VIA Pharmaceuticals announces results of phase 2 trials of VIA-2291 in cardiovascular disease

Nov 10 2008

VIA Pharmaceuticals, Inc. has announced the results of two Phase 2 studies of its lead drug, VIA-2291.

In each Phase 2 study, VIA-2291 effectively inhibited production of leukotrienes, proposed mediators of vascular inflammation. VIA-2291 was generally well-tolerated. The results were presented today during a Special Session at the American Heart Association 2008 Scientific Sessions being held in New Orleans.

"These trials accomplished our goal of demonstrating that VIA-2291 directly impacts the leukotriene pathway and potentially reduces vascular inflammation, which we believe leads to atherosclerosis and death in a broad population," said Lawrence K. Cohen, Ph.D., chief executive officer of VIA Pharmaceuticals. "We now look forward to designing studies that can link VIA- 2291's unique mechanism of action to improvement in atherosclerotic plaque and ultimately cardiovascular outcomes."

The first of these trials, the acute coronary syndromes (ACS) trial, met its primary endpoint by demonstrating a significant change from baseline in Leukotriene B4 (LTB4) production at all doses tested (p<0.001).

The second trial, the carotid endarterectomy (CEA) trial, missed its primary endpoint of percentage reduction in macrophage inflammatory cells in plaque tissue, but met key secondary endpoints including reduction of high sensitivity C-reactive protein (hs-CRP) (p<0.01).

"VIA-2291 has the potential to be the first drug to specifically target one cardiovascular inflammatory pathway," said Dr. Jean-Claude Tardif, Director of the Montreal Heart Institute Research Centre, professor of medicine at the University of Montreal and principal investigator of the VIA- 2291 ACS trial. "These data support further clinical development of this drug, including larger outcome trials."

Cardiologists have several therapies that help reduce heart disease risk factors, but none that specifically targets inflammation, an underlying cause of atherosclerosis, which leads to major adverse cardiac events, including heart attack and stroke.

VIA-2291 is designed to be a selective and reversible inhibitor of 5-LO, a key enzyme in the biosynthesis of leukotrienes, that are important mediators of inflammation believed to be involved in the development and progression of atherosclerosis.

The ACS Phase 2 study of VIA-2291 was designed to establish optimal dosing and safety data in 191 patients with ACS, who recently had a heart attack or unstable angina. Patients were treated once daily for 12 weeks with one of three doses of VIA-2291 or placebo. In order to further evaluate VIA-2291's effect over a longer timeframe, a sub-study of patients in the ACS trial continued for an additional 12 weeks of treatment at the same dose followed by a 64 slice multi-detector computed tomography (MDCT) scan following up on the baseline MDCT scan that all patients had received. The statistical outcomes for the ACS trial were validated by an independent academic statistics group at Montreal Heart Institute.

The CEA Phase 2 study evaluated VIA-2291's effect on atherosclerotic vascular inflammation in 50 patients scheduled for elective CEA. CEA is a surgical procedure to remove plaque from the carotid artery to increase blood flow to the brain and to reduce the risk of stroke in patients with significant blockage in the artery. Patients in the study were treated for 12 weeks with either 100 mg of VIA-2291 or placebo, and then underwent a CEA procedure. The CEA trial was designed to provide direct evaluation of VIA- 2291's effect on inflammation by analyzing plaque removed from the carotid arteries of patients treated with VIA-2291 or placebo. The trial also measured serum biomarkers of inflammation to measure reduction in inflammation in treated patients.

The ACS trial demonstrated a statistically significant, dose-dependent inhibition of ex vivo stimulated LTB4 production at 12 weeks. LTB4 production was measured at trough, just before the next dose of VIA-2291 was taken, indicating a sustained pharmacological effect of the drug between doses. The secondary endpoint of change from baseline in urine Leukotriene E4 (LTE4), also showed significant inhibition at all dose levels.

