.

Rresearchers used DG-031, an inhibitor of FLAP.

The trial included myocardial infarction patients who carry at-risk variants in the FLAP gene or in the leukotriene A4 hydrolase gene.

Of 268 patients screened, 191 were carriers of at-risk variants in FLAP ( 87 percent ) or leukotriene A4 hydrolase ( 13 percent ).

Individuals were enrolled in April 2004 and were followed up by designated cardiologists from the Landspitali University Hospital in Iceland until September 2004.

Patients were first randomized to receive 250 mg/d of DG-031, 500 mg/d of DG-031, 750 mg/d of DG-031, or placebo.

After a 2-week washout period, patients received DG-031 if they had received placebo first or placebo if they had received DG-031 first. Treatment periods lasted for 4 weeks.

The researchers found that levels of several biomarkers linked to arterial inflammation and risk of myocardial infarction decreased.

In response to 750 mg/d of DG-031, production of leukotriene B4 was significantly reduced by 26 percent and myeloperoxidase was significantly reduced by 12 percent.

The higher 2 doses of DG-031 produced a nonsignificant reduction in C-reactive protein ( 16 percent ) at 2 weeks.
However, there was a more pronounced reduction ( 25 percent ) in C-reactive protein ( CRP ) at the end of the washout period that was significant and persisted for another 4 weeks thereafter.

An 8-day, open-label follow-up study with 75 patients with the same genetic and disease profile as in the Phase IIa was conducted to further examine the effect of DG031 on CRP and myeloperoxidase.
The results of this study showed that the 750mg/d dose of DG031, when administered as 250 mg 3 times daily resulted in a 38 percent reduction in CRP levels, as well as a 31 percent reduction in myeloperoxidase levels measured 6 hours after dosing on day 8.

In both studies, the FLAP inhibitor DG-031 was well-tolerated and was not associated with any serious adverse events.

Source: Journal of American Medical Association, 2005


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