Kindolor word mark

Lohocla Development Pipeline

Preclinical
IND application
Phase I
Phase II
Phase III
Registration
Phase IV
Nezavist®
Kindolor®

Kindolor®: Brief Summary

Potassium Channel

Lohocla Research Corporation rationally designed a novel small molecule named Kindolor for treatment of chronic pain syndromes. The molecule simultaneously reduces the over-activity of NMDA (NR1-NR2B) receptors and the Nav1.7 and Nav1.8 sodium channels in chronic pain syndromes. Kindolor has negligible blood brain barrier penetrance which would reduce deleterious CNS side effects. Thus, Kindolor’s actions are confined to the peripheral nervous system. Kindolor’s proof of concept has been established and shows that it produces significant anti-hyperalgesia properties in four animal models of chronic pain. The metabolic fate profile of Kindolor is via glucuronidation and hydroxylation. No genotoxic effects of Kindolor have been noted. Acute dosing levels 50 times higher than doses producing therapeutic effects produced no overt signs of toxicity and we estimate the therapeutic index for Kindolor to be greater than 50. Following a second non-rodent species, one-month toxicity study, we plan to open a US IND and begin clinical testing.

Fig. A
Kindolor binding site cartoon.
Illustrates the interaction of NMDA receptors with TRPV1 receptors in the sensory terminals of nociceptors. NMDA receptors are co-localized with the TRPV1 receptors, and the activation of the NMDA receptors by glutamate released into the surrounding milieu upon local irritation, generates a phosphorylation cascade via PKC and PKA. The end-product of this cascade is the phosphorylation of TRPV1 and an increase in its activity in generating pain signals . Kindolor inhibits NMDA receptor function and significantly dampens this enhanced excitability.
Illustrates a schematic of the delta opiate receptor (DOR) coupled to adenylyl cyclase (AC) through the Gi protein trimer. Activation of DOR at peripheral nerve endings leads to dissociation of the Gi trimer and the Gαi subunit inhibits AC activity, lowering cellular cAMP, while the βɤ subunits inhibit voltage sensitive calcium channels and stimulates the GIRK type potassium channels. These actions reduce the potential for nociceptor depolarization and pain signal generation. Kindolor acts as an agonist at DORs.
Focuses attention on the conduction of pain information from the nociceptor terminals. Nav1.7 channels have a low (hyperpolarized) activation threshold, and this activation initially (prior to responding with an action potential) produces a change in membrane potential which can activate the Nav1.8 channels, which quickly respond with an action potential. Both the Nav1.8 and Nav1.7 action potentials are propagated to the dorsal root ganglia where the cell bodies of the sensory neurons reside. Kindolor inhibits both the Nav1.8 (more potently) and Nav1.7 channels and thus depresses both the excessive signal generation by Nav1.7 and increased conduction by both Nav1.8 and Nav1.7 in patients suffering from chronic pain.
Illustrates events happening within the sensory dorsal root ganglia. Within the dorsal root ganglia, a close juxtaposition is evident between two cell bodies of the sensory neurons and satellite glial cells. The satellite glial cells are “sandwiched” between the two cell bodies of the sensory neurons, and this structure is called a “sandwich synapse.” One of the principal functions of the sandwich synapse is to amplify the signals reaching the dorsal root ganglia. As illustrated, this occurs via release of ATP by the cell body of the initially activated neuron. The ATP activates the purinergic receptors (P2Y2) on the satellite glial cells, and the satellite glial cells respond by releasing glutamate. The glutamate activates NMDA receptors on the neighboring (juxtaposed) sensory neuron cell body and instigates depolarization and conduction of signal to the spinal cord. Kindolor, by inhibiting the NMDA receptor on cell bodies of the sensory neurons prevents the amplification of the signal mediated by the sandwich synapses.
Illustrates a schematic of the pentameric GABA-A receptor which gates chloride flux across a neuronal membrane. In the presence of low levels of GABA, Kindolor acts as a positive allosteric modulator (PAM) to promote channel opening. Kindolor acts at a novel site at the interface of the α+β- subunits extracellular domain (this is illustrated as a blue dot at the top of the rendition of the pentameric arrangement of the GABA-A receptor; top right of Box 5). Activation of GABA-A receptors in the DRG has been shown to inhibit signal propagation through the DRG.

Background

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 percent 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. The satisfactory completion of a pre-IND meeting with the FDA will allow for expedient completion of the IND application. Given approval of the IND application, we propose to complete the Phase 1a 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.

Public Health Relevance Statement

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.