XEN-D0501, a Novel Transient Receptor Potential Vanilloid 1 Antagonist, Does Not Reduce Cough in Patients with Refractory Cough

Abstract

What is the current scientific knowledge on this subject? Conclusive data regarding the importance of TRPV1 as a treatment target in chronic cough has been lacking due the absence of a safe, potent and efficacious tool compound for use in clinical studies. In a previous study, a TRPV1 antagonist (SB-705498) failed to improve spontaneous cough frequency in treatment resistant chronic cough patients but the reduction in capsaicin-evoked cough was only small. What does this study add to the field?This study rules out TRPV1 as an effective therapeutic target in refractory chronic cough patients. It also highlights the importance of pharmacodynamic pre-clinical and clinical models in the interpretation of negative clinical trial data, but questions the use of cough challenge models in target identification. Word Count 3917 words METHODS:XEN-D0501 and SB-705498 were profiled against capsaicin in a sensory nerve activation assay and in vivo potency established against capsaicin-induced cough in the guinea pig.Twenty patients with refractory chronic cough participated in a double-blind, randomised, placebocontrolled, crossover study evaluating the effect of 14 days XEN-D0501 (oral, 4mg bd) versus placebo on awake cough frequency (primary outcome), capsaicin-evoked cough and patient reported outcomes. MEASUREMENTS AND MAIN RESULTS:XEN-D0501 was more efficacious and 1000-fold more potent than SB-705498 at inhibiting capsaicin-induced depolarization of guinea pig and human isolated vagus. In vivo, XEN-D0501 completely inhibited capsaicin-induced cough whereas 100-times more SB-705498 was required to achieve the same effect. In patients, XEN-D0501 substantially reduced maximal cough responses to capsaicin (mean change from baseline XEN-D0501 -19.3(±16.4) coughs vs. placebo -1.8(±5.8), p<0.0001), but not spontaneous awake cough frequency (mean change from baseline XEN-D0501 6.7c/h(±16.9) vs. placebo 0.4c/h(±13.7), p =0.41).CONCLUSIONS: XEN-D0501 demonstrated superior efficacy and potency in pre-clinical and clinical capsaicin challenge studies; despite this improved pharmacodynamic profile, spontaneous cough

Nasal hyperreactivity in rhinitis: A diagnostic and therapeutic challenge

“…Similarly, Groneberg et al showed already many years ago an increased expression of TRPV1 in airways of patients with chronic dry cough. However, clinical trials with TRPV1 antagonists could not show clinical improvement in those patients.…”

Current management of refractory overactive bladder

“…In a rat model, a TRPV1 antagonist was shown to be a potential therapeutic target for OAB . TRPV1 antagonists have been developed as new medications for treating knee pain and chronic cough . Although no trials have yet been conducted for human OAB, TRPV1 may be a novel therapeutic target in the future.…”

What Is Chronic Cough? Terminology

“…Early phase clinical studies of novel antitussives have come with mixed success. While efficacy has been observed with gabapentin (18) and the blocker of the ATP receptor, P2X3 (19) trials of compounds that block TRPV1 (20) and TRPA1 (21) have been negative. This has raised two important issues; firstly, can we improve the predictive value of existing preclinical cough model systems and secondly, can we optimize clinical trial design.…”