Novel, Non-Opioid, Non-Addictive Intrathecal Therapy for the Treatment of Chronic Pain

人们一致认为，慢性疼痛是一个广泛存在的主要健康问题，需要开发更好的药物来满足这一未得到满足的需求，并与阿片类药物滥用危机作斗争。疼痛危机对患有严重疼痛的患者来说尤其沉重，他们中的许多人都在服用阿片类药物，而且所有其他措施都失败了。这些患者可能是一种简单但优雅的替代方案，即使用FDA批准的完全植入式泵进行鞘内(IT)药物输送。IT提供的剂量水平比系统提供所需的剂量低几个数量级，这极大地提高了安全边际。FDA只批准了两种用于这些微输液设备的止痛药，吗啡和齐康肽。虽然对许多患者有帮助，但副作用、安全性问题和疗效不足限制了它们的使用。CNTX-3001是一种新型、非阿片类、高效(微克分子KI和EC50)、高选择性的伤害性感受器(NOPR)小分子激动剂。包括非人类灵长类在内的多个物种的临床前数据表明，当通过IT管理直接将NOPR激动剂输送到脊髓时，它是强大的止痛剂。这项提议的目标是通过进行启用IND的研究和第一个人类阶段1试验来开发CNTX-3001。为了有效，NOPR激动剂必须直接应用于脊髓区域，因为大脑NOPR受体的激活可能会加剧疼痛。相比之下，在临床前研究(包括非人类灵长类动物)中，IT NOPR激动剂在治疗剂量水平上没有表现出行为副作用。CNTX-3001具有良好的IT传递的物理化学性质，包括理想的水溶度(传递到脑脊液)和脂溶性(局部分布到脊髓)的平衡。当通过团注将CNTX-3001注射到大鼠的腰髓时，CNTX-3001具有强大的止痛力，其疗效和行为副作用优于FDA批准的黄金标准选项IT吗啡。目标将是开发用于慢性IT交付的CNTX-3001，使用经批准的泵。这笔赠款将使我们能够扩大药物物质(DS)的生产，进行配方开发，并进行稳定性研究，以确保为IT交付提供稳定的药物产品(DP)。我们将生产GMP级DS和DP，并在两个临床前物种中进行非GLP和GLP毒性研究。来自这些研究的数据将导致一项第一阶段研究，评估顽固性慢性下腰痛患者的耐受性和有效性(IT交付不适合健康志愿者)。这笔赠款的结果将为进一步的临床开发(第二阶段和第三阶段试验)奠定基础，使用可持续输送CNTX-3001的植入式泵。我们相信Centrexion的IT候选药物CNTX-3001有能力在几乎没有其他选择的情况下彻底改变对严重疼痛的治疗。

There is a consensus that chronic pain is a widespread major health problem and that development of better drugs is needed to address this unmet need and combat the opioid abuse crisis. The pain crisis is particularly burdensome for patients with severe pain, many of whom are on opioids, and have failed all other measures. These patients may be candidates for a simple, but elegant alternative, namely intrathecal (IT) drug delivery using an FDA approved fully implantable pump. The dose level with IT delivery is orders of magnitude less than what is required for systemic delivery which greatly improves the safety margin. The FDA has approved only two pain drugs for these micro-infusion devices, morphine and ziconotide. Though helpful in many patients, side effects, safety issues, and inadequate efficacy limit their use. CNTX-3001 is a novel, non-opioid, highly potent (picomolar Ki and EC50), highly selective small molecule agonist of the nociception receptor (NOPr). Preclinical data in multiple species, including non-human primates, indicate that NOPr agonists are powerful analgesics when delivered directly to the spinal cord by IT administration. The goal of this proposal is to develop CNTX-3001 by conducting IND-enabling studies and a first-in-human Phase 1 trial. To be effective, NOPr agonists must be applied directly to the region of the spinal cord because activation of brain NOPr receptors may enhance pain. By contrast, IT NOPr agonists show no behavioral side effects at therapeutic dose levels in preclinical studies (including non-human primates). CNTX-3001 possesses favorable physiochemical properties for IT delivery, including an ideal balance of water solubility (for delivery to CSF) and lipid solubility (for local distribution into the spinal cord). When delivered via bolus to the lumbar spinal cord of rats, CNTX-3001 is powerfully analgesic with efficacy and behavioral side effect profiles superior to the gold- standard FDA-approved option, IT morphine. The goal will be to develop CNTX-3001 for chronic IT delivery using an approved pump. This grant will allow us to scale up production of drug substance (DS), undertake formulation development, and run stability studies to ensure a stable drug product (DP) for IT delivery. We will produce GMP-grade DS and DP and run non-GLP and GLP toxicity studies in two preclinical species. Data from these studies will lead to a Phase 1 study evaluating tolerability and efficacy in patients with intractable chronic low back pain (IT delivery is not appropriate for healthy volunteers). Results from this grant will lay the groundwork for further clinical development (Phase 2 and 3 trials) using implantable pumps for continuous delivery of CNTX-3001. We believe that Centrexion's IT drug candidate, CNTX-3001, has the capacity to revolutionize management of severe pain in patients with few or no other options.