MICA: Effect of CRTH2 Antagonist OC459 on Response to Rhinovirus Challenge in Asthma

Lead Research Organisation: Imperial College London
Department Name: National Heart and Lung Institute

Abstract

Asthma attacks are responsible for over 1000 deaths a year in the UK alone and are the main cause for hospitalisation for suffers of asthma. The most common trigger for asthma attacks is the common cold virus (rhinovirus). Currently available therapies fail to prevent virus-induced asthma attacks and asthmatic patients desperately need an effective, preventative treatment for this.
In light of the recognised relationship between rhinovirus and asthma attacks, an experimental model has been developed to study this association more closely. This involves inoculating asthmatics with rhinovirus via a spray in the nose under controlled conditions and allows the study of novel therapies. Due to careful selection of asthmatics without severe disease or a history of hospitalisation due to virus infections we have successfully used this model in over 50 asthmatics in a number of studies with great success. Unfortunately the only alternative option for studying asthma attacks (and the effect of therapies on them) is to recruit several hundred asthmatics and wait for asthma attacks to occur naturally. Such studies cost in excess of £30 million to conduct given the length of the study and the number of patients needed for recruitment (in order to capture enough attacks). The human experimental rhinovirus infection model therefore allows the study of asthma attacks and any treatment effects in a short amount of time and at a fraction of the cost.
A molecule known as prostaglandin D2 (PGD2 )has been shown to be a very important link in the pathway of inflammation known as 'type 2 immunity'. This pathway underlies many of the symptoms that asthmatics develop including breathlessness, cough, chest tightness and wheeze and has been shown to be particularly high in severe asthmatics. We have shown in a recent study using the human rhinovirus model that this type of inflammation (including prostaglandin D2) is increased by rhinovirus in the airway during the virus-induced asthma ttack and correlates strongly with the severity of the attack. Therefore blocking this molecule should halt the type 2 inflammation caused by the virus infection and limit the consequences of infection to simply a runny nose and a sore throat (as per non-asthmatic individuals) rather than the potentially life-threatening chest symptoms seen in asthma.
Fortunately several drug companies have already developed a drug that blocks the prostaglandin D2 receptor known as 'CRTH2' but none have taken the step to study its effect in preventing asthma exacerbations. Importantly, these drugs have already been trialled in a number of short studies involving several hundred asthmatics and shown to have an excellent safety profile. Additionally these studies have highlighted this type of therapy as very good at suppressing the asthmatic airway inflammation downstream of PGD2. Based on our own research findings of a rhinovirus-induced increase in PGD2, we wish to assess the effect of blocking PGD2 using the CRTH2 receptor blocker 'OC459' in the context of a controlled rhinovirus-induced asthma attack.
We have established that a study numbering 28 asthmatics, randomly assigned to either the drug or placebo would be sufficient to identify any benefit of this therapeutic approach to asthma care.

Technical Summary

Exacerbations of asthma are the main cause for morbidity, mortality and healthcare costs associated with the disease. Rhinovirus infection (the common cold) is the dominant cause for these exacerbations. The rhinovirus challenge model in asthma offers the ability to investigate treatment effects on exacerbations with a small number of volunteers. In contrast, trials of therapies powered to evaluate an effect on naturally occurring exacerbations require several hundred volunteers, a long study period to capture enough events and are significantly more expensive to carry out. Using this model we have shown that type 2 cytokines and PGD2 (a key mediator of type 2 inflammation) are significantly increased during a rhinovirus-induced exacerbation in asthma with levels of PGD2 strongly correlating with the severity of the exacerbation (P<0.001). In addition, previous trials with the CRTH2 antagonist OC459 have reported fewer respiratory tract infections than in patients treated with placebo. It is hypothesised that this effect is due to dampening of type 2 immunity which is opposing the beneficial effects of Th1 and innate immune responses. Blocking the PGD2 receptor CRTH2 therefore appears an extremely promising target with potential to limit the virus-induced Th2 inflammation underlying many asthma exacerbations. However to date trials of CRTH2 antagonists have been short in length and therefore not addressed the effect on exacerbations. This application requests funding for a phase 2a proof-of-concept study to determine the effect of CRTH2 blockade on the airway responses of asthmatics challenged with rhinovirus. We will utilise the virus challenge model and inoculate 28 asthmatics in conjunction with a double-blind, placebo-controlled trial of OC459 (noted for its excellent safety profile and a once-a-day tablet formulation). A treatment that is effective in reducing virus-induced exacerbations is a major unmet need in asthma and would be a huge benefit to patients.

Planned Impact

The beneficiaries of this research are broad firstly including other basic science and translational clinical researchers from around the world investigating any aspect of type 2 immunity. This applies to any atopic disease including asthma, allergy and eczema as well as other conditions in which type 2 immune pathways are activated including following parasitic, viral, fungal and some bacterial infections in susceptible individuals.
Secondly, a large number of major pharmaceutical companies already have a CRTH2 antagonist in varying stages of development including Novartis (QAW-039), Pulmagen (ADC63680), Merck (MK-1029) and Array Biopharma (ARRY502). As such the results of this study will provide the reassurance these companies inevitably require to commit the huge financial sums (~£30 million) necessary to carry out a study powered to evaluate the effect on naturally occurring exacerbations in asthma.
Currently a new wave of monoclonal antibodies directed at type 2 inflammatory mediators including IL-4, IL-5, and IL-13 are being trialled in asthma. For example, anti-IL-5 therapy (Pavord et al. Lancet 2012) significantly reduces airway eosinophilia and leads to a fall in exacerbations by 50% in selected asthmatics with evidence of type 2 inflammation. However in keeping with other monoclonal antibodies currently available for a large number of other diseases, these therapies are likely to cost well in excess of £10,000 per patient per year and will therefore be limited by health regulators to the most severe asthmatics only. Recently the CRTH2 antagonist QAW-039 (Novartis) has been shown to reduce airway eosinophilia to the same extent as anti-IL-5 therapies (data presented at ERS 2014) yet oral CRTH2 antagonist therapies are predicted to cost a fraction of the price of injected monoclonal antibodies. As such they represent a huge potential cost saving for healthcare systems whilst avoiding the need for subcutaneous administration and the added expenses and discfort for the patients associated with this. The large number of companies with these therapies in development will drive down costs further due to competition between them.
Taken together, healthcare systems and patients with asthma (that number over 5 million in the UK alone) as well as potentially those with other allergic diseases will be the ultimate beneficiaries. Sufferers of asthma who either develop exacerbations despite currently available therapies or who do not wish to take corticosteroids due to the well-known side-effect profile of these drugs will have access to a new asthma therapy with an excellent safety record in man, that can be taken orally once a day and potentially be capable of producing a marked reduction in the frequency and severity of asthma exacerbations.

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