AVANIR Discovers Novel Small Molecules Targeting Treatment of Atherosclerosis; Oral, New Chemical Entity Markedly Reduces Vascular ``Plaque'' in Animal Model

SAN DIEGO--(BUSINESS WIRE)--March 15, 2004--AVANIR Pharmaceuticals (AMEX:AVN) announced that it has discovered a series of orally-active small molecules that, in animal models, reduce the fatty deposits in blood vessel walls (commonly called plaque) typically associated with atherosclerosis. The experimental animal models that served to evaluate AVANIR's compounds also showed favorable effects on plasma cholesterol levels in lowering LDL cholesterol while increasing HDL cholesterol. The lead molecule in the series has been designated AVP 26452.

"Our compounds were discovered through a research program targeting Apolipoprotein A1," said Jagadish Sircar, Ph.D., Vice President of Drug Discovery at AVANIR Pharmaceuticals. "This protein, also known as ApoA1, is an important mediator of the reverse cholesterol transport pathway, which is responsible for removing excess cholesterol from the body. Recently, others have reported that injectable versions of ApoA1 resulted in regression of vascular plaque in atherosclerosis patients following a short course of therapy. We believe our compounds could have similar benefits but may have more extensive applications as they are orally active."

AVP 26452 was chosen as the lead candidate from a series of small molecules developed at AVANIR with the objective of providing the "next generation" of lipid lowering drugs. Unlike currently available drugs that focus on lowering plasma levels of LDL cholesterol, AVANIR's compounds are designed to have a more direct effect on the blood vessel wall by promoting a natural process known as reverse cholesterol transport. The reverse cholesterol transport pathway may be a more efficient mechanism to both prevent and reverse vascular disease because it actively removes cholesterol from the vessel wall rather than only preventing its accumulation.

"The reverse cholesterol transport pathway is a well-validated target for drug development," said Gerald J. Yakatan, Ph.D., President and CEO of AVANIR Pharmaceuticals. "We believe this program has great promise and I look forward to moving our lead compound into the clinic to begin the requisite human clinical studies."

Preclinical Findings on AVP 26452

  • AVP 26452 has demonstrated an ability to increase LDL-mediated cholesterol uptake in cultured human liver cells thereby facilitating the hepatic clearance of LDL.

  • AVP 26452 has demonstrated an ability to decrease oxidized LDL-mediated cholesterol and cholesteryl ester accumulation in cultured human vascular smooth muscle cells thereby protecting the cells from accumulation of excess cholesterol.

  • AVP 26452 has demonstrated an ability to decrease acetylated LDL-mediated cholesterol and cholesteryl ester accumulation in cultured human macrophages. It also appears to promote cholesterol efflux from acetylated-LDL-loaded human macrophages. In vivo, AVP 26452 has demonstrated an ability to inhibit foam cell formation (the hallmark of atherosclerosis/cardiovascular disease in humans).

In atherosclerosis-prone ApoE-deficient mice, AVP 26452 lowered plasma cholesterol associated with LDL. More importantly, following oral administration over 10 weeks, aortas from mice treated with AVP 26452 showed dose-dependent reduction in fatty atherosclerotic plaques compared to placebo-treated control mice.

"It is very rewarding to watch basic research give rise to prospective human drug therapies with the potential to help so many people," noted Dr. Linda K. Curtiss, a Professor at The Scripps Research Institute, who served as a scientific consultant for these studies. "If the animal data can be reproduced in humans, patients at risk of developing heart attacks or stroke may benefit from this approach," added Dr. Sircar.

About Cholesterol

Cholesterol is an essential component of all tissues and cells. However, it is a double-edged sword because cholesterol that is unused by tissues and cells may accumulate in blood vessels and is associated with increasing the risk for heart attacks and strokes. There are two major pathways for the movement of cholesterol in the body, one that delivers cholesterol from the liver or dietary sources to peripheral tissues, and one that returns cholesterol back to the liver for elimination from the body. This latter process is known as reverse cholesterol transport and is considered an important target for anti-atherosclerotic drug therapy. Under healthy conditions cholesterol delivery to cells and reverse cholesterol transport back to the liver are balanced. If this equilibrium is shifted in favor of cholesterol delivery over its elimination (as might occur when a high fat diet is regularly consumed), excess cholesterol starts accumulating in the body, resulting in elevated blood cholesterol. This elevation of blood cholesterol leads to accumulation of excess cholesterol in the arterial wall and foam cell formation that results in atherogenic plaque. The atherogenic plaque narrows the arteries, thus increasing the risk of heart attack, stroke, or both.

According to the American Heart Association's "Heart Disease and Stroke Statistics -- 2004 Update," coronary heart disease and stroke are the first and third leading causes of death, respectively, in the United States.

Current therapies for high cholesterol include diets to reduce cholesterol intake, cholesterol absorption inhibitors (such as cholestyramine resin), cholesterol synthesis inhibitors (such as statins) and various other lipid lowering agents. Statins are very effective in controlling the cholesterol levels in certain patient populations. However, they are not effective in all patient populations and in some instances can have serious side effects. The current market for cholesterol-lowering drugs is over $20 billion and the current market leader projects that annual sales of its drug will exceed $10 billion in 2004.

About the Company

AVANIR Pharmaceuticals is a drug discovery and development company focused on the development of treatments for chronic diseases. The Company's lead product candidate, Neurodex(TM), is in Phase III clinical development for the treatment of pseudobulbar affect, also known as emotional lability. Neurodex is also in Phase II clinical development for the treatment of neuropathic pain. An internally developed small molecule, AVP-13358, is in a Phase I clinical trial for the treatment of allergy and asthma. Using its proprietary Xenerex(TM) technology, AVANIR also develops human monoclonal antibodies for infectious diseases and other therapeutic applications. The Company's first commercialized product, Abreva(R), is marketed in North America by GlaxoSmithKline and is the leading over-the-counter product for the treatment of cold sores.

The information contained in this press release, including any forward-looking statements contained herein, should be reviewed in conjunction with the Company's most recent Annual Report on Form 10-K and other publicly available information regarding the Company. Copies of such information are available from the company upon request. Such publicly available information sets forth many risks and uncertainties related to the Company's business and technology. Forward-looking statements often contain such words like "estimate," "anticipate," "believe," "plan" or "expect." Our cholesterol reduction program is only in the early stages of development and competes with other research approaches and compounds under development by large pharmaceutical and biotechnology companies. Preclinical research findings are not always supportable by evidence obtained from subsequent clinical trials. Final review decisions made by the FDA and other regulatory agencies concerning clinical trial results are unpredictable and outside the influence and/or control of the Company. The company disclaims any intent or obligations to update these forward-looking statements.

CONTACT: AVANIR Pharmaceuticals
Patrice Saxon, 858-622-5202 (Investor Relations)
psaxon@avanir.com

SOURCE: AVANIR Pharmaceuticals