Neuropathic pain remains a challenging neurologic disorder that adversely affects quality of life and presents a large unmet medical need. Chemotherapy-induced peripheral neuropathy (CIPN) is a chronic, severely debilitating consequence of cancer therapy for which there are no effective management strategies. Upwards of 80-97% of CIPN patients reported using prescription opioids for this pain management. Mitochondrial dysfunction, oxidative stress, and inflammation have all been implicated in CIPN etiology. In a mouse model of paclitaxel-induced pain sensitivity, we have previously reported that cannabidiol (CBD) is effective in preventing the onset of this treatment consequence. Now a new CBD analogue (KLS-13019) has been discovered in our laboratory that has improved drug-like properties in comparison to CBD, while retaining neuroprotective properties. In our Phase 1 STTR, the previous neuroprotective effects of CBD to prevent the development of mechanical sensitivity in the presence of paclitaxel were confirmed and extended to the structural analogue KLS- 13019. Both compounds were equi-effective and equi-potent following oral administration. In the reversal studies, CBD did not attenuate mechanical sensitivity when administered after CIPN was induced by paclitaxel treatment. However, KLS-13019 significantly and dose-dependently attenuated tactile sensitivity in the reversal paradigm and was more potent and effective than treatment with morphine. Importantly, KLS-13019 also attenuated the reinforcing properties of morphine in a mouse model of morphine self-administration. In vitro, we have shown that KLS-13019 and CBD protect against paclitaxel-induced oxidative stress in dorsal root ganglia cultures, and that a mechanism underlying this neuroprotection is regulation of intracellular calcium via the mitochondrial Na+/Ca++ exchanger-1 (mNCX-1). Our central hypothesis is that administration of CBD or KLS-13019 preserves Ca2+ homeostasis by promoting activity of the mNCX-1. Furthermore, our new data demonstrates that the putative cannabinoid receptor GPR55 is induced following paclitaxel treatment and contributes to sensory neuron toxicity and inflammation that can be reversed by KLS-13019, but not CBD. These studies support a pro- nociceptive, pro-inflammatory role for GPR55 that mediates pain associated with CIPN. We predict bi-modal pharmacological effects of KLS-13019 that can both increase viability of sensory neurons exposed to paclitaxel acutely and decrease inducible GPR55 that contributes to long-term neuroinflammation. Evidence has been obtained that KLS-13019 is an antagonist to GPR55 as shown in a β-arrestin assay. In Phase 2, we will optimize the process to prepare KLS-13019, develop analytical methods, optimize formulation, and evaluate in pharmacokinetic studies. A fully battery of genotoxicity, safety pharmacology, toxicokinetic, and toxicology reports will be completed. KLS-13019 will be evaluated in a rat models of CIPN, tolerance, impairment, and abuse liability. At the conclusion of this grant, the data will be submitted to the FDA and a pre-IND meeting will be completed.

Narrative Chronic pain management continues to be a significant societal need with growing concerns about the efficacy of opiates and the risks of long-term dependence. Mitochondrial dysfunction, calcium dysregulation, oxidative stress, and inflammation have all been implicated in neuropathic pain. Cannabidiol (CBD) is a non-psychoactive component of Cannabis sativa that is effective in both treating neuropathic pain and relieving opiate dependence. However, CBD has severe limitations in terms of potency, safety, and oral bioavailability. Kannalife has solved these problems in its patented series of derivatives that include KLS-13019. This grant will further develop KLS-13019 for advancement to safety pharmacology evaluation, toxicology studies, and human clinical trials.