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

项目概要（摘要） 瘙痒，由于不愉快的感觉（急性和慢性）而产生的抓挠欲望，是最常见的症状 在皮肤病，如特应性皮炎（AD）。虽然瘙痒的起源还没有完全阐明，治疗慢性 瘙痒是照顾AD患者健康的重要部分。瘙痒影响睡眠、情绪、人际关系 并且可以显著降低生活质量。事实上，慢性瘙痒对患者健康的负面影响是 据报道，这与慢性疼痛相似。AD通常是由多种致炎介质引起的。抗组胺 可用于治疗急性瘙痒症，但对慢性瘙痒症或AD无效。管理 AD患者的慢性瘙痒代表了未满足的医疗需求，目前没有有效的治疗选择， 强调了需要针对非组胺能途径内的新靶点的新疗法。 非组胺能慢性瘙痒症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-HT水平增加。AD患者5-HT水平升高（血清） 和慢性湿疹（皮肤）的报道。最近的研究表明，肾上腺素能5-HT 7受体 在TRPA 1介导的瘙痒中起重要作用。5-HT 7和TRPA 1受体在细胞表面共表达。 皮肤中初级传入感觉神经元的子集。两种受体在功能上是偶联的，其中5-HT 7 刺激导致TRPA 1通道的开放促进神经元去极化和动作电位放电， 并最终引发瘙痒诱发的抓挠。体内研究强烈支持5-HT信号通路有助于 通过5-HT 7-TRPA 1信号通路参与瘙痒症的发病机制。Praeventix证实了5- 在MC 903诱导的AD模型中的HT 7/TRPA 1阻断。这些数据有力地证明了选择性抑制 5 HT 7/TRPA 1信号通路将转化为瘙痒/抓挠周期的有意义的抑制。 Praeventix已经确定了临床先导PRA-523，这是一种有效的选择性5-HT 7拮抗剂，可抑制5-HT 7中的Ca 2+通量。 HT 7/TRPA 1-HEK 293细胞。PRA-523表现出外周受限的药代动力学和良好的皮肤 该渗透性/渗透性对于局部施用的产品是理想的。MC 903诱导AD的研究 模型显示局部施用PRA-523显著且剂量依赖性地降低了抓挠行为 在雄性和雌性小鼠中。这些数据有力地证明了5-HT 7/TRPA 1的选择性抑制 信号通路将转化为瘙痒的有意义的抑制。 本提案旨在完成初始IND使能研究，以允许PRA-523进入GLP 毒理学研究，开发临床制剂并生产计划的 非临床研究。这项工作将在美国的高质量合同研究组织进行， 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.