Peripherally-restricted and long-acting kappa-opioid receptor (LA-KOR) agonists for pain

外周限制性长效 κ 阿片受体 (LA-KOR) 激动剂用于治疗疼痛

• 批准号: 9753194
• 负责人: Pierre Riviere
• 金额: $ 143.14万
• 依托单位: PEPTIDE LOGIC, LLC
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9753194
• 关键词: Absence of pain sensation; Acute; Address; Adult; Adverse effects; Alcohols; American; Amino Acids; Analgesics; Animals; Award; Biological Assay; Biological Availability; Brain; Cause of Death; Cessation of life; Chemistry; Chromatography; Chronic; Chronic inflammatory pain; Cleaved cell; Clinical; Clinical Trials; Constipation; Coupled; Cyclic AMP Receptors; Development; Disease; Dose; Drowsiness; Electrospray Ionization; Evaluation; Exclusion; Female; Filtration; Freund' s Adjuvant; Future; Goals; Half-Life; High Pressure Liquid Chromatography; High Prevalence; Hour; Human; Hydrophobic Interactions; Injections; Intravenous; Investigational Drugs; Investigational New Drug Application; Iodoacetates; Knowledge; Lead; Legal patent; Length; Light; Liquid Chromatography; Malignant Bone Neoplasm; Maximum Tolerated Dose; Medial; Mediating; Molecular; Monoclonal Antibodies; Mus; National Institute of Drug Abuse; Opioid; Opioid Receptor; Opioid agonist; Organ; Overdose; Pain; Pain management; Patients; Penetration; Peptide Synthesis; Peptide antibodies; Peptides; Performance; Peripheral; Pharmaceutical Preparations; Pharmacology; Phase; Physical Dependence; Plasma; Postoperative Pain; Process; Production; Psyche structure; Public Health; Quality of life; Rattus; Reaction; Reaction Time; Receptor Activation; Renal function; Residual state; Respiratory physiology; Route; Safety; Series; Small Business Innovation Research Grant; Societies; Solid; Structure; Structure-Activity Relationship; Surgical incisions; Temperature; Testing; Toxicology; Tranquilizing Agents; Ventilatory Depression; addiction; animal pain; antibody conjugate; azetidinone; base; cancer pain; chronic pain; clinical candidate; clinically relevant; commercialization; design; effective therapy; experience; follow-up; good laboratory practice; improved; in vivo; interest; kappa opioid receptors; lead series; male; mouse model; mu opioid receptors; nonhuman primate; novel; off-patent; opioid epidemic; osteoarthritis pain; pain model; patient safety; pharmacophore; pre-clinical; preclinical development; preclinical study; prescription opioid; programs; receptor; response; safety practice; screening; subcutaneous; success; time of flight mass spectrometry; treatment duration; tumor

PROJECT SUMMARY Pain management poses significant clinical challenges due to its very high prevalence, the diversity of patients and underlying mechanisms, and the lack of safe and effective treatment options. Approximately 50 million Americans experience acute post-operative pain, whereas about 100 million US adults suffer from chronic pain. Opioids remain the most effective class of analgesics for moderate-to-severe pain, and are thus broadly used. Their analgesic activity is mediated through activation of mu-opioid receptors (MOR). Unfortunately, MOR activation also results in serious adverse effects, especially respiratory depression, a primary cause of death in addict overdoses as well as in patients with compromised respiratory and kidney function or who self-medicate with other drugs (e.g., tranquilizers, alcohol). Other serious generally non-lethal adverse effects include mental clouding and somnolence, addiction, physical dependence, and constipation. Despite these concerns and for the lack of better options, the number of opioid prescriptions, dose per prescription, and number of days of treatment have increased in recent years. This has led to a “prescription opioid epidemic” resulting in unprecedented levels of addiction and overdose related deaths. Peripherally-restricted peptidic kappa-opioid receptor (KOR) agonists are emerging as a new class of non-addictive and safe analgesics. CR845, a first-in- class all D-amino acid tetrapeptide KOR agonist with high potency and selectivity for the KOR and lack of brain penetration, has established in clinical trials that peptidic KOR agonists (i) produce analgesia, (ii) lack central adverse effects, (iii) do not produce constipation or respiratory depression, and (iv) reduce the need for MOR agonist supplemental therapy in post-operative pain. CR845 is however short-acting, requiring multiple daily intravenous dosing, thus limiting its clinical utility and commercial interest. Under a previous SBIR Phase I award, we have established the feasibility to conjugate the above tetrapeptide KOR agonists to CVX-2000, a proprietary monoclonal antibody carrier previously used and clinically-validated to create long-acting peptide-antibody conjugates (PACs) enabling once-weekly subcutaneous dosing. Our current long-acting KOR (LA-KOR) agonist lead series has achieved potent KOR agonist activity and selectivity, and demonstrated preclinical analgesic activity. The proposed follow up SBIR Phase II program seeks to: Aim 1: further optimize the existing lead LA- KOR agonist series allowing selection of a LA-KOR agonist clinical candidate for development; Aim 2: characterize the antinociceptive profile of LA-KOR agonists in a broad range of disease-relevant pain models, in both male and female animals, to validate clinical indications; Aim 3: complete key preliminary preclinical studies to help design investigational new drug (IND)-enabling studies. IMPACT & Relevance to Public Health: If successful, this program will bring forward novel, efficacious, non-addictive, safe, and convenient analgesics able to reduce or replace opioids for the treatment of moderate-to-severe pain, thus improving pain control while maintaining patient safety and quality of life, and helping society to address the opioid crisis.

