A randomized study of BI 671800, a CRTH2 antagonist, as add-on therapy in poorly controlled asthma

Miller, David; Wood, Chester C.; Bateman, Eric D.; LaForce, Craig; Blatchford, Jon; Hilbert, James E.; Gupta, Abhya; Fowler, Andrew

doi:10.2500/aap.2017.38.4034

Cited by 26 publications

(27 citation statements)

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“…We hypothesised that inhibition of CRTH2 with BI 671800, a highly specific and potent CRTH2 antagonist [8], would result in improved lung function in adult patients with mild-to-moderate asthma. Here we report the results of 2 clinical trials e 1 in controller-naïve patients with symptomatic asthma (study 1268.17; Trial 1), the other in symptomatic patients taking inhaled corticosteroids (study 1268.16; Trial 2) e and provide evidence that antagonism of CRTH2 can improve lung function in patients with asthma.…”

Section: Introductionmentioning

confidence: 99%

Efficacy of BI 671800, an oral CRTH2 antagonist, in poorly controlled asthma as sole controller and in the presence of inhaled corticosteroid treatment

Hall

Fowler

Gupta

et al. 2015

Pulmonary Pharmacology & Therapeutics

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The prostaglandin D2 (PGD2) receptor, CRTH2, plays a role in allergic airway inflammation. The efficacy of BI 671800, a CRTH2 antagonist, was assessed in 2 separate trials in patients with asthma, in either the absence or the presence of inhaled corticosteroid (ICS) therapy. In this study, BI 671800 (50, 200 or 400 mg) and fluticasone propionate (220 μg) all given twice daily (bid) were compared with bid placebo in symptomatic controller-naïve adults with asthma (Trial 1), and BI 671800 400 mg bid compared with montelukast 10 mg once daily (qd), and matching placebo bid, in patients with asthma receiving inhaled fluticasone (88 μg bid) (Trial 2). The primary endpoint in both trials was change from baseline in trough forced expiratory volume in 1 s (FEV1) percent predicted. After 6 weeks' treatment, adjusted mean treatment differences (SE) for the primary endpoint compared with placebo in Trial 1 were 3.08% (1.65%), 3.59% (1.60%) and 3.98% (1.64%) for BI 671800 50, 200 and 400 mg bid, respectively, and 8.62% (1.68%) for fluticasone 220 μg bid (p = 0.0311, p = 0.0126, p = 0.0078 and p < 0.0001, respectively). In Trial 2, adjusted mean FEV1 (SE) treatment differences compared with placebo were 3.87% (1.49%) for BI 671800 400 mg bid and 2.37% (1.57%) for montelukast (p = 0.0050 and p = 0.0657, respectively). These findings suggest that BI 671800 is associated with a small improvement in FEV1 in symptomatic controller-naïve asthma patients, and in patients on ICS.

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Section: Introductionmentioning

confidence: 99%

Efficacy of BI 671800, an oral CRTH2 antagonist, in poorly controlled asthma as sole controller and in the presence of inhaled corticosteroid treatment

Hall

Fowler

Gupta

et al. 2015

Pulmonary Pharmacology & Therapeutics

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“…ILC2s express CRTH2 . BI 671800, a CRTH2 antagonist, has been demonstrated to inhibit type 2 response‐dominated eosinophilic inflammation and relieve AR symptoms induced by allergen exposure in environmental challenge chamber, and had a favourable safety profile at the dose of 200 mg, twice daily, although its effect in asthmatics remains unclear . It is possible that CRTH2 antagonist partially works through inhibiting ILC2s.…”

Section: Therapeutic Implications In Upper Airway Diseasesmentioning

confidence: 99%

“…Anti-TSLP (AMG157), anti-IL-33 and anti-IL-25 antibody Inhibiting transcription factors such as GATA-3 (SB010) CRTH2 antagonist (BI 671800) IL-4Ra monoclonal antibody (Dupilumab) IL-5 monoclonal antibody (Mepolizumab) 6,[110][111][112][113][114] Th22 cells Anti-IL-22 monoclonal antibody (ILV-094) IL-12/IL-23p40 antagonist (Ustekinumab) Avoiding diesel exhaust particle [115][116][117] Th9 cells Anti-IL-9 monoclonal antibody (MEDI-528) Anti-TNFa antibody (Infliximab) Anti-IL-25 antibody [119][120][121] Tfh cells Anti-ICOS ligand antibody (AMG557) Anti-IL-21 antibody (NNC0114-0006) Anti-CXCL13 antibody (VX5) Anti-PD-1 antibody (BMS-936558) Small molecules targeting STAT3 (ISIS-STAT3Rx/AZD9150) CTLA4-IgFc fusion protein (Abatacept) [122][123][124][125][126] Bregs Ex vivo expanded autologous Bregs transfer…”

