Abstract
Purpose of Review
Accumulating evidence has shown that prostaglandin D2 (PGD2)-chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) pathway plays an important role in promoting eosinophilic airway inflammation in asthma. We aimed to assess the efficacy and safety of CRTH2 antagonist fevipiprant in patients with persistent asthma compared with placebo.
Recent Findings
We identified eligible studies by searching PubMed, EMBASE, the Cochrane Central Register of Controlled Trials and ClinicalTrials.gov. The study was registered as CRD 42020221714 (http://www.crd.york.ac.uk/PROSPERO). Ten randomized controlled trials with 7902 patients met our inclusion criteria. A statistically significant benefit of fevipiprant compared with placebo was shown in improving forced expiratory volume in 1 s (MD 0.05 L, 95% CI: 0.02 to 0.07; p < 0.0001), Asthma Control Questionnaire score (MD -0.10, 95% CI: -0.16 to -0.04; p = 0.001), and Asthma Quality of Life Questionnaire score (MD 0.08, 95% CI: 0.03 to 0.13; p = 0.003). Fevipiprant decreased number of patients with at least one asthma exacerbation requiring administration of systemic corticosteroids for 3 days or more (RR 0.86, 95% CI: 0.77 to 0.97; p = 0.01). Some benefits were a little more pronounced in the high eosinophil population (with an elevated blood eosinophil count or sputum eosinophil percentage) and in the 450 mg dose group. Fevipiprant was well tolerated with no safety issues compared with placebo.
Summary
Fevipiprant could safely improve asthma outcomes compared to placebo. However, most of the differences didn’t reach the minimal clinically important difference (MCID), thus the clinical benefits remained to be confirmed.
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Abbreviations
- ACQ:
-
Asthma Control Questionnaire
- AQLQ:
-
Asthma Quality of Life Questionnaire
- AE:
-
Adverse events
- ASM:
-
Airway smooth muscle
- BAL:
-
Bronchoalveolar lavage
- CENTRAL:
-
Cochrane Central Register of Controlled Trials
- CIs:
-
Confidence intervals
- CRTH2:
-
Chemoattractant receptor-homologous molecule expressed on type 2 helper T (Th2) cells
- DP2 receptor:
-
PGD2 receptor 2
- E.g.:
-
For example
- \({FEV}_{1}\) :
-
ForcedFEV expiratory volume in 1 s
- FeNO:
-
Fraction exhaled nitric oxide
- GINA:
-
Global Initiative for Asthma
- ICS:
-
Inhaled corticosteroids
- IgE:
-
Immunoglobulin E
- IL:
-
Interleukin
- ILC2s:
-
Type 2 innate lymphoid (cells)
- LABA:
-
Long-acting β agonists
- MCID:
-
Minimal clinically important difference
- MD:
-
Mean difference
- \({\mathrm{PGD}}_{2}\) :
-
Prostaglandin D2
- RCTs:
-
Randomized controlled trials
- RR:
-
Risk ratio
- SABA:
-
Short acting β2-agonist
- SAE:
-
Serious adverse events
- SD:
-
Standard deviation
- Th2:
-
Type 2 helper T (cells)
- Tc2:
-
Type 2 cytotoxic T (cells
References
Wenzel SE. Asthma phenotypes: the evolution from clinical to molecular approaches. Nat Med. 2012;18(5):716–25.
Woodruff PG, Modrek B, Choy DF, et al. T-helper type 2-driven inflammation defines major subphenotypes of asthma. Am J Respir Crit Care Med. 2009;180(5):388–95.
Krings JG, McGregor MC, Bacharier LB, Castro M. Biologics for severe asthma: treatment-specific effects are important in choosing a specific agent. J Allergy Clin Immunol Pract. 2019;7(5):1379–92.
McGregor MC, Krings JG, Nair P, Castro M. Role of biologics in asthma. Am J Respir Crit Care Med. 2019;199(4):433–45.
Pelaia G, Vatrella A, Maselli R. The potential of biologics for the treatment of asthma. Nat Rev Drug Discovery. 2012;11(12):958–72.
