Novel small molecule HSP90 inhibitor for the management of atopic dermatitis

用于治疗特应性皮炎的新型小分子 HSP90 抑制剂

• 批准号: 10016726
• 负责人: Gautam Sudhir Ghatnekar
• 金额: $ 25.21万
• 依托单位: REGRANION, LLC
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10016726
• 关键词: Adaptive Immune System; Address; Adrenal Cortex Hormones; Affect; American; Animal Model; Animals; Anti-Inflammatory Agents; Antihistamines; Atopic Dermatitis; Bioavailable; Biological Availability; Biological Response Modifier Therapy; Biotechnology; Body Surface Area; Cardiovascular system; Chronic; Clinical; Clinical Research; Complex; Disease; Disease Management; Dose; Drug Kinetics; Drug Targeting; Drug Tolerance; Eczema; Emollients; Etiology; Exhibits; Expression Profiling; Foundations; Gene Expression; Heat-Shock Proteins 90; Heterogeneity; Histology; Human; Human Resources; IL17C gene; IgE; Immune; Immunohistochemistry; Immunomodulators; Infectious Skin Diseases; Inflammation; Inflammatory; Injections; Interleukin-13; Interleukin-17; Interleukin-4; Investigation; Investigational Therapies; Lesion; Mediating; Mediator of activation protein; Mitogen-Activated Protein Kinases; Modeling; Molecular; Mus; Oncology; Oral; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Personal Satisfaction; Pharmacology; Phase; Phenotype; Play; Pre-Clinical Model; Property; Proteomics; Pruritus; Psoriasis; Public Health; Quality of life; Reporting; Reverse Transcriptase Polymerase Chain Reaction; Risk; Role; Safety; Sampling; Self Administration; Serum; Signal Pathway; Signal Transduction; Skin; Skin Care; Societies; Symptoms; TNF gene; Technology; Therapeutic; Therapeutic immunosuppression; Thick; Time; Topical application; Toxicology; Up-Regulation; Visual; base; chemokine; chronic inflammatory skin; clinical development; clinical investigation; clinically relevant; clinically significant; commercialization; comparative efficacy; compliance behavior; cytokine; design; effective therapy; efficacy evaluation; efficacy study; improved; individualized medicine; inhibitor/antagonist; insight; interleukin-17C; keratinocyte; macrophage-derived chemokine; novel; profiles in patients; protein expression; psychosocial; research and development; research clinical testing; side effect; skin barrier; skin disorder; skin irritation; small molecule; standard of care; therapeutic target; transcriptome sequencing

PROJECT SUMMARY Atopic dermatitis/AD (or ‘atopic eczema’) is a complex, chronic, inflammatory skin disease that affects upwards of 35 million Americans. AD is characterized by a disruption of epidermal-barrier function, inflamed dry and thick skin, severe pruritus and significant impact on patients’ quality of life. Current standard of care involves topical emollients, avoidance of trigger factors and anti-inflammatory strategies including the use of corticosteroids, antihistamines, or broad and recently also specific immunommodulators, such as dupilumab. While broad immunosuppressive therapies can help partly manage the disease, chronic usage results in undesirable side- effects and drug tolerance, resulting in lowered patient compliance and inefficacy. Furthermore, dupilumab is ineffective in a significant portion of patients, suggesting the heterogeneity of AD and need for individualized treatment based on patient profiling. There is a pressing need for the clinical development of targeted immunomodulatory therapeutics, without immunosuppressive side effects, designed to take into account patient profiling and to safely and selectively target pathogenic mediators of AD. HSP90 has been recently classified as an ‘alarmin’ and has key roles in mediating the interplay between the innate and the adaptive immune system as well as known roles in the JAK/STAT and MAP kinase pathway and IL-4, IL-13, and IL-17 signaling. These pathways have key roles in AD-related immune dysregulation. Regranion has recently acquired a potent novel small molecule HSP90 inhibitor (RGRN-305, previously Debio0932) with a good safety profile and attractive pharmacological properties that shows alleviation of psoriatic symptoms, reduced epidermal thickness, and dramatic reduction in levels of TNFα and IL-17, pro-inflammatory cytokines in clinically relevant animal models of psoriasis. These studies laid the foundation for ongoing clinical evaluation in the treatment of moderate-to- severe psoriasis (ClinicalTrials.gov Identifier: NCT03675542) and set a precedence for investigation of HSP90 as a therapeutic target in AD. The focus of this proposal is to accomplish key milestones that will transition this technology for commercialization as a safe and efficacious oral AD therapeutic that targets the upstream proteomic mediators of the disease. The study aims involve i.) rigorous evaluation of the efficacy and mechanism of action of oral RGRN-305 in multiple clinically relevant AD models that incorporate a comparative efficacy study versus corticosteroid treatment, and ii.) characterization of the gene and protein expressions of HSP90 pathway- related markers in normal, nonlesional and AD lesional human skin samples from moderate-to-severe AD patients. A role for HSP90 in the pathogenesis and persistence of AD has not been elucidated. Given that the etiology of AD is multifaceted, characterizing the expression profile of epidermal HSP90 pathway and related cytokines and chemokines will permit insight into the therapeutic potential and opportunity for individualized therapy with RGRN-305.

