West Coast Editor

With its Reverse Cholesterol Transport (RCT) program only at the preclinical stage, Avanir Pharmaceuticals Inc. nailed down a potential $340 million development and commercialization deal with AstraZeneca plc, which has agreed to pay $10 million of that amount up front.

Avanir's stock (AMEX:AVN) closed Monday at $3.20, up 23 cents.

Martin Emanuele, vice president of business development for San Diego-based Avanir, said a drug could be in the clinic "actually quite soon. We're hoping that's still possible this year or early next year."

Under the terms, Avanir is eligible for $330 million if development and regulatory milestones are met and if sales targets are achieved, with royalties rising from single-digit to low-double-digit rates dependent on sales. AstraZeneca will be responsible for costs, with both parties contributing scientific expertise.

"It's a very typical license agreement," Emanuele told BioWorld Today. "The milestones, I would say, are predictable."

RCT is a natural process that involves the flow of cholesterol from all tissues, including the walls of blood vessels, and its transport to the liver for metabolism and removal from the body. A variety of specialized transporter molecules and carrier proteins take cholesterol out of body tissues into the liver, where it can be transported to the gall bladder for excretion.

London-based AstraZeneca's interest in dyslipidemia made it an especially good choice as a partner, although the overseas firm has run into some trouble with its marketed cholesterol-lowering statin Crestor (rosuvastatin), which the activist group Public Citizen tried to get removed from the market because of safety concerns. The FDA instead called for a revised label, warning of potential muscle side effects and kidney problems in some patients.

Crestor's difficulties are not over, though. In May, the American Heart Association's journal Circulation published its comparison of side effects counted in patients given the statins Lipitor, Pravachol and Zocor. The profile of AstraZeneca's drug proved poor, although adverse effects are uncommon in the class as a whole.

Is Avanir's program a backup for Crestor?

"I don't think so," Emanuele said. "This is a totally different kind of a drug. The statins largely are used to prevent extension of existing disease," whereas Avanir's compound is designed to strengthen blood vessels.

"This is going way out on a limb, but I think when these types of drugs enter clinical practice, it's going to change the paradigm," he said. "People will say, Who cares what your plasma cholesterol is? All that matters is how healthy your blood vessel wall is.'"

Avanir's research, Emanuele noted, builds on work done by the likes of Norwalk, Conn.-based Esperion Therapeutics Inc., which is developing its lead compound ETC-216, a human recombinant version of the ApoA-I Milano gene, combined with a phospholipid to form a complex that imitates the structure and function of HDL.

Esperion's Phase III candidate is designed to mimic the positive properties of HDL and enhance reverse lipid transport, the body's process of removing excess cholesterol.

"We tried to take the next step," Emanuele said. Many researchers believe that, "in order to perform RCT, you have to have a large molecule. For physical, chemical reasons, it has to be of a certain size. These lipids have to ride on something," he said.

Avanir, though, was "willing to violate that kind of thinking. It's almost like heresy," he said. Still, the company has come up with an oral small molecule that performs a similar function to the Esperion compound.

"It does most of [what the large molecule does] and, not surprisingly, it also does some really important things that [a large molecule] can't do," Emanuele said, but declined to be more specific.

In late June, Avanir completed the rolling submission of its new drug application for Neurodex for pseudobulbar affect, characterized by pathological laughing and crying, emotional lability and emotional incontinence. The drug also is being tested for diabetic neuropathic pain. (See BioWorld Today, July 1, 2005.)

Neurodex is made of dextromethorphan combined with an enzyme inhibitor that slows the otherwise rapid metabolism of the anti-tussive agent, an active ingredient in marketed cough medicines.

No Comments