The CEA trial confirmed the findings of statistically significant inhibition in leukotriene production observed in the ACS trial. In the CEA trial, LTB4 production was highly inhibited at 12 weeks (p < 0.001).

Leukotriene inhibition was seen early in both trials and was already highly significant after two weeks of drug treatment, the first time it was assessed after starting drug.

In the ACS trial, a statistically significant reduction from baseline as compared with placebo was observed in high-sensitivity C-reactive protein (hs- CRP) levels in the highest dose group of patients treated for 24 weeks. Significant reductions in hs-CRP levels were not observed in the ACS trial in patients treated for 12 weeks, perhaps due, in part, to variability in the level of hs-CRP at the baseline as a result of the recent heart attack or unstable angina.

In the CEA trial, a statistically significant reduction from baseline as compared with placebo in hs-CRP was observed over the 12 week treatment period.

While the results of the CEA trial did not demonstrate a reduction in macrophages in the plaque tissue in carotid arteries of patients treated with 100mg VIA-2291 compared to those treated with placebo, results of a post-hoc analysis did show a reduction in necrotic core thickness relative to plaque thickness. Furthermore, mRNA levels of IL-6, a pro-inflammatory cytokine, appeared to decrease in plaque tissue from patients treated with VIA-2291. These findings may indicate anti-inflammatory activity of VIA-2291 in plaque tissue.

The drug was generally well-tolerated in both trials. In the ACS trial, common (>10 percent) adverse events (AEs) with no clear difference between placebo and VIA-2291 treated patients included angina, fatigue, musculoskeletal pain, and headache. Laboratory abnormalities included generally mild, reversible >/= 3x upper limit of normal liver enzymes in the low dose VIA-2291 treated group (10 percent) and placebo (2 percent), not seen in the higher dose drug-treated groups; and asymptomatic >/= 1.5x lipase elevations that were more common in VIA-2291 treated patients. In the CEA study, common AEs (>7 percent) included fever, diarrhea and cystitis that occurred somewhat more commonly in VIA-2291 treated patients. Common laboratory abnormalities included mild reversible elevations of BUN and reversible decreases >1 gm/dL of hemoglobin that were more frequent in VIA- 2291 treated patients.

"We have conducted a preliminary review of the patient safety data for the VIA-2291 ACS and CEA trials and found that the drug was well-tolerated at the doses tested and support further development of VIA-2291," said Sidney Goldstein, M.D., Division of Cardiovascular Medicine, Henry Ford Hospital, Wayne State University and chairman of the VIA-2291 Data Safety Monitoring Board (DSMB), which monitored safety of the drug throughout both trials.

A third Phase 2 clinical trial is currently underway to measure reductions in plaque inflammation following dosing with VIA-2291 as measured with state- of-the-art FDG-PET imaging technology and assessment of standard biomarker measurements of inflammation in patients with ACS.

VIA will hold a conference call on Monday, November 10 at 8:30 a.m. ET (5:30 a.m. PT) to discuss this announcement. To participate in the conference call, please dial 888-684-1280 for domestic callers and 913-312-0952 for international callers. A telephone replay of the conference call will be available through Friday, November 14, 2008. To access the replay, please dial 888-203-1112 for domestic callers and 719-457-0820 for international callers and reference conference replay passcode 1268443.

A live audio webcast of the call can be accessed from the investor section of the VIA website, http://www.viapharmaceuticals.com/ beginning at 8:30am ET on Monday, November 10. The webcast will be archived for 30 days following the presentation.

VIA-2291 is designed to complement current standard of care therapies that treat cardiac risk factors, such as statins, antiplatelet and blood pressure medications. VIA-2291 is initially targeted to address the secondary prevention market for patients who have already suffered a major adverse cardiac event, but eventually could be beneficial to the broader 15.8 million patients in the U.S. who have coronary artery disease. VIA has exclusive worldwide rights to develop and commercialize VIA-2291. VIA-2291 has been tested in more that 1,300 patients in clinical trials.