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

瘙痒治疗 PRA-523 开发的 IND 启用研究

• 批准号: 10761395
• 负责人: Douglas Anthony Pippin
• 金额: $ 124.47万
• 依托单位: PRAEVENTIX, LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10761395
• 关键词: ANK1 gene; Action Potentials; Acute; Adult; Affect; Afferent Neurons; Alkaline Single-Cell Gel Electrophoresis Assay; Ames Assay; Antihistamines; Antipruritics; Area; Atopic Dermatitis; Behavior; Binding Proteins; Caring; Cattle; Cells; Chronic; Classification; Clinic; Clinical; Corneal Opacity; Coupled; Cyclic AMP; Data; Dermal; Dermatology; Dermis; Development; Diagnosis; Disease; Dosage Forms; Dose; Drug Kinetics; Eczema; Ensure; Epidermis; Esthesia; Evaluation; Exhibits; Eye; Family suidae; Female; Formulation; Foundations; Future; Healthcare; Human; In Vitro; Inflammatory; Ion Channel; Lead; Life; Maximum Tolerated Dose; Mediating; Mediator; Medical; Metabolism; Methods; Modeling; Moods; Mus; Neurons; Neutral Red; Pathogenesis; Pathway interactions; Patients; Penetration; Peripheral; Permeability; Personal Satisfaction; Pharmaceutical Preparations; Pharmacology Study; Phototoxicity; Plasma; Play; Program Development; Pruritus; Qualifying; Quality of life; Rattus; Reporting; Research; Research Contracts; Role; Route; Safety; Serotonergic System; Serotonin; Serum; Signal Pathway; Signal Transduction; Skin; Sleep; Symptoms; System; TRPA channel; Testing; Therapeutic; Topical application; Toxic effect; Toxicokinetics; Toxicology; Translating; Work; antagonist; care burden; chronic itch; chronic pain; comorbidity; comparative; effective therapy; experience; genotoxicity; in vivo; irritation; male; manufacture; micronucleus; novel; novel therapeutics; programs; receptor; research clinical testing; serotonin 7 receptor; skin disorder; skin lesion; uptake

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.

项目摘要（摘要） Pruritus是由于感觉不愉快（急性和慢性）引起的划痕的冲动，是最常见的症状 在特应性皮炎（AD）等皮肤疾病中。尽管瘙痒的起源未完全阐明，但治疗慢性 瘙痒是照顾广告患者福祉的重要组成部分。瘙痒会影响睡眠，情绪，人际关系 并可以大大降低生活质量。实际上，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通常是由多个培养基介体引起的。抗组胺药 可能具有治疗急性瘙痒的效用，但在慢性瘙痒或AD中没有有效。管理层 AD中的慢性瘙痒症代表了未满足的医疗需求，目前没有有效的治疗选择，并且 强调了针对非高速素途径内新靶标的新疗法的需求。 非 - 持续药慢性瘙痒的病理生理机制的重要组成部分涉及 支配的真皮/表皮中的5-HT水平增加。 AD患者的5-HT水平升高（血清） 据报道和慢性湿疹（皮肤）。最近的研究表明5-羟色胺能5-HT7受体 在TRPA1 Ca2+通量介导的瘙痒中起重要作用。 5-HT7和TRPA1受体共表达 皮肤中原发性感官神经元的子集。两个受体在功能上耦合，其中5-HT7 刺激导致打开TRPA1通道促进神经元沉积和动作电势射击， 并最终触发瘙痒诱发的刮擦。体内研究强烈支持5-HT信号传导有助于 通过5-HT7-TRPA1信号传导瘙痒的发病机理。 Praeventix已确认5-的作用 MC903诱导的AD模型中的HT7/TRPA1阻断。这些数据强烈证明了对 5HT7/TRPA1信号通路将转化为对瘙痒/刮擦周期的有意义的抑制。 Praeventix已经确定了临床铅PRA-523，这是一种潜在的选择性5-HT7拮抗剂，可抑制5--中Ca2+通量 HT7/TRPA1-HEK293细胞。 PRA-523展示了外围受限的药代动力学和良好的皮肤 穿透/渗透性是局部施用产品的理想选择。在MC903中的研究诱导了AD 模型表现出局部应用的PRA-523，并依赖剂量减少了刮擦行为 在男性和雌性小鼠中。这些数据强烈表明，选择性抑制5-HT7/TRPA1 信号通路将转化为对瘙痒的有意义的抑制。 该建议旨在完成初始的IND促进研究，以允许PRA-523的进步GLP 毒理学研究，开发临床公式并制造计划中所需的药物 非临床研究。这项工作将在美国的高质量合同研究组织（ 由Praeventix经验丰富的团队监督。