Biologic and New Therapies in Asthma

Tabatabaian, Farnaz; Ledford, Dennis K.; Casale, Thomas B.

doi:10.1016/j.iac.2017.01.007

Cited by 42 publications

(47 citation statements)

References 50 publications

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“…The Th2 high and Th2 low endotypes are primarily discussed, according to the characteristics of airway inflammation. Th2 high endotype is mediated by eosinophilic airway inflammation and Th2 low endotype by neutrophils or minimal inflammatory cells (paucigranulocytic) [40]. Type 2 high asthma is developed by both adaptive and innate immune pathways, mainly stimulating Th2 cells and ILC2s individually.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, asth-matic patients mediated by non-atopic stimuli such as virus, microbes, and pollutants have been shown to be different from traditional atopic, allergen-induced patients. Current biologics targeting eosinophilic airway inflammation in atopic patients include IL-5/IL-5 receptor antagonist and monoclonal antibody to IL-4/IL-13 [40]. However, targeting eosinophilic asthma without atopy is challenging, because agents directly targeting ILC2s have yet to be developed.…”

Section: Discussionmentioning

confidence: 99%

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Blockade of thymic stromal lymphopoietin and CRTH2 attenuates airway inflammation in a murine model of allergic asthma

Lee

Hur

et al. 2020

Korean J Intern Med

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Background/Aims: Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived cytokine that plays a key role in Th2-mediated inflammation, both directly by promoting the proliferation of naïve CD4 Th2 cells, and indirectly by activating dendritic cells (DCs). TSLP-activated DCs induce the expansion of chemoattractant receptor homologous molecule expressed on Th2 (CRTH2) + CD4 + Th2 memory cells, which undergo a Th2 response and express prostaglandin D2 (PGD2) synthase. CRTH2, a PGD2 receptor, is a selective Th2-cell surface marker. We investigated the effects of an anti-TSLP antibody (Ab) and a CRTH2 antagonist, as well as their mechanisms of action, in a mouse model of acute asthma. Methods: BALB/c mice were sensitized and challenged with ovalbumin. We then evaluated the effects of the administration of an anti-TSLP Ab either alone or together with a CRTH2 antagonist on cell counts, Th2 cytokine levels in bronchoalveolar fluid, and the levels of epithelium-derived cytokines such as TSLP, interleukin (IL) 33, and IL-25 in lung homogenates, as well as airway hyper-responsiveness (AHR). Results: Anti-TSLP Ab and the CRTH2 antagonist significantly attenuated eosinophilic airway inflammation, AHR, and the expression of Th2 cytokines. The expression of GATA-3 and the levels of IL-33 and IL-25 in lung tissues were affected by the combined anti-TSLP and CRTH2 antagonist treatment. Conclusions: These results suggest that the dual blockade of TSLP and CRTH2 may serve as an effective treatment target for eosinophilic asthma.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Blockade of thymic stromal lymphopoietin and CRTH2 attenuates airway inflammation in a murine model of allergic asthma

Lee

Hur

et al. 2020

Korean J Intern Med

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“…57 One agent targeting IgE, which plays a role in allergen sensitization and airway inflammation, is omalizumab, an anti-IgE monoclonal antibody approved by the US Food and Drug Administration (FDA) for asthma with atopy in patients aged ≥6 years. 58 One study in children aged 6-12 years showed that omalizumab treatment resulted in a larger median reduction in maintenance ICS dosage (100%) compared with placebo (66.7%, P = 0.001), and also significantly reduced the percentage of patients with severe exacerbations (18.2%) compared with placebo (38.5%, P < 0.001) during the 12-week ICS dose-reduction phase of the study. 59 In a subsequent study for the same age group, omalizumab treatment resulted in a 50% reduction in severe exacerbations over 52 weeks compared with placebo (P = 0.004).…”

Section: Biologic Therapiesmentioning

confidence: 98%

“…Furthermore, the long‐term effects of these therapies remain to be seen; more investigation is still necessary to determine if biologic therapy can prevent disease progression or even reverse airway damage . One agent targeting IgE, which plays a role in allergen sensitization and airway inflammation, is omalizumab, an anti‐IgE monoclonal antibody approved by the US Food and Drug Administration (FDA) for asthma with atopy in patients aged ≥6 years . One study in children aged 6‐12 years showed that omalizumab treatment resulted in a larger median reduction in maintenance ICS dosage (100%) compared with placebo (66.7%, P = 0.001), and also significantly reduced the percentage of patients with severe exacerbations (18.2%) compared with placebo (38.5%, P < 0.001) during the 12‐week ICS dose‐reduction phase of the study .…”

