Inhibition of capsaicin‐driven nasal hyper‐reactivity by SB‐705498, a TRPV1 antagonist

Abstract

Aims To assess the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of intranasal SB‐705498, a selective TRPV1 antagonist. Methods Two randomized, double‐blind, placebo‐controlled, clinical studies were performed: (i) an intranasal SB‐705498 first time in human study to examine the safety and PK of five single escalating doses from 0.5 to 12 mg and of repeat dosing with 6 mg and 12 mg twice daily for 14 days and (ii) a PD efficacy study in subjects with non‐allergic rhinitis (NAR) to evaluate the effect of 12 mg intranasal SB‐705498 against nasal capsaicin challenge. Results Single and repeat dosing with intranasal SB‐705498 was safe and well tolerated. The overall frequency of adverse events was similar for SB‐705498 and placebo and no dose‐dependent increase was observed. Administration of SB‐705498 resulted in less than dose proportional AUC(0,12 h) and Cmax, while repeat dosing from day 1 to day 14 led to its accumulation. SB‐705498 receptor occupancy in nasal tissue was estimated to be high (>80%). Administration of 12 mg SB‐705498 to patients with NAR induced a marked reduction in total symptom scores triggered by nasal capsaicin challenge. Inhibition of rhinorrhoea, nasal congestion and burning sensation was associated with 2‐ to 4‐fold shift in capsaicin potency. Conclusions Intranasal SB‐705498 has an appropriate safety and PK profile for development in humans and achieves clinically relevant attenuation of capsaicin‐provoked rhinitis symptoms in patients with NAR. The potential impact intranasal SB‐705498 may have in rhinitis treatment deserves further evaluation.

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

“…Yet there is no experimental evidence to imply a therapeutic potential for TRPV1 antagonists in the pharmacotherapy of allergic airway diseases. For example, the TRPV1 antagonist SB705498 when applied to the nasal mucosa reduced the capsaicin effect, proving target involvement (Holland et al, 2013); however, it did not provide any symptomatic relief in patients with seasonal allergic rhinitis (Alenmyr et al, 2012;Bareille et al, 2013). A number of TRPV1 antagonists have entered clinical trials as potential antitussive drugs (the latest addition is XEN-D0105; www.…”

BSACI guideline for the diagnosis and management of allergic and non‐allergic rhinitis (Revised Edition 2017; First edition 2007)

“…TRPV1 was considered a prime target for neurogenic rhinitis therapy, but a recent study proved negative when cold dry air challenges were used, 292 but antagonism did reduce the response to capsaicin. 293…”

Nasal hyperreactivity in rhinitis: A diagnostic and therapeutic challenge

“…Nasal provocations with hyperosmolar solutions, histamine, cold dry air (CDA), and capsaicin are described to diagnose NHR, mainly in research settings. Amongst those, CDA turned out to be the most physiological, safe, and tolerable stimulus for the nasal mucosa, as well as the most patient‐friendly in terms of application (nasal inhalation versus nasal instillation) (Table ).…”