RESUMO
Pruritus is an important symptom in psoriasis with no targeted treatment. Tropomyosin-receptor kinase A (TrkA) is associated with pruritus and psoriatic plaque formation. We report the efficacy of a TrkA inhibitor, CT327, on pruritus in psoriasis. A randomised, double-blind, vehicle-controlled Phase 2b clinical trial was conducted in 160 subjects. No effect was found on psoriasis severity using Investigator's Global Assessment (primary endpoint). However, clinically and statistically significant reductions in pruritus were observed in the 108 patient subset reporting at least moderate pruritus at baseline (37.1 mm visual analogue scale improvement (95% CI [-37.5, -6.2], p = 0.0067) for lowest dose; secondary endpoint). Significant modified Psoriasis Area and Severity Index reductions were found in this subset (p < 0.05). Experiments exploring capsaicin-mediated calcium influx, important in pruritus signalling, were performed in sensory neurons. CT327 inhibited capsaicin responses, indicating action at the nerve growth factor-TrkA-TRPV1 pathway. TrkA is a key target in pruritus, and CT327 has potential to become an effective and safe first-in-class treatment.
Assuntos
Inibidores de Proteínas Quinases/uso terapêutico , Prurido/tratamento farmacológico , Psoríase/tratamento farmacológico , Psoríase/patologia , Receptor trkA/antagonistas & inibidores , Administração Tópica , Adulto , Biópsia por Agulha , Capsaicina/farmacologia , Células Cultivadas , Doença Crônica , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Seguimentos , Humanos , Imuno-Histoquímica , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Segurança do Paciente , Prurido/enzimologia , Prurido/etiologia , Prurido/fisiopatologia , Psoríase/complicações , Psoríase/enzimologia , Receptor trkA/administração & dosagem , Resultado do TratamentoRESUMO
BACKGROUND/OBJECTIVES: A combination topical suspension/gel containing calcipotriene plus betamethasone dipropionate has been developed as a safe and effective treatment for patients with psoriasis vulgaris of the scalp. This same preparation has the potential to be a convenient, effective, and cosmetically appealing formulation for psoriasis on the body. This trial evaluated the efficacy and safety of a topical suspension containing calcipotriene plus betamethasone dipropionate compared with its constituent components and topical suspension vehicle in the treatment of mild to moderate psoriasis on the trunk and limbs. METHODS: This was a randomized, double-blind, vehicle-controlled, 4-arm trial in 1,152 subjects. The co-primary efficacy end points were the proportion of subjects achieving controlled disease based on the Investigators' Global Assessment of disease severity at weeks 4 and 8. Adverse events, vital signs, and clinical laboratory measurements were also assessed. RESULTS: At week 4, a greater proportion of subjects in the calcipotriene plus betamethasone group achieved controlled disease compared with subjects in the calcipotriene-only and vehicle-only treatment groups. At week 8, a statistically significantly (P<.01) greater proportion of subjects in the calcipotriene plus betamethasone group achieved controlled disease compared with subjects in the 3 other treatment groups. Adverse events and other safety assessments were similar between the groups. CONCLUSION: The topical suspension containing calcipotriene plus betamethasone dipropionate traditionally used for scalp psoriasis is also a safe and effective once-daily treatment for psoriasis vulgaris on the body.