P152 The Impact of a Selective oral TRPV1 Antagonist in Patients with Chronic Cough

Abstract

Poster sessions A128Thorax 2012;67(Suppl 2):A1-A204 Background Topical intranasal steroids are widely considered to be the most efficacious pharmacotherapy for the treatment of allergic rhinitis, and yet, for many, symptoms still remain troublesome. We hypothesise that the residual symptoms are a result of nasal neuronal hyperresponsiveness during the pollen season and should be ameliorated by a topical intranasal TRPV1 antagonist. SB705498 is a selective TRPV1 antagonist shown to produce significant inhibition in animal and human models involving nasal sensory nerves. Methods The study involved 70, male and female, subjects with proven rhinitis in a randomised, double-blind, placebo-controlled, 3-way incomplete block crossover design in a well validated Allergen Challenge Chamber paradigm in Vienna. Subjects received Placebo, FP (200ug), SB705498 (12mg), or FP+498. Subjects were dosed for 8 days, within the pollen season, before being exposed to a chamber challenge on the 8 th day. TNSS was the primary endpoint recorded for the 4 hours in the chamber. The comparisons of interest were FP+498 vs. FP, and 498 vs. Placebo. Additional endpoints consisted of symptoms over the 8 days of dosing, Active Anterior Rhinomanometry, Rhinoconjunctivitis QLQ, PK and tolerability. Each period was separated by 14-20 days. Results There was no evidence of a decrease in symptoms with FP+498 compared to FP alone, or for 498 compared to placebo. Statistically significant and clinically relevant reductions in TNSS compared with Placebo were observed at all time points during the challenge for FP and FP+498. The mean (95% CI) reduction in weighted mean TNSS was -2.94 (-3.38, -2.50) for FP alone and-2.28 (-2.79, -1.78) for the combination.

TRPV1 inhibition does not prevent cold dry air-elicited symptoms in non-allergic rhinitis

“…In parallel studies in cough, oral dosing of 600 mg resulted in 45% receptor occupancy at peak plasma concentrations, which was sufficient to shift the dose response to capsaicin by 4-fold [12]. This 4-fold shift also did not translate to a clinical effect in cough symptoms.…”

“…Early oral dosing studies have been completed in neuropathic pain [11], dental pain (NCT00281684), migraine (NCT00269022) as well as cough [12] and have demonstrated no clinically meaningful response. The hyperthermia associated with many of the oral TRPV1 antagonists led to termination of numerous early agents [11].…”

“…The hyperthermia associated with many of the oral TRPV1 antagonists led to termination of numerous early agents [11]. In a single-dose, cross-over placebo-controlled study evaluating oral doses of 600 mg SB-705498 in patients with chronic cough, TRPV1 receptor occupancy derived from plasma levels and factoring a plasma/lung ratio of 1 was ~ 45% at 2 hours and 25% at 24 hours [12]. This translated to a 4-fold shift in capsaicin dose -response on SB705498 administration and was maintained over the 24-hour period.…”

Changing the paradigm for cough: does ’cough hypersensitivity’ aid our understanding?

“…Several clinical trials are currently on the progress [ 93 ]. However, a preliminary report of a specific TRPV1 antagonist in chronic cough failed to demonstrate any efficacy, despite blocking the capsaicin induced cough [ 96 ], which is not only disappointing from the clinical point of view but also questions whether antagonism of the specific nociceptors is a correct therapeutic strategy. A more promising target appears to be the P2X3 receptor and specific antagonists have shown very promising efficacy for idiopathic cough [ 97 ].…”

Chronic cough in subjects with upper airway diseases - analysis of mechanisms and clinical applications

“…The research has brought new insight into the mechanisms participating in the pathogenesis, and also identified new therapeutic targets. As an example, the identification of TRPV1 channel as a "cough receptor" has led us to the development of TRPV1 antagonists and the initiation of clinical trials [9]. …”