IND Enabling Studies for the Development of Pruritus Therapeutic PRA-523

项目摘要(摘要) 瘙痒是最常见的症状，即由于不舒服的感觉(急性和慢性)而产生的抓挠冲动。 在特应性皮炎(AD)等皮肤病中。虽然瘙痒的起源尚未完全阐明，但治疗慢性 瘙痒是照顾AD患者健康的重要组成部分。瘙痒影响睡眠、情绪、人际关系 并且会显著降低生活质量。事实上，慢性瘙痒对患者健康的负面影响是 据报道就像慢性疼痛一样。AD通常是由多种致痒介质引起的。抗组胺药 可能对治疗急性瘙痒有效，但对慢性瘙痒或AD无效。管理层 AD患者的慢性瘙痒是一种未得到满足的医疗需求，目前没有有效的治疗选择，以及 强调了针对非组胺能途径中的新靶点的新疗法的必要性。 非组胺能慢性瘙痒的病理生理机制的一个重要组成部分涉及 神经支配的真皮/表皮中5-羟色胺水平升高。AD患者血清5-羟色胺水平升高 和慢性湿疹(皮肤)已有报道。最近的研究表明，5-羟色胺能5-HT7受体 在TRPA1钙通量介导的瘙痒中起重要作用。5-HT7和TRPA1受体共表达于 皮肤中初级传入感觉神经元的一个子集。这两个受体在功能上偶联，其中5-HT7 刺激导致TRPA1通道开放，促进神经元去极化和动作电位放电， 并最终触发瘙痒引起的抓挠。体内研究有力地支持了5-羟色胺信号的作用 通过5-HT7-TRPA1信号转导瘙痒的发病机制。Praeventix已经确认了5- HT7/TRPA1阻断MC903诱导的AD模型这些数据有力地证明了选择性抑制 5HT7/TRPA1信号通路将转化为对瘙痒/抓挠周期的有意义的抑制。 Praeventix已经确定了临床领先的PRA-523，一种有效的选择性5-HT7拮抗剂，它抑制5-HT7细胞内钙离子的流动。 HT7/TRPA1-HEK293细胞。PRA-523表现出外围受限的药代动力学和良好的真实感 渗透性/渗透性是外用产品的理想选择。MC903诱导阿尔茨海默病的研究 模型显示，局部应用PRA-523显著减少了划痕行为，并呈剂量依赖性 在雄性和雌性小鼠中都是如此。这些数据有力地证明了5-HT7/TRPA1的选择性抑制 信号通路将转化为有意义的瘙痒抑制。 该提案旨在完成初步的IND支持研究，以允许将PRA-523提升到GLP 毒理学研究，开发临床配方，并生产计划所需的药物产品 非临床研究。这项工作将在美国的高质量合同研究机构中进行， 由Praeventix经验丰富的团队监督。

PROJECT SUMMARY (ABSTRACT) Pruritus, the urge to scratch due to an unpleasant sensation (acute and chronic), is the most frequent symptom in skin diseases like Atopic Dermatitis (AD). Although the origin of itch is not fully elucidated, treating chronic itch is an important part of caring for AD patients’ well-being. Pruritus affects sleep, mood, personal relationships and can significantly reduce quality of life. In fact, the negative impact of chronic itch on patient’s well-being is reported to be like that of chronic pain. AD is typically caused by multiple pruritogenic mediators. Antihistamines may have utility in treating acute pruritus, but have not been effective in chronic pruritus or AD. The management of chronic pruritus in AD represents an unmet medical need, currently without effective treatment options, and underscores the need for new therapies against novel targets within non-histaminergic pathways. An important component of the pathophysiologic mechanism of non-histaminergic chronic pruritus involves the increase of 5-HT levels in the innervated dermis/epidermis. Elevated levels of 5-HT in patients with AD (serum) and chronic eczema (skin) have been reported. Recent studies demonstrate the serotonergic 5-HT7 receptor plays an important role in TRPA1 Ca2+ flux mediated pruritus. 5-HT7 and TRPA1 receptors are co-expressed on a subset of primary afferent sensory neurons in the skin. Both receptors are functionally coupled where 5-HT7 stimulation results in opening of TRPA1 channels promoting neuronal depolarization and action potential firing, and ultimately triggering itch-evoked scratching. In vivo studies strongly support that 5-HT signaling contributes to the pathogenesis of pruritus through 5-HT7-TRPA1 signaling. Praeventix has confirmed the role of 5- HT7/TRPA1 blockade in the MC903 induced AD model. These data strongly demonstrate selective inhibition of the 5HT7/TRPA1 signaling pathway will translate to a meaningful suppression of the itch/scratch cycle. Praeventix has identified clinical lead PRA-523, a potent selective 5-HT7 antagonist that inhibits Ca2+ flux in 5- HT7/TRPA1-HEK293 cells. PRA-523 exhibits peripherally restricted pharmacokinetics and good dermal penetration/permeability that is ideal for a topically administered product. Studies in the MC903 induced AD model demonstrated topically applied PRA-523 significantly and dose dependently reduced scratching behavior in both male and female mice. These data strongly demonstrate that selective inhibition of the 5-HT7/TRPA1 signaling pathway will translate to meaningful suppression of pruritus. This proposal aims to complete the initial IND enabling studies to permit the advancement of PRA-523 into GLP toxicology studies, develop the clinical formulation and manufacture the drug product needed for the planned nonclinical studies. This work will be performed at high quality contract research organizations in the USA, overseen by the experienced team at Praeventix.