Genetech: Mapping Asthma

Joe Arron, Director of Immunology Discovery, and members of the asthma team working in the lab.

Paul felt it coming — his voice had turned rough, like a three-pack-a-day smoker’s. He knew he should stop, should use his inhalers. But this was his first presentation since his promotion. He’d spent a week on it, and the six people he needed to convince were in front of him. Not much pain, but his chest was tight. Now trouble exhaling — like breathing through a straw. Now wheezing, stopping midway through sentences, couldn’t concentrate on his own slides. He gasped to his audience, “I need to stop here.”

Asthma is common — about twenty million people suffer from it in the United States alone, fifteen times that many worldwide. It can be an inflammatory disease, an overreaction by the human immune system to irritants. Allergens, infections, or air pollution can trigger an attack that inflames and constricts the airway. Most patients can find relief using inhalers — bronchodilators like albuterol to open the airway temporarily, and inhaled steroids like fluticasone to reduce inflammation.

But those treatments don’t work for everyone. “Severe asthma” is defined clinically as asthma that is not controlled well by conventional treatments, and Paul is among the 10% of asthma patients with that diagnosis. Some need oral steroids, which can have serious side effects when used long-term. Others don’t respond well to steroids at all.

Forty years ago, scientists and physicians recognized that there was more than one type of asthma; they classified patients by their symptoms and by their responses to medication. The modern approach is to examine asthma at a molecular level, to map the biological pathways behind the disease. As that map is inked in, it becomes possible to select “therapeutic targets,” points at which a roadblock might be thrown into an asthma pathway. Such roadblocks are potential medicines; both at Genentech and elsewhere, scientists design and then test them, first in the lab, then using animal models, then in human clinical trials.

Joe Arron, Genentech’s Director of Immunology Discovery, manages a department of ten laboratories that investigate possible drugs for chronic inflammatory diseases, including asthma. “Asthma is more complicated than we once thought it was,” he says. “In the 1980s, scientists discovered that a particular immune system component, the Th2 cell, releases substances called cytokines, several of which act on cells in the airway and can trigger an asthmatic response in susceptible people. That became the generally accepted biological model for asthma.

“Genentech collaborated with scientists and physicians at the University of California, San Francisco. We assumed that the Th2 pathway was important, but we suspected but that it might not be the whole story. We took bronchial biopsies from a group of asthma patients and looked for Th2 cytokines. We were surprised — about half the patients had low Th2 cytokine concentrations but still had asthma. And as a group, the low-Th2 patients didn’t respond as well to steroids as did the high-Th2 patients. Something else was going on in addition to the Th2 pathway, something we didn’t understand. And maybe not just one other thing, maybe several. Non-Th2 asthma is a significant unmet medical need, and we’ve made it a major research focus in our early development program.

“Asthma has been a priority at Genentech since the 1990s, when we first began identifying specific asthma types and investigating potential medicines. We were the first and, for the past 12 years, only company to bring a biologic treatment to asthma patients. But rather than resting on our past accomplishments, we’re pushing forward. We still have a lot of data to work through, measuring patients’ markers of inflammation and examining their genetic information, trying to map non-Th2 asthma pathways. Our strong legacy both of following the science and bringing treatments to those with unmet medical needs gives me reason to be optimistic, even though it’s still early. If we can map other pathways, we can pinpoint therapeutic targets, and then we can develop candidate drugs to be tested in the clinic.”

Direct measurement of cytokine levels in an asthma patient is not easy; many cytokines act directly on the cells that line the airway. That leaves free cytokines present only at very low concentrations in the blood, so they’re difficult to measure accurately. Besides, what patient wants to undergo a lung biopsy, which is what would be required for direct measurement? Arron and other Genentech scientists recently described three biomarkers, substances that can be detected in blood or exhaled breath, and whose levels mirror those of Th2 cytokines in the lung. (Sometimes it’s difficult to tell whether it’s raining just by looking out the window. But if people walk by with their umbrellas open, you know it’s raining; biomarkers are like those umbrellas.) Biomarkers have the potential to allow quick, non-invasive detection and assignment of a patient’s asthma pathway.

Clinical trials have traditionally compared two groups: a randomly selected group that receives a candidate medicine, and a similar control group that receives either a different medicine or a placebo. Getting statistically reliable information from that sort of trial often requires a large number of patients. Identifying each patient’s pathway can lead to improved trials, because patients can be grouped by biomarker levels, and those groups may have different responses to different treatments. By comparing the responses of specific groups, clinical trials can be much more informative.

Genentech’s approach has been to develop medicines that are as specific as possible — ideally, they should intervene at a single point in a single biological pathway. But, the human body is so complex that that’s not always possible. Here’s the hope for the future: A physician would test an asthma patient’s biomarkers and then prescribe a drug that’s an exact fit. Genentech’s commitment to personalized healthcare sums it up — “the right drug for the right patient,” according to Arron.

The day when there are precisely targeted medicines for each of the many asthma sub-types is still in the future, but, there are non-steroidal treatments available that may benefit patients with certain types of severe, uncontrolled asthma. Paul, for one, is doing much better. After his asthma attack interrupted his presentation, he and his pulmonologist explored options beyond steroids, and they’ve developed a treatment regimen that’s keeping him effective at work and at home. For hundreds of thousands of other patients, however, severe asthma remains uncontrolled. Genentech’s research approach — mapping asthma’s multiple pathways and developing targeted roadblocks as treatments — offers hope for those patients to have fewer asthma attacks and, ultimately, less restricted lives.

http://www.gene.com/stories/mapping-asthma


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