ADC3680 - Low dose, once-daily oral CRTh2 antagonist
|ADC3680, Pulmagen’s lead CRTh2 investigational drug is a new chemical entity (NCE) being developed
as a low dose, once daily oral CRTh2 antagonist suitable for use as a well-tolerated controller therapy in asthma.
Pulmagen believes that ADC3680 is the only truly low dose, once daily, compound in clinical development and is positioned to be ‘best in class’ with the potential to be first to market. The efficacy of ADC3680 is currently being studied in a global Phase II clinical study in both the US and Europe [ClinicalTrials.Gov].
Pulmagen Therapeutics presented two posters on ADC3680, Pulmagen’s lead CRTh2 antagonist, at ERS 2013 in Barcelona, 8th-11th September 2013. Download the ADC3680 ERS 2013 posters here.
Pulmagen has recently signed an exclusive licensing agreement granting Teijin Pharma the rights to develop, manufacture and market ADC3680 in Japan.
|Pulmagen believes that CRTh2 antagonists have a role to play across the complete spectrum of Asthma disease severity both as a standalone therapy and also as a fixed dose combination with other established once-daily oral therapies, specifically, montelukast.|
|Pulmagen also has two Phase I-ready CRTh2 back-up compounds: ADC9971 and ADC7405.|
Clinical Role for CRTh2 antagonists in Asthma
|There are several CRTh2 receptor antagonists already in clinical development. Published data for these
agents indicate that treatment with a CRTh2 antagonist can reduce allergen-induced sputum eosinophilia,
the late asthmatic response, and serum Immunoglobulin E (IgE) levels, and improve lung function in both
steroid naïve subjects [Singh et al, 2010, Barnes et al, 2012, Sutherland et al, 2012] and in patients
inadequately controlled on ICS [Hall et al, 2012] suggesting that CRTh2 antagonists may be an effective
controller therapy for asthma. |
Additionally, treatment with a CRTh2 antagonist has been shown to reduce allergen-induced increases in nasal eosinophils, IL 4, IL 5, IL 13 and eotaxin [Krug et al, 2012] in patients with allergic rhinitis, supporting the hypothesis that CRTh2 antagonists will effectively inhibit Th2 inflammatory responses.
The Biological Role of the CRTh2 Receptor
|The chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTh2) is expressed on a variety of cells
implicated in the allergic process, including Th2-lymphocytes, eosinophils, and basophils (Nagata et al, 1999,
Gosset et al, 2003). The endogenous agonist is Prostaglandin D2, (PGD2) levels of which have been shown to be elevated
in atopic asthmatics [Dworski et al, 1994] and in subjects with severe asthma [Balzar et al, 2011].
Antagonism of CRTh2 inhibits expression of the adhesion molecule CD11b on eosinophils, and eosinophil shape change induced by PGD2 in vitro [Schratl et al 2007]; CRTh2 antagonists also inhibit PGD2-induced chemotaxis of human Th2 cells and eosinophils.
It is believed that CRTh2 antagonists should inhibit recruitment and activation of Th2 cells, eosinophils and basophils in subjects with asthma, with consequent reduction in airway inflammation and hyper-reactivity all of which is supportive for CRTh2 antagonists being effective controller therapies for asthma.