Finally, a drug to fight jet-lag?

New York, Jan.7: It seemed like the offer of a lifetime - earn $2,500 by flying to France aboard a private luxury jet.

 

 

But as the fine print made clear, there would be no Eiffel Tower or chateaux, no foie gras or Bordeaux. Travelers were confined to a laboratory in either Toulouse or Rouffach with electrodes attached to their heads, testing whether a drug could keep their jet-lagged bodies awake.

That drug, Nuvigil from Cephalon, could become the first medicine specifically approved by the US Food and Drug Administration to combat jet-lag.

A jet-lag antidote might seem to be the latest lifestyle drug, a further step in the "medicalization" of something that is not an illness. But sleep specialists, who call the affliction "jet-lag disorder," say that while not exactly a disease, it is a condition that can be dangerous - as when someone tries to drive a car right after arriving in a distant time zone.

For Cephalon, a drug company in Frazer, Pa., with a reputation for aggressive business tactics, the approval for jet-lag is part of a plan to extend the patent protection for its core franchise in stay-awake drugs.

Nuvigil is a slight modification of Provigil, an older stimulant that will face generic competition in 2012. Provigil sales were about $1 billion in 2008, accounting for half of Cephalon’s revenue. Nuvigil, which first went on sale in June and has a longer patent life, had sales of $38 million through September.

The FDA, to the surprise of even Cephalon, agreed to review the Nuvigil application in six months, instead of the usual 10. Such a priority review is usually granted to drugs for serious diseases, though the agency says it can also give rapid reviews to the first drug for a less serious ailment.

But in late December, the agency delayed its decision until March 29, to allow more time to analyze the data, according to Cephalon. The agency does not comment on drugs under review.

Jet-lag results when the body’s internal clock is out of sync with daily life, making people sleepy when they want to be awake and wakeful when they want to sleep. It is one of several so-called circadian rhythm disorders that are attracting increasing attention from the pharmaceutical industry. Some studies suggest that disruption of the daily rhythms can contribute to obesity, mental illness and other ailments.

Nuvigil and its predecessor, Provigil, are already approved to treat the excessive sleepiness associated with narcolepsy, sleep apnea and "shift work sleep disorder" - which can affect people who work the graveyard shift. But the drugs are prescribed widely to treat the sleepiness associated with other diseases, or even just to help healthy people get by on less sleep.

For jet-lag, Nuvigil would be approved to treat only the sleepiness associated with jet lag disorder - not to shift the body’s clock to the new time zone.

"It’s something that can help you overcome the symptoms, but not the cause of the problem," said Charmane I. Eastman, director of the biological rhythms research laboratory at Rush University Medical Center in Chicago, who was not involved in Cephalon’s trial.

Cephalon plans to aim Nuvigil at business travelers who might go to Europe for a couple of days, not those staying longer term. For a short trip, "you don’t want to shift your circadian clock very much," said Dr. Lesley Russell, Cephalon’s chief medical officer.

The company’s executives are not predicting how much an approval for jet-lag would add to Nuvigil sales. The drug would be taken for only a day or two to treat jet lag, whereas other uses involve taking it for long periods.

A market challenge for Cephalon will be that Nuvigil costs at least $9 a pill, with one pill usually taken each day. Nuvigil will have to compete with inexpensive jet-lag treatments like coffee, sleeping pills and the nutritional supplement melatonin.

Nuvigil has not been clinically compared with those remedies, some of which might work as well but have never been specifically approved for jet-lag. Sleeping pills, for example, are approved to treat insomnia, whatever the cause, so there has been no need to seek a specific approval for jet-lag, said Thomas Roth, director of the sleep disorders and research center at Henry Ford Hospital in Detroit and a consultant to Cephalon.

And stimulants like caffeine and amphetamines, he said, are generic, so manufacturers have no incentive to conduct clinical trials.

But even if Nuvigil sales for jet-lag are small, FDA approval would help Cephalon advance its franchise-extending strategy.

But Provigil will face generic competition in April 2012 under terms of an agreement Cephalon made with several generic drug manufacturers. The Federal Trade Commission has sued Cephalon, saying it paid off those generic manufacturers to delay the advent of competition.

Cephalon, which denies the charges, is trying to shift patients from Provigil, also known as modafinil, to the very similar but slightly longer-acting Nuvigil, or armodafinil. Nuvigil has patent protection until 2024, although generic drug companies are already moving to challenge those patents.

To get patients to shift, Cephalon has raised the wholesale price of Provigil to $13.60, from about $5.50 a pill five years ago, including a 29 percent increase in November. So Provigil is now 50 percent more expensive than Nuvigil.

And Cephalon is also trying to have Nuvigil approved for new uses beyond those of Provigil.

Not only would jet-lag be the first of these new uses, but its formal approval for that condition would enable Cephalon to promote Nuvigil to a broad array of doctors, not just those who treat sleep disorders.

"What a jet-lag indication allows you to do is go to virtually every doctor, because every physician will at some point treat a patient who will have jet-lag," said Corey Davis, an analyst at Jefferies & Co.

Cephalon needs to be careful about which doctors it visits. The company pleaded guilty in 2008 to a misdemeanor and paid $443 million to settle federal and state charges that it had promoted Provigil and two other drugs for unapproved uses.

For jet-lag, Cephalon is seeking approval only for eastbound travel. Westbound travelers tend to adjust better, experts say.

The clinical trial involved 427 healthy adults who were flown from the East Coast, departing in the early evening and arriving in France around 7 a.m. local time.

The volunteers were allowed to sleep on the flight but were not allowed to tilt their seats back more than would be possible in economy class on a commercial flight. They were not allowed to drink coffee or alcohol or to take sleeping pills.

Each was given either Nuvigil or a placebo pill after arrival and on the next two mornings. At 10 a.m., noon, 2 pm and 4 pm each of those days, participants went to bed in a dark, quiet room. As soon as they fell asleep, as measured by brain waves, they were prodded awake.

Those who got the placebo took an average of only 3.4 minutes to nod off on the first day, 6.2 minutes on the second day and 8.2 minutes on the third.

"These folks are as sleepy as people with narcolepsy," said Dr. Richard K. Bogan, an investigator in the trial and chairman of SleepMed, a sleep disorder diagnosis center in Columbia, S.C.

But those who got the highest dose of Nuvigil stayed awake for an average of 9.7 minutes the first day, 13.8 minutes the second day and 14.8 minutes the third.

Experts say that level of wakefulness is close to or within the normal range, though it is still less than the 15 minutes on average that it took the participants to fall asleep on a similar test before they left for France.

Those who got Nuvigil did have somewhat more trouble sleeping at night in France than those who got the placebo, and also were more likely to suffer headaches, nausea, palpitations and anxiety. Since many people who might take a pill for jet-lag are otherwise healthy, the FDA might be stricter about safety than it would be for drugs used to treat diseases.

Seth B Miller, who took part in the trial, said that even though participants still did not know whether they got the drug or placebo, he thought he received the high dose of Nuvigil, "I was jittery," he said.

Still, Miller, an information technology consultant in Manhattan who blogs about his frequent flying at wanderingaramean.com, said he would be interested in using Nuvigil.

Miller said that since the participants were not allowed out of the laboratory, they did not really feel as if they were in France. Even the cuisine gave no clue.

"The food was miserable," he said.