For a long time, it was assumed that neurons were the only type of cells responsible for the development and maintenance of neuropathic pain. The glial cells surrounding the neurons were disregarded as little more than "housekeepers" providing support to the neurons.

Avigen CEO Kenneth Chahine

Watkins' laboratory was among the first to demonstrate that glia—cells formerly thought of simply as the "glue" that holds the brain together—enhance the neurotransmitters that relay pain information to the spinal cord. Even more striking, as Watkins and her collaborator Steven Maier wrote, they "release substances that increase the excitability of pain-responsive neurons in the spinal cord. These substances, called pro-inflammatory cytokines, create and maintain exaggerated or pathological pain responses. Blocking the activation of glia reduces pro-inflammatory cytokines and reverses pathological pain."

Watkins and others were working with IL-10, a classic reversal agent of inflammation. It was potent, but it could be used only intrathecally, as an injection into the spinal canal, a major drawback.

"Still, we knew what was happening," says Coffee. "So our team said, 'Let's look at the structure, and let's look for oral agents that have a structure and activity in the literature of glial attenuation.'"

What they found was ibudilast, a PDE inhibitor developed by Kyorin Japan for bronchial asthma and recently approved to treat dizziness secondary to chronic cerebral stroke.

"It was probably not a great product," says Coffee. "It never reached very large sales. And they didn't notice that it had any utility in pain because the doses were higher than the dose they were using in asthma."

Nonetheless, they deemed the molecule a good fit. "It can be given by mouth only once or twice a day," says Avigen CEO Kenneth Chahine. "It is fast-acting in the animal models of pain studied to date, does not sedate recipients, and does not require dose titration."

Ibudilast is a glial attenuator that, according to the company, suppresses pro-inflammatory cytokines IL-1 beta, TNF alpha, and IL-6, and may regulate the anti-inflammatory cytokine IL-10.

The first clinical study of ibudilast is under way in Australia—a Phase IIa trial, because the company can take advantage of safety data collected in Japan. Australia was ideal for the trial because of that country's mutual-recognition agreement with Japan. "It's considered a product that does not require an Investigational New Drug Application (IND). You can go right into the clinic," says Coffee. "In parallel, we're working toward filing a US IND, but rather than it necessarily all being sequential, we decided to go ahead."

Avigen hopes to obtain indications for ibudilast in opiate withdrawal—it is in late-stage discussions with the National Institute on Drug Abuse—and for chemotherapeutically induced neuropathic pain. –MARYLYN DONAHUE

HEALTHY HEARTS

A cardiovascular drug company builds stronger hearts with new blood vessels

The idea came as Thomas Stegmann walked down a hospital corridor in Fulda, Germany, after performing a triple-bypass on a patient with severe coronary artery disease. It was surgery he had performed countless times before, but this time Stegmann was struck by a thought, inspired by an article by Harvard's Judah Folkman on the use of anti-angiogenesis to halt tumor growth.