At Artelo Biosciences, our scientific research and clinical development are advancing our understanding of how lipid-signaling modification, including targeting the receptors of the endocannabinoid system (ECS), can have an impact in the treatment of cancer and other serious diseases. For cancer and its complications such as cancer anorexia cachexia syndrome, neuropathic pain, anxiety, and sleeplessness, we believe our unique platform may lead to meaningful therapies for patients who currently have few or no treatment options.
ART27.13 - Benzimidazole Derivative
ART27.13 is a once-a-day, orally administered, highly potent, peripherally restricted synthetic, dual G-protein-coupled receptor (GPCR) agonist, benzimidazole derivative believed to target the cannabinoid receptors CB1 and CB2, which has the potential to increase appetite, food intake and reduce muscle wasting.
What are the CB1 and CB2 receptors?
The modulation of the ECS can be affected by using selective or non-selective agonists, partial agonists, inverse agonists, and antagonists of the cannabinoid receptors, CB1 and CB2. The CB1 receptor is distributed in brain areas associated with motor control, emotional responses, motivated behavior and energy homeostasis. In the periphery, CB1 is ubiquitously expressed in the adipose tissue, pancreas, liver, gastrointestinal tract, skeletal muscles, heart and the reproductive system. The CB2 receptor is mainly expressed in the immune system regulating its functions and is upregulated in response to tissue stress or damage in most cell types. The ECS is therefore involved in pathophysiological conditions in both the central and peripheral tissues (read more about the ECS).
ART27.13 has demonstrated potential in cancer anorexia (appetite and weight loss) as well as cancer-induced muscle degeneration (cachexia) through its dual CB1 and CB2 receptor agonism. CB1 receptor activation has been shown to increase food intake, alter adipokine and satiety hormone levels, alter taste sensation, decrease lipolysis (fat break down), and increase lipogenesis (fat generation).1 In pre-clinical studies, ART27.13 has also been shown to result in protecting human muscle cells from cancer-induced muscle degeneration (cachexia) via a CB2 mediated mechanism of action.2
References:
- O’Sullivan SE, Yates AS, Porter RK. The Peripheral Cannabinoid Receptor Type 1 (CB1) as a Molecular Target for Modulating Body Weight in Man. Molecules. 2021 Oct 13;26(20):6178. doi: 10.3390/molecules26206178.
- https://ir.artelobio.com/news-events/press-releases/detail/80/artelo-biosciences-reports-positive-pre-clinical-results
ART26.12 - Fatty Acid Binding Protein (FABP) Inhibition
ART26.12 is Artelo’s lead compound from a platform of inhibitors to Fatty Acid Binding Proteins (FABPs) with three patents issued in the US and 14 pending patent applications.
What are FABPs?
Hydrophobic ligands such as fatty acids serve many biological functions within the cell. They serve as metabolic energy sources, substrates for membranes and signaling molecules for metabolic regulation. Being insoluble, fatty acids require chaperones to bind and transfer them throughout various cellular compartments including the peroxisomes, mitochondria, endoplasmic reticulum, and nucleus. A family of highly expressed intracellular lipid-binding proteins called FABPs serve to bind with these free ligands to make their transport and dissemination throughout the cell possible. There are ten known FABP family members, or isoforms, expressed in humans (FABP1 through FABP9 and FABP12).1 These ten FABP isoforms are thought to modulate different processes within the body to varying extents, either independently or in concert. FABPs are attractive therapeutic targets as the high degree of sequence and structural similarities among family members have made the creation of drugs targeting specific FABPs challenging.
Artelo’s FABP platform includes a novel, selective FABP5 inhibitor ART26.12. In addition to its potential as a synthetic endocannabinoid modulator, FABP5 plays an important role in lipid signaling and is believed to be an attractive target for cancer drug development. Large amounts of human biomarker and animal model data support FABP5 as an oncology target, including triple negative breast cancer and castration-resistant prostate cancer. Additionally, FABP5 inhibition may have therapeutic value in Chemotherapy-Induced Peripheral Neuropathy, also known as CIPN, a common and often painfully debilitating complication of cancer therapies, sometimes resulting in reduction or cessation of treatment. In pre-clinical models, inhibition of FABP5 using ART26.12 has demonstrated activity in analgesia, ameliorating the effects of CIPN, a condition for which no currently approved treatment exists.2
References
- Smathers, R.L., Petersen, D.R. The human fatty acid-binding protein family: Evolutionary divergences and functions. Hum Genomics 5, 170 (2011). https://doi.org/10.1186/1479-7364-5-3-170
- SE O’Sullivan, A Pereira, P Duffy, L Ruston, M Kaczocha, I Ojima and A Yates. Discovery and preclinical evaluation of a novel inhibitor of FABP5, ART26.12, effective in chemotherapy-induced pain. June 26, 2022, 32nd Annual International Cannabinoid Research Society (ICRS) Symposium
ART12.11 - Cannabidiol (CBD)-Tetramethylpyrazine (TMP) Cocrystal
ART12.11 is a proprietary cocrystal of cannabidiol (CBD) and tetramethylpyrazine (TMP) designed to reduce polymorphism and improve other pharmaceutical qualities of the CBD molecule. Artelo has been issued two patents covering composition-of-matter and method of use in the US for ART 12.11, with additional pending patent applications.
What is polymorphism?
Polymorphism in pharmaceuticals refers to the ability of a solid material to exist in two or more crystalline forms. Polymorphic forms typically differ in their physicochemical properties and exhibit differences in pharmacological properties including absorption rate and overall bioavailability. For this reason, a drug based on a specific polymorphic form or with reduced polymorphism is likely to have an improved safety and efficacy profile.
