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

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.

Transcriptomic Analysis of Hidradenitis Suppurativa: A Unique Molecular Signature with Broad Immune Activation.

Hidradenitis suppurativa is a chronic inflammatory skin disease with limited treatment options. The poorly understood pathogenesis hinders the development of effective treatments; therefore, a pressing need exists to further elucidate the molecular mechanisms in hidradenitis suppurativa. This study investigated the underlying inflammatory pathways and cell types in hidradenitis suppurativa using transcriptomic approaches with RNA sequencing of lesional and non-lesional skin biopsies from hidradenitis suppurativa, which was jointly analyzed with previously published transcriptomic data from atopic dermatitis and psoriasis patients. The differential expression and pathway enrichment analyses demonstrated the activation of multiple inflammatory processes, including the innate and adaptive immune systems, implicated in the hidradenitis suppurativa pathogenesis. In agreement, hidradenitis suppurativa exhibited a unique and heterogeneous cell type signature involving lymphoid and myeloid cells such as B cells and macrophages. Furthermore, hidradenitis suppurativa displayed increased expression of TH1/2/17 signatures with no predominant TH signatures unlike psoriasis (TH1/17) and atopic dermatitis (TH2). In summary, our study provides molecular insights into the pathomechanisms in hidradenitis suppurativa, revealing a strong and widespread immune activation, which may benefit from treatment strategies offering a broad immunomodulation of various key inflammatory pathways. Our data not only corroborate previously reported findings but also enhance our understanding of the immune dysregulation in hidradenitis suppurativa, uncovering novel and potential therapeutic targets.

Heat shock protein 90 inhibitor RGRN-305 potently attenuates skin inflammation.

Introduction: Chronic 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. Methods: This 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/Discussion: In 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.

Heat shock protein 90 inhibition attenuates inflammation in models of atopic dermatitis: a novel mechanism of action.

Background: Heat shock protein 90 (HSP90) is an important chaperone supporting the function of many proinflammatory client proteins. Recent studies indicate HSP90 inhibition may be a novel mechanism of action for inflammatory skin diseases; however, this has not been explored in atopic dermatitis (AD). Objectives: Our study aimed to investigate HSP90 as a novel target to treat AD. Methods: Experimental models of AD were used including primary human keratinocytes stimulated with cytokines (TNF/IFNγ or TNF/IL-4) and a mouse model established by MC903 applications. Results: In primary human keratinocytes using RT-qPCR, the HSP90 inhibitor RGRN-305 strongly suppressed the gene expression of Th1- (TNF, IL1B, IL6) and Th2-associated (CCL17, CCL22, TSLP) cytokines and chemokines related to AD. We next demonstrated that topical and oral RGRN-305 robustly suppressed MC903-induced AD-like inflammation in mice by reducing clinical signs of dermatitis (oedema and erythema) and immune cell infiltration into the skin (T cells, neutrophils, mast cells). Interestingly, topical RGRN-305 exhibited similar or slightly inferior efficacy but less weight loss compared with topical dexamethasone. Furthermore, RNA sequencing of skin biopsies revealed that RGRN-305 attenuated MC903-induced transcriptome alterations, suppressing genes implicated in inflammation including AD-associated cytokines (Il1b, Il4, Il6, Il13), which was confirmed by RT-qPCR. Lastly, we discovered using Western blot that RGRN-305 disrupted JAK-STAT signaling by suppressing the activity of STAT3 and STAT6 in primary human keratinocytes, which was consistent with enrichment analyses from the mouse model. Conclusion: HSP90 inhibition by RGRN-305 robustly suppressed inflammation in experimental models mimicking AD, proving that HSP90 inhibition may be a novel mechanism of action in treating AD.

Non-Atopic Chronic Nodular Prurigo (Prurigo Nodularis Hyde): A Systematic Review of Best-Evidenced Treatment Options.

