© 2007 American Thoracic Society doi: 10.1164/rccm.200708-1264ED
The Demise of Anti–IL-5 for Asthma, or Not
Firestone Institute for Respiratory Health Interleukin-5 (IL-5) is the cytokine primarily responsible for eosinophil differentiation, maturation, migration into the circulation, and survival (1), although other cytokines and chemokines also play a role in these processes (2, 3). Eosinophils are prominent in the airways of patients with poorly controlled asthma (4), and focusing treatment on reducing their numbers has resulted in fewer severe asthma exacerbations (5, 6). Inhaled corticosteroids (ICS) have a dramatic effect in many (but not all) patients with asthma in reducing airway eosinophilia, and this is associated with improved asthma control. However, ICS have many other beneficial pharmacologic effects in asthmatic airways, so their effect on eosinophil numbers could not be taken as strong evidence that eosinophils were participating in asthma pathobiology. The development of two humanized monoclonal antibodies directed against IL-5 (mepolizumab and SCH 55700) raised expectations that these high-affinity antibodies would clarify the importance of IL-5 in human eosinophil biology, as well as the role of eosinophils in asthma pathobiology. A study of the activity of mepolizumab on allergen-induced airway responses and inflammation (7) demonstrated that the antibody effectively prevented the rise in both blood and sputum eosinophils after inhaled allergen, but did not attenuate allergen-induced physiologic responses. Thus, IL-5 was shown to be important in the mobilization of eosinophils and trafficking into the airways, but the study concluded that eosinophils were not involved in causing allergen-induced asthmatic responses. However, issues with the study design, including sample size and methodology, limited these conclusions (8). The initial clinical study with SCH 55700 was conducted in a small group of patients with difficult-to-manage asthma, all of whom were taking high doses of ICS and/or oral corticosteroids (9). This clinical trial again demonstrated that the antibody reduced blood eosinophils and, at one of the doses administered, had a small, but significant, benefit in improving FEV1, but not in any of the other clinical outcomes.
The body of evidence of the efficacy of anti–IL-5 antibodies in asthma has now been extended by a report in this issue of the Journal (pp. 1062–1071) (10). This study evaluated the efficacy of mepolizumab at two doses (250 and 750 mg) on a variety of asthma outcomes in a group of more than 300 patients with moderate to severe asthma, all of whom were treated with ICS, but who had poor asthma control, as measured by reduced lung function and daily symptoms requiring, on average, four puffs of rescue There are, however, a number of issues that need to be considered before this treatment approach is administered last rites. Some of these issues are generic and some specific to anti–IL-5. The generic issues include the selection of the patient populations to study biologics as asthma treatments. There are already very effective and relatively inexpensive treatment options for most patients with asthma. This means that the study populations for much more expensive biologics are usually patients with very difficult to treat asthma, who are already taking and failing conventional treatments. This is a very high hurdle to achieve, because, by definition, the already accepted effective drugs are not working well. This is particularly a problem for biologics, such as anti–IL-5, which target a cell or cells, that are beneficially impacted by corticosteroids, such as eosinophils or lymphocytes. The ideal study population for an evaluation of anti–IL-5 would be a population of patients with poorly controlled asthma, so there is something to improve, with high numbers of airway eosinophils, and who are not already taking ICS. Unfortunately, this population is not accessible in most countries, as ICS are so readily available. A compromise position would be to select patients who require high-dose ICS and/or oral corticosteroids to control asthma, with documented high airway eosinophilia and worsening asthma control when the steroid doses are reduced. The study by Flood-Page and colleagues (10) did measure airway eosinophils in induced sputum and the effect of anti–IL-5 on these in a small subset (about 10%) of the patients studied. These results provided interesting insights in that some of the patients had an increase in sputum eosinophils, but few had high levels of greater than 10%. In both treatment groups, mepolizumab had a significant effect in reducing sputum eosinophil numbers, but in the low-dose treatment group, this effect was only partial and, in the high-dose group, there was not a large increase in sputum eosinophils at baseline. The lack of ability of mepolizumab to completely abolish airway eosinophils, while having marked effects in reducing blood eosinophils, has previously been documented (11). The final issue with defining the potential utility of anti–IL-5 for asthma is the choice of the primary outcome variable in studies targeting eosinophils. The study by Flood-Page and colleagues (10) did show a trend toward reducing severe asthma exacerbations with the higher dose of mepolizumab, although the study was not sufficiently powered to show a difference in exacerbations. This result is consistent with other studies that have used a treatment strategy titrating ICS doses based on minimizing airway eosinophils and which demonstrated impressive reductions in severe asthma exacerbations (5, 6). Taken together, these studies suggest an important role for eosinophils in causing asthma exacerbations. Anti–IL-5 has proven to be useful in managing hypereosinophilic syndrome (12, 13) and may also be shown to be beneficial in clinical trials in patients with asthma with airway eosinophilia associated with poor control, when corticosteroids are reduced. The results of these trials, which are underway, are eagerly awaited, because they have implications not only for the possible role of anti–IL-5 as a therapy for asthma but also in clarifying the role of airway eosinophils in its pathobiology. FOOTNOTES Conflict of Interest Statement: P.M.O. has been on advisory boards for AstraZeneca (AZ), Biolipox, GlaxoSmithKline (GSK), Nycomed, Topigen, and Resistentia, and has received lecture fees from these and other pharmaceutical companies including Chiesi and Ono Pharma; in addition, he has received grants-in-aid for research studies from AZ, Altana, Biolipox, Boehringer lngelheim, GSK, Medimmune, Merck, Pfizer, and Wyeth. REFERENCES
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2-agonist use per day. The study was adequately powered to find a clinically useful improvement in peak expiratory flows (PEF). In keeping with the other studies, the antibody caused an impressive reduction in blood eosinophils, but did not demonstrate any significant improvement in any of the clinical outcomes measured. These results, therefore, could be interpreted as the "final nail in the coffin" for anti–IL-5 as a treatment strategy for asthma. 
