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.

This grant is aimed at the development of a novel, small molecule, nociceptin receptor agonist to be given intrathecally via an implanted microinfusion pump for the management of chronic severe intractable pain. The focus of this proposal is to complete IND-enabling CMC and preclinical toxicology studies, followed by a delayed onset Phase 1 trial in patients.