Section: Ilc2smentioning

confidence: 99%

Novel innate and adaptive lymphocytes: The new players in the pathogenesis of inflammatory upper airway diseases

Liu

Yao

Wang

et al. 2018

Clin Experimental Allergy

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Host immunity (innate and adaptive immunity) plays essential roles in the pathogenesis of inflammatory upper airway diseases, including allergic rhinitis and chronic rhinosinusitis. Recently, the discovery of novel innate immune cells, particularly innate lymphoid cells, has renewed our view on the role of innate immunity in inflammatory upper airway diseases. Meanwhile, the identification of new subsets of T helper (Th) cells, including Th22, Th9 and follicular Th cells, and regulatory B cells in the adaptive immunity, has broadened our knowledge on the complex immune networks in inflammatory upper airway diseases. In this review, we focus on these newly identified innate and adaptive lymphocytes with their contributions to the immunological disturbance in allergic rhinitis and chronic rhinosinusitis. We further discuss the perspective for future research and potential clinical utility of regulating these novel lymphocytes for the treatment of allergic rhinitis and chronic rhinosinusitis.

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“…More recently, fevipiprant (QAW039) gave a typical EC 50 of 0.44 ± 0.19 nM (whole-blood ESC assay). 18 Based on previous data, [19][20][21] it is assumed that complete blockade of CRTH2 is required throughout the dosing interval for maximum clinical efficacy, which assumes coverage of the IC 95 of whole-blood eosinophil shape change (ESC), a mechanistic biomarker, throughout the dosing interval. It is predicted that a oncedaily dose of 50 mg achieves coverage of the IC 95 over a 24-hour period.…”

Section: Pharmacodynamicsmentioning

confidence: 99%

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Novel CRTH2 Antagonist BI 1021958 at Single Oral Doses in Healthy Men and Multiple Oral Doses in Men and Women With Well‐Controlled Asthma

Fowler

Koenen

Hilbert

et al. 2017

The Journal of Clinical Pharma

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BI 1021958, a novel antagonist of the chemoattractant-receptor-homologous molecule (CRTH2), targets airway inflammation in asthma by inhibiting prostaglandin binding to CRTH2 receptors. Two phase 1 studies assessed BI 1021958 safety/tolerability and pharmacokinetics (PK)/pharmacodynamics (PD) following single doses in healthy men and multiple doses in men/women with well-controlled asthma. Studies 1 had 2 parts: a placebo-controlled, fixed-sequence, single-blind, single-rising-dose part (n = 56) and a randomized, 2-way crossover, open-label, repeated-dose part studying the food effect on PK/PD (n = 12). Study 2 was a placebo-controlled, single-center, double-blind multiple-rising-dose study (n = 84). Primary end points were safety/tolerability and PK/PD (both studies); secondary end points were eosinophil shape change (ESC; study 1) and dose proportionality/linearity following first dose and at steady state (study 2). BI 1021958 was adequately tolerated in both studies; adverse events were infrequent, generally mild to moderate, and occurred similarly in treatment groups. Maximum measured concentration (C ) was achieved in ≤2.5 hours in study 1 and ≤2.0 hours in study 2. BI 1021958 exposure increased proportionally with dose. In study 1, following a single 60-mg dose, AUC parameters and C were 20% and 15% lower, respectively, after a high-fat meal compared with the fasted state. After ≥60-mg single doses (study 1) and >40-mg multiple doses (study 2), >95% ESC inhibition was observed for ≥24 hours. PK/PD was similar in healthy subjects and subjects with well-controlled asthma. Data support further investigation of CRTH2 antagonists for the treatment of asthma.

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A randomized study of BI 671800, a CRTH2 antagonist, as add-on therapy in poorly controlled asthma

Abstract: BI 671800 at a dose of 400 mg administered for 4 weeks with fluticasone propionate did not provide clinical improvement in patients with asthma; reasons for this are unclear, but it may be due to insufficient inhibition of the CRTH2 receptor at the doses used.

Cited by 26 publications

References 0 publications

Efficacy of BI 671800, an oral CRTH2 antagonist, in poorly controlled asthma as sole controller and in the presence of inhaled corticosteroid treatment

Efficacy of BI 671800, an oral CRTH2 antagonist, in poorly controlled asthma as sole controller and in the presence of inhaled corticosteroid treatment

Novel innate and adaptive lymphocytes: The new players in the pathogenesis of inflammatory upper airway diseases

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Novel CRTH2 Antagonist BI 1021958 at Single Oral Doses in Healthy Men and Multiple Oral Doses in Men and Women With Well‐Controlled Asthma

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