The Promise of Modulating Lipid-Signaling Pathways
Emerging science suggests that modulating lipid-signaling pathways can unlock novel therapeutic strategies for diseases and medical conditions for which there are no or limited options. Artelo Biosciences is at the forefront of advancing the application of lipid-modulating therapeutics.
Lipids are critical to certain cell signaling pathways. Lipid-signaling modulation is the alteration of the signaling of lipid molecules to change biological activity or function within cellular communication pathways.
Lipids contain various fatty acids as their building blocks and are the key components of lipid activity. Omega-3 Fatty Acids are a commonly known example of fatty acids with proven biologic activity. Fatty Acid Binding Proteins (FABPs) facilitate lipid-signaling by binding to fatty acids which control various cellular functions. FABPs are essential mediators of normal cell signaling processes and under certain conditions can be associated with dysfunctional signaling. Inhibition of specific FABPs may correct abnormal lipid-signaling which holds promise as new treatment modalities.
Artelo’s innovative approach targets acute and chronic conditions, including pain, cancer, anxiety, depression and other conditions through modulating lipid-signaling pathways.
Learn more about lipid-signaling modulation
Understanding the Language of Lipids
Lipids are fats and oils which play crucial roles as building blocks, signaling molecules, energy sources, antioxidants, and barriers within cells. Lipids are involved in many physiologic activities and lipidomics is the study of the complete set of lipids within a cell, tissue, or organism. By analyzing the lipidome, valuable insights are gained into lipid signaling pathways in both healthy and disease states.
Cellular Messengers – Lipids transmit messages within and between cells in different ways.
- Lipid mediators, such as endocannabinoids, are lipid-based neurotransmitters that modulate a wide range of physiologic functions, including pain, appetite, mood, and memory.
- Lipids, like diacylglycerol (DAG), are pivotal secondary messengers that are generated in response to extracellular stimuli such as neurotransmitters. They orchestrate intracellular cascades triggering various cellular responses.
- Hormones synthesized from cholesterol regulate diverse physiological functions including reproduction, metabolism, and stress response.
- Certain lipid-derived molecules, such as growth factors, stimulate cell proliferation and differentiation.
Diverse Roles – Lipids are essential components of living organisms. They serve a variety of crucial functions beyond signaling within cells and the body as a whole.
- Structural Components – Phospholipids form the primary structure of cell membranes and organelle membranes, creating a barrier between the inside and outside of the cell or organelle.
- Energy Storage – Triglycerides are the primary energy storage molecules in the body and provide a concentrated source of energy. Fatty acids derived from triglycerides can be broken down to generate Adenosine Triphosphate (ATP), the energy currency of cells.
Abnormal Function – When lipid-signaling pathways are disrupted or dysfunctional, cells may not receive the proper signals to function correctly. This can lead to impaired growth, proliferation, and metabolic processes manifesting in several disease states.
- Cancer – Increased lipid metabolism and signaling can contribute to uncontrolled cell growth and proliferation, a hallmark of cancer. Inflammation – Chronic inflammation can be triggered by dysregulated lipid signaling, leading to various inflammatory diseases.
- Metabolic Disorders – Dysregulation of lipid metabolism can contribute to conditions like obesity, type 2 diabetes, and fatty liver disease.
- Cardiovascular Disease – Abnormal cholesterol levels and altered lipid signaling in blood vessels can promote atherosclerosis, a buildup of plaque that increases the risk of heart attack and stroke.
- Neurodegenerative Diseases – Dysregulation of lipid signaling in the brain has been implicated in the development of Alzheimer’s disease and Parkinson’s disease.
Fatty Acid Binding Proteins (FABPs)
FABPs are a family of intracellular lipid-binding proteins that regulate the transport and metabolism of fatty acids and lipids within cells. There are ten known FABP isoforms in humans (FABP1 through FABP9 and FABP12),1 Dysregulation of FABPs can lead to excessive lipid binding and contribute to disease states.
Therapeutic Potential of FABP Inhibitors
FABP inhibition has been identified as a novel mechanism of action to address a wide range of disease states, including metabolic disorders, inflammatory diseases, neurodegenerative diseases, and cancer. Artelo is a leader in the development of these lipidome-altering agents, holding worldwide exclusive licenses to multiple FABP inhibitors, with three patents issued in the US and 14 pending patent applications. Artelo is the first pharmaceutical company to receive FDA approval to initiate human trials with a selective FABP5 inhibitor, named ART26.12.
