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A Randomized Trial of the Efficacy and Safety of Quilizumab in Adults with Inadequately Controlled Allergic Asthma Jeffrey M

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A Randomized Trial of the Efficacy and Safety of Quilizumab in Adults with Inadequately Controlled Allergic Asthma Jeffrey M Harris et al. Respiratory Research (2016) 17:29 DOI 10.1186/s12931-016-0347-2 RESEARCH Open Access A randomized trial of the efficacy and safety of quilizumab in adults with inadequately controlled allergic asthma Jeffrey M. Harris1*, Romeo Maciuca1, Mary S. Bradley1, Christopher R. Cabanski1, Heleen Scheerens1, Jeremy Lim1, Fang Cai1, Mona Kishnani1, X. Charlene Liao1, Divya Samineni1, Rui Zhu1, Colette Cochran1, Weily Soong2, Joseph D. Diaz3, Patrick Perin4, Miguel Tsukayama5, Dimo Dimov6, Ioana Agache7 and Steven G. Kelsen8 Abstract Background: Quilizumab, a humanized IgG1 monoclonal antibody, targets the M1-prime segment of membrane- expressed IgE, leading to depletion of IgE-switched and memory B cells. In patients with mild asthma, quilizumab reduced serum IgE and attenuated the early and late asthmatic reaction following whole lung allergen challenge. This study evaluated the efficacy and safety of quilizumab in adults with allergic asthma, inadequately controlled despite high-dose inhaled corticosteroids (ICS) and a second controller. Methods: Five hundred seventy-eight patients were randomized to monthly or quarterly dosing regimens of subcutaneous quilizumab or placebo for 36 weeks, with a 48-week safety follow-up. Quilizumab was evaluated for effects on the rate of asthma exacerbations, lung function, patient symptoms, serum IgE, and pharmacokinetics. Exploratory analyses were conducted on biomarker subgroups (periostin, blood eosinophils, serum IgE, and exhaled nitric oxide). Results: Quilizumab was well tolerated and reduced serum total and allergen-specific IgE by 30–40 %, but had no impact on asthma exacerbations, lung function, or patient-reported symptom measures. At Week 36, the 300 mg monthly quilizumab group showed a 19.6 % reduction (p=0.38) in the asthma exacerbation rate relative to placebo, but this was neither statistically nor clinically significant. Biomarker subgroups did not reveal meaningful efficacy benefits following quilizumab treatment. Conclusions: Quilizumab had an acceptable safety profile and reduced serum IgE. However, targeting the IgE pathway via depletion of IgE-switched and memory B cells was not sufficient for a clinically meaningful benefit for adults with allergic asthma uncontrolled by standard therapy. Trial registration: ClinicalTrials.gov NCT01582503 Keywords: Allergic asthma, Biomarkers, COSTA, IgE, M1 prime, Quilizumab, Exacerbations, FEV1 Background Asthma is a heterogeneous disorder with distinct Asthma, a chronic inflammatory disorder of the airways, endotypes, the pathogenic cellular and molecular mech- affects over 300 million people worldwide [1]. Some anisms that drive disease in different patient subgroups patients have persistent symptoms despite the use of [3–6]. Allergic asthma is a hypersensitivity driven by the steroids and other therapies. These patients are at the complex interaction of epithelial, dendritic, and type 2 highest risk for future exacerbations and unscheduled innate lymphoid cells, leading to activation of CD4+ T use of healthcare resources [2]. 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) * Correspondence: [email protected] class switching of B cells, increased IgE synthesis by 1Genentech, Inc, 1 DNA Way, South San Francisco, CA 94080-4990, USA Full list of author information is available at the end of the article plasma B cells, and recruitment and activation of © 2016 Harris et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Harris et al. Respiratory Research (2016) 17:29 Page 2 of 11 eosinophils and other inflammatory cells. When allergen sites from 14 countries: Argentina, Belgium, Bulgaria, cross-links IgE bound to IgE receptors on mast cells and Canada, Germany, Hungary, Mexico, New Zealand, Peru, basophils, cell activation and allergic mediator release Poland, Romania, Russia, Ukraine, and the United States) occur, which may lead to mucus production and airway that enrolled 578 adults with uncontrolled allergic asthma. hyperreactivity [8]. Biomarkers in sputum, bronchoalve- Patients were randomly assigned (1:1:1:1) to one of three olar lavage, blood, and bronchial biopsies may indicate a dosing regimens of quilizumab or placebo using an inter- particular endotype and potentially identify patients with active web response system. Randomization