Cracking the cold case: Not an easy task

When pediatrician Howard Markel, MD, PhD, sees a young patient with a cold, parents often expect him to offer up a cure for what ails the child -- a pill, syrup or some other pharmaceutical treatment.

This expectation, of course, is due in part to years of periodic headlines, all of which promise that a cold cure is finally in sight.

"It's something we talk about every year as being just around the corner, but that corner seems to be the farthest corner in the world," said Dr. Markel, who is also director of the Center for the History of Medicine at the University of Michigan Medical School in Ann Arbor.

The truth is that the challenge of curing something so basic and, well, common has proven to be more complex than researchers ever imagined when they first started discovering various cold viruses in the late 1950s and early 1960s.

Initially, the strategy was to hunt for a vaccine to offer widespread protection. The realization that hundreds of viruses -- rhinoviruses, coronaviruses, adenoviruses and others -- were the guilty culprits, though, led them to abandon the approach.

"It became obvious that it would not be possible to make a vaccine," said Jack Gwaltney Jr., MD, professor emeritus in internal medicine at the University of Virginia School of Medicine, Charlottesville, a center for much of the research done in this area. During his more than 40-year career at the university, he took part in many of the common cold discoveries that are now taken for granted, such as its transmission by hand-to-hand contact.

As a result of this finding, science next eyed hand lotions as a possible answer -- a way to prevent these colds from being passed on. None, though, proved to be both cosmetically appealing and effective. Thus, that idea was eventually set aside.

Treatment then became the watchword in cold research. This concept, too, became complicated, because the ideal anti-cold drug faces an almost impossible risk-benefit ratio. The drug would have to be extremely effective at battling hundreds of constantly changing viruses while still causing very few, if any, side effects. Such risks would be unacceptable as a trade-off for treating a condition, which, for the most part, is an innocuous disease that doesn't last very long.

"Most feel the common cold to be almost a trivial clinical event," said A. Mark Fendrick, MD, professor of internal medicine and health management and policy at the University of Michigan, who has studied the ailment's economic impact. "The safety burden on these agents is enormous."

This issue is what derailed one promising treatment, pleconaril, which received attention in 2001 but hasn't yet made it to market, primarily because of evidence that its oral form interfered with the birth control pill. But work on it has not ended. The pharmaceutical company Schering-Plough recently licensed for $10 million a nasal version, now in phase II trials, from ViroPharma, which originally developed it.

"When you administer it intranasally, the dose is about a thousandfold less, so you should not see any drug interactions," said Mark McKinlay, PhD, who worked closely with pleconaril when he was ViroPharma's vice president of research and development. He is now the chief scientific officer at the Malvern, Pa.-based cancer drug company, Gentara.

Other approaches are also in the research and development pipeline. Pfizer Co. has a 3C protease inhibitor, formerly known as AG7088 and now called Ruprintrivir, in phase II trials. The Australian company Biota Holdings Ltd. is developing a capsid-binding inhibitor.

A commercial gamble

These treatments, however, are not the tip of the iceberg. For the most part, they are the iceberg. Despite the size of the problem and the size of the market, scientists have consistently struggled with a lack of commercial interest.

On the one hand, finding a cure for the common cold could make a company's fortunes. The United States alone experiences an estimated half billion colds a year. This number prompts 110 million visits to doctors and translates into $2.9 billion spent on over-the-counter medications and $400 million on prescription medications, according to a study published in the Feb. 24, 2003, Archives of Internal Medicine.

"A large percentage of people get a cold a year, and those that get a cold get more than one," said Dr. Fendrick, lead author of that paper. "The market is gigantic."

On the other hand, seeking this pot of gold also could break a company, and many question whether the gamble would pay off.

"These compounds are expensive to develop. They're more expensive to test, and if it costs $100 to treat a benign, self-limiting disease, is anybody going to pay for it?" asked José R. Romero, MD, a professor of pediatrics, pathology and microbiology at the University of Nebraska Medical Center in Omaha, who has studied several potential compounds.