Section: Biologic Therapiesmentioning

confidence: 99%

Can early intervention in pediatric asthma improve long‐term outcomes? A question that needs an answer

Lanz

Gilbert

Szefler

et al. 2019

Pediatric Pulmonology

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Objective Although many children with asthma do not experience persistence into adulthood, recent studies have suggested that poorly controlled asthma in childhood may be associated with significant airflow obstruction in adulthood. However, data regarding disease progression are lacking, and clinicians are not yet able to predict the course of a child's asthma. The goal of this article was to assess the current understanding of childhood asthma treatment and progression and to highlight gaps in information that remain. Data Sources Nonsystematic PubMed literature search and authors’ expertise. Study Selection Articles were selected at the authors’ discretion based on areas of interest in childhood asthma treatment and progression into adulthood. Results Uncontrolled asthma in early childhood can potentially have lasting effects on lung development, but it is unclear whether traditional interventions in very young children preserve lung function. Although not all children respond to standard interventions, certain asthma phenotypes have been identified that can help to understand which children may respond to a particular treatment. Conclusion Clinicians should monitor children's asthma control and pulmonary function over time to assess the long‐term impact of an intervention and to minimize the effect of uncontrolled asthma, especially exacerbations, on lung development. New biologic therapies have shown promise in treating adults with severe, uncontrolled asthma, and some of these therapies are approved in the United States for children as young as age 6. However, knowledge gaps regarding the efficacy and safety of these treatments in younger children hamper our understanding of their effect on long‐term outcomes.

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“…The second therapeutic option involves several infusions or subcutaneous injections per month. Therefore, there remains a medical need for additional efficacious and safe oral drugs …”

Section: Introductionmentioning

confidence: 99%

Pharmacokinetics, pharmacodynamics, tolerability and prediction of clinically effective dose of ACT‐774312: A novel CRTH2 antagonist

Géhin

Lott

Farine

et al. 2019

Basic Clin Pharma Tox

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ACT-774312 is an antagonist of the chemoattractant receptor-homologous molecule expressed on T helper (Th) 2 cells (CRTH2), in development for the treatment of nasal polyposis or other allergic and type-2 inflammatory diseases. Placebo, single doses of 1-1000 mg, or multiple doses of 30-500 mg either once or twice daily for 4 days of ACT-774312 were administered orally to healthy subjects. The single-and multiple-dose pharmacokinetics (PK) of ACT-774312 were dose proportional and characterized by a time to attainment of maximum plasma concentrations between 1 and 3 hours and a terminal elimination half-life of about 12 hours In the presence of food, t max was delayed by 1 hour and exposure to ACT-774312 slightly decreased. Full blockade (>90% of the maximum effect, E max ) of CRTH2 as measured in a whole blood internalization assay was observed after 50 mg ACT-774312 twice daily and lasted for at least 9 hours The relationship between ACT-774312 concentration and CRTH2 blockade was described by a E max model. The estimated twicedaily dose of ACT-774312 at which full blockade of CRTH2 is achieved at trough in at least 80% of subjects was estimated at 109 mg. Administration of ACT-774312 was safe and well tolerated at all doses. For none of the recorded adverse events, a relationship to dose was discerned, and there were no clinically relevant findings on the measured ECG, clinical laboratory and vital signs variables. The observed PK, pharmacodynamics and safety profile warrant further development of ACT-774312. K E Y W O R D SACT-774312, CRTH2, entry-into-man study, pharmacokinectics, receptor internalization

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Biologic and New Therapies in Asthma

Cited by 42 publications

References 50 publications

Blockade of thymic stromal lymphopoietin and CRTH2 attenuates airway inflammation in a murine model of allergic asthma

Blockade of thymic stromal lymphopoietin and CRTH2 attenuates airway inflammation in a murine model of allergic asthma

Can early intervention in pediatric asthma improve long‐term outcomes? A question that needs an answer

Pharmacokinetics, pharmacodynamics, tolerability and prediction of clinically effective dose of ACT‐774312: A novel CRTH2 antagonist

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