Deep inside our brain, near where the optic nerve transits through our mind, there’s a tiny, rice-grain-sized area called the suprachiasmatic nucleus. This region’s 20,000-odd cells make up a clock that tracks day and night, tuning our physiological processes accordingly. In the morning light, this clock wakes us up and activates the genes concerned with digestion, cognition, sensory systems, and motion. At night, this clock directs our body to do housekeeping chores, such as regenerating the immune system and storing long-term memories.
Over the past several years, researchers who study these circadian rhythms have discovered that many genes in our body are expressed only at certain times of the day. This keeps energy-intensive protein production under efficient control.
This reality should give many in the pharma industry serious pause for thought, says Timothy M. Willson, the director of chemical biology for GlaxoSmithKline at Research Triangle Park, N.C.
Because most drugs target proteins, and if many proteins are produced only at certain times of the day, Willson argues that it’s possible many drugs navigating the discovery pipeline have been tossed into the garbage because they were tested on people or mice at the wrong time of day.
What’s more, most lead compounds are optimized so that they have long lifetimes in the human body—ideally maintaining a constant concentration over 24 hours, Willson explains. Drug leads are thrown out regularly because their side effects are too severe over 24 hours. Yet if the protein target is expressed for just a couple of hours a day, the drug might actually be viable if it were delivered to a patient over that short period, Willson says.
Then there’s the issue that many leads are first tested on mice, which have rhythms opposite those of humans. “Traditionally we give drugs to mice at 9 o’clock in the morning when it is convenient to dose the animals”—that’s when the technician arrives at work, Willson says. “Well, that’s giving the drugs right at the start of the less active period for the mice—the equivalent of giving the drugs to humans at nighttime. We almost always give our drugs [to humans] at 9 AM.” This results in a disconnect between human and mouse data, he says.
To avoid comparing apples and oranges, Willson has spearheaded the creation of a mouse lab at GSK that adjusts mouse circadian cycles so that they correspond with human ones—and so that technicians don’t have to work only night shifts.
In the new, experimental lab, lights are turned on at nighttime, while the lab is kept dark during the day. The mice are thus naturally awake at 9 AM, when it’s convenient for technicians to dose them. “Technicians actually use night-vision goggles so they can see what they are doing,” Willson says.
That’s not the only thing Willson has instituted at GSK to investigate the effect of circadian clocks on drug discovery programs. “We are also going back on our targets and looking to see when they are expressed and if that varies with the circadian period,” he adds. As for compounds that the company has already developed for clinical trials, GSK scientists are looking to see “which of them have a half-life which is short enough that we can do the critical experiment of dosing day versus night in patients.” This is not always possible because “many times shorter-acting compounds are discarded during lead optimization process because traditionally it has been thought that a 24-hour-acting compound was the optimal drug,” he explains.
One company trying to deliver drugs according to the circadian timing is Northbrook, Ill.-based Horizon Pharma, Willson says. They’ve licensed an anti-inflammatory drug from Merck KGaA called Lodotra, approved in the European Union but not the U.S., which has side effects that preclude long-term use by many patients. Horizon Pharma scientists encapsulated the drug for middle-of-the-night delivery to rheumatoid arthritis patients so that the drug is in place to deal with morning joint stiffness.
Willson says he doesn’t know if other pharmaceutical companies are also paying attention to chronobiology’s potential impact on the drug discovery process. “I can tell you that it’s new in GSK,” he says. GSK sent four scientists to a Gordon Research Conference on chronobiology this past summer. No other major pharma was represented.
Willson initially became interested in circadian cycles about five years ago, because he thought the molecular pathways that chronobiology researchers were beginning to delineate might supply new targets for drug discovery.
“But as I talked to some of the leading academics in the field, I began to realize that the bigger application of all of that fundamental biology was on existing drugs,” Willson says. Our circadian clock has potential impact on “every target we work on,” he says.
“I still think there are some interesting new targets, but clearly the concept of when you dose your drugs is something we should all be thinking about with drug development.”