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

仅在英国，哮喘发作每年就导致1000多人死亡，是哮喘患者住院的主要原因。引发哮喘发作的最常见诱因是普通感冒病毒(鼻病毒)。目前可用的治疗方法无法预防病毒诱导的哮喘发作，哮喘患者迫切需要有效的预防性治疗。鉴于鼻病毒和哮喘发作之间的已知关系，已经开发了一个实验模型来更密切地研究这种联系。这包括在受控条件下通过鼻腔喷雾给哮喘患者接种鼻病毒，并允许研究新的治疗方法。由于仔细选择了没有严重疾病或因病毒感染而住院的哮喘患者，我们已经在许多研究中成功地在50多名哮喘患者中使用了这一模型，并取得了巨大成功。不幸的是，研究哮喘发作(以及治疗对他们的影响)的唯一替代选择是招募数百名哮喘患者，并等待哮喘发作自然发生。考虑到研究的时间长短和招募所需的病人数量(为了捕获足够的攻击)，进行这种研究的费用超过3000万GB。因此，人类实验性鼻病毒感染模型允许在短时间内以极小的成本研究哮喘发作和任何治疗效果。一种名为前列腺素D2(PGD2)的分子已被证明是被称为2型免疫的炎症途径中非常重要的一环。这一途径是哮喘患者出现的许多症状的基础，包括呼吸困难、咳嗽、胸闷和喘息，并已被证明在严重哮喘患者中尤其严重。我们在最近的一项使用人类鼻病毒模型的研究中表明，在病毒诱导的哮喘发作期间，这种类型的炎症(包括前列腺素D2)在呼吸道中被鼻病毒增加，并与发作的严重程度密切相关。因此，阻断这种分子应该会阻止病毒感染引起的II型炎症，并将感染的后果限制在流鼻涕和喉咙痛(根据非哮喘患者)，而不是哮喘出现的潜在威胁生命的胸部症状。幸运的是，几家制药公司已经开发出一种阻断前列腺素D2受体的药物，称为CRTH2，但还没有一家公司采取措施研究其预防哮喘恶化的效果。重要的是，这些药物已经在涉及数百名哮喘患者的一些短期研究中进行了试验，并显示出良好的安全性。此外，这些研究强调这种类型的疗法在抑制PGD2下游的哮喘呼吸道炎症方面非常有效。基于我们自己关于鼻病毒诱导的PGD2增加的研究结果，我们希望评估在受控的鼻病毒诱导的哮喘发作的背景下使用CRTH2受体阻滞剂‘OC459’阻断PGD2的效果。我们已经确定，一项对28名哮喘患者进行的研究，随机分配到药物或安慰剂，将足以确定这种治疗方法对哮喘护理的任何好处。

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 attack 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.