Brave Neuro World - Pharmaceutical Executive

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Brave Neuro World
Cosmetic neurology is a massive off-label market, but pharma has tended to look the other way. FDA may be about to change all that


Pharmaceutical Executive


The Gray Area

There are currently more than 500 compounds with CE properties in the industry pipeline. Virtually all are being developed as treatments for schizophrenia, Alzheimer's, ADHD, or some other CNS conditions. But disease-based R&D is far from the ideal setting to develop cosmetic neurology. For example, increasing dopamine levels in the prefrontal cortex looks like the simplest way to boost attention and learning. But until recently, most dopamine-oriented drug development has focused on schizophrenia, a disease in which the brain is already producing too much of the neurotransmitter. As a result, researchers have hunted for dopamine-receptor antagonists that lower dopamine levels. For a CE, you need to flip the switch the other way.

But with "lifestyle enhancement" being a forbidden phrase inside pharma, CE development is set to remain on the disease-only path. (Neuroscientists at Merck and Roche, who are developing some of pharma's most innovative CEs, refused to comment on their potential use in healthy people.) It may fall to the aging process, with its many cognitive and memory impairments, to eventually provide the necessary impetus for regulatory approval.

"When asked about its neglect of age-related brain loss, the drug industry tends to lay the blame on FDA," says Ferris, a former FDA committee member. "They say, 'We could never get approval for that indication.'" Ferris disagrees. While careful not to give aid and comfort to the forces of lifestyle drugs, agency officials have been equally careful not to bar the door to conditions that fall into the gray area between disease treatment and health enhancement. The effects of aging top the list. "The official line is, 'There are no unique regulatory barriers to this treatment indication,'" says Ferris.

Russell Katz, director of FDA's Division of Neurology Products at the Center for Drug Evaluation and Research, confirmed this position in a 2009 Journal of Alzheimer's Disease discussion of cognitive enhancement. "There are not any approved treatments for age-associated memory impairment, but only presumably because industry seems to have abandoned the project. The regulatory requirements were worked out with the sponsors," he said.

The resistance to treating age-related memory loss extends beyond pharma. "There is a widespread assumption in the entire medical establishment that aging is 'normal,' and that the profession does not 'treat' normal processes," Ferris says. But the reverse is plainly true. "We do this for virtually every other age-related problem, from our eyes, ears, and teeth to our cholesterol, blood pressure, and bone density. We 'treat' all sorts of cosmetic effects of aging, too. But our brain seems to be off-limits."

By age 65, Ferris explains, the performance of the average human brain has fallen by 50 percent from its optimal point at around age 20. The real-world consequences are often merely annoying, but sometimes they compromise daily performance. And with the risk of developing Alzheimer's rising to 50 percent after age 85, a neuroprotective anti-aging agent could slow disease progression.

Yet even Ferris acknowledges that producing age-related smart drugs presents pharma with a triple threat of risk, cost, and controversy. At a time when firms like AstraZeneca are jettisoning entire drug-discovery capabilities, negotiating this particular neuroscientific minefield would seem to be a nonstarter. The Phase III clinical trials could prove immensely complex and pricey, requiring thousands of healthy people representing the general population—with a safety standard exceeding any yet seen. Demonstrating efficacy would span five years, the length of time it takes to measure the effects of normal aging. As for cognitive enhancement in healthy people, proving a "therapeutic" effect could be done under specific short-term conditions, such as a transatlantic flight (at night, from the East Coast to France, in Cephalon's Nuvigil jet-lag trial) or an all-day school exam. But such data's application to other situations, let alone long term use, will be harder to demonstrate. And after years of being bashed for producing too many Viagras and too few Avastins, the industry is hardly eager to beat the drum for lifestyle enhancement.

Aversion to risk is not limited to pharma. At the University of Pennsylvania, home to the neuroethics-pioneering Center for Neuroscience and Society, "it took enormous effort just to start a small study of ADHD drugs for cognitive enhancement," Chatterjee says. "The investigational review board kept asking us, 'Why is any adverse-event risk worth taking by people who are healthy?'"

The argument that more than a quarter of the school's students already admit to taking that risk finally persuaded them.


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