ART26.12: Lead FABP Inhibitor Compound
ART26.12 is a novel and selective FABP5 inhibitor from Artelo’s proprietary FABP library. In pre-clinical models, ART26.12 demonstrated efficacy in treating Chemotherapy-Induced Peripheral Neuropathy (CIPN), a debilitating complication of cancer therapies often impacting treatment strategies, including stopping treatment altogether. Similar to diabetic neuropathy, CIPN can cause intense and debilitating pain in hands and feet. There is no FDA approved treatment for CIPN.
By deciphering the language of lipids, Artelo Biosciences is on a mission to unlock transformative and novel treatments using lipid-signaling modulation to improve the lives of patients suffering from multiple diseases.
1. 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
ART27.13 – Dual Cannabinoid Receptor Agonist
ART27.13 is being developed as 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?
Lipid-signaling modulation can be affected via several approaches, including use of 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. Lipid-signaling within the endocannabinoid system (ECS) is therefore involved in pathophysiological conditions in both the central and peripheral tissues.
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
1. 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.
2. 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 a potent, selective inhibitor of Fatty Acid Binding Protein 5 (FABP5). It is Artelo’s lead compound identified from the Company’s platform of inhibitors to Fatty Acid Binding Proteins (FABPs). Artelo’s FABP inhibitor library is covered by three patents issued in the US and 14 pending international patent applications.
What are FABPs?
Hydrophobic ligands such as fatty acids serve many biological functions within the cell, including as metabolic energy sources, substrates for membranes, and signaling molecules for metabolic regulation. Being insoluble in water, fatty acids require chaperones to bind and transfer them throughout various water containing 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. Through transportation of lipids through the cell, FABP5 mediates energy production, lipid signalling, and gene expression.
There are ten known FABP family members, or isoforms, expressed in humans (FABP1 through FABP9 and FABP12).1 FABPs are believed to be attractive therapeutic targets as inhibiting abnormal or excess lipid-signaling is potentially significant for multiple conditions and diseases. Artelo’s FABP platform includes the novel, selective FABP5 inhibitor designated ART26.12. Artelo completed a successful Phase 1 Single Ascending Dose and food effect clinical study with ART26.12 demonstrating linear dose-dependant pharmacokinetics and there were no drug-related adverse effects (AEs) and no tolerability issues or safety signals were detected across multiple assessments. FABP5 plays an important role in lipid signaling and is believed to be an attractive target for drug development in pain, inflammation and cancer.
One of the potentially attractive aspects of targeting FABP5 inhibition as a medicine would be the low observed toxicology and risk of toxicology, safety pharmacology and adverse events Artelo has reported so far from the GLP non-clinical IND package, a review of the literature examining toxicological events from knock-out and knock-down of FABP2 and the data that was obtained from a Single Ascending Dose study in healthy volunteers. It is believed that this is an important consideration in ART26.12’s benefit-risk profile which will be investigated further in forthcoming clinical studies.
FABP5 as a novel target for treating pain
The first identified indication for which FABP5 inhibition may be beneficial was in the treatment of pain through modulation of the endocannabinoid system. Researchers at Stoneybrook University discovered that FABP5 was a chaperone for the human body’s own cannabinoid-like compounds (anandamide and palmitoylethanolamide) and inhibiting FABP5 was analgesic and anti-inflammatory in many preclinical models of pain by increasing levels of these natural cannabinoids, leading to activation of cannabinoid receptor targets. FABP5 has now been identified to be expressed in key regions related to pain signaling and is co-expressed with known pain targets such as c (CGRP), peripherin, cannabinoid receptor type 1 (CB1), tropomyosin receptor kinase A and transient receptor potential cation channel subfamily V member 1 (TRPV1). Knocking out the FABP5 protein in nociceptors that contain the TRPV1 receptor produces anti-nociceptive effects by preventing the sensitisation of TRPV1.3
ART26.12 is Artelo’s lead FABP5 inhibitor compound being developed for the prevention and treatment of chemotherapy-induced peripheral neuropathy (CIPN), supported by numerous studies in preclinical CIPN models. In an established model of oxaliplatin-induced peripheral neuropathy (OIPN), acute oral dosing of ART26.12 (25–100 mg/kg) reversed mechanical allodynia, with the effects of the 100 mg/kg dose lasting more than 8 hours.4 When coadministered with antagonists of CB1, CB2, PPARα, or TRPV1, the effect of ART26.12 were blocked. In a prevention model, where ART26.12 was dosed alongside oxaliplatin, ART26.12 reversed cold hyperalgesia and attenuated mechanical allodynia. Lipidomic analysis showed that ART26.12 upregulated N-acyl amino acids in the spinal cord, a group of lipids known to regulate pain through many well-established pain targets (Figure 1).
