HSP90 inhibitor RGRN-305 for oral treatment of plaque type psoriasis: efficacy, safety and biomarker results in an open-label proof-of-concept study

A Bregnhøj*, K K H Thuesen, T Emmanuel, T Litman, C L Grek, G S Ghatnekar, C Johansen, L Iversen

*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

Abstract

BACKGROUND: HSP90 is a downstream regulator of tumor necrosis factor α (TNFα) and interleukin (IL)-17A signaling and may therefore serve as a novel target in the treatment of psoriasis.

OBJECTIVE: This phase 1b 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.

METHODS: An open-label, single-arm, dose-selection, single-center 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 Psoriasis Area and Severity Index (PASI), body surface area (BSA), and Physician Global Assessment (PGA) scores and by Dermatology Life Quality Index (DLQI). Skin biopsies collected at baseline and at 4, 8, and 12 weeks after treatment start were used for immunohistochemical staining and for gene expression analysis. Safety was monitored via laboratory tests, vital signs, ECG, and physical examinations.

RESULTS: Six of the eleven patients completing 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 due to study treatment. Two patients chose to discontinue the study due to this exanthematous eruption. RGRN-305 treatment resulted in pronounced inhibition of the IL-23, TNFα, and IL-17A signaling pathways and normalization of both histological changes and psoriatic lesion gene expression profiles in patients responding to treatment.

CONCLUSION: Treatment with RGRN-305 showed an 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.

OriginalsprogEngelsk
TidsskriftBritish Journal of Dermatology
Vol/bind186
Nummer5
Sider (fra-til)861-874
Antal sider14
ISSN0007-0963
DOI
StatusUdgivet - maj 2022

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