Brave Neuro World

April 1, 2010

Pharmaceutical Executive

Pharmaceutical Executive, Pharmaceutical Executive-04-01-2010, Volume 0, Issue 0

Cognitive enhancement is a $20 billion market of aging Boomers, cramming students, global travelers, and battling soldiers. What's pharma going to do about it.

Is President Obama popping the stimulant Provigil? The gossipy Daily Beast Web site floated that question in February following the release of the president's annual medical exam, including the notation "jet lag/time zone management, direct physician prescribed program, occasional medication use." The Cadillac of cognitive enhancers, Provigil has a narrow indication (excessive daytime sleepiness associated with narcolepsy, sleep apnea, and shift work), but a wide off-label reach because it is generally viewed as improving on the drawbacks of Ritalin and other amphetamine-type drugs—less of a rush and crash, fewer jitters, and allegedly minimal abuse or addiction potential. The little white pill with the sleek name comes closer than any other drug to conferring control over the body's sleep cycle.

That there is a significant craving for such control, especially among professional elites in a world increasingly defined by frequent global travel and a nonstop stream of digital information is abundantly evident. Approved in 2002, Provigil has enjoyed phenomenal sales growth: $5 million in 2005, $1 billion in 2009, and projections of $7 to $10 billion by 2018. Along the way, it has turned Cephalon into a top-10 biotech. The Philadelphia-based firm has returned the favor by nearly tripling the pill's price, a move that scarcely made a dent in its off-label use, which accounts for 90 percent of all prescriptions.

Boosting the brain artificially is as commonplace as the consumption of caffeine and nicotine, but the off-label use of drugs for lifestyle enhancement remains officially off-limits. The medical establishment, the drug industry, and FDA have all strictly hewed to the time-honored disease model of healthcare. Yet after a decade in which consumer demand has risen to a din, Provigil—or, more specifically, Nuvigil, the new longer-acting version—may prove to be the tipping point, the right drug at the right time to shatter the old paradigm. Last year, Cephalon applied for the first "medical treatment" for "jet lag disorder," potentially opening the floodgates to the first neuro-lifestyle indication and a market of tens of millions of travelers.

The significance that FDA attaches to this decision was signaled by its granting the submission "priority review" status typically reserved for serious or rare diseases. The agency's ambivalence about approval may explain why it then missed the deadline by months.

"FDA is in a real quandary," says Anjan Chatterjee, professor of neuroscience at the University of Pennsylvania medical school. "If they open a regulatory door to cognitive enhancement, even a crack, the genie will be out of the bottle once. On the other hand, there's a larger public health imperative to do something because so many people are already using these drugs."

Booming Consumer Trend

Public speculation that Obama uses Provigil is only the most novel evidence that cognitive enhancement (CE) has hit critical mass, both as an industry and as an issue. Surveys regularly show the use of ADHD drugs by the nation's exam-cramming college students at seven to 25 percent. In 2008, the journal Nature reported that in an informal tally of 1,400 readers, 20 percent said that they use Provigil, an ADHD drug, or a beta-blocker to "improve concentration" at work. Meanwhile, Tech Crunch, a Silicon Valley webzine, reported that local entrepreneurs increasingly equate Provigil with a competitive edge. Many users admit to acquiring the drug over the Internet or on the street, where quality and safety are a crap shoot.

The trend is a mainstay of the media in stories predictably registering either alarm or allure. The popularity of the practice has even introduced its own lingo, such as smart drugs, brain doping, mind hacking, and brain botox, reflecting other leading consumer obsessions.

The value of this market is the stuff that pharma dreams are made of. Steven Ferris, a psychiatry professor at New York University's school of medicine, estimates that a treatment for age-related memory loss alone could pull in $20 billion. "Pharma doesn't even have to build the market," says Chatterjee. "The market will come to pharma."

The value of this market is the stuff that pharma dreams are made of. Steven Ferris, a psychiatry professor at New York University's school of medicine, estimates that a treatment for age-related memory loss alone could pull in $20 billion. "Pharma doesn't even have to build the market," says Chatterjee. "The market will come to pharma."

Yet so far pharma, all too attentive to the many risks, has resisted. "As long as pharma doesn't step up to the plate, the charlatans will," Ferris says of the consumer treasure wasted on nutraceuticals making bogus claims of boosting brain functions, such as the billion-dollar "memory enhancer," ginkgo biloba. The market has also been flooded with technology like brain-fitness software, much of it aimed at Baby Boomers anxious about senior moments and worse.

The Social vs. Scientific Debate

In a seminal paper in a 2004 issue of Neurology, Chatterjee coined the controversial term cosmetic neurology to spark professional discussion about the medical and moral ramifications of a trend that he saw as inevitable. Since then, a mob of adherents ranging from opportunists to visionaries have mobilized around the cause, the social acceptance of which hinges on FDA regulatory approval.

