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Therapy advances improve asthma management

Two new asthma therapies treat mechanistic aspects of the disease by attempting to limit the allergic response that causes asthma.

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September 2000

BOSTON - The development of targeted therapeutic strategies for asthma that are based on mechanistic aspects of the disease may soon impact treatment options for children, according to Joshua A. Boyce, MD, assistant professor of medicine, Brigham and Women's Hospital, Harvard Medical School, Boston.

Asthma Strategies in Preclinical Development Antagonism of other cytokines, particularly IL-13 Blockade of adhesion pathways that are essential for recruiting eosinophils and activating mast cells Blockade of chemokine receptors, particularly chemokine-receptor III, which is important for eosinophils and for mast cells Manipulating antigen presentation and several immunomodulatory vaccine strategies to potentially polarize the immune response to a nonallergic type of response

"This is a tremendously exciting time because finally, after years of basic investigation, we're reaching the point where we will have targeted therapies for asthma," Boyce said at the Joint Meeting of the Pediatric Academic Societies and the American Academy of Pediatrics here. "These therapies will not only impact the lives of the kids that we treat for asthma, but they're going to impact the practices of the primary care physician, perhaps more so than anybody else, because asthma is so common that the primary care physician really holds the burden of caring for the vast majority."

Boyce reported that some of the most promising developments are those directed at interleukin-4 (IL-4) and immunoglobulin E (IgE), both of which represent a component of the immune response that occur downstream of the T-helper zone, which regulates airway inflammation.

IL-4 is a pivotal T-cell derived cytokine that dictates many of the events that occur during an allergic response so that interference with this cytokine is a powerful inhibitory strategy for airway inflammation, Boyce said.

The attack on IL-4 uses a soluble IL-4 receptor. When IL-4 binds to its receptor, the receptor triggers a signaling cascade that responds by turning on several genes in the nucleus that are important inflammatory signals. When the soluble receptor is present, it competes with the cell surface receptor for IL-4 binding so that no binding and signaling occur.

Although soluble IL-4 receptor is awaiting phase-3 studies and pediatric trials, there have been studies in adults. The first human study of soluble IL-4 receptor included 25 adults with moderate asthma, all of whom were on inhaled steroids but stopped using them cold turkey upon receiving the receptor. Patients were divided into three dosage groups: one received a nebulized dose of 1.5 mg; a second received 0.5 mg and a third group received a placebo.

The results demonstrated that the highest dosage was highly protective against deterioration in asthma control. The groups who received the low dose and the placebo had inferior results that included decreased lung function and higher levels of exhaled nitric oxide when compared with the highest dosage group. "This suggests that the mode of action of this is indeed to inhibit the inflammatory response, even completely off of inhaled steroids," Boyce said.

"I think if one is looking for an agent where you can literally nip this disease in the bud, and perhaps prevent the development of the Th2 slanted immune response, this might be the one," Boyce said.

Researchers have also pursued the correlation between asthmatic disease severity and absolute levels of IgE, finding that the higher a patient's IgE in general, the more agitated their airways tend to be. In the initial human studies, a monoclonal antibody to IgE, named rhuMab-E25 (Olizumab, Genentech), was very safe, well tolerated and successful in reducing serum IgE in a cohort of adults with allergic rhinitis, Boyce said.

A phase 2 study done in adults with moderate to severe asthma who were symptomatic despite being on inhaled steroids demonstrated both safety and efficacy. Over a 20-week treatment period with a placebo control, patients taking rhuMab-E25 experienced improved symptoms, diminished frequency of exacerbations and increased peak flows relative to the placebo group. These results occurred despite the fact that the patients on rhuMab-E25 were able to reduce their inhaled steroid requirement to a much greater extent than those receiving the placebo.

Boyce reported that phase 3 studies on rhuMab-E25 involving both adults and children were recently completed with promising results that were presented in a late-breaking science session at the 56th Annual Meeting of the American Academy of Allergy, Asthma and Immunology.

Boyce said other strategies currently in preclinical development include:

• antagonism of other cytokines, particularly IL-13;
• blockade of adhesion pathways that are essential for recruiting eosinophils and activating mast cells;
• blockade of chemokine receptors, particularly chemokine-receptor III, which is important for eosinophils and for mast cells;
• manipulating antigen presentation and several immunomodulatory vaccine strategies to potentially polarize the immune response to a nonallergic type of response.

For more information:

• Boyce, J. Advances in pharmacotherapy of asthma in children. Presented at Joint Meeting of the Pediatric Academic Societies and the American Academy of Pediatrics. May 12-16,2000. Boston.

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Copyright 2000, SLACK Incorporated. Revised 15 September 2000.