BACKGROUND: Chronic nodular prurigo (CNPG) is a chronic, inflammatory skin disease, characterized by intense and debilitating pruritus. The pathophysiology is not fully understood, and the condition is difficult to treat with no targeted therapies. The aim of this systematic review was to review the evidence of therapies for non-atopic CNPG and conduct a meta-analysis of the results. SUMMARY: We conducted a systematic review of the literature concerning effect of treatment for non-atopic CNPG. Due to few randomized controlled trials (RCTs) and case series, the literature was unfortunately too sparse to conduct a meta-analysis of the results. Instead, we thoroughly report important data from the three existing RCTs and 6 case studies with more than 15 patients. Evaluated therapies include nemolizumab, aprepitant, topical therapy with hydrocortisone and pimecrolimus, thalidomide, UVA phototherapy, pregabalin, and naltrexone. Included RCTs and case studies all had a heterogeneous methodology making direct comparison almost impossible. KEY MESSAGES: There is sparse evidence for the currently used therapies for non-atopic CNPG. Several RCTs on new therapies are running or in the pipeline, hopefully providing new, effective, and targeted treatment possibilities for CNPG patients both with and without an atopic predisposition.

Pyoderma Gangrenosum and Interleukin Inhibitors: A Semi-Systematic Review.

BACKGROUND: Pyoderma gangrenosum (PG) is a rare ulcerating skin disease associated with multiple comorbidities and increased mortality. In recent decades, newer biologics such as interleukin inhibitors have been used to treat PG; however, the literature is scarce, consisting predominantly of case reports and caseseries. The aim of our review was to evaluate the effectiveness and safety of interleukin inhibitors for the treatment of PG in adults. SUMMARY: A literature search was conducted using search terms related to PG and interleukin inhibitors in databases such as PubMed, Embase, Scopus, Web of Science, and Cochrane Library. The study eligibility criteria included patients diagnosed with PG, over the age of 18, and treated with an interleukin inhibitor. Our study included 60 papers describing 81 patients fulfilling the eligibility criteria. The treatment with interleukin inhibitors resulted in 70% (95% CI 59-80%) response and 57% (95% CI 45-68%) complete response rates, and few (4%) mild adverse events, hence supporting the off-label use for the treatment of recalcitrant PG in adults. The response and complete response rates were 59% (17/29) and 38% (11/29) for anakinra, 64% (7/11) and 55% (6/11) for canakinumab, and 79% (27/34) and 71% (24/34) for ustekinumab, respectively. Limitations include publication bias that might have overestimated the efficacy as successful cases responding to treatment are more likely to be reported than nonresponding cases. Additionally, the heterogeneity of the treatment groups does not allow conclusions of superiority or inferiority of the different interleukin inhibitors to be drawn. Further studies are needed to investigate the efficacy of the different interleukin inhibitors and to investigate the importance of underlying disease for treatment response.

Key Signaling Pathways in Psoriasis: Recent Insights from Antipsoriatic Therapeutics.

Psoriasis is a common chronic inflammatory skin disease associated with several comorbidities and reduced quality of life. In the past decades, highly effective targeted therapies have led to breakthroughs in the management of psoriasis, providing important insights into the pathogenesis. This article reviews the current concepts of the pathophysiological pathways and the recent progress in antipsoriatic therapeutics, highlighting key targets, signaling pathways and clinical effects in psoriasis.

Pyoderma gangrenosum and tumour necrosis factor alpha inhibitors: A semi-systematic review.

Pyoderma gangrenosum (PG) is a rare ulcerative skin disease that presents a therapeutic challenge. Tumour necrosis factor alpha (TNFα) inhibitors have been reported to successfully control PG. Our aim was to systematically evaluate and compare the clinical effectiveness of TNFα inhibitors in adults with PG. A literature search including databases such as PubMed, Embase, Scopus, and Web of Science was conducted, using search terms related to PG and TNFα inhibitors. Studies and case reports were included if patients were diagnosed with PG, over the age of 18 and administered TNFα inhibitor. A total of 3212 unique citations were identified resulting in 222 articles describing 356 patients being included in our study. The study we report found an 87% (95% CI: 83%-90%) response rate and a 67% (95% CI: 62%-72%) complete response rate to TNFα inhibitors. No statistically significant differences in the response rates (P = 0.6159) or complete response rates (P = 0.0773) to infliximab, adalimumab, and etanercept were found. In our study TNFα inhibitors demonstrated significant effectiveness with response and complete response rates supporting the use of TNFα inhibitors to treat PG in adults. Our study suggests that there is no significant difference in effectiveness among infliximab, adalimumab, and etanercept.