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

有一个共识是，慢性疼痛是一个普遍的主要健康问题，需要开发更好的药物来解决这一未满足的需求，并打击阿片类药物滥用危机。疼痛危机对于患有严重疼痛的患者来说尤其沉重，其中许多人服用阿片类药物，并且所有其他措施都失败了。这些患者可能是简单但优雅的替代方案的候选人，即使用FDA批准的完全植入式泵的鞘内（IT）药物递送。IT输送的剂量水平比全身输送所需的剂量水平低几个数量级，这大大提高了安全裕度。FDA只批准了两种止痛药用于这些微量输液装置，吗啡和齐考诺肽。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（皮摩尔Ki和EC 50）、高选择性的伤害感受受体（NOPr）小分子激动剂。包括非人灵长类动物在内的多个物种的临床前数据表明，NOPr激动剂在通过IT给药直接递送至脊髓时是强效镇痛剂。该提案的目标是通过进行IND使能研究和首次人体I期试验来开发CNTX-3001。为了有效，NOPr激动剂必须直接应用于脊髓区域，因为脑NOPr受体的激活可能会增强疼痛。相比之下，IT NOPr激动剂在临床前研究（包括非人灵长类动物）中在治疗剂量水平下没有表现出行为副作用。CNTX-3001具有用于IT递送的有利理化性质，包括水溶性（用于递送至CSF）和脂溶性（用于局部分布至脊髓）的理想平衡。当通过推注递送至大鼠的腰脊髓时，CNTX-3001是强效镇痛剂，其功效和行为副作用特征上级优于FDA批准的黄金标准选择IT吗啡。我们的目标是开发CNTX-3001，用于使用经批准的泵进行长期IT输送。这笔赠款将使我们能够扩大原料药（DS）的生产，进行配方开发，并进行稳定性研究，以确保稳定的药品（DP）用于IT交付。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I期研究，评估难治性慢性腰痛患者的耐受性和疗效（IT输送不适合健康志愿者）。这项资助的结果将为使用可植入泵持续输送CNTX-3001的进一步临床开发（2期和3期试验）奠定基础。我们相信，Centrexion的IT候选药物CNTX-3001有能力彻底改变很少或没有其他选择的患者的严重疼痛管理。

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.