Figure 1. Lipids modulated by ART26.12 in OIPN studies and secondary targets affected by these lipids, which are known to be involved in mediating analgesia
Further preclinical studies showed that ART26.12 is also effective in another chemotherapy-induced pain (using paclitaxel), and in other neuropathic pain models such as diabetic neuropathy and cancer-induced bone pain.5 FABP5 inhibition offers a novel therapeutic opportunity for the treatment of neuropathies, a space which is lacking in licenced medications.
FABP5 inhibition in other indications
Osteoarthritis
Osteoarthritis (OA) is a very common condition characterised by pain, stiffness and inflammation of the affected joint. Data has shown FABP5 inhibition is effective as both an analgesic and anti-inflammatory. , Stony Brook University carried out a study showing that FABP5 was expressed in human synovium and FABP5 inhibition reduced the secretion of pronociceptive cytokines and chemokines.6 In an animal model of OA, two FABP5 inhibitors were effective at reducing pain with single or repeated drug administration. More recently, Artelo confirmed these findings using ART26.12 in a rat surgical model of OA, showing that daily oral treatment with ART26.12 was as effective as the commonly prescribed NSAID, Naproxen®. This is an ongoing area of research at Artelo.
Cancer
FABP5 has been identified as a novel key target in prostate cancer7 and in multiple other cancer types.8 FABP5 is upregulated in and a negative prognostic indicator for a range of cancers. FABP5 knockdown reduces tumor growth in multiple studies in pre-clinical models of cancer. Multiple compounds from the Artelo FABP5 inhibitor library have antiproliferative, anti-migratory and anti-invasiveness effects in in vitro cancer cell lines. Artelo’s FABP5 inhibitors reduce tumor growth in vivo in prostate, colorectal and liver cancer. FABP5 inhibitors show synergy with traditional chemotherapy drugs in vitro and in vivo.9 Figure 2 shows the effect of ART26.12 on colorectal tumor growth. Ongoing studies are addressing the hypothesis that FABP5 inhibition reduces triple-negative breast cancer tumorigenicity.10
Figure 2. The effects of ART26.12 in HCT-116-luc orthotopic xenograft (day 34 of treatment). Three mice in the ART26.12 group were tumor free at the end of treatment.
Psoriasis
FABP5 is also known as the epidermal FABP (EFABP) and was first identified in psoriasis tissue. FABP5 is upregulated in psoriatic skin lesions and plasma of patients with psoriasis, and FABP5 levels are modulated by treatment. Deletion of the FABP5 protein (globally or just within keratinocytes) reduces the development of psoriasis.11 In the imiquimod mouse model of psoriasis, two compounds from the Artelo library were effective at reducing symptoms of psoriasis, including the lead compound ART26.12.12 Oral treatment with both Artelo FABP5 inhibitors were as effective as the tyrosine kinase 2 inhibiting oral medicine deucravacitinib, which is approved for the treatment of adults with moderate-to-severe plaque psoriasis (Figure 3). Histopathology showed that ART26.12 reduced hyperkeratosis, parakeratosis, epidermal acanthosis, and inflammatory infiltrates. Lipidomic analysis showed widespread modulation, including ceramides and linoleic acid derivatives after ART26.12 treatment.
Figure 3. Two FABP5 inhibitors (ART26.12 and SBFI103) reduce the symptoms of psoriasis (psoriasis area and severity index, or “PASI”) to the same extent as an oral tyrosine kinase 2 inhibitor (deucravatinib) in an imiquimod (Aldara) mouse model.
Anxiety and depression
Lipid dysregulation is implicated in multiple neuropsychiatric conditions, including mood and anxiety disorders. Systemic (intraperitoneal) or central (e.g., amygdala or prefrontal cortex) injections of the second generation FABP5 inhibitor SBFI103 reduces anxiety and fear behaviors in mice. The anxiolytic effects of SBFI103 are linked to modulation of endocannabinoids and the cannabinoid receptor type 2 (CB2). SBFI103 reduces activity in the amygdala, a brain region in which hyperactivity is associated with anxiety and fear.13 A peer-review study indicated that pharmacologically targeting FABP-mediated pathways holds considerable potential as a novel therapeutic strategy for addressing the symptoms associated with mood and anxiety disorders.14
Beyond FABP5 inhibition
FABP3 and FABP715 are also emerging as key targets in cancer development and metastasis. Artelo has a library of specific FABP3, 5 and 7 inhibitors, as well as dual and pan inhibitors of these key novel cancer targets.
