Discontinued drug projects in the respiratory therapeutic area during 2012

Snell, Noel

doi:10.1517/13543784.2014.873785

Cited by 8 publications

(4 citation statements)

References 21 publications

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“… 3 , 13 , 27 – 29 A number of inhibitors of CRTH2 have already been tested in the treatment of various disease states. Although some studies reported that inhibition of CRTH2 was unsuccessful in ameliorating symptoms of COPD or asthma and allergic rhinitis in patients, 31 , 37 , 38 other clinical trials targeting CRTH2 have shown promising efficacy data in the treatment of asthma and allergic rhinitis. 28 , 39 , 40 Notably, our results showed that chemical inhibition of CRTH2 ameliorated some, but not all, effects of helminth infection in the lung, as OC000459 treatment did not appear to decrease helminth-induced pulmonary goblet cell hyperplasia.…”

Section: Discussionmentioning

confidence: 99%

The prostaglandin D2 receptor CRTH2 regulates accumulation of group 2 innate lymphoid cells in the inflamed lung

et al. 2015

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Group 2 innate lymphoid cells (ILC2s) promote type 2 cytokine-dependent immunity, inflammation and tissue repair. While epithelial cell-derived cytokines regulate ILC2 effector functions, the pathways that control the in vivo migration of ILC2s into inflamed tissues remain poorly understood. Here, we provide the first demonstration that expression of the prostaglandin D2 (PGD2) receptor CRTH2 (chemoattractant receptor homologous molecule expressed on Th2 cells) regulates the in vivo accumulation of ILC2s in the lung. While a significant proportion of ILC2s isolated from healthy human peripheral blood expressed CRTH2, a smaller proportion of ILC2s isolated from non-diseased human lung expressed CRTH2, suggesting that dynamic regulation of CRTH2 expression might be associated with the migration of ILC2s into tissues. Consistent with this, murine ILC2s expressed CRTH2, migrated towards PGD2 in vitro and accumulated in the lung in response to PGD2 in vivo. Further, mice deficient in CRTH2 exhibited reduced ILC2 responses and inflammation in a murine model of helminth-induced pulmonary type 2 inflammation. Critically, adoptive transfer of CRTH2-sufficient ILC2s restored pulmonary inflammation in CRTH2-deficient mice. Together, these data identify a role for the PGD2-CRTH2 pathway in regulating the in vivo accumulation of ILC2s and the development of type 2 inflammation in the lung.

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Section: Discussionmentioning

confidence: 99%

The prostaglandin D2 receptor CRTH2 regulates accumulation of group 2 innate lymphoid cells in the inflamed lung

et al. 2015

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“…The authors concluded that generation of mucus metaplasia involves a complex interplay among IL-25, IL-33 and TSLP. Nevertheless, blocking the TSLP pathway alone appears sufficient to suppress inflammation, as shown so far in the tezepelumab studies, albeit other anti-TSLP biologics such as RG7258 were not successfully developed into asthma therapies [108]. To date, no clinical studies have investigated the potential interactions between alarmins in patients with asthma, but it would be of importance to understand such interactions, both in terms of effects on the efficacy and safety of these treatments.…”

Section: Outstanding Questions Regarding Anti-alarminsmentioning

confidence: 99%

Anti-alarmins in asthma: targeting the airway epithelium with next-generation biologics

et al. 2020

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Monoclonal antibody therapies have significantly improved treatment outcomes for patients with severe asthma; however, a significant disease burden remains. Available biologic treatments, including anti-immunoglobulin (Ig) E, anti-interleukin (IL)-5, anti-IL-5Rα and anti-IL-4Rα, reduce exacerbation rates in study populations by approximately 50% only. Furthermore, there are currently no effective treatments for patients with severe, type 2 (T2)-low asthma. Existing biologics target immunologic pathways that are downstream in the T2 inflammatory cascade, which may explain why exacerbations are only partly abrogated. For example, T2 airway inflammation results from several inflammatory signals in addition to IL-5. Clinically, this can be observed in how fractional exhaled nitric oxide (FeNO), which is driven by IL-13, may remain unchanged during anti-IL-5 treatment despite reduction in eosinophils, and how eosinophils may remain unchanged during anti-IL-4Rα treatment despite reduction in FeNO. The broad inflammatory response involving cytokines including IL-4, IL-5 and IL-13 that ultimately results in the classic features of exacerbations (eosinophilic inflammation, mucus production and bronchospasm) is initiated by release of “alarmins” thymic stromal lymphopoietin (TSLP), IL-33 and IL-25 from the airway epithelium in response to triggers. The central, upstream role of these epithelial cytokines has identified them as strong potential therapeutic targets to prevent exacerbations and improve lung function in patients with T2-high and T2-low asthma. This article describes the effects of alarmins and discusses the potential role of anti-alarmins in the context of existing biologics. Clinical phenotypes of patients who may benefit from these treatments are also discussed, including how biomarkers may help identify potential responders.

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“…78,114 However, AZX100 was later not pursued owing to financial reasons. 115 The safety and tolerability of the cationic carriers as demonstrated in these clinical trials emphasizes that using cationic carriers for drug delivery applications is practical if the dosing needed to induce an effective biological response remains below the cytotoxic concentration of the carrier.…”

Section: Clinical Translationmentioning

confidence: 99%

Bioelectricity for Drug Delivery: The Promise of Cationic Therapeutics

2020

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Biological systems overwhelmingly comprise charged entities generating electrical activity that can have significant impact on biological structure and function. This intrinsic bio-electrical activity can also be harnessed for overcoming the tissue matrix and cell membrane barriers, which have been outstanding challenges for targeted drug delivery, by using rationally designed cationic carriers. The weak and reversible long-range electrostatic interactions with fixed negatively charged groups facilitate electro-diffusive transport of cationic therapeutics through full-tissue thickness to effectively reach intra-tissue, cellular, and intracellular target sites. This article presents a perspective on the promise of using rationally designed cationic biomaterials in targeted drug delivery, the underlying charge-based mechanisms, and bio-transport phenomena while addressing outstanding concerns around toxicity and methods to mitigate them. We also discuss electrically charged drugs that are currently being evaluated in clinical trials and identify areas of further development that have the potential to usher in new treatments.

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Discontinued drug projects in the respiratory therapeutic area during 2012

Cited by 8 publications

References 21 publications

The prostaglandin D2 receptor CRTH2 regulates accumulation of group 2 innate lymphoid cells in the inflamed lung

The prostaglandin D2 receptor CRTH2 regulates accumulation of group 2 innate lymphoid cells in the inflamed lung

Anti-alarmins in asthma: targeting the airway epithelium with next-generation biologics

Bioelectricity for Drug Delivery: The Promise of Cationic Therapeutics

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