New Products, Findings Breathe Life Into Asthma Market As Companies Expand Drug Development Opportunities

Sidebar : Asthma Products - Delivering the Dosage Asthma Products - More Information CHEMICAL BLOCKER: Accolate was the first new asthma drug approved by FDA since the 1970s. New research is breathing life into the asthma drug market. Inspired by improving knowledge of asthma's biochemistry, more than 40 companies worldwide are investigating drugs to control the disease. This effort translates into new opportunities for creative chemists and biologists. For 25 years, a handful of drug firms, like Rhône-Poulenc Rorer and Schering Plough, have dominated the asthma market. But in the past decade, a growing number of biotech and drug companies have entered the fray. Last fall, the United States Food and Drug Administration (FDA) approved the first entirely new asthma drug since the 1970s. Called Accolate (generic: zafirlukast), the drug blocks leukotrienes, chemicals in the lungs that contribute to asthma attacks. Accolate is produced by Wilmington, Del.-based Zeneca Pharmaceuticals, a unit of Britain's Zeneca Group PLC. MANY OPPORTUNITIES: Frederick Brown notes that Zeneca is looking for chemists and biologists as it steps up asthma drug research efforts. Other companies are following closely on Zeneca's heels. Biochemical pathways in the lungs are home to many chemicals linked to asthma, including cytokines and the protease enzyme tryptase. Like leukotrienes, these substances also are drug targets. "There's a lot of research interest and excitement in asthma," observes Michael King, Jr., vice president and biotechnology analyst at Vector Securities International Inc. in Deerfield, Ill. King and others estimate the U.S. asthma market at $2.2 billion. Clearly, King says, there is room for new drugs. Up to 15 million Americans suffer from asthma. The number has been rising for three decades. According to the Asthma and Allergy Foundation of America in Washington, D.C., self-reports of asthma jumped 46 percent from 1982 to 1993. In particular, more children seem to suffer from asthma than ever before. Researchers are unsure why. For the most part, scientists say, existing asthma drugs do work-if taken properly. But many popular drugs are delivered via inhalers, which patients often misuse (see story on page 7). They may inhale medication too fast, for example, or exhale when the medicine is released. As a result, patients may get less than the prescribed amount of medication, and their asthma may not improve. Some long-term asthma drugs, such as beta agonists and corticosteroids, also may have side effects like insomnia and heart rate problems. These effects were spotlighted in new asthma management guidelines released last month by the National Asthma Education and Prevention Program, a National Heart, Lung, and Blood Institute program created in 1988 to raise awareness of the disease among patients and health care providers. AN OPEN MARKET: There is room for new asthma drugs, according to biotechnology analyst Michael King, Jr. The problems of improper inhaler techniques and medicine side effects have prompted companies to develop asthma drugs in pill form that patients can safely take every day to prevent attacks. Accolate is the first example. The new research calls for teams of chemists and biologists, according to Frederick Brown, associate director of biomedical research at Zeneca. "We have been looking for good chemists who would have the ability to make any kind of molecule that was needed. In bioscience, we would be interested in people who have specialized in lung physiology and who understand the animal models of the lung." Across the board, he says, it's a good time to get interested in asthma. The wheezing misery of asthma begins when chemicals in the lungs overreact to allergens (dust mites, for example), exercise, cold air, or other stimuli. A number of chemicals, including leukotrienes, are involved. Together, these substances force airway muscles to tighten, increase mucus secretion, and attract inflammatory cells to lung tissue. Asthma drugs fall into two categories: relievers and controllers. Relievers-for example, bronchodilators such as beta-2 agonists-soothe spasming muscles during an asthma attack. Controllers include anti-inflammatory medications like corticosteroids. These work on a daily basis to prevent asthma attacks from occurring. Most of the asthma drugs now in development are controllers. At least 15 companies worldwide have been exploring the role of leukotrienes. These efforts date to the late 1970s, when researchers began learning how these substances mediate lung inflammation. Zeneca's Accolate is a leukotriene receptor antagonist: It blocks the protein receptor that binds to leukotrienes before they can work. Merck and Co. Inc. in Whitehouse