References
1. The human fatty acid-binding protein family: Evolutionary divergences and functions – Human Genomics
2. Potential safety implications of fatty acid-binding protein inhibition – ScienceDirect
3. FABP5 deletion in nociceptors augments endocannabinoid signaling and suppresses TRPV1 sensitization and inflammatory pain – PubMed
4.Discovery and Preclinical Evaluation of a Novel Inhibitor of FABP5, ART26.12, Effective in Oxaliplatin-Induced Peripheral Neuropathy – The Journal of Pain
5.ART26.12, a novel fatty acid‐binding protein 5 inhibitor, shows efficacy in multiple preclinical neuropathy models – Warren – 2025 – European Journal of Pain – Wiley Online Library
6.Fatty acid binding protein 5 inhibition attenuates pronociceptive cytokine/chemokine expression and suppresses osteoarthritis pain: A comparative human and rat study – ScienceDirect
7.FABP5 as a novel molecular target in prostate cancer – ScienceDirect
8.The emerging role of fatty acid binding protein 5 (FABP5) in cancers – PubMed
9.Fatty acid binding protein 5 regulates docetaxel sensitivity in taxane-resistant prostate cancer cells – PLOS One
10.Direct sensing of dietary ω-6 linoleic acid through FABP5-mTORC1 signaling – Science
11.Keratinocyte FABP5-VCP complex mediates recruitment of neutrophils in psoriasis – PubMed
12.ART26.12, an FABP5 Inhibitor, Shows Efficacy in Preclinical Psoriasis Models – PubMed
13.Inhibition of fatty acid binding protein-5 in the basolateral amygdala induces anxiolytic effects and accelerates fear memory extinction – PubMed
14.Fatty acid binding proteins and their involvement in anxiety and mood disorders – PubMed
15.The emerging role of fatty acid binding protein 7 (FABP7) in cancers – PubMed
ART12.11 - CBD:TMP Cocrystal
ART12.11 is a proprietary cocrystal of cannabidiol (CBD) and tetramethylpyrazine (TMP) designed to improve pharmaceutical qualities of the CBD molecule. CBD has proven pharmacological effects and is approved as a prescription medicine worldwide in two different products (Epidyolex/Epidiolex® and Sativex®); however, its pharmaceutical properties make the development of an oral solid-dosage form challenging.
What is a cocrystal ?
Engineering of the crystalline structure of drug molecules by cocrystalization is a well-established pharmaceutical strategy of enhanced pharmaceutics and complies with US FDA guidance. Cocrystals are defined as crystalline materials composed of two or more molecules within the same crystal lattice. Crystallization overcomes problematic drug properties by utilising one or more coformer(s) to change physical form and aid bioavailability, solubility, dissolution rate, melting point, tableting, stability, or permeability. Compared to other classes of solid forms, cocrystals possess particular scientific and regulatory advantages. Importantly, cocrystals are viewed as patentable subject matter. Thus, a pharmaceutical cocrystal offers the opportunity to develop a CBD-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 CBD. The team was successful and identified a structure that meets all the criteria for an attractive pharmaceutical cocrystal.
What are the benefits of the ART12.11 cocrystal?
A key problem in delivering CBD orally in a solid dosage form is its poor solubility, leading to low dissolution rates and subsequently poor bioavailability. TMP by contrast is highly soluble, and acts as a driving force that CBD can ‘piggyback’ on, pushing CBD into solution thereby increasing solubility, dissolution rate and bioavailability. We have found that cocrystallizing CBD with the hydrophilic TMP leads to greatly improved aqueous solubility and dissolution rate in biorelevant fluids. Additionally, use of TMP as a coformer improves the melting point of either solid substance, aiding manufacturability of solid dosage forms.
The improved solubility and rate of dissolution overcomes a key barrier in formulating semisolid and solid presentations of CBD with adequate bioavailability to reach efficacious doses. Aided by improved manufacturability provided by increased melting point, we have demonstrated proof-of-principle compression tablets that were validated in vivo.
