银屑病面积及严重程度指数
银屑病
医学
皮肤科生活质量指数
不利影响
内科学
斑块性银屑病
生物标志物
胃肠病学
皮肤病科
体表面积
皮肤活检
外科
活检
生物化学
化学
作者
Anne Bregnhøj,Katrine Kyd Holstein Thuesen,Thomas Emmanuel,Thomas Litman,Christina L. Grek,Gautam S. Ghatnekar,Claus Johansen,Lars Iversen
摘要
HSP90 is a downstream regulator of tumour necrosis factor (TNF)-α and interleukin (IL)-17A signalling and may therefore serve as a novel target in the treatment of psoriasis.This phase Ib proof-of-concept study was undertaken to evaluate the safety and efficacy of a novel HSP90 inhibitor (RGRN-305) in the treatment of plaque psoriasis.We conducted an open-label, single-arm, dose-selection, single-centre proof-of-concept study. Patients with plaque psoriasis were treated with 250 mg or 500 mg RGRN-305 daily for 12 weeks. Efficacy was evaluated clinically using the Psoriasis Area and Severity Index (PASI), body surface area (BSA), Physician's Global Assessment (PGA) scores and the Dermatology Life Quality Index (DLQI). Skin biopsies collected at baseline and at 4, 8 and 12 weeks after initiation of treatment were used for immunohistochemical staining and for gene expression analysis. Safety was monitored via laboratory tests, vital signs, electrocardiogram and physical examinations.Six of the 11 patients who completed the study responded to RGRN-305 with a PASI improvement between 71% and 94%, whereas five patients were considered nonresponders with a PASI response < 50%. No severe adverse events were reported. Four of seven patients treated with 500 mg RGRN-305 daily experienced a mild-to-moderate exanthematous drug-induced eruption owing to the study treatment. Two patients chose to discontinue the study because of this exanthematous eruption. RGRN-305 treatment resulted in pronounced inhibition of the IL-23, TNF-α and IL-17A signalling pathways and normalization of both histological changes and psoriatic lesion gene expression profiles in patients who responded to treatment.Treatment with RGRN-305 showed acceptable safety, especially in the low-dose group, and was associated with clinically meaningful improvement in a subset of patients with plaque psoriasis, indicating that HSP90 may serve as a novel future target in psoriasis treatment.
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