Many a commercial research program has been abandoned in favor of easier prospects that might have a smaller but more eager potential pool of customers. In this instance, there is some evidence suggesting that despite the sheer number of people who get colds, the appeal of a prescription antiviral, no matter what the price, could be limited, especially among those for whom a cold is only an inconvenience.

A study presented at the American Academy of Family Physicians annual meeting in Orlando in October 2004 found that patients wanted an average of more than three days of relief from a prescription cold medication. Most drugs in the pipeline shorten the duration of a cold by only a day or so.

"The amount of benefit that people say they would want in exchange for the costs and risks of antivirals or any kind of anti-cold treatment is quite a bit larger than what the trials are showing exists," said Bruce Barrett, MD, PhD, lead author and assistant professor of family medicine at the University of Wisconsin Medical School, Madison.

Experts indicate that these medications could be more popular among asthmatics and people with other chronic conditions.

"Common colds are a nuisance for most people," said James E. Gern, MD, professor of pediatrics at the University of Wisconsin Medical School, who helped run some common cold medication trials. "But there is a subset of people who get really sick. We would love to have a new treatment for people who get these severe bouts of terrible respiratory distress when they get colds."

Some experts suspect that a successful cold treatment probably will be a combination of one of the antivirals currently being researched plus an anti-inflammatory. This one-two punch would address the impact of hundreds of viruses as well as the aftermath when the virus is long gone, and the patient is still dealing with his or her body's discomfort.

"You need a combination of ingredients to really effectively treat a cold," Dr. Gwaltney said. "You need to block the virus, and then you need other ingredients which will block those inflammatory pathways."

A new prize

Increasingly, scientists are turning away from the concept of treatment or cure and looking more closely at the idea of a prophylaxis. The goal here is to reduce the number of common colds an individual catches during peak season.

"A preventive is more likely than treatment, and something that carries more than one punch, no matter what the agent is, is more likely than a single agent," Dr. Markel said.

One company is going directly to this approach. San Diego-based Perlan Therapeutics is working on an ICAM-1 receptor blocker that would prevent rhinoviruses from thriving. The goal is to create a nasal spray that would be used regularly during the cold season. The product is in preclinical testing.

"We've tested it against 89 rhinoviruses. It blocked them all, and it may block others," said Catherine Charles, PhD, Perlan's head of research and development. "Obviously we have to do it in people to see, but the idea is that you stop the virus so you never get the symptoms."

Scientists also are returning to the concept of hand treatments that could prevent spread. A paper published in the July 2004 issue of Antimicrobial Agents and Chemotherapy found that several different solutions of organic acids could kill rhinoviruses within 15 minutes of contact. The number of colds caught by study volunteers also was reduced from 10 in the control group to only two in the study group.

"It's not ready for prime time, but the organic acids are really the first things to come along that look like they have staying power," said Ronald B. Turner, MD, lead author on that paper and professor of pediatrics at the University of Virginia School of Medicine. "There's real reason to believe this might work."

But although many scientists refer to a common cold cure as a holy grail of pharmaceuticals, there is a great deal of disagreement about the potential impact of any of these products. Some suspect it would make a significant reduction in the number of unnecessary antibiotic prescriptions and reduce the number of trickle-down effects of colds.

"It's not just colds," said Frederick Hayden, MD, professor of internal medicine and a longtime cold researcher at the University of Virginia, Charlottesville. "It's a whole host of common medical problems that are initiated by rhinovirus infections that drive a lot of health care seeking behavior and commonly lead to antibiotic use. If we could tackle the primary problem, it would be a benefit not just for the individual patient but from a public health perspective as well."

Others are not so sure the result would be that striking. Many infectious disease experts speculate that defeating one or more cold viruses could just make others more prevalent and have no impact on the total number of cold cases.

"If we get rid of the common cold, I'm sure there's going to be some other disease state that takes its place," said Tina Tan, MD, an infectious disease specialist at Children's Memorial Hospital in Chicago.