Phase II year
2019
(last award dollars: 2021)
Phase II Amount
$3,694,180
The successful management of chronic pain is inadequate in many patients and has contributed to theabuse of and addiction to opioids, a continuing major public health crisis in the United States andworldwide. The development of non-addictive pain therapeutics can help counter opioid addiction andbenefit patients, including those who suffer from neuropathic pain, and in particular diabetic neuropathicpain (DNP). Our project's goal is to develop a safe, efficacious and non-addictive small-molecule drugthat activates Kv7 voltage-gated potassium channels to address overactive neuronal activity in DNP.The first specific aim is discover Kv7 activators that favor Kv7 isoforms altered in DNP and found indorsal root ganglia, namely the Kv7.2/3 isoforms. Through iterative lead optimization studies on ournovel series of Kv7 activators, we are targeting Kv7.2/3 activation with selectivity over both Kv7.4channels and another off target of other Kv7.2/3 activators, GABAA receptors. This approach isexpected to decrease off-target side effects observed with the use of earlier non-biased Kv7 activatorsincluding urinary retention (mediated by Kv7.4), and somnolence and dizziness (mediated byenhancement of GABAA receptor function). This phase also includes optimization of absorption,distribution, metabolism, excretion, and toxicity profiles and building correlations between in-vitroactivities to in-vivo efficacies in a neuropathic rat DNP model. A second animal model, the L5/L6 spinalnerve constriction model, will also be used to test the ability of candidate compounds to generalize toother forms of neuropathic pain. The second specific aim will be to further characterize two to fouradvanced compounds by assessing additional pharmacological properties including CYP450induction/time dependent inhibition and in-vitro safety/selectivity panels. The third aim is to select acandidate for study in non-GLP toxicology and pharmacokinetic studies in rodent and non-rodentspecies. Specific aims four and five involve completing the studies needed to prepare an InvestigationalNew Drug (IND) application. These studies include Chemical Manufacturing Controls activities such asformulation studies and Good Manufacturing Practices synthesis of drug candidate followed bycardiovascular and safety pharmacology studies, and 28-day Good Lab Practices toxicology studies intwo animal species. This screening paradigm is intended to establish a clinic-ready, well-tolerated andwidely effective product to treat neuropathic pain.
Public Health Relevance Statement: Project Narrative
The management of pain is a growing challenge for health providers and patients with over 32 million adults
estimated as having neuropathic pain, leading to increased prescription of opioids contributing to the recent
rise in opioid misuse and addiction. The unmet need for the treatment of neuropathic pain include products
with greater response rates, effectiveness in multiple types of pain, convenience in use, reduced abuse and
addiction risk, activity via novel mechanisms, and the potential for safety and effectiveness in combination with
established treatments. The goal of this program is to develop a non-addictive selective Kv7.2/3 potassium
channel activator to treat neuropathic pain and alleviate the reliance on addictive opioids, with an initial focus
on diabetic neuropathic pain.
Project Terms: <21+ years old>