项目总结 疼痛管理带来了巨大的临床挑战，因为它的患病率非常高， 患者和潜在机制，以及缺乏安全有效的治疗选择。大约50 数百万美国人经历着手术后的急性疼痛，而大约1亿美国成年人患有慢性疼痛 疼痛。阿片类药物仍然是治疗中重度疼痛最有效的镇痛剂，因此被广泛 使用。它们的镇痛活性是通过激活Mu-阿片受体(MOR)介导的。不幸的是，更多 激活还会导致严重的不良反应，特别是呼吸抑制，这是#年死亡的主要原因。 吸毒者过量以及呼吸和肾功能受损或自我用药的患者 与其他药物(如镇静剂、酒精)一起使用。其他严重的、一般非致命性的不良影响包括精神 乌云密布、嗜睡、上瘾、身体依赖和便秘。尽管有这些担忧，但为了 缺乏更好的选择，阿片类药物处方的数量，每个处方的剂量，以及 近年来，治疗方法有所增加。这导致了“处方阿片类药物的流行”，导致 与吸毒和服药过量有关的死亡人数达到前所未有的水平。外周限制性多肽类kappa-阿片 受体(KOR)激动剂是一类新型的非成瘾、安全的镇痛药。CR845，一流的- 类全D-氨基酸四肽KOR激动剂，对KOR和脑缺乏症具有高效和选择性 已在临床试验中证实，多肽KOR激动剂(I)产生镇痛，(Ii)缺乏中枢 不良反应，(Iii)不会导致便秘或呼吸抑制，(Iv)减少对更多药物的需求 术后疼痛的激动剂补充治疗。然而，CR845是短效的，每天需要多次 静脉给药，从而限制了其临床应用和商业利益。根据之前的SBIR第一阶段奖， 我们已经确定了将上述四肽KOR激动剂偶联到专利药物CVX-2000上的可行性 用于制备长效多肽抗体的先前使用并经临床验证的单抗载体 结合物(PAC)，可实现每周一次皮下给药。我们目前的长效KOR(LA-KOR)激动剂 铅系列具有很强的KOR激动剂活性和选择性，并显示出临床前止痛作用。 活动。拟议的后续SBIR第二阶段计划旨在：目标1：进一步优化现有的Lead LA- KOR激动剂系列，可选择临床候选的LA-KOR激动剂进行开发；目标2： 在广泛的疾病相关疼痛模型中表征LA-KOR激动剂的抗伤害性特征 雄性和雌性动物，以验证临床适应症；目标3：完成关键的初步临床前研究 帮助设计研究性新药(IND)使能研究。对公共卫生的影响和相关性：如果 该项目的成功，将带来新颖、有效、不上瘾、安全、方便的镇痛药。 能够减少或取代阿片类药物治疗中重度疼痛，从而改善疼痛控制，同时 维护患者安全和生活质量，并帮助社会解决阿片类药物危机。