Kostenis E, Ulven T. Emerging roles of DP and CRTH2 in allergic inflammation. Trends Mol Med. 2006;12(4):148–58.
Xue L, Stoeger L, Marchi E, et al. Interaction of type 2 cytotoxic T lymphocytes and mast cell lipid mediators contributes to pathogenesis of eosinophilic asthma. Am J Respir Crit Care Med. 2017;195:A5301.
Xue L, Salimi M, Panse I, et al. Prostaglandin D2 activates group 2 innate lymphoid cells through chemoattractant receptor-homologous molecule expressed on TH2 cells. J Allergy Clin Immunol. 2014;133(4):1184–94.
Saunders R, Kaul H, Berair R, et al. DP(2) antagonism reduces airway smooth muscle mass in asthma by decreasing eosinophilia and myofibroblast recruitment. Sci Trans Med 2019;11(479):eaao6451.
Palikhe NS, Laratta C, Nahirney D, et al. Elevated levels of circulating CD4(+) CRTh2(+) T cells characterize severe asthma. Clin Experiment Allergy : J British Soc Allergy Clinic Immunol. 2016;46(6):825–36.
Liu MC, Hubbard WC, Proud D, et al. Immediate and late inflammatory responses to ragweed antigen challenge of the peripheral airways in allergic asthmatics. Cellular, mediator, and permeability changes. Am Rev Respir Dis 1991;144(1):51–8.
Balzar S, Fajt ML, Comhair SA, et al. Mast cell phenotype, location, and activation in severe asthma. Data from the Severe Asthma Research Program. Am J Respir Critic Care med 2011;183(3):299–309.
Fajt ML, Gelhaus SL, Freeman B, et al. Prostaglandin D2 pathway upregulation: relation to asthma severity, control, and TH2 inflammation. J Allergy Clin Immunol 2013;131(6):1504–1512.
Sykes DA, Bradley ME, Riddy DM, et al. Fevipiprant (QAW039), a slowly dissociating CRTh2 antagonist with the potential for improved clinical efficacy. Mol Pharmacol. 2016;89(5):593–605.
Hardman C, Chen W, Luo J, et al. Fevipiprant, a selective prostaglandin D(2) receptor 2 antagonist, inhibits human group 2 innate lymphoid cell aggregation and function. J Allergy Clin Immunol. 2019;143(6):2329–33.
Gonem S, Berair R, Singapuri A, et al. Fevipiprant, a prostaglandin D2 receptor 2 antagonist, in patients with persistent eosinophilic asthma: a single-centre, randomised, double-blind, parallel-group, placebo-controlled trial. Lancet Respir Med. 2016;4(9):699–707.
Bateman ED, Guerreros AG, Brockhaus F, et al. Fevipiprant, an oral prostaglandin DP(2) receptor (CRTh2) antagonist, in allergic asthma uncontrolled on low-dose inhaled corticosteroids. Eur Respir J. 2017;50(2):1700670.
Erpenbeck VJ, Popov TA, Miller D, et al. The oral CRTh2 antagonist QAW039 (fevipiprant): A phase II study in uncontrolled allergic asthma. Pulm Pharmacol Ther 2016;39:54–63.
https://clinicaltrials.gov/show/NCT03226392.[cited 2021 Feb 28].
https://clinicaltrials.gov/show/NCT03215758.[cited 2021 Feb 28].
Brightling CE, Gaga M, Inoue H, et al. Effectiveness of fevipiprant in reducing exacerbations in patients with severe asthma (LUSTER-1 and LUSTER-2): two phase 3 randomised controlled trials. The Lancet Respir Med 2020.
Shamseer L, Moher D, Clarke M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ (Clin Res ed) 2015;350:g7647.
Cochrane. Handbook for Systematic Reviews of Interventions. Version 5.2.0 2017 http://handbook.cochrane.org/.Cochrane.
https://clinicaltrials.gov/show/NCT03629249.[cited 2021 Feb 28].
Higgins JP, Altman DG, Gotzsche PC, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ (Clin Res ed) 2011;343:d5928.
Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ (Clinical research ed). 2003;327(7414):557–60.
https://clinicaltrials.gov/show/NCT01836471.[cited 2021 Feb 28].
https://clinicaltrials.gov/show/NCT02555683.[cited 2021 Feb 28].
https://clinicaltrials.gov/show/NCT03052517.[cited 2021 Feb 28].
https://clinicaltrials.gov/show/NCT02563067.[cited 2021 Feb 28].
Rabe KF, Nair P, Brusselle G, et al. Efficacy and safety of dupilumab in glucocorticoid-dependent severe asthma. N Engl J Med. 2018;378(26):2475–85.
Castro M, Corren J, Pavord ID, et al. Dupilumab efficacy and safety in moderate-to-severe uncontrolled asthma. N Engl J Med. 2018;378(26):2486–96.
Wenzel S, Castro M, Corren J, et al. Dupilumab efficacy and safety in adults with uncontrolled persistent asthma despite use of medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist: a randomised double-blind placebo-controlled pivotal phase 2b dose-ranging trial. Lancet (London, England). 2016;388(10039):31–44.
Normansell R, Walker S, Milan SJ, Walters EH, Nair P. Omalizumab for asthma in adults and children. Cochrane Data System Rev 2014;(1):Cd003559.
Farne HA, Wilson A, Powell C, Bax L, Milan SJ. Anti-IL5 therapies for asthma. Cochrane Data System Rev 2017;9(9):Cd010834.
Juniper EF, Svensson K, Mörk AC, Ståhl E. Measurement properties and interpretation of three shortened versions of the asthma control questionnaire. Respir Med. 2005;99(5):553–8.
Juniper EF, Guyatt GH, Willan A, Griffith LE. Determining a minimal important change in a disease-specific Quality of Life Questionnaire. J Clin Epidemiol. 1994;47(1):81–7.
Santanello NC, Zhang J, Seidenberg B, Reiss TF, Barber BL. What are minimal important changes for asthma measures in a clinical trial? Eur Respir J. 1999;14(1):23–7.
White C, Wright A, Brightling C. Fevipiprant in the treatment of asthma. Expert Opin Investig Drugs. 2018;27(2):199–207.
Diamant Z, Sidharta PN, Singh D, et al. Setipiprant, a selective CRTH2 antagonist, reduces allergen-induced airway responses in allergic asthmatics. Clin Experiment Allergy : J British Soc Allergy Clin Immunol. 2014;44(8):1044–52.
Busse WW, Wenzel SE, Meltzer EO, et al. Safety and efficacy of the prostaglandin D2 receptor antagonist AMG 853 in asthmatic patients. J Allergy Clin Immunol. 2013;131(2):339–45.
Wenzel SE, Hopkins R, Saunders M, et al. Safety and efficacy of ARRY-502, a potent, selective, oral CRTh2 antagonist, in patients with mild to moderate Th2-driven asthma. J Allergy Clin Immunol 2014;133(2): AB4-AB.
Kuna P, Bjermer L, Tornling G. Two phase II randomized trials on the CRTh2 antagonist AZD1981 in adults with asthma. Drug Des Dev Ther. 2016;10:2759–70.
Hall IP, Fowler AV, Gupta A, et al. Efficacy of BI 671800, an oral CRTH2 antagonist, in poorly controlled asthma as sole controller and in the presence of inhaled corticosteroid treatment. Pulm Pharmacol Ther. 2015;32:37–44.
Pettipher R, Hunter MG, Perkins CM, et al. Heightened response of eosinophilic asthmatic patients to the CRTH2 antagonist OC000459. Allergy. 2014;69(9):1223–32.
Barnes N, Pavord I, Chuchalin A, et al. A randomized, double-blind, placebo-controlled study of the CRTH2 antagonist OC000459 in moderate persistent asthma. Clin Experiment Allergy : J British Soc Allergy Clin Immunol. 2012;42(1):38–48.
Ortega H, Fitzgerald M, Raghupathi K, et al. A phase 2 study to evaluate the safety, efficacy and pharmacokinetics of DP2 antagonist GB001 and to explore biomarkers of airway inflammation in mild-to-moderate asthma. Clin Experiment Allergy : J British Soc Allergy Clin Immunol. 2020;50(2):189–97.