Station, N.J., and Philadelphia-based SmithKline Beecham are also testing leukotriene receptor antagonists in Phase III clinical trials. DISRUPTER: Abbott Laboratories’ Zyflo, approved by FDA last fall, is a leukotriene pathway inhibitor. Shortly after Accolate was approved, FDA also okayed Zyflo (generic: zileuton), produced by Abbott Laboratories Inc. of Abbott Park, Ill. This drug is the other new asthma medicine already on the market. Rather than block leukotrienes directly, Zyflo prevents them from forming in the first place. It works by disrupting an enzyme-called 5-lipoxygenase (5-LPO)-that leads to leukotrienes. It is taken as a pill four times a day. At least 10 other companies are exploring asthma drugs that inhibit 5-LPO. Developing a leukotriene pathway inhibitor like Zyflo has been challenging because the drug is the first in the field, explains Louise Dube, head of immunoscience R&D at Abbott. Scientists have had to create new animal models-rather than use existing ones-to test the drugs' unique biochemical effects. "It has been a joint effort between pharmacologists and biochemists to come up with new models," says Dube. "Scientists [at Abbott] have developed a guinea pig bronchoconstriction model that didn't exist 10 years ago." Dube notes that there is room for a variety of asthma drugs because the disease is caused by a range of interacting chemicals, each of which may affect patients differently: "You won't have everybody responding to one class of drug." At Abbott, researchers are now trying to reformulate Zyflo into a liquid that's safe, effective-and yummy-for kids. Though they are popular, leukotrienes aren't the only asthma mediators attracting attention. More than a half-dozen biotech and pharmaceutical firms are exploring various cytokines for their anti-asthma potential. A subset of these proteins, called chemokines, attract white blood cells to lung tissue at specific intervals, exacerbating an asthma attack. Cambridge, Mass.-based LeukoSite Inc. is collaborating with Roche Bioscience of Palo Alto, Calif., in preclinical studies of the chemokine eotaxin. A drug that blocks eotaxin from binding with its receptor might also prevent asthma attacks. FOR FURTHER INFORMATION Abbott Laboratories Inc. http://www.abbott.com Arris Pharmaceutical Corp. http://www.arris.com Boehringer Ingelheim http://199.79.148.67 Sequana Therapeutics http://www.sequana.com 3M Pharmaceuticals http://www.3M.com Zeneca Pharmaceuticals http://www.zeneca.com The National Asthma Education and Prevention Program's recently released "Guidelines for the Diagnoses and Management of Asthma" can be accessed on the Internet at http://www.nhlgbi.nih.gov. "The whole area of chemokine receptors is still very much in its infancy, and I think there's going to be a lot of new and interesting work," comments Walter Newman, vice president of research and drug discovery at LeukoSite. "It's very possible that these receptors are playing multiple roles." APPLICATIONS BEING ACCEPTED: LeukoSite’s Walter Newman says his company is "very much in a hiring mode." Newman says scientists looking to join the asthma industry have a choice: If they long for strength, security, and the traditional work of late-stage drug development, pharmaceutical firms might be good places to work. If, however, job hunters are risk-takers, they might enjoy the creative, early-stage drug research at biotech companies. LeukoSite itself is "very much in a hiring mode," Newman reports. He notes that he hopes to add about 12 people to the company's staff of 45 scientists. The new hires will be biologists, chemists, and pharmacologists. DIFFERENT STROKES: Biotech companies are willing to take on ideas that a pharmaceutical company might avoid, notes Arris’s Richard Tanaka. Richard Tanaka, senior director of preclinical development at San Francisco-based Arris Pharmaceutical Corp., agrees that biotech offers researchers a unique chance to explore the latest concepts. "Biotech companies are willing to take on different paradigms," Tanaka says. "In [big pharmaceutical firms], it can be difficult to propose a new idea." Arris is exploring asthma at a earlier point in its chemical cascade, before leukotrienes enter the picture. Working with German drug giant Bayer AG, Arris is conducting clinical trials of a compound that inhibits tryptase, a type of protease enzyme that helps trigger asthmatic reactions. Tryptase resides in mast cells, which release mediators like leukotrienes. "Tryptase is a new target, and we're still defining its physiological role in asthma," Tanaka says. This tryptase inhibitor is Arris's top compound. The company-also researching osteoporosis, blood-clotting disorders, and other diseases-employs about 120 scientists. Roughly 20 of them participate in asthma research. HOT JOBS: Computational biologists are needed to integrate genetic information and channel it into new drugs, notes Sequana’s Tim Harris. A couple of biotech companies are approaching asthma from a very different angle: genetics. Millennium Pharmaceuticals Inc. in Cambridge, Mass., and La Jolla, Calif.