Dataset Information

Efficacy and Safety of the Heat Shock Protein 90 Inhibitor RGRN-305 in Hidradenitis Suppurativa: A Parallel-Design Double-Blind Trial.

ABSTRACT:

Importance

Hidradenitis suppurativa is a painful immune-mediated disorder with limited treatment options; hence, a need exists for new treatments.

Objective

To evaluate the feasibility of heat shock protein 90 inhibition by RGRN-305 as a novel mechanism of action in treating moderate to severe hidradenitis suppurativa.

Design, setting, and participants

This was a parallel-design, double-blind, proof-of-concept, placebo-controlled randomized clinical trial conducted between September 22, 2021, and August 29, 2022, at the Department of Dermatology, Aarhus University Hospital in Denmark. The study included a 1- to 30-day screening period, a 16-week treatment period, and a 4-week follow-up period. Eligibility criteria included age 18 years or older and moderate to severe hidradenitis suppurativa with 6 or more inflammatory nodules or abscesses in at least 2 distinct anatomic regions. Of 19 patients screened, 15 patients were enrolled in the study. Intention-to-treat analysis was performed.

Interventions

Patients were randomly assigned (2:1) to receive oral RGRN-305, 250-mg tablet, or matching placebo once daily for 16 weeks.

Main outcomes and measures

The primary efficacy end point was the percentage of patients achieving Hidradenitis Suppurativa Clinical Response 50 (HiSCR-50) at week 16. Secondary efficacy end points included HiSCR-75 or HiSCR-90, Hidradenitis Suppurativa Physician's Global Assessment, Dermatology Life Quality Index scores, and a pain numeric rating scale. Safety was assessed by adverse events, physical examinations, clinical laboratory measurements, and electrocardiograms.

Results

A total of 15 patients were enrolled, completed the study, and were included in all analyses (10 [67%] female; median age, 29 [IQR, 23-41] years). The primary end point HiSCR-50 at week 16 was achieved by a higher percentage in the RGRN-305 group (60% [6 of 10]) than in the placebo group (20% [1 of 5]). Improvements were also observed across all secondary end points at week 16, including higher rates of the harder-to-reach HiSCR levels; 50% (5 of 10) achieved HiSCR-75 and 30% (3 of 10) achieved HiSCR-90, whereas none of the placebo-treated patients achieved HiSCR-75 or HiSCR-90. RGRN-305 was well tolerated, with no deaths or serious adverse events, and treatment-emergent adverse events were similarly frequent between the RGRN-305 and placebo groups.

Conclusions and relevance

The findings of this trial suggest that heat shock protein 90 inhibition by RGRN-305 offers a novel mechanism of action in treating hidradenitis suppurativa, warranting further evaluation in larger trials.

Trial registration

ClinicalTrials.gov Identifier: NCT05286567.

SUBMITTER: Ben Abdallah H

PROVIDER: S-EPMC10701664 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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Publications

Efficacy and Safety of the Heat Shock Protein 90 Inhibitor RGRN-305 in Hidradenitis Suppurativa: A Parallel-Design Double-Blind Trial.

Ben Abdallah Hakim H Bregnhøj Anne A Emmanuel Thomas T Ghatnekar Gautam G Johansen Claus C Iversen Lars L

JAMA dermatology 20240101 1

<h4>Importance</h4>Hidradenitis suppurativa is a painful immune-mediated disorder with limited treatment options; hence, a need exists for new treatments.<h4>Objective</h4>To evaluate the feasibility of heat shock protein 90 inhibition by RGRN-305 as a novel mechanism of action in treating moderate to severe hidradenitis suppurativa.<h4>Design, setting, and participants</h4>This was a parallel-design, double-blind, proof-of-concept, placebo-controlled randomized clinical trial conducted between ...[more]