Yang J, Luo J, Yang L, et al. Efficacy and safety of antagonists for chemoattractant receptor-homologous molecule expressed on Th2 cells in adult patients with asthma: a meta-analysis and systematic review. Respir Res. 2018;19(1):217.
Carstensen S, Müller M, Erpenbeck V, Kazani S, Sandham D. Fevipiprant inhibits eosinophil activation induced by multiple metabolites of prostaglandin D2. Euro Respir J 2019;54(Supplement 63): PA4391.
Shamri R, Erpenbeck VJ, Dubois G, Sandham D, Levi-schaffer F. Fevipiprant, a potent selective antagonist of the prostaglandin D2 receptor 2, modulates the allergic effector unit via inhibition of eosinophil migration towards mast cells. Am J Respir Critic Care Med 2018;197(MeetingAbstracts).
Kazani S, Hasler F, Jaeger P, Maurer C, Sandham D, Roehn T. Fevipiprant is superior to montelukast in suppressing type 2 cytokine production from mast cell stimulated human Th2 cells. Euro Respir J 2019; 54(Supplement 63): OA3808.
Chen W, Borst R, Luo J, et al. Fevipiprant antagonises prostaglandin D2-induced activation of type-2 CD8 T cells (Tc2). Euro Respir J 2019;54.
Xue L, Hardman C, Chen W, et al. Fevipiprant, a selective prostaglandin d2 receptor 2 antagonist, potently inhibits chemotaxis and cytokine production by group 2 innate lymphoid cells. Am J Respir Critic Care Med 2018;197(MeetingAbstracts).
Gervais FG, Sawyer N, Stocco R, et al. Pharmacological characterization of MK-7246, a potent and selective CRTH2 (chemoattractant receptor-homologous molecule expressed on T-helper type 2 cells) antagonist. Mol Pharmacol. 2011;79(1):69–76.
Bain G, Lorrain DS, Stebbins KJ, et al. Pharmacology of AM211, a potent and selective prostaglandin D2 receptor type 2 antagonist that is active in animal models of allergic inflammation. J Pharmacol Exp Ther. 2011;338(1):290–301.
Stebbins KJ, Broadhead AR, Correa LD, et al. Therapeutic efficacy of AM156, a novel prostanoid DP2 receptor antagonist, in murine models of allergic rhinitis and house dust mite-induced pulmonary inflammation. Eur J Pharmacol. 2010;638(1–3):142–9.
Lukacs NW, Berlin AA, Franz-Bacon K, et al. CRTH2 antagonism significantly ameliorates airway hyperreactivity and downregulates inflammation-induced genes in a mouse model of airway inflammation. Am J Physiol Lung Cell Mol Physiol. 2008;295(5):L767–79.
Uller L, Mathiesen JM, Alenmyr L, et al. Antagonism of the prostaglandin D2 receptor CRTH2 attenuates asthma pathology in mouse eosinophilic airway inflammation. Respir Res. 2007;8(1):16.
Sandham D, Asano K, Barker L, et al. Fevipiprant, a potent selective prostaglandin D2 receptor 2 (DP2) antagonist, dose-dependently inhibits pulmonary inflammation in a mouse model of asthma. Am J Respir Critic Care Med 2018; 197(MeetingAbstracts).
GB001 Phase 2 Clinical Trial Topline Results. [cited 2021 Feb 28]. Available from: https://ir.gossamerbio.com/node/7301/html. 2020.
Funding
This study was supported by the National Natural Science Foundation of China (Grant No. 81770035).
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Yang, D., Guo, X., Liu, T. et al. Efficacy and Safety of Prostaglandin D2 Receptor 2 Antagonism with Fevipiprant for Patients with Asthma: a Systematic Review and Meta-analysis of Randomized Controlled Trials. Curr Allergy Asthma Rep 21, 39 (2021). https://doi.org/10.1007/s11882-021-01017-8
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DOI: https://doi.org/10.1007/s11882-021-01017-8