Impact case study database

The major impact of our research has been to characterise chronic cough as a disease distinct from asthma and Chronic Obstructive Pulmonary Disease (COPD) and to develop methodology to study it; subsequently, this has allowed drug development in a new therapeutic area. Hence, pharmaceutical companies have novel products in which to invest, and most importantly are able to bring relief to previously undiagnosed and untreatable patients.

2.1 & 2.2 Disease classification and Patient benefit

The simple diagnostic questionnaire, Hull Airway Reflux Questionnaire (HARQ), which the Hull team developed is now validated in 39 different countries and is available in 20 different languages. It is freely available online on ISSC.info; 8,546 UK patients accessed and completed the questionnaire in a single year (Evidence 1). In 2020, the use of these online resources was endorsed in the new International Guidelines (Evidence 2). The relief afforded to patients, who are able at last to understand their symptoms as cough hypersensitivity is difficult to understate (Evidence 3).

Patients who were previously dismissed as neurotic because no clear label could be attached, can now be told they have cough hypersensitivity, a disorder of the vagal afferent nerves. Such patients have usually undergone multiple investigation such as endoscopy, CT scan and challenge testing only to be told there is nothing wrong. Inappropriate treatment in the form of anti-asthma, antibiotic, or anti-acid therapy is prescribed, frequently on a long term basis. One patient’s account is detailed as an example of the huge impact the Hull team’s work has had: “ I have suffered from all the symptoms you describe in your article, to a chronic degree for the last 7 or more years. I have seen so many consultants and specialists they are too numerous to mention. I have undergone all the tests relating to this problem several times over and have taken all the prescribed medications for reflux to no avail and I am still no nearer any sort of a fix. I am depressed and anxious (medicated) due to the worry of the condition of my lungs, airway and throat and the possibility of long term damage or even cancer. ... Your article is the first time in those 7 years that I have seen a diagnosis that entirely matches my symptoms! I am elated ...” (Evidence 4).

The international guidelines provide guidance to clinicians, impact positively on the patient pathway, decrease the chances of costly risks associated with cough management, i.e. CT scan induced breast cancer, and provide effective advice on often unconsidered therapeutic options (Evidence 2).

2.3 Developing new drugs for chronic cough

Hull’s work, defining at least two different pathways for the pathophysiology of chronic cough, explained why several costly clinical studies blocking the irritant receptors failed in the clinic, as a result of these findings drug development by GSK has now been abandoned. The Clinical Development Director of GlaxoSmithKline stated, “This study investigated the efficacy and safety of GSK2798745 (a TRPV4 inhibitor) in patients with chronic cough. The results of this study allowed a clear decision to be made regarding termination of development of this compound in this indication. The impact of this work was that there was a cost saving to the project with spending until study completion not required. Because of the specific design of the study, the work also prevented unnecessary recruitment of patients to a study with an ineffective drug.” ( Evidence 5).

Conversely, Hull’s research has led to the substantial investment in the development of a series of effective, novel, therapeutics by various other pharmaceutical companies. Afferent Pharmaceuticals were the first to develop an effective agent blocking vagal afferent hypersensitivity; Gefapixant (AF219/MK7264) was trialled in several phase 2 studies where Prof Morice advised on the study design and conduct. As a result of further studies on Gefapixant, Afferent Pharmaceuticals was acquired by Merck, a major global pharmaceutical company. The commercial decision was attributed in part due to Hull’s research data ( Evidence 6). The deal involved an immediate payment of $500 million, with a further $750 million payable when the drug was licensed by the US Federal Drugs Agency (application in progress). Prof Morice has continued to work with Merck and indeed was responsible for providing the advice as to the primary endpoint of their pivotal, phase 3, clinical studies (Cough 1 and Cough 2; presented at the ERS Congress September 2020). The Clinical Director of Merck wrote, “Alyn (Prof Morice) has done a wonderful job of helping educate the overall Merck team on the field of chronic cough and he has provided valuable input on the chronic cough clinical program with regards to appropriate endpoint selection, rigorous patient selection, and expert opinion support during the course of the trial.” (Evidence 7).

Finally, first data from Merck’s phase III studies of Gefapixant (Cough 1 and Cough 2), studying over 2000 patients with objectively proven chronic cough, clearly showed the effectiveness of using HARQ as a diagnostic tool. The HARQ score at baseline for these patients was 40/70, whereas the upper limit of normal people is 14; demonstrating for the first-time HARQ’s global utility (Evidence 8).

In anticipation of a UK licencing application for these new drugs the Hull team have been advising the UK’s National Institute for Health and Care Excellence (NICE) as to the correct metrics to use in their assessment of antitussive drugs. Commonly used scores such as Short-form (SF) 35 which measure quality of life (QOL) are inappropriate since patients with chronic cough are rarely physically disabled even if their lives are ruined.

Three other compounds of this new class of drug, exploiting Hull’s research that defined a mechanistic pathway, are currently in phase 2 trials. Bayer, Shionogi, and Bellus Health, have all made multi-million investments in these clinical trials; and Prof Morice is supporting the companies by advising as chief or principal investigator, e.g. “The unique combination of scientific & clinical expertise of Prof. Alyn together with this ability to optimally run and steer clinical studies has informed our research and development programs and allowed us to progress our P2X3 projects to successful demonstrating efficacy in patients with refractory chronic cough(RCC)” ( Evidence 9). Preliminary trial results show treatment success in over two thirds of patients and therefore it is highly likely that the first effective drugs for chronic cough in over 40 years will soon be available ( Evidence 10).