Development of a Selective Inhibitor of NaV1.7 for the Treatment of Ocular Pain

开发用于治疗眼痛的 NaV1.7 选择性抑制剂

• 批准号: 10326026
• 负责人: Sheri Denet Klas
• 金额: $ 108.11万
• 依托单位: SITEONE THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10326026
• 关键词: Acute; Acute Pain; Address; Amino Acid Sequence; Analgesics; Anesthetics; Animal Model; Anosmia; Binding Sites; Businesses; Chemicals; Chronic; Clinical; Clinical Research; Congenital Pain Insensitivity; Cornea; Development; Dose; Dry Eye Syndromes; Enrollment; Erythromelalgia; Exhibits; Eye; Formulation; Genetic; Goals; Health; High Prevalence; Human; Human Genetics; In Vitro; Inhalation; Injury; Intravenous; Investigational Drugs; Investigational New Drug Application; Ions; Ketorolac; Licensing; Link; Local Anesthetics; Medical; Methodology; Modeling; Molecular Conformation; Nervous System Physiology; Neurologic; Non-Steroidal Anti-Inflammatory Agents; Operative Surgical Procedures; Ophthalmic Solutions; Oral; Pain; Pain intensity; Paroxysmal extreme pain disorder; Patients; Pattern; Pharmaceutical Preparations; Pharmacology; Pharmacology Study; Pharmacotherapy; Phase; Photorefractive Keratectomy; Procedures; Process; Rattus; Reflex action; Rodent; Route; Safety; Saxitoxin; Schedule; Self Administration; Series; Small Business Innovation Research Grant; Sodium Channel; Sterility; Surface; Testing; Therapeutic; Toxicokinetics; Toxicology; Toxin; Variant; Vision; Work; base; candidate selection; chronic pain; clinical development; design; efficacy study; experience; extracellular; eye dryness; first-in-human; gain of function mutation; genotoxicity; good laboratory practice; guanidinium; in vivo; inhibitor/antagonist; meetings; mutation assay; nanomolar; nonhuman primate; novel; ocular pain; pain patient; pain signal; patient population; preclinical safety; product development; programs; public health relevance; research clinical testing; safety study; scale up; side effect; small molecule inhibitor; subcutaneous; therapy development; transmission process; voltage

PROJECT SUMMARY The absence of safe and effective strategies for the management of ocular pain is motivating the development of a novel topical drug suitable for patient self-administration. Conventional local anesthetics, such as proparacaine, inhibit voltage-gated sodium channels (NaV) and are highly effective for the management of ocular pain in acute, in-office settings. However, these anesthetic agents block protective ocular reflexes and are toxic to the corneal surface, which limits their use to a few in-office administrations. Other agents, such as topical NSAIDs, are relatively ineffective at relieving ocular discomfort, or have side effects that limit their use. SiteOne Therapeutics has discovered a novel chemical series of exquisitely selective inhibitors of human NaV1.7, a voltage-gated sodium channel subtype implicated in the transmission of pain signals by human genetics. These compounds exhibit excellent dose-dependent analgesic effects in multiple animal models of acute and chronic pain including a rat dry eye model. In preclinical safety and efficacy studies, topical ocular administration is effective, safe, well tolerated, and leads to good intraocular exposure. The goal of this Phase 2 SBIR proposal is to advance IND-enabling development of a topical ocular analgesic product. The Specific Aims are to complete GLP nonclinical safety studies, drug product development, and to prepare the first GMP batch in order to initiate clinical studies to determine if the new topical drug has an adequate safety and efficacy profile to justify further clinical development for the treatment of ocular pain.

项目摘要 缺乏安全有效的治疗眼部疼痛的策略， 一种适合患者自我给药的新型外用药物。传统的局部麻醉剂，如 丙美卡因，抑制电压门控钠通道（NaV），并高度有效的管理 急性眼痛，在办公室设置。然而，这些麻醉剂阻断保护性眼反射， 对角膜表面是有毒的，这限制了它们的使用，仅限于几次在办公室给药。其他代理商，如 局部NSAID在缓解眼部不适方面相对无效，或者具有限制其使用的副作用。 SiteOne Therapeutics发现了一种新的化学系列，具有精细的选择性抑制剂， NaV1.7，一种参与人痛觉信号传递的电压门控钠通道亚型 遗传学这些化合物在多种动物模型中表现出优异的剂量依赖性镇痛作用， 急性和慢性疼痛，包括大鼠干眼模型。在临床前安全性和有效性研究中， 给药有效、安全、耐受性好，并导致良好的眼内暴露。这个阶段的目的 2 SBIR提案旨在推进IND能够开发的局部眼部镇痛产品。具体 目的是完成GLP非临床安全性研究、药品开发和准备第一个GMP 批次，以启动临床研究，以确定新的局部药物是否具有足够的安全性， 有效性特征，以证明用于治疗眼部疼痛的进一步临床开发的合理性。