A Novel Topical HSP90 Inhibitor (CTXT-102) in the Treatment of Mild to Moderate Plaque Psoriasis

一种治疗轻至中度斑块状银屑病的新型外用 HSP90 抑制剂 (CTXT-102)

• 批准号: 9572916
• 负责人: Christina Grek
• 金额: $ 57.15万
• 依托单位: REGRANION, LLC
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-26 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9572916
• 关键词: Adaptive Immune System; Address; Adverse effects; Affect; American; Animal Model; Area; Atrophic condition of skin; Biological Assay; Calcineurin inhibitor; Cavia; Chronic small plaque psoriasis; Clinical; Clinical Research; Clinical Trials; Comparative Study; Cream; Data; Dermal; Development; Disease; Disease remission; Dose; Employment; Exhibits; Family suidae; Food and Drug Administration Drug Approval; Formulation; Future; Heat-Shock Proteins 90; Human; Human Resources; Hypersensitivity; Imiquimod; Immune; Immune system; Infection; Inflammatory; Interleukin-12; Interleukin-17; Investigational Drugs; Lead; Lesion; Link; Malignant Neoplasms; Measures; Mediator of activation protein; Medical; Modality; Modeling; New Drug Approvals; Oral; Pathway interactions; Patients; Personal Satisfaction; Phase; Phototherapy; Predisposition; Preparation; Proteomics; Psoriasis; Quality of life; Reaction; Regimen; Risk; Role; Safety; Side; Skin; Small Business Innovation Research Grant; Steroids; Surface; Symptoms; System; Systemic Therapy; TNF gene; Therapeutic; Thick; Tissues; Topical Corticosteroids; Topical agent; Topical application; Toxic effect; Toxicokinetics; Toxicology; Transplantation; Up-Regulation; Vitamin D; Vitamin D Analog; Xenograft procedure; base; chronic inflammatory skin; clinical development; clinical efficacy; comparative efficacy; cost; cytokine; efficacy evaluation; efficacy study; experience; good laboratory practice; improved; inhibitor/antagonist; mouse model; new therapeutic target; novel; oncology; oncology trial; phase 2 study; pre-clinical; preclinical study; research and development; research clinical testing; response; skin disorder; small molecule; therapeutic target; treatment duration; ultraviolet

PROJECT SUMMARY Psoriasis is a chronic inflammatory skin disease affecting approximately 7.5 million Americans that can become debilitating and severely impact quality of life. While an estimated 20% of patients suffer moderate to severe disease forms that require systemic therapy with immune suppressants and ultraviolet phototherapy, the majority (80%) of patients exhibit milder symptoms. For these patients, topical agents such as steroids, vitamin D analogues, and calcineurin inhibitors are prescribed but remain associated with poor efficacy and tolerability. Despite advances in the development of targeted biologics, including cytokine inhibitors, many psoriasis patients remain inadequately treated due to the risk of serious adverse side effects, loss of efficacy and high cost. There is a pressing need for the clinical development of effective, safe, easy to use, affordable topical psoriasis therapeutics that target the upstream proteomic mediators of the disease. Human psoriatic lesions have a profound upregulation of HSP90 versus normal skin, where data support a role in the interplay between the innate and the adaptive immune system. Regranion has recently acquired a potent novel small molecule HSP90 inhibitor with a good safety profile and proven preclinical and anecdotal clinical efficacy data for the treatment of psoriasis. In a xenograft transplantation model of psoriasis, oral delivery of CTXT-102 (previously called Debio 0932) resulted in significant clinical alleviation of psoriasis, reduced epidermal thickness, and dramatic reduction in levels of TNFα and IL-17, pro-inflammatory cytokines linked to the persistence of psoriasis. Similarly, topical delivery of CTXT-102 significantly decreased psoriatic symptoms in psoriasis mouse models. Clinical safety of CTXT-102 has been validated in a CTXT-102 Phase 1 oncology trial; where after 43 days of daily treatment with 800mg CTXT-102, a patient with severe psoriasis covering more than 40% of the skin surface showed complete remission. Based on this supporting preclinical data and serendipitous clinical finding, we plan to develop CTXT-102 in a topical formulation targeting patients with mild to moderate forms of plaque psoriasis. Our strategy is to address the wider and pressing unmet need for patients with mild to moderate from of psoriasis with topical delivery of CTXT-102; to be followed by an oral form in the future for severe psoriasis. The major objectives of this SBIR Phase II proposal are threefold. 1.) A rigorous evaluation of the efficacy and mechanism of action of topical CTXT-102 will be performed in a clinically validated psoriasis model that incorporates a comparative efficacy study versus topical corticosteroid treatment; 2.) completion of necessary IND-enabling GLP dermal sensitivity, dermatopharmacokinetic, and toxicokinetic studies, and 3.) preparation and submission of an IND-package for a future Phase 1b/2 human clinical study. Furthermore, the proposal will enable the formulation of a clinical and regulatory strategy for accelerated development. The completion of the Phase II SBIR aims will provide full characterization of CTXT- 102 in a topical formulation in order to advance into clinical trials following IND approval.

