Department of Dermatology, Aarhus University Hospital, Aarhus, Denmark.
Department of Immunology and Microbiology, University of Copenhagen, Copenhagen, 2200, Denmark.
Br J Dermatol. 2022 May;186(5):861-874. doi: 10.1111/bjd.20880. Epub 2022 Mar 30.
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.
热休克蛋白 90（HSP90）是肿瘤坏死因子（TNF）-α 和白细胞介素（IL）-17A 信号的下游调节剂，因此可能成为治疗银屑病的新靶点。
本研究旨在评估新型 HSP90 抑制剂（RGRN-305）治疗斑块状银屑病的安全性和疗效。
我们开展了一项开放性、单臂、剂量选择、单中心概念验证研究。将斑块状银屑病患者分为两组，分别接受 250mg/d 和 500mg/d 的 RGRN-305 治疗，为期 12 周。采用银屑病面积和严重程度指数（PASI）、体表面积（BSA）、医生总体评估（PGA）和皮肤病生活质量指数（DLQI）评估临床疗效。在治疗开始后 4、8 和 12 周时采集基线和皮肤活检标本，进行免疫组织化学染色和基因表达分析。通过实验室检查、生命体征、心电图和体格检查监测安全性。
11 例完成研究的患者中，有 6 例对 RGRN-305 有反应，PASI 改善率为 71%至 94%，而 5 例患者被认为是无应答者，PASI 反应<50%。未报告严重不良事件。7 例接受 500mg/d RGRN-305 治疗的患者中，有 4 例因研究治疗出现轻度至中度疹样药物性发疹。由于这种疹样发疹，有 2 例患者选择退出研究。RGRN-305 治疗可显著抑制 IL-23、TNF-α 和 IL-17A 信号通路，并使应答患者的组织学改变和银屑病病变基因表达谱正常化。
RGRN-305 的治疗具有可接受的安全性，尤其是在低剂量组中，并且与一组斑块状银屑病患者的临床显著改善相关，表明 HSP90 可能成为银屑病治疗的新靶点。