PMID: 38055242

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Project description:IntroductionChronic inflammatory skin diseases may have a profound negative impact on the quality of life. Current treatment options may be inadequate, offering an unsatisfactory response or side effects. Therefore, ongoing efforts exist to identify novel effective and safe treatments. Heat shock protein (HSP) 90 is a chaperone that promotes the activity of a wide range of client proteins including key proinflammatory molecules involved in aberrant inflammation. Recently, a proof-of-concept clinical trial of 13 patients suggested that RGRN-305 (an HSP90 inhibitor) may be an oral treatment for psoriasis. However, HSP90 inhibition may be a novel therapeutic approach extending beyond psoriasis to include multiple immune-mediated inflammatory skin diseases.MethodsThis study aimed to investigate (i) the anti-inflammatory effects and mechanisms of HSP90 inhibition and (ii) the feasibility of topical RGRN-305 administration (new route of administration) in models of inflammation elicited by 12-O-tetradecanoylphorbol-13-acetate (TPA) in primary human keratinocytes and mice (irritative dermatitis murine model).Results/discussionIn primary human keratinocytes stimulated with TPA, a Nanostring® nCounter gene expression assay demonstrated that HSP90 inhibition with RGRN-305 suppressed many proinflammatory genes. Furthermore, when measured by quantitative real-time polymerase chain reaction (RT-qPCR), RGRN-305 significantly reduced the gene expression of TNF, IL1B, IL6 and CXCL8. We next demonstrated that topical RGRN-305 application significantly ameliorated TPA-induced skin inflammation in mice. The increase in ear thickness (a marker of inflammation) was significantly reduced (up to 89% inhibition). In accordance, RT-qPCR of the ear tissue demonstrated that RGRN-305 robustly reduced the gene expression of proinflammatory markers (Tnf, Il1b, Il6, Il17A and Defb4). Moreover, RNA sequencing revealed that RGRN-305 mitigated TPA-induced alterations in gene expression and suppressed genes implicated in inflammation. Lastly, we discovered that the anti-inflammatory effects were mediated, at least partly, by suppressing the activity of NF-κB, ERK1/2, p38 MAPK and c-Jun signaling pathways, which are consistent with previous findings in other experimental models beyond skin inflammation. In summary, HSP90 inhibition robustly suppressed TPA-induced inflammation by targeting key proinflammatory cytokines and signaling pathways. Our findings suggest that HSP90 inhibition may be a novel mechanism of action for treating immune-mediated skin disease beyond psoriasis, and it may be a topical treatment option.

Project description:Heat shock protein (Hsp) 90 is a key component of the super-chaperone complex that maintains functionally active conformation of various client proteins. Many of these client proteins regulate important nodal points in multiple signalling pathways that promote cancer cell growth and survival. Inhibitors of Hsp90, therefore, have the potential of functioning as anti-cancer agents with pleiotropic effects. Identification of novel Hsp90 inhibitors with more favourable pharmacological properties is a priority in cancer therapy. To achieve this goal, we screened a compound library using a biochemical assay based on refolding of denatured firefly luciferase. The assay revealed high sensitivity, reliability and reproducibility with a Z-factor of 0.81 ± 0.17. Six Hsp90 inhibitory compounds identified by this screening with IC50 values between 1.0 and 6 μM were further characterised for anti-proliferative activity by Cell Titer-Blue Cell Viability Assay using multiple tumour cell lines. Of particular interest was ONO4140 with lowest GI50 values in three different cancer cell lines viz; DU-145, BT-474 and K562 cell lines. This study also revealed that short-term exposure of tumour cells with ONO4140 is sufficient to inhibit the catalytic activity of Hsp90, evaluated through disruption of Hsp90-p23 association by immunoprecipitation. This short term exposure appears to initiate events like degradation of Hsp90 client proteins such as ErbB2/Her-2 and Akt with concomitant inhibition of survival signalling leading to the apoptotic death of tumour cells as seen by western blotting and Caspase Glow-3,7 assay. The study also reveals that apoptosis following Hsp90 inhibition with ONO4140 occurs via Caspase9-Caspase3 intrinsic apoptotic pathway, a process that is likely triggered by inactivation of Akt. In conclusion, we have identified a novel class of synthetic compounds which show potent Hsp90 inhibitory action in preclinical studies. The discovery of this novel class of synthetic Hsp90 inhibitors with simple chemical backbone allows us to conduct further structural modifications to improve their potency and pharmacokinetic properties for use in cancer therapy.

Dataset Information

Efficacy and Safety of the Heat Shock Protein 90 Inhibitor RGRN-305 in Hidradenitis Suppurativa: A Parallel-Design Double-Blind Trial.

Importance

Objective

Design, setting, and participants

Interventions

Main outcomes and measures

Results

Conclusions and relevance

Trial registration

Publications

Efficacy and Safety of the Heat Shock Protein 90 Inhibitor RGRN-305 in Hidradenitis Suppurativa: A Parallel-Design Double-Blind Trial.

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