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

项目摘要 牛皮癣是一种慢性炎症性皮肤病，影响约750万美国人， 使人衰弱，严重影响生活质量。虽然估计有20%的患者患有中度至 需要免疫抑制剂和紫外线光疗的系统治疗的严重疾病形式， 大多数（80%）患者的症状较轻。对于这些患者，局部药物如类固醇， 维生素D类似物和钙调磷酸酶抑制剂被处方，但仍然与疗效差有关， 耐受性尽管靶向生物制剂（包括细胞因子抑制剂）的开发取得了进展，但许多药物仍然存在。 银屑病患者由于存在严重的不良副作用、疗效丧失的风险， 且成本高。临床上迫切需要开发有效、安全、使用方便、价格实惠的 靶向疾病的上游蛋白质组介质的局部银屑病治疗剂。人银肩病 与正常皮肤相比，病变具有HSP 90的显著上调，其中数据支持在相互作用中的作用。 先天免疫系统和适应性免疫系统之间的联系。Regranion最近获得了一个强大的小说小 分子HSP 90抑制剂，具有良好的安全性特征和经证实的临床前和临床疗效数据 牛皮癣的治疗方法在银肩病的异种移植物移植模型中，CTXT-102的口服递送 （以前称为Debio 0932）导致银屑病的临床显著缓解，减少表皮 厚度，以及TNFα和IL-17水平的显著降低，这些促炎细胞因子与 牛皮癣的危害类似地，CTXT-102的局部递送显著降低了银屑病患者的银屑病症状。 银屑病小鼠模型。CTXT-102的临床安全性已在CTXT-102 1期肿瘤学中得到验证 试验;其中在每天用800 mg CTXT-102治疗43天后，患有严重银屑病的患者 超过40%的皮肤表面显示完全缓解。基于这些支持性临床前数据， 偶然的临床发现，我们计划开发CTXT-102的局部制剂，针对轻度 中度斑块型银屑病。我们的战略是满足更广泛和迫切的需求， 患有轻度至中度银屑病的患者，局部给予CTXT-102;随后口服 牛皮癣的危害有哪些？SBIR第二阶段提案的主要目标有三个方面。1.）的人。一 对局部CTXT-102的疗效和作用机制的严格评价将在 临床验证的银屑病模型，包括与局部皮质类固醇的比较有效性研究 治疗; 2.）完成必要的IND使能GLP皮肤敏感性、皮肤药代动力学和 毒代动力学研究，和3.）为未来的1b/2期人类研究准备和提交IND包 临床研究此外，该建议将有助于制定临床和监管策略， 加快发展。第二阶段SBIR目标的完成将提供CTXT的完整特征- 102在局部制剂中，以便在IND批准后进入临床试验。

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.