Drug Offers Hope in War on Colds--and More
Certainly a cure for the common cold would be a big story all by itself. But how about a medicine that also stops viral meningitis? The summer flu? Deadly newborn infections? Even polio?
One drug that holds enormous promise for all of this is surprisingly close. It is called pleconaril, and if large-scale testing turns out well, it could be in drugstores within a year.
Pleconaril is the latest in a short list of medicines that kill viruses. This drug, in fact, blocks an entire category of them, a collection of 169 distinctly different nasties that together cause more human disease than any other.
Almost as remarkable as what pleconaril does, however, is how it came to be. This drug was not so much discovered as designed. Developers worked their way through 1,500 versions of pleconaril before settling on the one now in human testing.
Once drug development was a kind of organized serendipity, screening thousands of random compounds to see what happened. But in the last decade, a quiet series of breakthroughs has transformed the way drugs are developed. Now scientists explore the shape and innards of their target right down to the last molecule. Then they fashion chemical monkey wrenches to throw into the works.
Pleconaril is the latest, and one of the most impressive, examples of this new way of creating medicines. It is an exquisitely precise sort of monkey wrench. The drug fits neatly into a groove on the surface of the virus, gumming up the machinery it needs to infect the body’s cells.
The Promise of Spinoff Treatments
Experts believe the same research techniques will lead to treatments for many other kinds of viruses, predators that are still mostly beyond the powers of modern medicine.
“Pleconaril represents a class of drugs that were designed with the knowledge of the three-dimensional structure of the virus,” says Dr. Catherine Laughlin, chief of virology at the National Institute of Allergy and Infectious Diseases. “It provides a lot of hope for the eventual design of drugs for virtually every viral infection.”
Pleconaril is made by ViroPharma Inc., a 5-year-old, 102-employee pharmaceutical firm in the Philadelphia suburbs. The publicly traded company is sponsoring two large studies, due out in the spring, that will determine whether the drug works well enough to win Food and Drug Administration approval.
The company wants to get the drug approved first for viral meningitis, but it is the common cold--the most prosaic of infections--that is likely to be the medicine’s biggest market.
“Everyone talks about the cure for the common cold,” says Dr. Jose Romero of Creighton University in Nebraska, who has tested the drug on patients. “This is the cure for the common cold.” Some might quibble over that word. “Cure,” after all, implies that pleconaril will make the sniffles evaporate instantly, which it won’t. Still, the research indicates the medicine can shorten a bad cold by three or four days and help people feel considerably less miserable along the way.
Pleconaril does this by disabling the rhinovirus, the most common human virus. But that’s just the start.
It also neutralizes the second-most common human virus, the enterovirus. Various versions of enteroviruses cause an amazingly broad range of illnesses: lingering summer colds, head-splitting meningitis, childhood fevers, inflammation of the heart, polio, plus overwhelming infections that sometimes kill newborns.
One drug can stop both rhinoviruses and enteroviruses because they are close cousins, members of a large family called the picornaviruses.
“There have been a number of anti-picornavirus agents over the past 25 years, but they’ve had all sorts of problems,” notes Dr. Mark Pallansch, an enterovirus expert at the U.S. Centers for Disease Control and Prevention. “Pleconaril is the first true, viable product that is potentially licensable.”
Potential Market Is Vast
ViroPharma estimates that every year, Americans get between 400 million and 500 million picornavirus infections that are serious enough to make them feel bad. It plans to charge between $50 and $100 for enough medicine to cure one infection.
You do the math.
Certainly other drug makers have. However, only one other company appears to be close to ViroPharma for now. Agouron Pharmaceuticals, a part of Warner-Lambert Co., is experimenting this fall on 900 cold victims to see whether its nasal spray, code-named AG7088, will speed their recovery. Agouron’s drug is a protease inhibitor, a lot like the ones that revolutionized AIDS treatment, but is intended only for colds. And that ailment is the least of the reasons why many doctors are so enthusiastic about pleconaril.
More than 2,000 people ranging in age from 84 to less than a week have taken pleconaril. Almost all of them have been in formal studies of viral meningitis or colds, neither of which is a dire illness in otherwise healthy people.
However, enterovirus infections are occasionally medical emergencies. Over the last two years, the FDA has allowed the company to dispense pleconaril outside of organized experiments for infections that are life-threatening or especially gruesome.
So far, nearly 100 people have been treated this way, often with seemingly spectacular results. Doctors say these back-from-the-almost-dead anecdotes offer some of the most impressive hints of the drug’s potency. Among the apparent success stories are Carter and Skyler Stephens, twins born Sept. 9, 1998, in Topeka, Kan.
Back From the Brink
Everything seemed fine until four days after their birth. The boys’ mother, Lisa Stephens, woke at 4 a.m. to nurse Carter. He wouldn’t eat and had a boiling fever. The parents took his temperature--a scary 104--and raced to the emergency room. By then, Carter was having trouble breathing.
Two hours later, he was flown to Children’s Mercy Hospital in Kansas City. But things only got worse. Now Skyler, who was also at the hospital with his mother, wouldn’t eat, either. Suddenly, he stopped breathing and had to be revived. So Skyler caught the next evacuation flight to Kansas City, right behind his brother.
