The success of a drug is understandably measured by its impact on health and consequent sales. Drugs that do not meet primary endpoints in late phase trials are headlined as failures and perceived to have derailed clinical development, however they can still provide enormous insights into disease mechanisms and inform important relationships between clinical outcomes and underlying pathobiology. Learning from these setbacks helps to refine future clinical programmes, but only if biological outcomes are included in the studies.
Severe asthma has been an excellent example of how success and failure have led to incredible breakthroughs. The immunobiology in the majority of asthma sufferers is characterised by elevated type 2 immunity-mediated cytokines such as interleukin (IL)-4, -5, and -13 with associated eosinophilic inflammation. Monoclonal antibodies targeting interleukin-5 and its receptor are now in the clinic. However, anti-IL5 was initially unsuccessful until trialled in patients in a single-centre in the UK with severe asthma, evidence of eosinophilic inflammation and with asthma attacks as the primary endpoint. All of these features are now part of the drug’s indications. Monoclonal antibodies targeting IL-13 in severe asthma even in those with eosinophilic inflammation have had limited effects upon the rate of asthma attacks in phase III trials, but have consistently improved lung function and asthma control.
Targeting IL-4 has also had limited success. In contrast, targeting the IL-4Ra receptor, which blocks both IL-4 and IL-13 signalling, has led to reductions in asthma attacks as well as improvements in lung function and symptoms. These benefits were most marked in those patients with eosinophilic inflammation.
Other biologics and small molecules are targeting upstream cytokines such as IL-33, TSLP and the CRTh2/DP2 receptor which have impacts on eosinophilic inflammation. What is required to unpick these apparent anomalies and to understand how attenuation of different cytokines can have different clinical consequences requires further mechanistic studies.
Experimental medicine studies in asthma require sampling the airway which can be achieved by collection of sputum samples or direct bronchoscopic sampling. Bronchoscopy studies are rarely undertaken as part of clinical programmes as they are seen as difficult to undertake logistically, expensive and a risk to patients. In the UK, the National Institute for Health Research (NIHR) has established disease-specific Translational Research Collaborations (TRC), to enable Industry to carry out early phase research with the UK’s leading medical centres of excellence. In the recent anti-IL13 (tralokinumab) programme the MESOS trial the NIHR Respiratory TRC provided a network of centres that together with international colleagues were able to undertake a comprehensive bronchoscopy study ahead of time. This study was published in Lancet Respiratory Medicine alongside the phase III programme STRATOS I/II in May 2018. MESOS demonstrated improvements in airway physiology in keeping with STRATOS with additional effects observed in airway morphometry determined by computed tomography but no impact upon airway inflammation in bronchial biopsies or sputum samples.
It is likely the lack of an effect on airway inflammation was the rationale for why the phase III programme STRATOS I/II failed to meet its primary endpoint of reduction in asthma attacks. It is likely the benefits observed with anti-IL13 are due to effects upon the airway smooth muscle. Whether targeting IL-4Ra affects airway inflammation and whether other interventions that reduce eosinophilic inflammation impact upon asthma attacks is under investigation.
Research networks such as the NIHR TRC working with Industry can provide the capability and scientific know-how to undertake experimental medicine studies in which both clinical success and failure both inform disease understanding and can redirect future clinical programmes to help get drugs to market.
Professor Chris Brightling is an NIHR Senior Investigator at the NIHR Leicester Biomedical Research Centre, a partnership between Leicester’s Hospitals, the University of Leicester and Loughborough University.
