New drugs take more precise aim at asthma

<b>By Laura Beil / The Dallas Morning News</b><br><br>The difference between asthma drugs of today and asthma drugs of tomorrow may be like the difference between a nuclear weapon and a smart bomb. Both

Monday, September 11th 2000, 12:00 am

By: News On 6

By Laura Beil / The Dallas Morning News

The difference between asthma drugs of today and asthma drugs of tomorrow may be like the difference between a nuclear weapon and a smart bomb. Both can hit a target, but the first one may be a lot more effective than anyone wants.
Scientists are working, though, to develop more precise weapons against the deadly lung disease, which affects about 17 million Americans. After decades of tinkering with the mechanism behind an asthma attack, scientists have discovered ways to short-circuit a misguided immune system. The first drugs to specifically target asthma â€“ and not just inflammation in the lungs â€“ came on the market in 1996. A second class of drugs is awaiting approval for release, and many others are in various stages of testing.

The current treatment for asthma sufferers â€“ inhaled steroids â€“ has already freed millions from the threat of an asthma attack. During an attack, the inside lining of the lungs becomes inflamed, and the airways become dangerously narrow. Steroids work so well to control this reaction that attempts to come up with new asthma drugs are measured against the performance of steroids.

"We've got a pretty good treatment," said Dr. Bruce Bochner of Johns Hopkins University. "This is in many respects fine-tuning."

But some doctors worry that inhaled steroids, because they work broadly to counteract inflammation and not specifically to derail asthma, might not be safe to take over a lifetime. And because for the time being asthma can't be cured, only controlled, chronic asthma sufferers can't wean themselves completely from any drug they're prescribed.

"We don't know what the long-term effects on the lungs will be. We just don't know," said Dr. Ken Adams, chief of the asthma and inflammation section of the National Institute of Allergy and Infectious Diseases. Inhaled steroids have been widely used since the mid-1980s.

But coming up with new asthma drugs is no easy undertaking. An asthma attack is usually caused by a complicated riot of the immune system. At least a dozen different types of cells and more than two dozen chemicals conspire to make the airway constrict. Use a drug to knock out one cell, or one chemical, and a fleet of replacements may be standing by.

Plus, asthma is as unique as the names and faces of its sufferers. Researchers have found that immune system components that make one person miserable may be only minor players in the next.

All of these complications have faded dreams of a magic bullet for asthma. But researchers do envision the day when asthma drugs might be specially mixed cocktails for each patient.

The ingredients for the cocktail are inspired by study of the immune system's role in an asthma attack. More than a generation ago, scientists blamed a substance called histamine for instigating asthma and allergies. This research led to the development of antihistamines. About two decades ago, researchers discovered other accomplices. During an asthma attack, white blood cells dump substances called leukotrienes into the lungs. These leukotrienes cause the tissue inside the lungs to narrow, which contributes to the wheezing and shortness of breath that asthmatics know too well.

Although drug companies rushed to find antileukotriene drugs, the effort took more than 15 years of research. Since the first antileukotriene drugs became available in 1996, they haven't had as wide an impact on asthma as doctors had hoped. This is because the importance of leukotrienes varies from person to person.

"You just have to try it," Dr. Bochner said. "Probably some people are more sensitive" to the effects of leukotrienes.

A new class of asthma drug, called anti-IgE, is likely to be the next asthma medication to come on the market. This drug works by neutralizing IgE antibodies, large molecules produced by certain cells in the immune system.

The immune system normally makes antibodies in response to infections. Get a cold this winter, and the immune system is going to send out armies of antibodies designed to recognize your cold virus. But IgE antibodies are not nearly so helpful. For reasons that aren't understood, these antibodies become programmed to recognize ordinary cat dander, pollen or some other benign substance as a dangerous infection. These antibodies then alert other cells to release histamine, leukotrienes and other chemicals that affect the lungs. In short, IgE is a high-powered, and misinformed, colonel in allergy-related asthma.

Researchers have developed a drug that will mop up the vast majority of the body's IgE antibodies. Without IgE, the immune system doesn't view pollen, dust or other particles as a threat.

That's the idea, and human studies of anti-IgE have shown promise. In a study published last December, researchers reported in The New England Journal of Medicine that some patients who took anti-IgE in clinical trials, after 20 weeks, were able to stop using their steroids completely. But even though most people experienced a dramatic plunge in their levels of IgE, their asthma didn't go away.

Dr. Adams from the National Institute of Allergy and Infectious Diseases believes that the role of anti-IgE in the treatment of asthma is still unclear. For one thing, he said, many people's asthma isn't triggered by allergies. Also, he said, even getting rid of more than 90 percent of the IgE still couldn't get rid of the asthma.

"There are reasons perhaps for the less-than-spectacular effect" of antiIgE, Dr. Adams said. Perhaps it takes only a little bit of leftover IgE to arm the body's immune cells. Or IgE, despite appearances, might not have the pivotal role scientists believe.

"I think it will find its place," Dr. Adams said of the anti-IgE class of drug. But he also said it hasn't been used long enough to answer key questions, such as whether the body uses IgE for something other than asthma. "What we need to know is if there are any long-term reactions. We don't know what the role of IgE is, but it's unlikely that it's there to just give us allergies."

Plus, he said, the new drug will be expensive; doctors expect it to cost thousands of dollars a year.

Many other methods of asthma control are in the first stages of human trials. Some of these target a chemical called IL-4, which is also produced by the immune system. Research suggests that IL-4, and a cousin substance called IL-5, are important players in asthma.

Animal studies that involve blocking the action of either IL-4 or IL-5 in mice have suggested that drugs targeting these substances might be promising in controlling asthma. Human studies of the IL-4 and IL-5 approach are under way, but it's still too early to know whether the research will lead to new asthma drugs, and when.

Still other approaches are even more sophisticated than knocking out one step in the chain reaction that leads to an asthma attack. Dr. Bochner and his colleagues at John Hopkins are working on a vaccine that might reprogram the body's misguided immune reaction, turning pollen and other asthma triggers back into harmless particles. More than half of adults with asthma have an allergic component to their conditions.

Researchers are pursing other targeted asthma treatments, all the while not knowing whether asthma may be too complicated for such precise attacks, said Dr. William Busse of the University of Wisconsin-Madison. Knocking out only one or two steps in the reaction might not be enough to stop the dozens of other chemicals that are also involved.

"Specificity is possible, but is it good?" he said. "It may be that broad is better. We don't know that right now."

Still, he said, asthma experts should keep learning more about the condition. Studies of genetics, for example, represent a whole new arena of asthma research. If scientists can learn the genes involved, and their function in the body, they might learn even more of the basic interactions that lead the immune system astray.

Meanwhile, people with asthma should know that the data so far on steroids hasn't found high numbers of side effects, said Dr. Mark Millard of the Baylor Asthma and Pulmonary Rehabilitation) Center. "The gold standard is pretty good right now," he said.

For instance, a study published just last month in The New England Journal of Medicine suggested that the use of low-dose inhaled steroids could lower the death rate from asthma. The more canisters of steroids a person with asthma used, the less their risk of dying from an asthma attack.

"The fact of the matter is that 90 percent of patients with asthma can be controlled with the medications we have right now," Dr. Millard said.