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.
The U.S. and other countries around the world are facing ?dual crises of pain and opioid addiction.? Lohocla Research Corporation has responded to the opioid crisis and medication development challenge by designing, synthesizing and demonstrating, in pre-clinical studies, the efficacy and safety of a non-opiate, non-addictive new chemical entity for treatment of chronic pain. This new chemical entity, called Kindolor, has significant additional benefits of being able to prevent the development of chronic pain if administered soon after tissue injury, including post-operative conditions. Kindolor also has a highly significant ?opiate sparing? effect in conditions that may require the use of opiates, since Kindolor demonstrates a strong synergistic effect with morphine. In this grant application we are requesting funds to complete cGMP synthesis and GLP studies necessary for an IND application to the FDA, and given the FDA approval of the IND status, the completion of the first in human, Phase I clinical studies for safety and Phase 2a studies of efficacy to bring our medication to chronic pain sufferers.