A randomized trial of the efficacy and safety of quilizumab in adults with inadequately controlled allergic asthma

Asthma, a chronic inflammatory disorder of the airways, affects over 300 million people worldwide [1]. Some patients have persistent symptoms despite the use of steroids and other therapies. These patients are at the highest risk for future exacerbations and unscheduled use of healthcare resources [2].

Asthma is a heterogeneous disorder with distinct endotypes, the pathogenic cellular and molecular mechanisms that drive disease in different patient subgroups [3‐6]. Allergic asthma is a hypersensitivity driven by the complex interaction of epithelial, dendritic, and type 2 innate lymphoid cells, leading to activation of CD4⁺ T helper 2 (Th2) cells in response to allergen exposure [7]. Th2 cells produce interleukin (IL)-4, IL-5, IL-13, and other cytokines that promote immunoglobulin E (IgE) class switching of B cells, increased IgE synthesis by plasma B cells, and recruitment and activation of eosinophils and other inflammatory cells. When allergen cross-links IgE bound to IgE receptors on mast cells and basophils, cell activation and allergic mediator release occur, which may lead to mucus production and airway hyperreactivity [8]. Biomarkers in sputum, bronchoalveolar lavage, blood, and bronchial biopsies may indicate a particular endotype and potentially identify patients with increased responsiveness to endotype-specific treatments [5, 9]. For example, elevated levels of serum periostin, an extracellular matrix protein induced by IL-4 and IL-13 in airway epithelium, identified a subset of asthma patients who responded better to lebrikizumab, an anti-IL-13 monoclonal antibody [10]. Similarly, patients with high levels of exhaled nitric oxide (NO), blood eosinophils, or serum periostin, had fewer asthma exacerbations following treatment with omalizumab, a neutralizing anti-IgE antibody, than patients with low biomarker levels [11]. These data suggest that IgE may drive allergic asthma in a subset of patients.

Quilizumab is a humanized, monoclonal IgG1 that binds to the M1-prime segment present only on membrane IgE [12], but not on soluble IgE in serum [13‐15]. Membrane IgE is expressed on IgE-switched B cells, IgE memory B cells, and IgE plasmablasts, but not on IgE plasma cells [16]. In animal studies, anti-M1 prime bound membrane IgE on IgE-switched B cells and plasmablasts and depleted them through apoptosis and antibody-dependent cell-mediated cytotoxicity, leading to fewer IgE plasma cells and less production of soluble IgE [17].

We previously evaluated the safety, tolerability, and activity of quilizumab in Phase Ia (31 healthy volunteers) [18], Phase Ib (24 allergic rhinitis patients) [19] and Phase IIa (15 mild asthma patients) [19] studies. In these studies, quilizumab reduced serum total IgE by approximately 25 %. These decreases were sustained for at least 6 months after the last dose, in contrast to omalizumab, which must be administered every 2–4 weeks to maintain reduced IgE levels [20]. Quilizumab also abrogated the increase in challenge-specific IgE in patients with mild asthma following a whole-lung allergen challenge, and reduced the early and late asthmatic reactions [19]. Quilizumab may reset the IgE repertoire by targeting IgE production and provide a more sustained effect with a lower dose frequency then omalizumab. The primary purpose of this study was to evaluate the efficacy, safety, and pharmacokinetics of quilizumab after 36 weeks of treatment in adults with allergic asthma inadequately controlled despite high-dose inhaled corticosteroids (ICS) and a second controller.

In this study, we evaluated the efficacy and safety of quilizumab, a monoclonal antibody that targets the M1-prime segment of membrane IgE, in adult patients with allergic asthma that was inadequately controlled with standard therapy. After 36 weeks of treatment, quilizumab was well tolerated, with a safety profile consistent with previous clinical studies [18, 19].

Quilizumab demonstrated clear pharmacological activity by reducing both serum total and allergen-specific IgE an average of 30–40 % from baseline in all three treatment arms, in agreement with our previous work [18, 19]. However, quilizumab treatment did not show consistent and clinically meaningful benefits in reducing asthma exacerbations or improving lung function, symptoms, or quality of life. Subgroup analysis in patients with elevated serum periostin, blood eosinophils, FeNO, or serum IgE did not demonstrate a consistent treatment effect for quilizumab.

