Clinical Phase I trials on an IND single molecule dual inhibitor of Cav3 channels and soluble epoxide hydrolase for treatment of neuropathic pain

Cav3通道和可溶性环氧化物水解酶的单分子双重抑制剂治疗神经性疼痛的IND临床I期试验

• 批准号: 10760089
• 负责人: Xinmin Simon Xie
• 金额: $ 149.99万
• 依托单位: AFASCI, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-21 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10760089
• 关键词: Absence Epilepsy; Absence of pain sensation; Address; Affect; American; Analgesics; Animal Model; Animals; Anti-Inflammatory Agents; Antiinflammatory Effect; Biological; Biological Assay; Biological Availability; Brain; Businesses; Calcium Channel; Canis familiaris; Cardiac; Cardiac Myocytes; Cardiotoxicity; Clinical; Clinical Research; Clinical Trials; Data; Degenerative polyarthritis; Development; Diabetes Mellitus; Dose; Dose Limiting; Double-Blind Method; Drug Design; Drug Interactions; Drug Kinetics; Drug Targeting; Economic Burden; Electrocardiogram; Electroencephalography; Electromyography; Electrophysiology (science); Enzymes; Epoxide hydrolase; Fatty Acids; Genes; Glycols; Half-Life; Heart Diseases; Human; Hyperalgesia; Inflammation; Inflammation Mediators; Inflammatory; Ion Channel; Irritable Bowel Syndrome; Ligand Binding; Malignant Neoplasms; Maximum Tolerated Dose; Measures; Microglia; National Institute of Neurological Disorders and Stroke; Nervous System; Neurons; Neuropathy; Opioid; Oral; Pain; Pain management; Pathway interactions; Patients; Peripheral; Peripheral Nerves; Persistent pain; Pharmaceutical Preparations; Pharmacology; Phase; Phase I Clinical Trials; Phenotype; Plasma; Polypharmacy; Progress Reports; Rattus; Reporting; Rodent; Safety; Sensory; Signal Pathway; Spinal Cord; Spinal Ganglia; T-Type Calcium Channels; Testing; Therapeutic; Tissues; Touch sensation; Toxic effect; Up-Regulation; Visceral pain; allodynia; animal efficacy; capsule; chemotherapy; chronic neuropathic pain; chronic pain; clinical investigation; cohort; cost; experience; first-in-human; gabapentin; gain of function mutation; genotoxicity; healthy volunteer; improved; in vivo; inflammatory pain; inhibitor; innovation; knockout gene; manufacture; medication nonadherence; nerve injury; new chemical entity; non-opioid analgesic; opioid epidemic; opioid mortality; osteoarthritis pain; pain model; pain relief; pain signal; painful neuropathy; pediatric patients; phase I trial; phase II trial; pill; placebo controlled study; pregabalin; response; screening; side effect; single molecule; small molecule; social; spared nerve; success; targeted biomarker; tissue injury

7. PROJECT SUMMARY We propose conducting clinical Phase I trials on an active IND (157314), AFA-281, a non-opioid, single small molecule that inhibits both T-type Cav3 calcium channels and soluble epoxide hydrolase (sEH) to treat chronic neuropathic pain. Millions of Americans suffer from chronic pain, especially neuropathic and inflammatory types. Yet less than 50% of patients respond to current treatments, leading to increased reliance on opioids. There is strong rationale to target Cav3 and sEH jointly. Tissue and nerve injury trigger inflammation, which increases neuronal hyperexcitability. This increases activation of the Cav3.2 channel subtype in the sensory nervous system, exacerbating pain and touch sensitivity. Cav3.2 upregulation and overactivation were observed in human patients with chemotherapy-induced neuropathic pain, irritable bowel syndrome (IBS) and osteoarthritis (OA), with similar findings in animals. In addition, sEH breaks down the body’s anti-inflammatory mediators, epoxy-fatty acids (EpFAs), into inflammatory diols. sEH is involved in inflammatory OA pain and IBS visceral pain in humans. Single sEH inhibitors mitigate inflammatory and neuropathic pain in animals. Therefore, a single drug inhibiting both Cav3.2 and sEH could produce complementary analgesia and anti- inflammatory effects. As a dual-inhibitor fitting this profile, AFA-281 could improve the patient experience by reducing polypharmacy, pill burden, medication nonadherence, dose-limiting side effects, and drug-drug interactions. AFA-281 potently inhibits both Cav3.2 and sEH, whereas it causes 50- to 500-fold weaker inhibition against 81 off-targets tested. AFA-281 produces significant analgesia and reduction of brain microglia activation in a neuropathic pain model of spared nerve injury (SNI) in rats. GLP safety pharmacology, toxicity, and genotoxicity studies indicate AFA-281 has no cardiac toxicity concerns and is a safe drug meriting first-in-human studies. The FDA thoroughly reviewed our IND application and determined "IND 157314 Study may proceed" on November 11, 2022. Therefore, we propose conducting clinical Phase I trials with three Specific Aims: Aim 1. Phase I Part 1: A double-blind, placebo-controlled study of single ascending doses (SAD) of oral AFA- 281 in healthy volunteers will investigate the safety, tolerability, and pharmacokinetics (PK) of AFA-281. Aim 2. Phase I Part 2: A double-blind, placebo-controlled study of multiple ascending doses (MAD) of oral AFA- 281 in healthy volunteers will characterize the safety and PK for up to 14 days of dosing. Aim 3. Explore target engagement during the Part 2 MAD trial. In vivo sEH inhibition will be measured by plasma EpFA/diol ratio increases. Electroencephalogram/electromyography (EEG/EMG) will be used to assess Cav3 channel engagement, as EEG changes by a Cav3 blocker have been reported in human and rodent EEG. Phase I trial success by achieving the primary safety objective can advance AFA-281 to proof-of-concept studies on neuropathic pain in Phase II trials. Ultimately, an effective and safe, non-opioid, non-NSAID and non-addictive analgesic will provide an alternative for neuropathic pain treatment and help end the opioid crisis.