The FDA further amplifies the challenge with drug substances associated with polymorphism in their guidance to drug developers, “Polymorphic forms of a drug substance can have different chemical and physical properties, including melting point, chemical reactivity, apparent solubility, dissolution rate, optical and mechanical properties, vapor pressure, and density. These properties can have a direct effect on the ability to process and/or manufacture the drug substance and the drug product, as well as on drug product stability, dissolution, and bioavailability. Thus, polymorphism can affect the quality, safety, and efficacy of the drug product.” 1
The crystal structure of cannabidiol (CBD) has been shown to exist in different forms indicating polymorphism is inherent.2 A preparation of cannabidiol with reduced polymorphism would be anticipated to have improved pharmaceutical properties.
What is a cocrystal and how can it address polymorphism?
Engineering of the crystalline structure of drug molecules by cocrystalization is a well-developed pharmaceutical strategy of enhanced pharmaceutics. Cocrystals are defined as crystalline materials composed of two or more molecules within the same crystal lattice. Compared to other classes of solid forms, cocrystals possess particular scientific and regulatory advantages. Although polymorphisms may also occur in cocrystals, their rational design offers the opportunity to reduce polymorphism to a greater extent compared to other pharmaceutical forms. Importantly, cocrystals are viewed as patentable subject matter.3 Thus, a pharmaceutical cocrystal offers the opportunity to develop a cannabidiol-based drug product with the potential for improved safety and efficacy from a strong proprietary position in a market searching for exclusivity advantages.
Recognizing the potential advantages of cocrystals, Artelo scientists and external collaborators set about to create a novel cocrystal of cannabidiol. The team was successful and identified a structure that meets all the criteria for an attractive pharmaceutical cocrystal, including only one polymorph (no polymorphism). In 2020, the U.S. Patent and Trademark Office issued a “composition of matter” patent with claims covering the Company’s cocrystal. The U.S. patent, No. 10,604467 for “Solid Forms of Cannabidiol and Uses Thereof,” provides intellectual property protection for ART12.11 until 2038.4
Artelo’s CBD cocrystal uses the coformer, tetramethylpyrazine (TMP; also called ligustrazine). TMP is a plant-derived compound widely used in Chinese, Korean and Native American medicine in higher doses for several diseases and conditions. In a lower quantity, TMP is also approved by the European Food Safety Authority as a food flavoring with a profile of cocoa, coffee, and mocha. The median lethal dose (estimated in rats after oral administration) is very high, about 2g/kg. Because TMP has the potential of additive or synergistic effects with CBD, Artelo’s CBD cocrystal may also benefit from pharmacologic advantages over CBD alone and on top of providing Artelo with an enviable patent protected CBD product.
References
- Andre S. Raw, Director- Division of Chemistry I FDA-CDER-Office of Generic Drugs Regulatory Consideration on Pharmaceutical Solids: Polymorphs / Salts and Cocrystals
- Tobias Mayr, et al., Cannabidiol revisited IUCrData (2017). 2, x170276
- Trask AJ. Molecular Pharmaceutics (2007) 4: (3) 301 – 309
- https://ir.artelobio.com/news-events/press-releases/detail/31/artelo-biosciences-awarded-composition-of-matter-patent-for
What is the Endocannabinoid System (ECS)?
The ECS is composed of cannabinoid receptors, endogenous receptor ligands (“endocannabinoids”) and their associated transporter mechanisms, as well as enzymes responsible for the synthesis and degradation of endocannabinoids and has emerged as a considerable target for pharmacotherapy approaches of numerous human diseases. As a widespread modulatory and lipid-signaling system, the ECS plays important roles in the CNS, development, synaptic plasticity, and the response to endogenous and environmental factors.
The modulation of the ECS can be affected by using selective or non-selective agonists, partial agonists, inverse agonists, and antagonists of the cannabinoid receptors, CB1 and CB2. The CB1 receptor is distributed in brain areas associated with motor control, emotional responses, motivated behavior and energy homeostasis. In the periphery, CB1 is ubiquitously expressed in the adipose tissue, pancreas, liver, gastrointestinal tract, skeletal muscles, heart and the reproductive system. The CB2 receptor is mainly expressed in the immune system regulating its functions and is upregulated in response to tissue stress or damage in most cell types. The ECS is therefore involved in pathophysiological conditions in both the central and peripheral tissues.
The actions of endogenous ligands can be enhanced or attenuated by targeting mechanisms that are associated with their transport within the cellular and extra cellular matrix as well as their synthesis and breakdown. Small molecule chemical modulators of the ECS can be derived from plants (“phytocannabinoids”), can be semi-synthetic derivatives of phytocannabinoids or endocannabinoids, or can be completely synthetic new chemical entities. We plan to develop approaches within our portfolio that address receptor binding and endocannabinoid transport modulation using only synthetic new chemical entities. Future approaches may also involve targeting synthesis or breakdown enzymes.
ECS targeting cannabinoid-based medicines are already approved and used to treat numerous medical conditions. The ECS is further implicated in many disease states within the peer reviewed literature including conditions which involve the regulation of food intake, central nervous system, pain, cardiovascular, gastrointestinal, immune and inflammation, behavioral, antiproliferative and reproductive functions. These areas of ECS pathophysiology are aligned with our therapeutic areas of focus: anxiety, pain, inflammation, anorexia, and cancer.
Publications
Select a program to view related publications and posters by Artelo’s researchers and advisors