It is important to understand that reducing serum IgE levels is not quilizumab’s proposed mechanism of action. Quilizumab did not reduce serum IgE as effectively as omalizumab (89–98 % reduction of median free IgE) [26], but these two antibodies target the IgE pathway in distinctly different ways. Quilizumab targets both B-cell switching to IgE and the new stimulation of IgE memory B cells and plasmablasts that lead to enhanced IgE production, processes that occur locally in the airways of allergic patients [16]. Quilizumab’s ability to suppress the challenge-specific increase in serum IgE in our whole lung allergen challenge study in mild asthmatics supports this mechanism [19]. We therefore hypothesize that quilizumab prevents the formation of short-lived IgE plasma cells in the airway. Long-lived IgE plasma cells, which lack IgE on the surface, are not targeted by quilizumab and may be responsible for the remaining serum IgE detected in our studies [16]. Another source of IgE not eliminated by quilizumab may be a subpopulation of IgG1 memory B cells that undergo a secondary switch to IgE when reactivated, and thereby become IgE memory cells [27].

The current study assessed the relevance of this mechanism on exacerbations in patients with inadequately controlled allergic asthma. In the EXTRA study that examined a similar patient population, omalizumab significantly reduced asthma exacerbations by 25 % in the all-patients group [24], by 53 % in the FeNO-high subgroup, and by 32 % in the eosinophil-high subgroup, relative to placebo. In addition, asthma exacerbations were substantially reduced in the periostin-high subgroup (30 %) relative to placebo [11]. In contrast, in our study, quilizumab did not show significant clinical benefit in this population (Fig. 3) or in any subgroup (Fig. 4), possibly because local IgE production by short-lived IgE plasma cells is not critical for exacerbations and other clinical endpoints. For this to be true, we must assume that: 1) quilizumab depleted all M1-prime-positive B cells, and 2) the doses in this study were sufficient to deplete all M1-prime-positive cells. Despite our extensive efforts, we have not been able to accurately detect M1-prime-positive cells in patients with asthma [19], so we have no direct evidence of depletion. However, all three quilizumab dose regimens led to a similar reduction in serum IgE levels, suggesting that quilizumab depleted all target cells, and indicating that higher doses would not have provided additional activity. Interestingly, after stopping quilizumab dosing, serum IgE levels gradually increased, indicating that IgE-switching and formation of short-lived IgE plasma cells may occur continuously in this patient population, a finding not previously reported.

The allergen-challenge model used in our previous studies where quilizumab was shown to be effective [19] may not represent the asthma processes occurring in the patient population in this study, especially given that alternate sources of IgE appear to play a more dominant role. However, the model was key in first demonstrating the effectiveness of omalizumab in patients with mild asthma, where omalizumab significantly reduced both the early and late asthmatic responses following allergen challenge and reduced serum IgE almost completely [28, 29]. Although less effective than omalizumab in a similar population, quilizumab showed reductions of 26 and 36 % in the early and late asthmatic responses, respectively, and a 25 % reduction in serum IgE [19]. Allergen-challenge studies are generally exploratory and are designed to follow biomarkers that trend with early and late asthmatic responses. They are usually conducted in patients with mild asthma, which is not the typical target population for new biologic therapies. At least one therapy, mepolizumab (anti-IL-5), is effective for reducing asthma exacerbations in patients with eosinophilic asthma, yet does not appear to affect early/late asthmatic responses during allergen challenge [30, 31]. It is therefore crucial that appropriate patient populations and outcome measures are selected for future trials.

Whether quilizumab could have a clinically meaningful effect in another subgroup of allergic asthma patients or whether a treatment period beyond 36 weeks would show efficacy, are questions we are unable to address with the current study. The type 2 biomarkers, serum periostin, blood eosinophils, and FeNO, which identified patients with increased clinical benefit from lebrikizumab and omalizumab [10, 11], did not consistently enrich for increased benefit from quilizumab in this study. Similarly, patients with elevated serum IgE levels at baseline did not respond better to quilizumab nor was there a correlation between serum IgE reduction and exacerbation reduction or FEV₁ improvement (data not shown).

In adults with uncontrolled allergic asthma, a 36-week treatment with quilizumab, an anti-M1-prime monoclonal antibody that targets IgE-switched and IgE memory B cells, did not result in a clinically significant impact on exacerbation rate, lung function, or quality of life. Our data on quilizumab activity indicate that there are major pathological mechanisms that extend beyond the new, local production of IgE in patients with inadequately controlled allergic asthma.