Inhibition of heat shock protein: A novel way to treat psoriasis?

Inhibition of heat shock protein 90 (HSP90) may emerge as a potential novel treatment target in psoriasis. In a proof-of-concept trial, therapy with RGRN-305 showed marked efficacy with an acceptable safety profile. An evaluation of gene expression showed that the agent acts by downregulating the IL-12/23 JAK/STAT signalling pathway.

HSP90 protein plays an important role in maintaining cellular protein homeostasis by acting as an intracellular molecular chaperone involved in stabilisation, correct folding, and activity of many proteins. The HSP90 inhibitor RGRN-305 is a small molecule originally developed for anti-cancer therapy. A surprising result of the first clinical RGRN-305 trial in oncology was a previously untreated psoriasis patient, who achieved complete remission of their skin manifestation [1]. Further, a xenograft mouse model showed alleviating effects on psoriatic lesions after administration of RGRN-305 [1]. This was the rationale for Dr Anne Bregnhøj (Aarhus University Hospital, Denmark) and her colleagues to evaluate the safety and efficacy of RGRN-305 in a phase 1b, proof-of-concept study in patients with plaque psoriasis [2].

In this open-label, single-arm, dose-selection study, 13 patients were treated with RGRN-305, either 250 mg or 500 mg daily RGRN-305 for 12 weeks. At week 16, 2 participants had dropped out of the study, and 6 out of 13 participants were clinical responders, defined as an improvement of the Psoriasis Area and Severity Index (PASI) of ≥50%. All responders maintained improvement until the end of the study at week 16. “The total PASI reduction was between 71% and 94%,” Dr Bregnhøj said.

Histopathology and immunohistochemistry were assessed in 1 patient from the responder group. Histological evaluation showed a decreased epidermal thickness in lesional skin at week 12 with a significant reduction of T-cell infiltrates and decreased epidermal proliferation. An evaluation of gene expression revealed that key psoriasis-associated genes (e.g. DEFB4, LCN2, S100A7A, IL-36A, CCL20, and CXCL8) were present among the top 25 downregulated genes. Already at week 4, downregulation of the IL-12/23 JAK/STAT signalling pathway could be demonstrated, and thereby a pronounced suppression of IL-17A/F.

No severe adverse events were reported. A mild-to-moderate exanthematous drug-induced eruption due to study medication was experienced by 4 of the 7 patients who were treated with the higher dose, due to which 2 patients decided to stop treatment. After treatment ended. drug eruptions and psoriasis lesions resolved in all 4 patients.

Due to these encouraging results and acceptable safety, especially in the low-dose group, treatment with RGRN-305 may serve as a novel future treatment option in psoriasis.

 

1. 
   
   1. Stenderup K, et al. Acta Derm Venereol 2014;94:672–6.
   2. Bregnhøj A, et al. Heat shock protein 90 inhibitor RGRN-305 for oral treatment of plaque-type psoriasis: efficacy, safety and biomarker results in an open-label, proof-of-concept study. FC19, Psoriasis from Gene to Clinic 2021, 9–11 December.

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Posted on 2 February 20229 April 2024