Zack Lynch, executive director of the Neurotechnology Industry Organization and editor of its Brain Waves blog, works a keep-America-innovative angle. "Neurotechnology holds the promise of ... accelerating economic growth for entire countries," he says. "Think of millions of workers in India or China cognitively enhanced ... [to] boost productivity. Will the US be able to place these drugs off-limits and compete?"

Nick Bostrom, director of the Future of Humanity Institute at Oxford University, promotes an enhancement-as-evolution approach. "Human nature [is] ... a half-baked beginning that we can learn to remold in desirable ways: to live much longer and healthier lives, to enhance our memory and other intellectual faculties ... and generally to achieve a greater degree of control over our own lives," his homepage declares.

Still, scientific skepticism persists, starting with the fundamental assumption that a healthy human brain's performance can even be significantly enhanced. "In principle you can adjust your cognition pharmacologically if you are not operating at optimal levels, but the closer you are to optimal, the harder it is to improve," says Michael Minzenberg, associate professor of clinical psychology at the University of California at Davis.

"I don't believe that the current drugs can help people with healthy cognition," says Paul Solomon, professor of psychology at Williams College and founder of the Memory Clinic in Bennington, VT. "There's reason to believe that people with adequate levels of these neurotransmitters will never benefit."

The brain remains science's ultimate black box. Steady advances over the past three decades have shed light on the neuronal processes of memory, learning, and aging, while imaging techniques that map the brain's activity have deepened our understanding of drug effects. Yet the journey from bench to bedside is notoriously tortuous. Given that after a quarter-century of major investment, pharma has failed to develop a truly effective treatment for Alzheimer's, why should we expect steroids for the healthy brain?

The Developing Drug Story

The current crop of CEs were all discovered in the classic trial-and-error method of testing various chemicals in cells or animals until the desired effect is achieved. But how they work their magic is only partially understood. ADHD stimulants, such as Ritalin, Adderall, and Concerta, juice the prefrontal cortex with the neurotransmitters dopamine and norepinephrine, apparently improving concentration and attention. Provigil raises levels of norepinephrine in the same area, but additional dynamics are in play. In a 2008 Science paper, Minzenberg helped explain the mystery when he reported that functional MRIs show that the drug also defuses neuronal activity in the brain stem by way of an interconnected signaling network. "Provigil increases the activity in one part of the brain and reduces it in another part," Minzenberg says. "Even though they are far apart, both are necessary to cause the attention-stimulating effect."

Only with identification of such systems will rational drug design produce more selective and effective CEs. "Many of the next generation are being developed around the question, 'Here is a healthy system that effects cognition, how can we enhance or improve its effects—and then use that in disease studies?'" says Chatterjee.

One of the most hyped classes of compounds in the pipeline are ampakines, which aim to maximize the benefits of glutamate, a neurotransmitter key promoting the plasticity of the brain's synapses and, therefore, aiding learning and memory. "Ampakines make the neurons respond to less neurotransmitter, and do so longer and stronger," says Mark Varney, CEO of Cortex Pharmaceuticals, the Irvine, CA, biotech which boasts one of the industry's most productive ampakine platforms —although its lead products have failed in clinical trials for ADHD and schizophrenia. The biotech's Phase II candidate for respiratory depression may have prove luckier.

More interesting is Cortex's so-called high-impact ampakine, which features the added bonus of increasing brain-derived neurotrophic factor (BDNF), a protein that promotes neurogenesis and the formation of long term memories. Lilly, GSK, and Pfizer are also exploring high-impact ampakines. But these potent compounds present safety problems, including seizures.

Varney is amused by media reports of ampakines as the next big thing in cosmetic neurology. "My own belief is that it is very difficult to improve cognition, and especially memory, in healthy people," he says.

The press has also heaped coverage on nicotinic-receptor agonists because of the off-beat equation of nicotine and health benefits. Whether the class deserves such attention is a question: No nicotinic-receptor agonist has made it to Phase III. Nicotine acts as a brain stimulant by binding to so-called nicotinic receptors, causing the release of the neurotransmitter acetylcholine, which in turn spurs attention to and retention of information. Leading in nicotinic-receptor drug development is Targacept, a spinoff of the tobacco company R.J. Reynolds's pharma research division. The North Carolina–based biotech has four Phase II candidates spread across ADHD, Alzheimer's, depression, and cognitive dysfunction in schizophrenia, all being codeveloped with AstraZeneca following a $200 million deal. But its lead product bit the dust in Phase II trials for cognitive dysfunction in Alzheimer's. Roche, Abbott, and EnVivo also have promising Phase II candidates.

Equally news-grabbing are studies linking the blocking of the brain's cannabinoid receptors to potential smart-drug development. This discovery has given second-chance hopes to the class of cannabinoid-receptor antagonists in which pharma invested so intensely as an anti-obesity treatment until Sanofi-Aventis' first-in-class Acomplia crashed and burned after reports of suicides and other psychiatric problems. Yet it seems plain that only extreme refinements will make these blunt instruments sufficiently selective to effect cognition without also messing with mood and other mental functions.

