This is the largest double-blind, placebo-controlled, dose-ranging study performed to date to determine whether an anti-IL-9 monoclonal antibody has any clinical benefits in subjects with poorly controlled, moderate-to-severe asthma. The results indicate that adding MEDI-528 to existing controller medications was not associated with any major safety concerns, but failed to achieve a clinically important effect on mean ACQ-6 scores at 13 weeks or on asthma exacerbation rates, lung function, or asthma-related quality of life at the pre-specified time points. However, this study was powered to detect a change in the primary study endpoint of mean ACQ-6 score from baseline to week 13, thus statistical results for the secondary endpoints must be viewed in this context.
Data from preclinical studies provide strong evidence that an IL-9 mast cell axis regulates airway inflammation, mucus production, airway hyperresponsiveness, and subepithelial fibrosis, with increased IL-9 expression in the airways in humans with asthma . For example, both Th9 and Th17 are involved in asthma pathogenesis and produce IL-9 . Kim et al. demonstrated in Balb/c mice that cellular infiltration related to chronic airway inflammation and remodeling can be reduced by an anti-IL-9 antibody. In addition, the number of Th9 cells, Th17 cells, mast cells, eosinophils, and neutrophils in the airway were reduced; the synthesis and secretion of cytokines was inhibited; and IgE synthesis in B cells was reduced . These reported observations support our hypothesis that targeting IL-9 via an anti-IL-9 mAb would be an effective treatment for patients with poorly controlled asthma. Despite convincing in vitro and animal model data, there have been very few studies in humans examining IL-9 involvement in asthma.
In a previous small study in subjects with mild asthma, fewer subjects experienced ≥ 1 asthma exacerbation in the combined MEDI-528 group (1/27) compared with the placebo group (2/9; p = 0.15). The subject in the MEDI-528 group who experienced an exacerbation received the lowest dose (0.3 mg/kg), which indicated that it was not due to a dose effect. These results suggested a potential improvement in asthma exacerbation rates in subjects with mild asthma . However, in the current study, no significant differences in the asthma exacerbation rate occurred between placebo and MEDI-528 in adults with uncontrolled moderate-to-severe persistent asthma. Likewise, the mean increase from baseline in pre-bronchodilator FEV1 was similar between the MEDI-528 and placebo groups, which is consistent with the earlier study where FEV1 was essentially unchanged and short-acting beta agonist use was comparable among groups . Studies with other monoclonal antibodies, including omalizumab  and mepolizumab , also reported modest, if any, improvements in FEV1.
Although the study did not meet its primary endpoint, all groups, including placebo, demonstrated improvements in mean ACQ-6 score at 13 weeks. The placebo response has been well described in asthma studies and various explanations have been proposed. For example, Wise et al. reported that the placebo effect on asthma symptoms could be augmented by an optimistic message from the physician that enhanced the subject’s expectation of benefit from the drug . Similarly, a large placebo response was observed in two pivotal studies of omalizumab and was explained by improved compliance with ICS treatment and/or intensive medical input .
It is becoming increasingly apparent that asthma is a heterogeneous disease, and that identification of potential subgroups or individual subject characteristics is likely to be key in delivering optimal response with therapeutics such as MEDI-528 that target specific immunological mechanisms. Subgroup analyses of the mean ACQ-6 score results provided no evidence that MEDI-528 may be effective in subjects with atopic asthma, peripheral blood eosinophilia, or in those taking moderate or high doses of ICS at entry to the study. Interpretation of these results should take into account the small numbers of subjects in some subgroups.
The heterogeneous nature of asthma makes it difficult for a targeted therapy with monoclonal antibodies such as MEDI-528 to show significant beneficial effects in a non-selected asthma population. Identification of biological markers may be of great help in determining more accurate asthma diagnosis and severity, predicting treatment response, or monitoring of disease control. Corren et al. showed that lebrikizumab increased FEV1 and reduced exacerbations in the high Th2 subgroup vs placebo . Unfortunately, a pharmacodynamic marker for the IL-9 pathway has not been identified and IL-9 levels couldn’t be measured in blood or sputum in this study. Furthermore, subgroup analyses of the primary endpoint in pre-specified subpopulations, stratified by atopic status or medium- vs high-dose ICS at screening, and other pre-specified subpopulations based on FEV1, ACQ score, reversibility, and blood eosinophilia at randomization did not identify a subpopulation with improved efficacy over placebo.
Overall, the safety profile of MEDI-528 was similar to earlier clinical studies [11, 12] and no new safety concerns were identified. ADAs were detected in the placebo and all three MEDI-528 treatment groups. None of these events were considered to be serious, but it is unclear why ADAs were detected in the placebo group or in some subjects prior to administration of MEDI-528. Our ADA assays may nonspecifically detect cross-reacting antigen or other epitopes; however, it is not uncommon for subjects to develop antibodies against a biologic agent .