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

项目总结 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，严重影响生活质量。而据估计，20%的患者患有中度到 严重的疾病形式，需要用免疫抑制剂和紫外线光疗进行系统治疗， 大多数患者(80%)表现出较轻的症状。对于这些患者，局部用药，如类固醇， 维生素D类似物和钙调神经磷酸酶抑制剂被开出，但仍然与较差的疗效和 耐受性。尽管在开发靶向生物制品方面取得了进展，包括细胞因子抑制剂，但许多 银屑病患者仍然没有得到充分的治疗，因为有可能出现严重的副作用，失去疗效 而且成本很高。临床迫切需要开发有效、安全、易用、经济实惠的药物。 针对牛皮癣上游蛋白质组介质的局部牛皮癣疗法。人类牛皮癣 与正常皮肤相比，皮损中HSP90的表达显著上调，数据支持这一相互作用的作用 在先天免疫系统和获得性免疫系统之间。Regranion最近获得了一部强有力的小说Small 分子HSP90抑制剂具有良好的安全性和临床前和轶事临床疗效数据 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)导致银屑病的临床显著缓解，表皮减少 肿瘤坏死因子α和IL-17水平显著降低，这两种促炎细胞因子与 银屑病的持续性。同样，CTXT-102的局部给药显著减少了银屑病患者的症状 银屑病小鼠模型。CTXT-102的临床安全性已在CTXT-102一期肿瘤学中得到验证 试验：每天服用800 mg CTXT-102 43天后，一名严重银屑病患者 40%以上的皮肤表面完全缓解。基于这一支持临床前数据和 偶然的临床发现，我们计划开发CTXT-102的局部制剂，针对轻度 至中度斑块型牛皮癣。我们的战略是解决更广泛和迫切的未得到满足的需求 轻至中度银屑病患者局部应用CTXT-102；随后口服 在未来形成严重的牛皮癣。这项SBIR第二阶段提案的主要目标有三个。1)一个 对外用CTXT-102的疗效和作用机制将进行严格的评估 临床验证的银屑病模型，合并了与外用皮质类固醇的疗效比较研究 治疗；2.)完成必要的IND-Enabling GLP皮肤敏感性、皮肤药代动力学和 毒代动力学研究；3)为未来的1b/2阶段人类编制和提交IND一揽子计划 临床研究。此外，该建议将有助于制定临床和监管战略，以 加快发展。第二阶段SBIR目标的完成将提供CTXT的全面表征- 102，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.