The problem eventually turned out to be overwhelming enterovirus infection. This is a mercifully rare condition, but it can happen if a mother catches the virus late in pregnancy and unknowingly passes it to her baby. Uncontrolled by the newborn’s immature immune system, the virus may eventually attack the liver, the heart and other organs. There has been no treatment, and the death rate is high, somewhere between 40% and 80%.
For the next three days in intensive care, the babies’ blood counts dropped, and they received transfusions. Spinal taps found the virus in their central nervous systems. This was especially worrisome, because there it can lead to brain damage.
Antibiotics, which kill bacteria, do nothing for viral infections. Then someone mentioned an experimental antiviral drug that might help.
“I don’t know how, but one of the doctors had heard of pleconaril,” Lisa Stephens says. “It was some sort of a miracle. On Wednesday, they gave them the drug. The next day we saw improvement. They were awake five minutes out of the whole day, but it was improvement. Friday they were awake a little more, and Saturday they were taken off oxygen.”
The next Monday, the babies were sent home, and “since then, they are just perfectly healthy, normal guys,” the mother says.
About two-thirds of babies like these getting pleconaril have survived, even though many were desperately ill before treatment started.
The drug has also been given to adults with defective immune systems who suffer enteroviral brain infections that simply will not go away. The usual course is inexorably downhill. Doctors say some of these people have fully recovered after a few days of pleconaril. Their symptoms go away, leaving no trace of the virus.
Doctors have also successfully treated people with myocarditis, an inflammation that can destroy the heart, and with polio, which is also caused by an enterovirus. Overall, doctors estimate that about three-quarters of these emergency cases appear to have benefited from pleconaril.
“Some of these patients had been ill for years, and they appeared to improve with seven to 10 days of treatment,” says Dr. Harley Rotbart of the University of Colorado Health Science Center. “Without overstating the results, I am very encouraged.”
The True Test: Large-Scale Trials
Compelling as these cases are, they actually prove little about pleconaril’s worth. Even the sickest enterovirus victim may spontaneously recover. For proof, the FDA requires large, carefully designed experiments to compare the medicine with standard care.
ViroPharma hopes first to prove that pleconaril cures viral meningitis. This common infection, which doctors sometimes called aseptic meningitis, is an inflammation of the covering of the brain and spine. Bacteria can also cause it, but vaccinations have made that form of meningitis rare.
The CDC estimates that about 50,000 Americans are hospitalized each year with viral meningitis, but perhaps 500,000 actually get it, many of them probably riding it out at home without seeing a doctor.
Beyond painkillers, there is little a doctor can offer. Even though rarely fatal, this is a miserable disease. Many feel desperately ill with pounding headaches, stiff necks, fever and nausea.
Small pleconaril studies on patients with viral meningitis certainly have looked promising. One of them suggests the drug begins to ease headaches within a day. People felt completely back to normal within seven days, compared with nine days in those getting dummy pills.
The results of two large meningitis studies on adults and adolescents are expected in the spring. If they turn out as ViroPharma hopes, research director Mark A. McKinlay says, the company will immediately seek approval to sell the drug. With a speedy FDA review, this could put a liquid form of pleconaril on the market by the end of 2000.
Next would come a pleconaril pill, intended for treating colds, that the company hopes to sell in 2001. ViroPharma estimates Americans make between 30 million and 36 million doctor visits a year for colds, making this the most common medical complaint doctors hear. But the fact is, doctors can do nothing for the common cold.
Not that this stops them from trying.
Estimates vary, but doctors prescribe antibiotics for perhaps half of all cold patients they see. These drugs will not cure colds. Except in the rare cases in which people have bacterial complications, they do nothing to ease the symptoms. They are just expensive placebos. All of this suggests that if pleconaril actually does something to ease a cold, it will be avidly prescribed. The results of cold studies so far suggest it may truly help.
In the first of these, doctors intentionally infected intrepid volunteers with coxsackie virus, a kind of enterovirus that causes an especially obnoxious cold. Treatment began the day before they were exposed to the bug. Thirteen percent on pleconaril developed colds, contrasted with 65% taking dummy pills.
This was the first evidence that a medicine could change the course of a cold. But it was hardly a fair test. After all, most people will not take drugs in advance to ward off a cold.
So Dr. Frederick G. Hayden of the University of Virginia tested pleconaril’s effects on victims of garden-variety sniffles. Slightly more than 1,000 who went to doctors with fresh colds agreed to be randomly put on pleconaril or placebos.
Those on pleconaril got better an average 3 1/2 days sooner, plus their colds were less severe. On the second day of treatment, those on pleconaril blew their noses half as much as those on the dummy medicine. By the third day, they felt 40% better than the others.
In September, Hayden began another comparison study to accumulate the kind of detailed data needed by the FDA to decide whether to approve pleconaril pills for cold.
If that study pans out and the pills are approved, they will almost certainly be used for more than colds. For instance, experts expect they will work on what are called summer colds or summer flu. This is not really the flu but a bad, lingering, often feverish cold that hits in the summer or fall. Enteroviruses are a frequent culprit.
Before any drug is routinely given to millions of mildly ill people, however, the FDA must be convinced it is extremely safe. In testing so far, pleconaril seems to be free of side effects.
