Profiling the impact of two JAK inhibitors in a pre-clinical model of allergic asthma

Introduction: Asthma is a chronic inflammatory disease of the airways with typical symptoms manifesting in coughing, wheezing and dyspnoea. Whilst current treatments can be effective, some patients are not properly controlled, and the medications are not ideal and are associated with unwanted side effects. Thus, new therapies are urgently required. Typically, the chronic inflammation endotype is associated with increased levels of type 2 cytokine such as IL-4, IL-5, IL-9 & IL-13. These pro-inflammatory signalling pathways critically depend on Janus Kinase (JAK) I or II signal transduction, therefore the inhibition of JAK pathways represents a promising therapeutic target in asthma. Aims and Objectives: To assess the potential benefit of JAK inhibition using two structurally distinct inhibitors in a in vivo model system. Methods: Two JAK inhibitors, AZD4604 & AZD0449, were intratracheally dosed into sensitised Brown Norway rats one hour prior to aerosolised allergen (OVA) challenge. In one set of animals we assessed target engagement (TE) in the lung tissue by measuring levels of pSTATs. In a parallel set, we measured the Late Asthmatic Response (LAR) and lung inflammation. Results: Administration of both AZD4604 and AZD0449 resulted in dose related reduction of pSTAT3 and pSTAT5, indicating TE in the lung. Furthermore, AZD4604 & AZD0449 administration suppressed LAR and airway inflammation to a similar level to that achieved with the ICS comparator, budesonide. Conclusions: These data indicate that JAK inhibition may be of benefit to patients suffering from allergic asthma.