-based Sequana Therapeutics Inc. are both studying families with a history of asthma to find genes linked to the disease. "Genetics studies will either help us confirm [asthma] drug targets or find new ones," explains Geoffrey Duyk, vice president of genomics at Millennium. "In the end, it gives you the ultimate explanation of what is involved in a disease." Millennium is collaborating with the Astra Group in Sweden. Tim Harris, senior vice president of research at Sequana, reports that his company is zeroing in on a gene that appears to increase a person's susceptibility to asthma. This work is done with collaborators at Boehringer Ingelheim GmbH in Germany. "The genetics of asthma is pretty hot right now," Harris states. As with genetics in general, he notes, the top candidates for jobs in asthma are computational biologists. "There are a lot of potential [asthma] genes. Now companies have to identify targets within all those genes. So you need computational biologists to integrate information from biology, genetics, and chemistry and channel it into drug discovery." It remains to be seen which new drug targets will pan out-and who will get there first. Abbott's Dube points out that in these days of managed care, only the first one or two drugs in a unique class make it to market: "[A company's] chance of losing out during drug development is very high." However, the demand for new asthma drugs is strong, so early-stage asthma research should continue. "There is still a lot of work to do," Dube says. For more than 30 years, asthmatics have walked around with portable inhalers in their pockets. Taking a puff of medication from an inhaler, patients can stifle an asthma attack. If they inhale medicine daily, they may even prevent asthma attacks entirely. But there's a problem. Studies suggest that many asthma patients use inhalers incorrectly and end up with less medicine than they need. They might inhale their medication too quickly, for example. In many cases, asthma patients end up swallowing the medicine rather than breathing it into their lungs. In response, many companies are working on asthma drugs that would be taken as pills rather than inhaled. But researchers at Aradigm Corp. in Hayward, Calif., say they've got a better solution: automated inhalers. The Food and Drug Administration (FDA) recently approved Aradigm's SmartMist inhaler system, which should hit pharmacy shelves later this year. "Taking [asthma] drugs by inhalation is effective because it delivers the drug directly to the site of action," says Igor Gonda, vice president of R&D at Aradigm. These drugs work quickly, he explains, and may have fewer unwanted side effects than oral drugs. Photo: Aradigm Corp. AUTOMATED INHALER: Devices like Aradigm’s SmartMist Inhaler System, which monitors users’ breathing patterns to deliver prescribed amounts of medication, offer an effective way to deliver drugs directly, contends Igor Gonda. Most normal metered dose inhalers (MDIs) will fit into the hand-held SmartMist device. Rather than try to coordinate breathing with medicine release, an asthma patient using SmartMist just begins to slowly inhale. The system senses one's breathing pattern and automatically delivers a prescribed amount of medicine at the right time. If a patient breathes in correctly, a green light appears on SmartMist. If patients breathe medicine in too fast, a red light comes on. SmartMist keeps track of how much medicine a patient has taken over time, and it also allows patients to measure their lung function. Other inhaler makers are also trying to improve the products. In January, 3M Pharmaceuticals in St. Paul, Minn., released an environmentally friendly inhaler that doesn't use chlorofluorocarbons (CFCs) to propel drug droplets into the lungs (most inhalers do). In coming years, all new inhalers will have to be CFC-free to comply with international environment standards. Still other companies are trying to refine the delivery of drugs to the lungs, improving the ability of aerosol droplets to settle in lung tissue. In general, inhaler research like this calls for adaptable scientists who can learn new things, says Gonda. "You could not have been trained in research and development of many of these technologies because they simply didn't exist before. We need logical thinkers who are problem-driven." -K.S.B. Kathryn S. Brown is a freelance science writer based in Columbia, Mo.

New Products, Findings Breathe Life Into Asthma Market As Companies Expand Drug Development Opportunities

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