Two Phase II randomized trials on the CRTh2 antagonist AZD1981 in adults with asthma

Abstract

BackgroundChemoattractant receptor-homologous molecule expressed on T helper type 2 (Th2) cell (CRTh2) receptor antagonists is being investigated for asthma.ObjectivesThe aim of this study was to assess the effects of the CRTh2 receptor antagonist, AZD1981 (with/without inhaled corticosteroids [ICSs]), on lung function and asthma control.Patients and methodsAdults aged 18–60 years were enrolled in two randomized, placebo-controlled, parallel-group trials (protocol number: D9830C00003 [study 1, n=209] and protocol number: D9830C00004 [study 2, n=510]). In study 1, patients with stable asthma (forced expiratory volume in 1 second [FEV1]: 65%−110%) were withdrawn from ICS (<400 µg/d) and randomized to AZD1981 1,000 mg twice daily (bid) or placebo. In study 2, patients with uncontrolled asthma (FEV1: 40%−85%) despite ICS therapy (≥500 µg/d) were randomized to 50 mg, 400 mg, or 1,000 mg bid AZD1981 or placebo. The primary efficacy variable for both trials was the change in morning peak expiratory flow after 4 weeks of treatment. Secondary variables included Asthma Control Questionnaire (ACQ-5) scores, FEV1 assessments, safety, and tolerability. In study 2, efficacy was also assessed according to atopic status.ResultsFollowing 4 weeks of treatment, there was a nonsignificant increase in morning peak expiratory flow on AZD1981 1,000 mg bid (9.5 L/min vs placebo, P=0.086 [study 1] and 12 L/min vs placebo, P=0.16 [study 2]). In study 2, all doses of AZD1981 provided significant improvements in ACQ-5 scores (0.26–0.3 units vs placebo, P=0.010–0.022); however, there was no dose–response relationship. Improved ACQ-5 scores and FEV1 were observed in the majority of atopic patients treated with AZD1981. AZD1981 was well tolerated across treatment groups.ConclusionFurther research may be warranted in atopic patients to fully evaluate the clinical efficacy of AZD1981.

Prostaglandin‐cytokine crosstalk in chronic inflammation

“…It should be mentioned, therefore, that although we believe in great potential of PG receptor type-selective agonists and antagonists, the application of these drugs should be carefully thought out by analysing the clinical and pathological context of each disease in the background of experimental studies. One successful example among this line may be the application of DP 2 antagonists to asthmatic patients (Erpenbeck et al, 2016;Kuna et al, 2016). As seen there, experimental studies to date have now accumulated enough amount of information as the base and framework for identifying a clinical indication.…”

Neuroendocrine cells derived chemokine vasoactive intestinal polypeptide (VIP) in allergic diseases

“…Generally, PGD2 is a major arachidonic acid metabolite released from immune cells such as mast cell [45], and Th2 cells [46]. In addition, several other studies implicate PGD2-induced inflammatory cells recruitment in allergic diseases that are mediated via CRTH2 receptor [40, 47] and blockage of this novel CRTH2 receptor attenuates the allergic manifestation in the patients [48, 49]. However, recently, the novel association between VIP and CRTH2 receptor in recruiting eosinophils in allergic rhinitis patients have been reported.…”

New and developing non-adrenoreceptor small molecule drugs for the treatment of asthma

“…The oral CRTH2 receptor antagonist BI 671800 administered for 6 weeks to patients with mild asthma produced small improvement in FEV1 compared to placebo , but the changes were significantly less than those with fluticasone propionate, 440 μg daily 38 . Four weeks treatment with the oral CRTH2 antagonist AZD1981 failed to improve lung function in patients with asthma after ICS withdrawal or while receiving ICS 39 . An oral dual antagonist of human DP1 and CRTH2 receptors AMG 853, when added to ICS treatment, did not improve symptoms and lung function or reduce sputum eosinophils in patients with poorly controlled moderate to severe asthma 40 .…”