Targeting TRP channels for novel topical treatment of atopic dermatitis

靶向 TRP 通道用于特应性皮炎的新型局部治疗

• 批准号: 10005547
• 负责人: George Walter Koszalka
• 金额: $ 30.23万
• 依托单位: TRPBLUE, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10005547
• 关键词: Accounting; Acetone; Address; Adult; Adverse effects; Affect; Allergens; Allergic inflammation; Animal Model; Antipruritics; Atopic Dermatitis; Attenuated; Automobile Driving; Behavior; Benchmarking; Biodistribution; Blood; Blood Circulation; Blood specimen; Child; Chronic; Clinical; Complement; Contact Dermatitis; Country; Data; Dermal; Dermatitis; Detection; Development; Dinitrofluorobenzene; Disease Management; Disease remission; Dose; Drug Kinetics; Dryness; Environment; Ethyl Ether; Exanthema; Eye; Family suidae; Financial Hardship; Formulation; Future; Histamine; Histology; Human; Immune system; Immunomodulators; Inflammation; Inflammatory; Integumentary system; Ion Channel; Joints; Limb structure; Measures; Metabolism; Modeling; Molecular; Mus; Neck; Pain; Patients; Penetration; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Play; Positioning Attribute; Pre-Clinical Model; Preparation; Prevalence; Process; Production; Property; Protocols documentation; Pruritus; Punch Biopsy; Quality of life; Records; Redness; Relapse; Risk; Role; Safety; Scientist; Series; Serotonin; Side; Signal Transduction; Skin; Stimulus; Swelling; Symptoms; TRP channel; Testing; Therapeutic; Time; Topical application; Toxicology; Work; absorption; base; chemical synthesis; chronic itch; cost; design; drug metabolism; effective therapy; experimental study; improved; in vivo; inhibitor/antagonist; intradermal injection; irritation; liquid chromatography mass spectrometry; molecular marker; mouse model; neurosensory; novel; novel therapeutics; pre-clinical; reduce symptoms; response; side effect; skin disorder; skin irritation; small molecule; tissue injury

SUMMARY We have developed TB16-8, a small molecule that is an effective inhibitor of both TRPV4 and TRPA1 ion channels. These two ion channels are associated with atopic dermatitis (Atopic Derm) and its dominating clinical hallmark, chronic and debilitating pruritus (itch). We have demonstrated that the topical application at low microgram amounts of this compound effectively inhibits itch and inflammation in mice and swine—used as animal models—for various symptoms of Atopic Derm. Currently there are treatments approved for Atopic Derm and its symptoms; however, none is a universal drug, and not all Atopic Derm drugs are appropriate for all the patients. TB16-8 is intended as a single therapy, applied topically, potentially replacing immunomodulatory drugs, or as a complement for current treatments with a perspective of lowering applied doses. TB16-8 is intended for topical application; therefore, in addition to providing short term relief, an objective is chronic use for extended periods of time with minimal or no adverse effects. In the present Phase I proposal we will perform studies intended to position TB16-8 in pre-IND status. First, an optimized chemical synthesis will be achieved. Every step of the synthesis process will be carefully analyzed and optimized to generate a final drug product that satisfies FDA and ICH GMP requirements. The effect of TB16-8 will be studied in mouse preclinical models for contact dermatitis by sensitizing them with DNFB (2,4- dinitrofluorobenzene) and by chronic pruritogenic dermatitis using a dry skin model based on acetone-diethyl ether. Scratching behavior and skin inflammation will be measured. Skin inflammation and biodistribution of TB16-8 in the blood and integument of swine will also be evaluated. Our preliminary data are strong and could be perceived as if our product ought to be considered for a Direct to Phase II; however, dermal concentrations and detection of TB16-8 in the systemic circulation following topical administration in swine, a relevant model for topical administration in humans, have not been collected, making this Phase I a necessary stage prior to reaching pre-IND status. We will complement the safety and up to 48h biodistribution data of TB16-8 currently available in two animal models, and we will optimize the chemical synthesis of TB16-8. These studies will be followed by a Phase II application in which IND-required studies such as eye-irritation analysis, toxicology, and other relevant studies will be performed. These future studies will provide data required to meet with the FDA and discuss the necessary experiments to position TB16-8 for a topical treatment of Atopic Derm.

总结 我们已经开发了TB 16 -8，一种小分子，是TRPV 4和TRPA 1离子的有效抑制剂 渠道这两种离子通道与特应性皮炎（特应性皮炎）及其主要临床表现相关。 标志性慢性和使人衰弱的瘙痒（痒）。我们已经证明，局部应用在低 微克量的这种化合物有效地抑制小鼠和猪的瘙痒和炎症， 动物模型-各种症状的特应性皮肤。 目前有治疗特应性皮肤及其症状的批准;然而，没有一个是通用的药物， 并不是所有的特应性皮肤病药物都适合所有的患者。TB 16 -8预期作为单次治疗， 局部，可能替代免疫调节药物，或作为目前治疗的补充， 降低应用剂量的前景。TB 16 -8旨在用于局部应用;因此，除了 提供短期缓解，目标是长期使用，具有最小或无不良反应 方面的影响. 在目前的I期计划中，我们将进行旨在将TB 16 -8定位为IND前状态的研究。一是 将实现优化的化学合成。合成过程的每一步都会被仔细分析 并进行优化以产生满足FDA和ICH GMP要求的最终药物产品。的影响 TB 16 -8将在接触性皮炎的小鼠临床前模型中进行研究，方法是用DNFB（2，4-二硝基氟苯）致敏。 二硝基氟苯）和慢性致炎性皮炎，使用基于丙酮-二乙基 乙醚将测量皮肤肿胀行为和皮肤炎症。皮肤炎症和生物分布 还将评价猪血液和外皮中的TB 16 -8。 我们的初步数据是强有力的，可以被认为是如果我们的产品应该被考虑直接 II期;然而，局部给药后全身循环中TB 16 -8的皮肤浓度和检测 猪中局部给药的相关模型，尚未收集，使得 I期是达到IND前状态的必要阶段。我们将补充安全和长达48小时 TB 16 -8的生物分布数据目前在两种动物模型中可用，我们将优化化学 TB 16 -8的合成。 这些研究之后将进行II期申请，其中IND要求的研究，如眼刺激 将进行分析、毒理学和其他相关研究。这些未来的研究将提供所需的数据 与FDA会面并讨论将TB 16 -8定位为异位性局部治疗所需的实验 皮肤