was stratified increased responsiveness to endotype-specific treatments basedonserumperiostinlevel(<50ng/mL,≥50 ng/mL), ex- [5, 9]. For example, elevated levels of serum periostin, an acerbation history (number of exacerbations (1, >1) requir- extracellular matrix protein induced by IL-4 and IL-13 ing use of systemic corticosteroids in the prior 18 months), in airway epithelium, identified a subset of asthma pa- IgE level (≤75 IU/mL, 75–200 IU/mL, >200 IU/mL), and tients who responded better to lebrikizumab, an anti-IL- country. Patients and study site personnel were blinded to 13 monoclonal antibody [10]. Similarly, patients with treatment assignments until all follow-up data through high levels of exhaled nitric oxide (NO), blood eosinophils, Week 84 were collected and verified. or serum periostin, had fewer asthma exacerbations fol- Quilizumab (Genentech, Inc., South San Francisco, lowing treatment with omalizumab, a neutralizing anti- CA) was delivered subcutaneously at nine monthly inter- IgE antibody, than patients with low biomarker levels [11]. vals at 300 mg per dose (300 mg M), or at three quar- These data suggest that IgE may drive allergic asthma in a terly intervals and at Week 4 at 150 or 450 mg per dose subset of patients. (150 or 450 mg Q). The treatment period ended Quilizumab is a humanized, monoclonal IgG1 that 36 weeks after randomization and was followed by a 48- binds to the M1-prime segment present only on mem- week period to assess the sustained efficacy and safety of brane IgE [12], but not on soluble IgE in serum [13–15]. quilizumab (see Additional file 1: Figure S1). Membrane IgE is expressed on IgE-switched B cells, IgE memory B cells, and IgE plasmablasts, but not on IgE Ethics, consent, and permissions plasma cells [16]. In animal studies, anti-M1 prime bound Quorum Review based in Seattle, WA was the primary membrane IgE on IgE-switched B cells and plasmablasts central IRB used by sites in North America, however and depleted them through apoptosis and antibody- multiple other site-specific institutional review boards at dependent cell-mediated cytotoxicity, leading to fewer IgE other global sites approved the protocol and patients plasma cells and less production of soluble IgE [17]. gave written, informed consent. The trial was conducted We previously evaluated the safety, tolerability, and ac- in full conformance with the International Conference tivity of quilizumab in Phase Ia (31 healthy volunteers) on Harmonisation E6 guidelines and the Declaration of [18], Phase Ib (24 allergic rhinitis patients) [19] and Helsinki, or laws and regulations of the country where Phase IIa (15 mild asthma patients) [19] studies. In these the research was conducted, whichever afforded greater studies, quilizumab reduced serum total IgE by approxi- protection to the individual. mately 25 %. These decreases were sustained for at least 6 months after the last dose, in contrast to omalizumab, Participants which must be administered every 2–4 weeks to main- Inclusion criteria tain reduced IgE levels [20]. Quilizumab also abrogated Adult asthma patients, aged 18–75 years, were re- the increase in challenge-specific IgE in patients with quired to have: bronchodilator reversibility of either mild asthma following a whole-lung allergen challenge, ≥12 % β-agonist reversibility using 4 puffs of a short- and reduced the early and late asthmatic reactions [19]. acting β − agonist (SABA) or a PC20 FEV1 methacholine Quilizumab may reset the IgE repertoire by targeting IgE (provocative concentration of methacholine producing a production and provide a more sustained effect with a 20 % fall in FEV1 (forced expiratory volume in 1 s)) of lower dose frequency then omalizumab. The primary 8 mg/mL or less, within the last 2 years; a pre- purpose of this study was to evaluate the efficacy, safety, bronchodilator FEV1 at screening of 40–80 % predicted; and pharmacokinetics of quilizumab after 36 weeks of daily use of ICS (≥400 μg/day total daily dose of flutica- treatment in adults with allergic asthma inadequately sone propionate or equivalent) and a second controller for controlled despite high-dose inhaled corticosteroids a minimum of 3 consecutive months; inadequately- (ICS) and a second controller. controlled asthma as documented by a 5-item Asthma Control Questionnaire (ACQ-5) [21] score ≥1.50 at Methods screening and randomization, despite compliance with Trial design asthma controller therapy; at least one positive The COSTA trial of quilizumab was a Phase II, randomized, aeroallergen-specific IgE (≥0.35 kU(A)/L), or a total serum double-blind,
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