7。项目摘要 我们建议在主动IND（157314），AFA-281（一种非阿片，单一的小型小型）上进行I期临床试验 抑制T型Cav3钙通道和可溶性环氧化物水解酶（SEH）的分子以治疗慢性 神经性疼痛。数以百万计的美国人患有慢性疼痛，尤其是神经性和炎症类型。 然而，不到50％的患者对当前治疗做出反应，从而增加了对阿片类药物的依赖。 靶向CAV3和SEH共同有很强的理由。组织和神经损伤触发注射，这是 增加神经元过度兴奋性。这增加了感觉中Cav3.2通道亚型的激活 神经系统，加剧疼痛和触摸敏感性。 CAV3.2观察到上调和过度激活 在患有化学疗法诱发的神经性疼痛的人类患者中，肠易激综合征（IBS）和 骨关节炎（OA），在动物中有类似的发现。此外，SEH分解了人体的抗炎 介体，环氧脂肪酸（EPFAS）成炎症二醇。 SEH参与炎症OA疼痛和IBS 人类内脏疼痛。单SEH抑制剂减轻动物的炎症和神经性疼痛。 因此，一种抑制cav3.2和seh的单一药物可以产生完全镇痛和抗 炎症作用。作为拟合此配置文件的双重抑制剂，AFA-281可以通过 降低多种药物，药丸伯嫩，药物不遵守，剂量限制副作用和药物药物 互动。 AFA-281可能会抑制CAV3.2和SEH，而它会引起50至500倍的抑制作用 针对81个脱离目标测试。 AFA-281产生明显的镇痛作用并减少脑小胶质细胞活化 在大鼠中保存神经损伤（SNI）的神经性疼痛模型中。 GLP安全药理学，毒性和 遗传毒性研究表明AFA-281没有心脏毒性问题，是一种安全的药物，是人类的首次人为 研究。 FDA彻底审查了我们的IND应用程序，并确定了“ IND 157314研究可以进行” 因此，2022年11月11日。因此，我们提议进行I阶段试验的三个特定目标： 目标1。I期第1部分：双盲，安慰剂对照研究的单一升剂剂量（SAD）口服Afa- 281在健康的志愿者中，将研究AFA-281的安全性，耐受性和药代动力学（PK）。 AIM 2。第一阶段第2部分：一项双盲，安慰剂对照研究的多种升剂剂量（MAD）的口服AFA- 281在健康的志愿者中，将以最长14天的剂量来表征安全性和PK。 目标3。在第2部分MAD试验期间探索目标参与。体内SEH抑制作用将通过血浆测量 EPFA/二醇比增加。脑电图/肌电图（EEG/EMG）将用于评估CAV3 频道的参与度，随着人类和啮齿动物脑电图中的CAV3阻滞剂的变化。 通过实现主要安全目标，I阶段试验成功可以将AFA-281推进到概念证明研究 关于II期试验中的神经性疼痛。最终，有效且安全，非阿片类药物，非NSAID和非依恋 镇痛药将提供神经性疼痛治疗的替代方法，并有助于结束阿片类药物危机。