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

项目摘要 疼痛管理由于其非常高的患病率， 患者和潜在机制，以及缺乏安全有效的治疗方案。大约50 100万美国人经历急性术后疼痛，而大约1亿美国成年人患有慢性疼痛。 痛苦阿片类药物仍然是中重度疼痛最有效的一类镇痛药，因此广泛用于治疗疼痛。 采用它们的镇痛活性通过μ-阿片受体（莫尔）的活化介导。不幸的是，莫尔 活化还导致严重的副作用，尤其是呼吸抑制，这是在哺乳动物中死亡的主要原因。 成瘾者过量以及呼吸和肾功能受损或自我调节的患者 与其它药物（例如，镇静剂、酒精）。其他严重的一般非致命的不良反应包括精神 混浊和嗜睡、成瘾、身体依赖和便秘。尽管存在这些问题， 缺乏更好的选择、阿片类药物处方的数量、每张处方的剂量以及服用天数 近年来，治疗有所增加。这导致了“处方阿片类药物流行病”， 吸毒和过量导致的死亡人数达到前所未有的水平。外周限制性肽类κ-阿片 受体（KOR）激动剂正作为一类新的非成瘾性和安全的镇痛剂出现。CR 845，一款 类全D-氨基酸四肽KOR激动剂，对KOR具有高效力和选择性，并且缺乏脑 在临床试验中已经确定肽KOR激动剂（i）产生镇痛作用，（ii）缺乏中枢神经系统功能， 副作用，（iii）不产生便秘或呼吸抑制，和（iv）减少对莫尔的需要 术后疼痛的激动剂补充治疗。然而，CR 845是短效的，需要每天多次 静脉内给药，因此限制了其临床应用和商业利益。根据之前的SBIR第一阶段合同， 我们已经确定了将上述四肽KOR激动剂与CVX-2000（专利的 先前使用并经临床验证的单克隆抗体载体，以产生长效肽-抗体 在一些实施方案中，药物缀合物（PAC）能够每周一次皮下给药。我们目前的长效KOR（LA-KOR）激动剂 先导化合物系列已实现了有效的KOR激动剂活性和选择性，并显示出临床前镇痛作用 活动拟议的后续SBIR第二阶段计划旨在：目标1：进一步优化现有的铅LA- 允许选择LA-KOR激动剂临床候选药物用于开发的KOR激动剂系列;目标2： 在广泛的疾病相关疼痛模型中表征LA-KOR激动剂的抗伤害感受特性， 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）启动研究。对公共卫生的影响和相关性：如果 成功，这一计划将带来新的，有效的，非成瘾性的，安全的，方便的镇痛药 能够减少或替代阿片类药物用于治疗中度至重度疼痛，从而改善疼痛控制， 维持患者的安全和生活质量，并帮助社会解决阿片类药物危机。

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.