Results of a Phase 2b Trial With GB001, a Prostaglandin D2 Receptor 2 Antagonist, in Moderate to Severe Eosinophilic Asthma

Moss, Mark H.; Lugogo, Njira L; Castro, Mario; Hanania, Nicola A.; Ludwig-Sengpiel, Andrea; Saralaya, Dinesh; Dobek, Rafał; Ojanguren, Íñigo; Vyshnyvetskyy, Ivan; Bruey, Jean‐Marie; Osterhout, Robin; Tompkins, Cindy‐ann; Dittrich, Karen; Raghupathi, Kartik; Ortega, Héctor

doi:10.1016/j.chest.2022.02.038

Cited by 2 publications

(6 citation statements)

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“…Study results for seven RCTs [ 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 ] were retrieved from ClinicalTrials.gov, results for five RCTs [ 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 ] were published in full text articles, and data for two RCTs [ 40 , 41 , 42 , 43 ] were obtained through the European Union (EU) Clinical Trial Register. Results for two RCTs [ 44 , 45 , 46 , 47 ] were available only from conference abstracts or posters, data for one RCT [ 48 , 49 , 50 ] were retrieved from both the EU Clinical Trial Register and abstract, and for another RCT, they were retrieved from both ClinicalTrials.gov and the abstract [ 51 , 52 ].…”

Section: Resultsmentioning

confidence: 99%

“…The LEDA Phase IIb RCT [ 36 , 37 ] demonstrated that the DP2 antagonist GB001 given orally at 20 mg, 40 mg, and 60 mg, in addition to the standard of care therapy, induced an effect on FEV 1 , PEF, and ACQ5 that was comparable to PCB in moderate to severe asthmatic patients with a BEC of ≥250 cells/μL. Across all doses, GB001 numerically reduced the odds of asthma worsening vs. PCB, with no dose–response effect; subgroup analysis based on baseline BEC and/or FENO did not indicate greater treatment efficacy with higher values.…”

Section: Resultsmentioning

confidence: 99%

“…GB001 20 mg and 60 mg induced a significant ( p < 0.05) delay in the time to first asthma worsening compared to PCB (HR 0.72 (95% CI 0.52–0.995) and HR 0.70 (95% CI, 0.51–0.97), respectively), while GB001 40 mg induced a numerical delay vs. PCB. Treatment with GB001 20 mg, 40 mg, and 60 mg significantly ( p < 0.05) reduced the annualised rate of asthma worsening vs. PCB (RR 0.56 (95% CI 0.39–0.80), RR 0.65 (95% CI 0.46–0.93), and RR 0.68 (95% CI 0.48–0.96), respectively) [ 36 , 37 ].…”

Section: Resultsmentioning

confidence: 99%

“…There was a numerical reduction in the annualised rate of severe asthma exacerbations compared to PCB [ 36 , 37 ].…”

Section: Resultsmentioning

confidence: 99%

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Investigational Treatments in Phase I and II Clinical Trials: A Systematic Review in Asthma

et al. 2022

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Inhaled corticosteroids (ICS) remain the mainstay of asthma treatment, along with bronchodilators serving as control agents in combination with ICS or reliever therapy. Although current pharmacological treatments improve symptom control, health status, and the frequency and severity of exacerbations, they do not really change the natural course of asthma, including disease remission. Considering the highly heterogeneous nature of asthma, there is a strong need for innovative medications that selectively target components of the inflammatory cascade. The aim of this review was to systematically assess current investigational agents in Phase I and II randomised controlled trials (RCTs) over the last five years. Sixteen classes of novel therapeutic options were identified from 19 RCTs. Drugs belonging to different classes, such as the anti-interleukin (IL)-4Rα inhibitors, anti-IL-5 monoclonal antibodies (mAbs), anti-IL-17A mAbs, anti-thymic stromal lymphopoietin (TSLP) mAbs, epithelial sodium channel (ENaC) inhibitors, bifunctional M3 receptor muscarinic antagonists/β2-adrenoceptor agonists (MABAs), and anti-Fel d 1 mAbs, were found to be effective in the treatment of asthma, with lung function being the main assessed outcome across the RCTs. Several novel investigational molecules, particularly biologics, seem promising as future disease-modifying agents; nevertheless, further larger studies are required to confirm positive results from Phase I and II RCTs.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

“…There was a numerical reduction in the annualised rate of severe asthma exacerbations compared to PCB [ 36 , 37 ].…”

Section: Resultsmentioning

confidence: 99%

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Investigational Treatments in Phase I and II Clinical Trials: A Systematic Review in Asthma

et al. 2022

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“…16,17 Similarly, in a Phase IIb study, GB001 failed to significantly reduce the odds of asthma worsening. 18 Precisely why the DP2 antagonists were ineffective in these latter trials remains unclear, as does the mechanism of action by which fevipiprant successfully reverses ASM remodelling.…”

Section: Introductionmentioning

confidence: 99%

Dual therapy with corticosteroid ablates the beneficial effect of DP2 antagonism in chronic experimental asthma

Ullah,

Rittchen,

et al. 2023

Preprint

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BackgroundProstaglandin D2 (PGD2) signals via the DP1 and DP2 receptors. In Phase II trials, DP2 antagonism decreased airway inflammation and airway smooth muscle (ASM) area in patients with moderate-to-severe asthma, but in the Phase III clinical trials, DP2 antagonism failed to significantly lower the rate of exacerbations. Here, we hypothesised that DP2 antagonism resolves established ASM remodeling via endogenous PGD2/DP1 activation and that this beneficial effect is ablated by dual corticosteroid therapy.MethodsNeonatal mice were co-exposed to pneumonia virus of mice (PVM) and cockroach extract in early life to induce severe bronchiolitis, then re-infected with PVM and challenged to cockroach extract in adulthood to progress disease to chronic experimental asthma (CEA). The efficacy of DP2 antagonism monotherapy or various dual therapies was assessed in the setting of a rhinovirus (RV)-induced exacerbation.ResultsRV inoculation increased PGD2 release, mucus production, collagen deposition, transforming growth factor (TGF)-β1 expression and type-2 inflammation. Treatment with a DP2 antagonist or DP1 agonist ablated the aforementioned phenotypes, increased type-1 immunity, and decreased ASM area. Dual DP1-DP2 antagonism or dual corticosteroid/DP2 antagonism, which attenuated endogenous PGD2 levels, prevented the resolution of ASM area induced by DP2 antagonism alone. The resolution of ASM remodelling following DP2 antagonism was mediated by IFN-γ and associated with decreased TGF-β1 expression.ConclusionDP2 antagonism resolved ASM remodelling via PGD2/DP1-mediated upregulation of interferon-γ expression. Dual DP2 antagonism/corticosteroid therapy, as occurred in many of the human trials, suppressed PGD2 and IFN-γ production, impairing the efficacy of DP2 antagonism.

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Results of a Phase 2b Trial With GB001, a Prostaglandin D2 Receptor 2 Antagonist, in Moderate to Severe Eosinophilic Asthma

Cited by 2 publications

References 18 publications

Investigational Treatments in Phase I and II Clinical Trials: A Systematic Review in Asthma

Investigational Treatments in Phase I and II Clinical Trials: A Systematic Review in Asthma

Dual therapy with corticosteroid ablates the beneficial effect of DP2 antagonism in chronic experimental asthma

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