项目概要 牛皮癣是一种慢性炎症性皮肤病，影响着大约 750 万美国人。 变得虚弱并严重影响生活质量。虽然估计 20% 的患者患有中度至 需要使用免疫抑制剂和紫外线光疗进行全身治疗的严重疾病形式， 大多数（80%）患者表现出较轻微的症状。对于这些患者，可以使用类固醇等外用药物， 维生素 D 类似物和钙调神经磷酸酶抑制剂已被处方，但仍然与疗效不佳和 耐受性。尽管包括细胞因子抑制剂在内的靶向生物制剂的开发取得了进展，但许多 由于存在严重不良副作用和疗效丧失的风险，牛皮癣患者仍未得到充分治疗 且成本高。临床迫切需要开发有效、安全、易于使用、负担得起的药物 针对疾病上游蛋白质组介质的局部银屑病治疗。人类银屑病 与正常皮肤相比，病变部位的 HSP90 显着上调，数据支持了相互作用中的作用 先天免疫系统和适应性免疫系统之间。 Regranion 最近获得了一本强有力的小说小 分子 HSP90 抑制剂，具有良好的安全性和经过验证的临床前和临床疗效数据 用于治疗牛皮癣。在银屑病异种移植模型中，口服 CTXT-102 （以前称为 Debio 0932）可显着缓解牛皮癣的临床症状，减少表皮 厚度，以及 TNFα 和 IL-17 水平的显着降低，促炎细胞因子与 牛皮癣持续存在。同样，局部给药 CTXT-102 显着减轻了患者的银屑病症状 牛皮癣小鼠模型。 CTXT-102 的临床安全性已在 CTXT-102 1 期肿瘤学中得到验证 审判;一名患有严重银屑病的患者每天接受 800 毫克 CTXT-102 治疗 43 天后， 超过40%的皮肤表面显示出完全缓解。基于此支持性临床前数据和 偶然的临床发现，我们计划开发针对轻度患者的局部制剂 CTXT-102 至中度斑块状银屑病。我们的战略是解决更广泛且紧迫的未满足需求 局部给药 CTXT-102 的轻度至中度银屑病患者；随后进行口头 未来形成严重的牛皮癣。 SBIR 第二阶段提案的主要目标有三个。 1.) A 对局部 CTXT-102 的功效和作用机制的严格评估将在 经过临床验证的牛皮癣模型，其中包含与外用皮质类固醇的疗效比较研究 治疗; 2.) 完成必要的 IND 支持的 GLP 皮肤敏感性、皮肤药代动力学，以及 毒代动力学研究，以及 3.) 为未来 1b/2 期人体准备和提交 IND 包 临床研究。此外，该提案还将有助于制定临床和监管策略 加速发展。第二阶段 SBIR 目标的完成将提供 CTXT- 的完整特征 102 采用局部制剂，以便在 IND 批准后进入临床试验。