项目摘要 特应性皮炎/AD（或“特应性湿疹”）是一种复杂，慢性，炎症性皮肤疾病，会影响向上 3500万美国人。 AD的特征是表皮轰炸功能的破坏，发炎干燥 皮肤，严重的瘙痒以及对患者生活质量的重大影响。当前的护理标准涉及局部 润肤剂，避免触发因素和抗炎策略，包括使用皮质类固醇， 抗组胺药，或近期且最近的特定免疫养分剂，例如杜皮鲁马布。 虽然广泛 免疫抑制疗法可以帮助部分管理该疾病，长期使用导致不良的侧面 作用和药物的耐受性，导致患者依从性和效率低下。此外，Dupilumab是 在很大一部分患者中无效，表明AD的异质性和需要个性化的 基于患者分析的治疗。迫切需要目标的临床发展 免疫调节理论，没有免疫抑制副作用，旨在考虑患者 分析并安全，有选择地靶向AD的致病介质。 HSP90最近被分类 作为“警报”，在调解先天和自适应免疫系统之间的相互作用中具有关键作用 以及在JAK/STAT和MAP激酶途径以及IL-4，IL-13和IL-17信号传导中的已知作用。这些 途径在与AD相关的免疫失调中具有关键作用。 Regranion最近获得了一部有力的小说 小分子HSP90抑制剂（RGRN-305，以前的Debio0932）具有良好的安全性和吸引人 药理学特性显示出减轻银屑病症状，表皮厚度降低和 临床相关的动物模型中TNFα和IL-17的促炎细胞因子的急剧降低 牛皮癣。这些研究奠定了持续临床评估的基础 严重的牛皮癣（临床库），GOV标识符：NCT03675542），并为HSP90的研究设定了优先级 作为AD的治疗靶标。该提议的重点是实现将过渡这一点的关键里程碑 商业化技术是针对上游的安全有效的口服广告疗法 该疾病的蛋白质组学介体。该研究的目的涉及i。）严格评估效率和机制 口服RGRN-305在多个临床相关的AD模型中的作用，这些AD模型包含了比较有效的研究 与皮质类固醇治疗相比，ii。）hsp90途径的基因和蛋白质表达的表征 来自中度至重度AD的正常，非病变和病变的人体皮肤样品中的相关标记 患者。 HSP90在AD的发病机理和持久性中的作用尚未阐明。鉴于那个 AD的病因是多方面的，表征表皮HSP90途径的表达曲线和相关 细胞因子和趋化因子将允许深入了解个性化的治疗潜力和机会 RGRN-305治疗。