After safety concerns, the problem of trade-offs may be the highest hurdle for CE drug development. "Benefits in one area of cognition may come at a cost in another," concludes Reinoud de Jongh, psychopharmacologist and professor at Utrecht University in the Netherlands, in a comprehensive survey of current CE research published in 2008 in the journal Neuroscience and Biobehavioral Reviews. He also notes a third hurdle: "It's likely that there are different optimal levels of neurotransmitters for different types of cognitive tasks, and therefore enhancement may not be possible across all aspects of cognition at once."

San Diego–based Helicon Therapeutics is one of many biotechs attempting an end-run around this law of unintended consequences. Helicon is targeting a gene, dubbed CREB, responsible for the conversion of memory from short to long term (more than three hours). In theory, increasing the expression of CREB could speed up learning in healthy people or slow down memory loss in the aging. Helicon has said that its lead product has shown benefits in Phase II trials in enhancing recall without apparently impeding attention. Yet memory is far from the only brain function in which CREB is involved, and Helicon's efforts to prime the memory pump may cause cracks in the pipes elsewhere with extended use.

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.

FDA and the Road to Approval

That argument may also carry the day at FDA under its current leadership. Commissioner Margaret Hamburg and Deputy Commissioner Joshua Sharfstein are both physicians who have displayed a striking fidelity to science (rather than politics or other influences) when setting policy in their careers as public-health officials. Given the fact that a growing segment of the public is regularly mind-hacking with off-label and black market CEs, it would seem logical for them, at the very least to call for more science, including clinical studies to assess the risks and benefits in healthy consumers.

Not surprisingly, most researchers also back more science, even those like Minzenberg who question whether cosmetic neurology is viable. "We know how these drugs work at the cellular level, but there's still a lot we don't know," he says. "What is their effect on the entire circuitry of the brain? How does that translate into cognitive function? What are the unintended consequences?" Clinical trials could help identify potential trade-offs in a drug's effect or potential links between individual "patient" differences and variations in response.

FDA denied Pharm Exec's request to interview Russell Katz with an email that read: "We cannot comment at this time on what the regulatory pathway for CE drugs might be. Each new drug application is judged on its own merits." Yet Katz offered some clues in his Journal of Alzheimer's Disease comments regarding increased safety monitoring of off-label use. The drug industry, he said, can expect to be required to conduct additional Phase III trials for all cognitive enhancers, both those that are submitted for approval specifically for use in healthy or aging people and those that are simply likely to be prescribed off-label for such use. These studies will test the compound in a representative healthy (albeit sleep deprived, jet lagged, or aging) population, and a squeaky-clean safety profile will be expected. In short, the onus for more science will fall to pharma. Gone are the days when Cephalon could reap the profits of the 90 percent of Provigil prescribed off-label while mostly evading accountability for knowing the potential dangers posed to consumers.

Meanwhile, the American Academy of Neurology last year gave its stamp of approval to the off-label prescribing of cognitive enhancers to healthy people, arguing that society will come to endorse CE as akin to cosmetic surgery because its benefits will outweigh its risks. In February, Britain's former health minister and surgeon Lord Ara Darzi announced that he is launching such a clinical study at Imperial College London. "We know people are doing these drugs anyway, but we don't know about their long term safety," Barbara Sahakian, a neuroscientist involved in the project, told the London Times. "The government has a responsibility to think about what they should do about that. Maybe they should be letting pharmaceutical companies brand these medications via a safe route. Wouldn't that be better?"

On March 29, Cephalon announced that it had received a "complete response" letter from FDA—at best, postponing; at worst, denying approval of Nuvigil for jet lag. The agency reportedly found the "robustness" of some data wanting. The stimulant's benefits, although statistically significant, were admittedly slight. (For example, the Nuvigil group took an average of 9.7 minutes to fall asleep the first day after their transatlantic night flight, compared to the placebo group's 3.4 minutes.) FDA's cost/benefit analysis may have concluded that six extra minutes of sleeplessness may not be worth the increased risk of headaches, palpitations, anxiety, and other side effects.

Still, cosmetic neurology, however controversial, appears destined to come in from the cold. After all, a technologically wired global economy demands a chemically wired workforce. If not by Nuvigil, the road to regulatory approval will be paved by the first drug for the aging brain. Or FDA will carve out exceptions for a Provigil-type drug for soldiers, air-traffic controllers, surgeons, and other high-risk occupations, followed by a gradual expansion to the general population. Or China will pioneer approval.

For even as neuroethicists fret over issues like unequal access to enhancement's competitive edge and how that edge may have a coercive influence, the iron law of ever-increasing productivity must be obeyed. In the end, we may not much like this new world—it is certain to contain many more accountants and far fewer artists than the old one. But fear not, a pill may be coming to manage that low mood, too.

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