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

Abstract

BackgroundQuilizumab, 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.MethodsFive 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).ResultsQuilizumab 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.ConclusionsQuilizumab 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 registrationClinicalTrials.gov NCT01582503Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-016-0347-2) contains supplementary material, which is available to authorized users.

Fifty years later: Emerging functions of IgE antibodies in host defense, immune regulation, and allergic diseases

“…Unfortunately, although quilizumab reduced circulating IgE levels to greater than 40%, it did not significantly affect asthma flares, lung function, or quality of life in adults with poorly controlled asthma. 71 This result is consistent with the past observations of Casale et al 72 that the effectiveness of IgE blockade in reducing clinical symptoms correlates with reduction of IgE to very low levels. Because omalizumab does not displace IgE bound to FcεRI at current treatment doses, the onset of clinical benefit is delayed for weeks or months until preexisting cell-associated IgE is internalized.…”

IgE-Related Chronic Diseases and Anti-IgE-Based Treatments

“…These decreases were sustained for at least six months after the last dose, in contrast to OmAb, which must be administered every 2–4 weeks to maintain reduced IgE levels [100]. Unfortunately, in adults with uncontrolled allergic asthma, a 36-week treatment with quilizumab did not have a clinically significant impact on exacerbation rate, lung function, or quality of life [101]. Nor did its use in patients with refractory CSU achieve a clinically significant improvement, although it reduced median serum IgE by approximately 30% [102].…”

Personalisierte Medizin bei Asthma und chronisch-obstruktiver Lungenerkrankung

“…Interessanterweise könnte die auf fehlender Wirksamkeit und auf Therapieabrüchen bei anderen neuartigen Anti-IgE-Therapien (z.B. Quilizumab, MEDI-4212 [46]) basierende Beobachtung, dass einige Allergiepatienten mit schwerem Asthma nicht gut auf Omalizumab ansprechen, dazu führen, dass der Wirkungsmechanismus von Omalizumab besser erforscht wird und eine Definition eines „Responders“ auf der Basis spezifischer inflammatorischer Signalwege erarbeitet wird.…”