A Randomised Trial Evaluating the Effects of the TRPV1 Antagonist SB705498 on Pruritus Induced by Histamine, and Cowhage Challenge in Healthy Volunteers

Abstract

BackgroundTransient 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.ObjectivesTo 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.MethodsA 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.ResultsFollowing 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.ConclusionsThe 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 RegistrationClinicalTrials.gov NCT01673529

Preclinical and human surrogate models of itch

“…Antihistamines do not suppress itch evoked by BAM8‐22, supporting a histamine‐independent mechanism . Cowhage‐induced itch is in part suppressed by strontium chloride, butorphanol and polidocanol, but not a novel TRPV1 antagonist . The presented studies of modulation of itch produced in human surrogate models confirm the validity and applicability of these models in clinical research and drug development.…”

“…Human surrogate models of itch have been used to test pathway‐specific antipruritic efficacy of various compounds. Histamine‐induced itch is partially suppressible by aspirin, botulinum toxin A, butorphanol, naltrexone, a cannabinoid receptor agonist, strontium nitrate, lidocaine cream and to a large extent antihistamines, but not polidocanol, lidocaine/prilocaine cream or a TRPV1 antagonist . Antihistamines do not suppress itch evoked by BAM8‐22, supporting a histamine‐independent mechanism .…”

Topical TrkA Kinase Inhibitor CT327 is an Effective, Novel Therapy for the Treatment of Pruritus due to Psoriasis: Results from Experimental Studies, and Efficacy and Safety of CT327 in a Phase 2b Clinical Trial in Patients with Psoriasis

“…Topically applied CT327 could be expected to bind to TrkA receptors expressed by cutaneous epidermal afferents to provide symptom relief, in the acute phase through inhibition of NGF-TrkA-TRPV1 signalling at cutaneous nerve terminals (as modeled in the cultured sensory neuron studies which demonstrate on-target activity), but also chronically, involving down-regulation of TRPV1 and neuropeptide expression over several days/ weeks via inhibition of retrograde transport of NGF by TrkA from cutaneous nerve terminals to the DRG soma. A recent report on the lack of efficacy of topical TRPV1 inhibitor SB705498 on acute itch in a healthy human volunteer study (24) suggests that chronic sensitization and phenotypic changes in this pathway, including expression of other NGF-TrkA dependent putative mediators of itch such as TRPA1, may be important in clinical pruritus (21). In support, the greatest effects on pruritus observed in our Phase 2b trial were after 4-8 weeks of treatment with CT327.…”

Trp channels and itch

“…Intranasal SB-705498 attenuated capsaicin driven nasal hyper-reactivity in non-allergic rhinitis[161], but had only limited effect in treating symptoms of allergic rhinitis symptoms[162]. Topical SB-705498, however, failed to demonstrate clinically relevant efficacy in relieving histamine or non-histamine itch[163]. …”