Development of KLS-13019 for Neuropathic Pain

神经病理性疼痛仍然是一种具有挑战性的神经系统疾病，对生活质量产生不利影响，并表现为 大量未得到满足的医疗需求。化疗所致周围神经病(CIPN)是一种慢性、严重的 癌症治疗的衰弱后果，目前还没有有效的管理策略。以上的 80-97%的CIPN患者报告使用处方阿片类药物来控制疼痛。线粒体 功能障碍、氧化应激和炎症都与CIPN的病因有关。在小鼠模型中 在紫杉醇诱导的疼痛敏感性方面，我们之前已经报道过大麻二醇(CBD)在预防 这种治疗后果的发生。现在发现了一个新的CBD类似物(KLS-13019)在我们的 与CBD相比，实验室具有更好的类药物特性，同时保持神经保护 属性。在我们的第一阶段STTR中，CBD先前的神经保护作用阻止了 证实了紫杉醇存在下的机械敏感性，并将其推广到结构类似物KLS- 13019。这两种化合物在口服后都是同等有效和同等效力的。在逆转研究中， 在紫杉醇诱导CIPN后给予CBD并不能降低机械敏感性。 然而，KLS-13019显著且呈剂量依赖性地减弱了反转范式中的触觉敏感性 而且比吗啡治疗更有效和有效。重要的是，KLS-13019还减弱了 在吗啡自我给药的小鼠模型中增强吗啡的特性。在体外，我们已经证明 KLS-13019和CBD对紫杉醇诱导的背根节细胞氧化应激的保护作用，以及 这种神经保护的一种机制是通过线粒体调节细胞内钙 Na+/Ca++交换器-1(mNCX-1)。我们的中心假设是，给予CBD或KLS-13019可以 促进mNCX-1活性的钙离子动态平衡。此外，我们的新数据表明， 紫杉醇治疗后可能的大麻素受体GPR55被诱导并参与感觉神经元 毒性和炎症可以被KLS-13019逆转，但不能被CBD逆转。这些研究支持一个有利的-- GPR55的伤害性、促炎作用，介导了CIPN相关的疼痛。我们预测多式联运 KLS-13019对紫杉醇诱导的感觉神经元活性的药理作用 急性和减少诱导的GPR55，这有助于长期的神经炎症。有证据表明 β-arrestin分析表明，KLS-13019是GPR55的拮抗剂。在第二阶段，我们将优化 制备KLS-13019，开发分析方法，优化配方，并在 药代动力学研究。完整的遗传毒性、安全药理学、毒代动力学和毒理学 报告将完成。KLS-13019将在大鼠CIPN、耐受性、损害和 滥用责任。在这笔赠款结束时，数据将提交给FDA，IND前会议将 才能完成。

Neuropathic pain remains a challenging neurologic disorder that adversely affects quality of life and presents a large unmet medical need. Chemotherapy-induced peripheral neuropathy (CIPN) is a chronic, severely debilitating consequence of cancer therapy for which there are no effective management strategies. Upwards of 80-97% of CIPN patients reported using prescription opioids for this pain management. Mitochondrial dysfunction, oxidative stress, and inflammation have all been implicated in CIPN etiology. In a mouse model of paclitaxel-induced pain sensitivity, we have previously reported that cannabidiol (CBD) is effective in preventing the onset of this treatment consequence. Now a new CBD analogue (KLS-13019) has been discovered in our laboratory that has improved drug-like properties in comparison to CBD, while retaining neuroprotective properties. In our Phase 1 STTR, the previous neuroprotective effects of CBD to prevent the development of mechanical sensitivity in the presence of paclitaxel were confirmed and extended to the structural analogue KLS- 13019. Both compounds were equi-effective and equi-potent following oral administration. In the reversal studies, CBD did not attenuate mechanical sensitivity when administered after CIPN was induced by paclitaxel treatment. However, KLS-13019 significantly and dose-dependently attenuated tactile sensitivity in the reversal paradigm and was more potent and effective than treatment with morphine. Importantly, KLS-13019 also attenuated the reinforcing properties of morphine in a mouse model of morphine self-administration. In vitro, we have shown that KLS-13019 and CBD protect against paclitaxel-induced oxidative stress in dorsal root ganglia cultures, and that a mechanism underlying this neuroprotection is regulation of intracellular calcium via the mitochondrial Na+/Ca++ exchanger-1 (mNCX-1). Our central hypothesis is that administration of CBD or KLS-13019 preserves Ca2+ homeostasis by promoting activity of the mNCX-1. Furthermore, our new data demonstrates that the putative cannabinoid receptor GPR55 is induced following paclitaxel treatment and contributes to sensory neuron toxicity and inflammation that can be reversed by KLS-13019, but not CBD. These studies support a pro- nociceptive, pro-inflammatory role for GPR55 that mediates pain associated with CIPN. We predict bi-modal pharmacological effects of KLS-13019 that can both increase viability of sensory neurons exposed to paclitaxel acutely and decrease inducible GPR55 that contributes to long-term neuroinflammation. Evidence has been obtained that KLS-13019 is an antagonist to GPR55 as shown in a β-arrestin assay. In Phase 2, we will optimize the process to prepare KLS-13019, develop analytical methods, optimize formulation, and evaluate in pharmacokinetic studies. A fully battery of genotoxicity, safety pharmacology, toxicokinetic, and toxicology reports will be completed. KLS-13019 will be evaluated in a rat models of CIPN, tolerance, impairment, and abuse liability. At the conclusion of this grant, the data will be submitted to the FDA and a pre-IND meeting will be completed.