# Development of KLS-13019 for Neuropathic Pain

> **NIH NIH R42** · KANNALIFE SCIENCES, INC. · 2022 · $991,944

## Abstract

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, toleran...

## Key facts

- **NIH application ID:** 10493291
- **Project number:** 5R42NS120548-03
- **Recipient organization:** KANNALIFE SCIENCES, INC.
- **Principal Investigator:** Douglas Eric Brenneman
- **Activity code:** R42 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $991,944
- **Award type:** 5
- **Project period:** 2021-09-30 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10493291

## Citation

> US National Institutes of Health, RePORTER application 10493291, Development of KLS-13019 for Neuropathic Pain (5R42NS120548-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10493291. Licensed CC0.

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