A novel therapeutic to ameliorate chronic pain and reduce opiate use

Lohocla Research Corporation, Aurora CO

Investigators

Linked publications, trials & patents

Abstract

Original Project Abstract Over 100 million adults in the U.S. suffer from intermittent or constant chronic pain, and chronic pain affects at least 10% of the world’s population. The primary pharmaceuticals for treatment of chronic pain have been natural or synthetic opioids and the use of opioids for pain treatment has resulted in what has been called an “epidemic” of opioid abuse, addiction and lethal overdoses. We have, through a process of rational drug design, generated a new chemical entity (NCE) and have given it the name Kindolor. Kindolor is a non-opiate, non-addicting molecule that was developed specifically to simultaneously control the aberrant activity of three targets on the peripheral sensory system that are integral in the development and propagation of chronic pain. Kindolor acts as an inhibitor of the pain propagating Nav1.7 and Nav1.8 sodium channels and as an inhibitor of NMDA receptors that act to magnify pain signals (Fig A). We have generated a process to synthesize Kindolor at 99% purity. In our pre-clinical studies, we have demonstrated the efficacy of Kindolor to reduce or eliminate chronic pain generated in five animal models at doses compatible with use of Kindolor in humans. We have generated evidence that this broad range of efficacy is a result of the multi-target engagement by Kindolor. We have generated the initial evidence for the safety (high TI) of Kindolor and its uneventful metabolism. Additional attractive features of Kindolor are that it can prevent the development of chronic pain if given soon after tissue injury. And if combined with low doses of opiates, Kindolor produces a substantial “opiate sparing” effect through synergistic actions with the opiates. To bring Kindolor to the public, we are proposing to complete the pre-clinical studies necessary for an IND application to the FDA and, if the IND is approved, the completion of a Phase 1a and 1b, first in human, study of the safety of our compound, and then a Phase 2a study of efficacy on pain of osteoarthritis. To start, we will have Kindolor synthesized using cGMP procedures. This will include development of methods for scaling up production quantities. We will produce a formulation for oral drug administration to humans and will use this formulation for GLP studies of pharmacokinetics and toxicokinetics in two species of animals (rat and minipig). We will complete GLP studies of safety of the formulation in the two species, including escalating dose experiments and sub-chronic dosing for 28 days with low, moderate, and high doses of the drug product. These studies will include a 14-day recovery period to assess delayed toxicity. Genotoxicity studies will also be completed, as will specific assessments of cardiovascular and respiratory toxicity prior to a pre-IND meeting with the FDA. The satisfactory completion of the pre-IND meeting will allow for expedient completion of the IND application. Given approval of the IND application, we propose to complete the Phase Ia and 1b study and the Phase 2a study. In all, our goal is to bring our compound to a full Phase 2 ready stage for licensing or partnering with a Pharma company willing and able to bring the medication to the chronic pain sufferer. Abstract: Supplement to UH3DA047680 (project period 7/01/21 to 6/30/24) Major accomplishments of the UH3 project to date include the completion of nonclinical toxicology studies, the formulation of kindolor tosylate enteric-coated tablets, and submission of an IND application for Phase 1a clinical trial in August 2022. The FDA placed a Full Clinical Hold on the clinical trial in October 2022, requiring further studies. These studies were completed and a response to the clinical hold was submitted in September 2023. The clinical hold was removed in October 2023. Because of the delay associated with the Clinical Hold, and because of modification of the clinical trial protocol requested by the FDA, the budget for the Phase 1 trial has increased from the budget that was included with the UH3 application (March 2021). This supplement is requested in order to provide the funding needed to perform the approved phase 1a clinical trial.