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

人们一致认为，慢性疼痛是一个普遍存在的重大健康问题，需要开发更好的药物来解决这一未满足的需求，并应对阿片类药物滥用危机。疼痛危机对严重疼痛的患者来说尤其沉重，他们中的许多人正在服用阿片类药物，并且没有采取所有其他措施。这些患者可能是一种简单但优雅的替代方案的候选者，即使用FDA批准的全植入式泵进行鞘内给药。注射IT的剂量水平比全身注射所需的剂量低几个数量级，这大大提高了安全边际。FDA只批准了两种用于微输液器的止痛药，吗啡和齐iconotide。虽然对许多患者有帮助，但副作用、安全性问题和功效不足限制了它们的使用。CNTX-3001是一种新型、非阿片类、高效（微摩尔Ki和EC50）、高选择性的痛觉受体（NOPr）小分子激动剂。包括非人灵长类动物在内的多种物种的临床前数据表明，当通过IT给药直接给药到脊髓时，NOPr激动剂是强效镇痛药。该提案的目标是通过开展ind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，因为大脑NOPr受体的激活可能会增强疼痛。相比之下，在临床前研究（包括非人灵长类动物）中，IT NOPr激动剂在治疗剂量水平下没有表现出行为副作用。CNTX-3001具有良好的IT递送理化性质，包括水溶性（递送至CSF）和脂溶性（局部分布至脊髓）的理想平衡。当给药给药到大鼠腰椎脊髓时，CNTX-3001具有强大的镇痛作用，其疗效和行为副作用优于fda批准的黄金标准选择，IT吗啡。目标是开发CNTX-3001，使用经批准的泵进行长期IT交付。这项拨款可让我们扩大原料药（DS）的生产规模、进行配方开发和进行稳定性研究，以确保提供稳定的药物产品（DP）。我们将生产gmp级的DS和DP，并在两个临床前物种中进行非GLP和GLP毒性研究。这些研究的数据将用于评估顽固性慢性腰痛患者的耐受性和疗效的1期研究（IT不适合健康志愿者）。这笔拨款的结果将为进一步的临床开发（2期和3期试验）奠定基础，使用植入式泵连续输送CNTX-3001。我们相信，centrrexion的IT候选药物CNTX-3001有能力彻底改变那些没有或很少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.