In 2020, the U.S. Patent and Trademark Office issued composition-of-matter (U.S. patent No. 10,604467, “Solid Forms of Cannabidiol and Uses Thereof”) and method of use patents with claims covering the Company’s cocrystal until December 10, 2038. Artelo has also received notice that ART12.11 patents have been granted or validated in 19 additional countries.
ART12.11 contains no THC or other controlled substances, and US Drug Enforcement Agency affirmed ART12.11 is not a scheduled substance.
Why is TMP the ideal coformer for CBD?
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 in stroke, angina, chronic pulmonary heart disease, and diabetic nephropathy. 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 2 g/kg. Other TMP cocrystals show physical and biological superiority over single compounds (most recently demonstrated with a TMP:aspirin cocrystal).
How does ART12.11 compare to other CBD products like Epidiolex?
Epidyolex/Epidiolex sales were $972.4 million in 2024 and is only available in an oily oral solution, which has a very short shelf life and limited oral bioavailability. Cocrystalization can enhance drug oral bioavailability and, importantly, CBD alone has a bioavailability of ~10%. Artelo has developed compressed tablet formulations of ART12.11 that contain 100 mg of CBD. The ability to formulate ART12.11 in solid and semi-solid formats has considerable patient (convenience, familiarity, compliance) and pharmaceutical (shelf life, lower cost to manufacture, scalability) benefits.
Through numerous preclinical pharmacokinetic (PK) studies, Artelo has also shown that ART12.11 is superior to CBD alone when presented in a capsule or as a suspension in the fed or fasted state, leading to higher exposures of CBD and its metabolites. This could not be mimicked by simply co-administering CBD and TMP.
In dog PK studies, two tablets of ART12.11 (B and C) each containing 100mg of CBD showed similar total CBD plasma exposure (AUC) to 100mg dose of Epidiolex (see chart below). Tablet B showed a similar PK profile (Cmax and Tmax), while tablet C showed a later Tmax and lower Cmax, but with longer lasting CBD levels and therefore similar total CBD exposure (AUC) to Epidiolex.
The CBD metabolite levels were similar or higher than Epidiolex such that the cumulative CBD (parent and metabolite) exposure after in vivo administration was greatest with Tablet B.
What target indications are planned for ART12.11?
Artelo plans to develop ART12.11 to treat anxiety and depression. Anxiety and mood disorders are the most common psychiatric conditions with an ever-growing prevalence. Many clinical trials investigating purified CBD (usually dissolved in oil) have shown that single acute doses or chronic dosing with CBD can significantly reduce anxiety in patients with generalized anxiety disorder, social anxiety disorders, anxiety associated with drug withdrawal, PTSD, Parkinson’s disease or psychosis (see table below).
In Artelo’s preclinical studies, in collaboration with the University of Western Ontario, ART12.11 has consistently shown strong anxiolytic, anti-depressive, and pro-social effects in chronically stressed mice. When compared to a higher dose of CBD alone (10 mg/kg), ART12.11 (5 mg/kg; containing 3.5 mg/kg CBD, 1.5 mg/kg TMP) was more effective in reversing stress-induced anxiety, depression, and anti-sociality. ART12.11 had no deleterious effects on working and spatial memory. Co-administration of CBD and TMP, at an equivalent ratio and dose, did not produce the same efficacy as ART12.11. This highlights that the therapeutic potential of ART12.11 is unique to the cocrystal.
In a more recent preclinical study using chronically stressed mice, ART12.11 was compared against the first-line anti-depressant sertraline (Zoloft®), with an ART12.11 + sertraline arm included to test for synergistic effects. The results showed that ART12.11 had a comparable anti-depressant effect to sertraline, with co-administration showing an additive anti-depressant effect. Importantly, ART12.11 also reversed the cognitive dysfunction observed in the stressed mice, which was not observed with sertraline. Artelo continues to investigate ART12.11 as a potent novel therapy in anxiety and mood disorders.
References
- Evaluation of the efficacy, safety, and pharmacokinetics of nanodispersible cannabidiol oral solution (150 mg/mL) versus placebo in mild to moderate anxiety subjects: A double blind multicenter randomized clinical trial – PubMed
- Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naïve social phobia patients – PubMed
- Anxiolytic Effects of Repeated Cannabidiol Treatment in Teenagers With Social Anxiety Disorders – PubMed
- Simultaneous improvement of physical stability, dissolution, bioavailability, and antithrombus efficacy of Aspirin and Ligustrazine through cocrystallization – ScienceDirect
Publications
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