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.
But then Linda Watkins, a professor of neuroscience at the University of Colorado in Boulder, observed something else going
on. That something, she believed, was glial activity.
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 had basically made a link in the brain between pain and inflammation. "The hypothesis then was if you could reverse
glial attenuation, you could reduce or reverse neuropathic pain," says Michael Coffee, CBO of Avigen, a California biopharmaceutical
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
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
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.