A randomised trial evaluating the effects of the TRPV1 antagonist SB705498 on pruritus induced by histamine, and cowhage challenge in healthy volunteers

Rachel A Gibson, Jon Robertson, Harshna Mistry, Stewart McCallum, Disala Fernando, Melody Wyres, Gil Yosipovitch, Rachel A Gibson, Jon Robertson, Harshna Mistry, Stewart McCallum, Disala Fernando, Melody Wyres, Gil Yosipovitch

Abstract

Background: Transient receptor potential vanilloid type 1 (TRPV1) is a non-selective cation channel widely expressed in skin tissues, and peripheral sensory nerve fibres. Activation of TRPV1 releases neuropeptides; the resulting neurogenic inflammation is believed to contribute to the development of pruritus. A TRPV1 antagonist has the potential to perform as an anti-pruritic agent. SB705498 is a TRPV1 antagonist that has demonstrated in vitro activity against cloned TRPV1 human receptors and when orally administered has demonstrated pharmacodynamic activity in animal models and clinical studies.

Objectives: To select a topical dose of SB705498 using the TRPV1 agonist capsaicin; to confirm engagement of the TRPV1 antagonistic action of SB705498 and assess whether the dose selected has an effect on itch induced by two challenge agents.

Methods: A clinical study was conducted in 16 healthy volunteers to assess the effects of 3 doses of SB705498 on skin flare induced by capsaicin. Subjects with a robust capsaicin response were chosen to determine if the selected topical formulation of SB705498 had an effect on challenge agent induced itch.

Results: Following capsaicin challenge the greatest average reduction in area of flare was seen for the 3% formulation. This dose was selected for further investigation. Itch intensity induced by two challenge agents (cowhage and histamine) was assessed on the Computerised Visual Analogue Scale. The difference in average itch intensity (Weighted Mean Over 15 Mins) between the 3% dose of SB705498 and placebo for the cowhage challenge was -0.64, whilst the histamine challenge showed on average a -4.65 point change.

Conclusions: The 3% topical formulation of SB705498 cream was clinically well tolerated and had target specific pharmacodynamic activity. However there were no clinically significant differences on pruritus induced by either challenge agent in comparison to placebo. SB705498 is unlikely to be of symptomatic benefit for histaminergic or non-histaminergic induced itch.

Trial registration: ClinicalTrials.gov NCT01673529.

Conflict of interest statement

Competing Interests: Rachel A. Gibson, Jon Robertson, Harshna Mistry, Stewart McCallum, Disala Fernando and Melody Wyres are all paid employees of GlaxoSmithKline. Gil Yosipovitch has previously worked as a paid consultant for GlaxoSmithKline/Stiefel and is in receipt of funding support for ongoing projects. This does not alter the authors' adherence to all PLOS ONE policies on sharing data and materials.

Figures

Figure 1. CONSORT diagram.
Figure 1. CONSORT diagram.
Figure 2. Geometric Mean Profile Plot of…
Figure 2. Geometric Mean Profile Plot of Area of Flare.
Figure 3. Mean profile plot of average…
Figure 3. Mean profile plot of average itch intensity (weighted mean over 15 minutes).

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