Efficacy and safety of fevipiprant in patients with uncontrolled asthma: Two replicate, phase 3, randomised, double-blind, placebo-controlled trials (ZEAL-1 and ZEAL-2)

Castro, Mario; Kerwin, Edward; Miller, David; Pedinoff, Andrew; Sher, Lawrence; Cardenas, Pamela; Knorr, Barbara; Lawrence, David; Ossa, Diego; Wang, Wei; Máspero, Jorge

doi:10.1016/j.eclinm.2021.100847

Cited by 27 publications

(20 citation statements)

References 17 publications

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“…However, Philip et al reported that laropiprant did not demonstrate efficacy in patients with asthma or allergic rhinitis [ 23 ], suggesting that targeting DP1 for airway disease may not be clinically useful. Fevipiprant, a selective DP2 inhibitor, has also been tested in clinical trials and showed acceptable safety and tolerability in Phase II studies [ 14 ]; however, the drug recently failed to achieve clinically relevant endpoint reductions in patients receiving current standard-of-care treatment for moderate-to-severe asthma [ 37 ]. Moreover, AMG853, a selective dual antagonist of DP1 and DP2, also failed to improve asthma symptoms or lung function in patients [ 38 ], further suggesting the futility of targeting DP receptors in airway inflammation and asthma.…”

Section: Discussionmentioning

confidence: 99%

Role of prostaglandin D2 receptors in the pathogenesis of abdominal aortic aneurysm formation

et al. 2022

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PGD2 released from immune cells or other cell types activates its receptors, DP1 and DP2, to promote inflammatory responses in allergic and lung diseases. Prostaglandin-mediated inflammation may also contribute to vascular diseases such as abdominal aortic aneurysms (AAA). However, the role of DP receptors in the pathogenesis of AAA has not been systematically investigated. In this study, DP1 deficient mice and pharmacological inhibitors of either DP1 or DP2 were tested in two distinct mouse models of AAA formation: angiotensin II (AngII) infusion and calcium chloride (CaCl2) application. DP1 deficient mice [both heterozygous (DP1+/-) and homozygous (DP1-/-)] were protected against CaCl2-induced AAA formation, in conjunction with decreased MMP activity and adventitial inflammatory cell infiltration. In the AngII infusion model, DP1+/- mice, but not DP1-/- mice, exhibited reduced AAA formation. Interestingly, compensatory upregulation of the DP2 receptor was detected in DP1-/- mice in response to AngII infusion, suggesting a potential role for DP2 receptors in AAA. Treatment with selective antagonists of DP1 (laropiprant) or DP2 (fevipiprant) protected against AAA formation, in conjunction with reduced elastin degradation and aortic inflammatory responses. In conclusion, PGD2 signaling contributes to AAA formation in mice, suggesting that antagonists of DP receptors, which have been extensively tested in allergic and lung diseases, may be promising candidates to ameliorate AAA.

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Section: Discussionmentioning

confidence: 99%

Role of prostaglandin D2 receptors in the pathogenesis of abdominal aortic aneurysm formation

et al. 2022

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“…From a clinical perspective, treatment with fevipiprant can improve pre-dose trough FEV 1 and symptom scores, as well as reduce AAER ( Erpenbeck et al, 2016 ). Conversely, other trials did not show improvement in symptom scores or FEV 1 ( Castro et al, 2021 ). Overall, findings have been inconsistent with respect to clinical efficacy of fevipiprant treatment.…”

Section: Currently Available Biological Therapy and Suboptimal Responses In Severe Asthmamentioning

confidence: 97%

Biologics in Asthma: A Molecular Perspective to Precision Medicine

2022

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Recent developments in therapeutic strategies have provided alternatives to corticosteroids as the cornerstone treatment for managing airway inflammation in asthma. The past two decades have witnessed a tremendous boost in the development of anti-cytokine monoclonal antibody (mAb) therapies for the management of severe asthma. Novel biologics that target eosinophilic inflammation (or type 2, T2 inflammation) have been the most successful at treating asthma symptoms, though there are a few in the drug development pipeline for treating non-eosinophilic or T2-low asthma. There has been significant improvement in clinical outcomes for asthmatics treated with currently available monoclonal antibodies (mAbs), including anti-immunoglobulin (Ig) E, anti-interleukin (IL)-4 receptor α subunit, anti-IL-5, anti-IL-5Rα, anti-IL-6, anti-IL-33, and anti-thymic stromal lymphopoietin (TSLP). Despite these initiatives in precision medicine for asthma therapy, a significant disease burden remains, as evident from modest reduction of exacerbation rates, i.e., approximately 40–60%. There are numerous studies that highlight predictors of good responses to these biologics, but few have focused on those who fail to respond adequately despite targeted treatment. Phenotyping asthmatics based on blood eosinophils is proving to be inadequate for choosing the right drug for the right patient. It is therefore pertinent to understand the underlying immunology, and perhaps, carry out immune endotyping of patients before prescribing appropriate drugs. This review summarizes the immunology of asthma, the cytokines or receptors currently targeted, the possible mechanisms of sub-optimal responses, and the importance of determining the immune make-up of individual patients prior to prescribing mAb therapy, in the age of precision medicine for asthma.

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“…Two studies reported results from two trials each, so we included seven trials with a total of 4784 patients in the review and meta-analysis. The main characteristics are given in Table 1 [ 13 ] (GB001 is another potent DP2 pathway antagonist under investigation right now for the control of asthma [ 14 ] and is not included in this meta-analysis) [ 15 - 18 ].…”

Section: Reviewmentioning

confidence: 99%

“…Overall exacerbations in 150mg daily dose: Two studies [ 13 , 15 ] with four trials reported asthma exacerbation rate with 150mg dose with a combined MH risk ratio of 0.789 (0.593-1.049) with an I2 of 96.18. As with the 450mg dose, there was a substantial deviation towards Fevipiprant but was not statistically significant (Figure 5 ).…”

Section: Reviewmentioning

confidence: 99%

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Efficacy and Safety of Fevipiprant in Asthma: A Review and Meta-Analysis

Sattar¹,

Niazi²,

Muhammad³

et al. 2022

Cureus

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Fevipiprant is a non-steroidal oral prostaglandin D2 (PGD2) receptor 2 antagonist that reduces bronchial wall inflammation, possibly improving clinical outcomes in the asthmatic population. A systemic review search was conducted on PubMed, Embase, and Central Cochrane Registry. Randomized clinical trials were included with Fevipiprant as an intervention arm compared to placebo. For continuous variables, the standardized mean difference, and for discrete variables, Mantel-Haenszel Risk Ratio (MH Risk ratio) was used for analysis. Confidence interval of 95% and p-value < 0.05 was considered significant. The analysis was done using a random-effects model irrespective of heterogeneity. Heterogeneity was evaluated using the I2 statistic. A total of five articles, including seven trials, were included in the analysis. There was significant increase in post-bronchodilator forced expiratory volume in one second (FEV1) 0.249 (0.157-0.341), p<0.001 and pre-bronchodilator FEV1 0.115 (0.043 to 0.188), p=0.002. A decrease in asthma control questionnaire (ACQ) score of -0.124 (-0.187 to -0.062), p<0.001, was reported. Statistically significant asthma exacerbation reduction was reported in the high eosinophil count population with a daily dose of 450mg 0.77 relative risks (RR) (0.61-0.97). There was a positive deviation toward Fevipiprant 450mg dose for asthma reduction in the overall population, but it was not statistically significant. Fevipiprant produced a slight statistically significant reduction in asthma exacerbations in the high eosinophil count population with favorable deviation in the overall population. It significantly increased pre-and post-bronchodilator FEV1 and improved ACQ scores in treated patients. The benefits, though statistically significant, failed to translate into clinical importance.

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Efficacy and safety of fevipiprant in patients with uncontrolled asthma: Two replicate, phase 3, randomised, double-blind, placebo-controlled trials (ZEAL-1 and ZEAL-2)

Cited by 27 publications

References 17 publications

Role of prostaglandin D2 receptors in the pathogenesis of abdominal aortic aneurysm formation

Role of prostaglandin D2 receptors in the pathogenesis of abdominal aortic aneurysm formation

Biologics in Asthma: A Molecular Perspective to Precision Medicine

Efficacy and Safety of Fevipiprant in Asthma: A Review and Meta-Analysis

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