Realizing the Promise of Therapeutics Targeting the Endocannabinoid System

The endocannabinoid system (ECS) plays an important role in regulating many biological functions throughout the human body. Artelo Biosciences is developing small molecule drugs that target receptors and other signaling mediators in the ECS.

Role of the Endocannabinoid System

The ECS is a widespread neuromodulatory system involved in human central nervous system (CNS) development, synaptic plasticity, and the body’s response to endogenous and environmental insults. It comprises a family of receptors and neurotransmitters that form a biochemical communication network throughout the body and maintain a healthy state in response to environmental changes.

Numerous peer-reviewed publications have shown its importance in human physiology as a modulator of cardiovascular, gastrointestinal, and immune function, metastatic transformation, and key aspects of CNS function, including movement disorders, pain, and behavior. The ECS is therefore an attractive and validated pathway to target for pharmacological intervention.

For the treatment of disease, stress, and adverse medical conditions, modulating the vast potential of the ECS may lead to new and significantly improved treatments. According to the National Institutes of Health, “Modulating ECS activity holds therapeutic promise for a broad range of diseases, including neurodegenerative, cardiovascular and inflammatory disorders, obesity/metabolic syndrome, cachexia, chemotherapy-induced nausea and vomiting, tissue injury and pain, among others.”¹

Indeed, cannabinoids that target the ECS are already used clinically to treat indications such as multiple sclerosis, epilepsy, and nausea associated with cancer, and there are several pharmaceutical products that modulate the ECS already available in many countries.

Applying Biopharma Rigor to ECS Therapeutic Development

Artelo Biosciences, Inc. was formed to develop and commercialize proprietary therapeutics targeting the endocannabinoid system. We are rapidly advancing a portfolio of broadly applicable product candidates designed to address significant unmet needs in multiple diseases and conditions, including anorexia, cancer, pain, and inflammation. 

Importantly, we are applying true biopharma discipline in this effort, because we believe this approach with large, well-controlled randomized trials will lead to novel therapeutics that harness the full potential of the ECS. Led by seasoned biopharmaceutical executives collaborating with highly respected researchers and technology experts, Artelo applies leading-edge scientific, regulatory, and commercial discipline to develop high-impact therapies.

Our business model is to develop multiple pharmacological approaches to ECS modulation, and our focused, science- and portfolio-based approach and de-risked and nimble business strategy position Artelo for significant growth.

Candidate therapeutic compounds within our portfolio are based on targeting cannabinoid receptors and endocannabinoid transport inhibition and have the potential to dramatically improve patient care in major markets. Two of these compounds were licensed from established and respected organizations that have already conducted preclinical research and some clinical development. Our science and regulatory teams are leveraging this prior research to speed development and commercialization timelines.

High-Potency GPCR Agonist

Our lead candidate ART27.13 is a clinical stage, potent, peripherally selective dual synthetic cannabinoid agonist in development for the treatment of cancer-related anorexia and weight loss originally developed at AstraZeneca. Cancer-related anorexia (cancer anorexia and cachexia syndrome, CACS) affects approximately 60% of advanced-stage cancer patients and contributes to wasting and a poor prognosis for survival. Stimulation of food consumption can lead to a higher quality of life and potentially increase the participation with anticancer therapies. However, no therapies have been specifically approved for the treatment of CACS in any major global market.² 

ART27.13 is a highly potent agonist to both the CB₁ and CB₂ receptors and was selected to target receptors in the body’s periphery, not the brain. As a result, it stimulates appetite while avoiding psychoactivity in the CNS by targeting receptors in the gut that send a feeding signal to the brain. In adipose tissue and the liver, CB₁ agonists increase lipogenesis. It also causes the release of appetite-stimulating hormones in adipose tissue (leptin) and the stomach (ghrelin) and decreases production of the satiety hormone cholecystokinin in the stomach.

Within five phase I clinical studies including over 200 subjects, ART27.13 demonstrated a statistically significant and dose-proportional increase in body weight.³ For CACS, ART27.13 is differentiated from other current clinical programs by its dual full agonist activity targeting cannabinoid receptors CB₁ and CB₂, and its rationally designed safety profile, which enables systemic metabolic effects while minimizing CNS-mediated toxicity.

Under regulatory authority approval, we plan to advance ART27.13 as a multimodal supportive care therapy for cancer patients suffering from anorexia and weight loss. Our intent is to initiate a phase Ib/IIa, randomized, placebo-controlled trial of ART27.13 in patients with cancer anorexia and weight loss by the end of 2020. The phase Ib safety dose-escalation open-label study will determine the most safe and effective dose for use in the randomized placebo-controlled phase IIa study, which will determine point estimates of activity of ART27.13 in terms of weight gain, lean body mass, and improvement of anorexia.

All current clinical sites are located in the UK and we have the option to expand to North America. We expect the trial to last approximately 12 months and will open the study to cancer patients once the National Health Service permits new studies not related to COVID-19 to begin and upon successful manufacture of clinical material and regulatory clearance. We anticipate the initial data readout will occur in the summer of 2021.

FABP5 Inhibitor

ART26.12 is a fatty acid–binding protein 5 (FABP5) inhibitor product candidate for the treatment of cancer, inflammation, and pain. We are developing ART26.12 under an exclusive worldwide license from and in collaboration with the Research Foundation of the State University of New York Stony Brook.

FABPs have been identified as intracellular transporters for the endocannabinoid anandamide (AEA), a neurotransmitter produced in the brain. Inhibition of FABP5 has been shown to increase levels of AEA and may have significant potential in treating pain. Animal studies have demonstrated that elevated levels of endocannabinoids can result in beneficial pharmacological effects on stress, pain, and inflammation and may ease the effects of drug withdrawal.

Additionally, FABP5 and PPARß/δ are critical mediators of epidermal growth factor receptor (EGF)-induced carcinoma cell growth. In cervical, breast, and prostate cancer and some forms of melanoma, FABP5 has been shown to be upregulated, while inhibition of FABP5 has been shown to suppress the growth and migration of breast and prostate cancers by interrupting the signaling mechanism for vascular endothelial growth factor. 

Initial studies in mouse cancer models have shown significant reduction in cancer growth for animals given ART26.12 versus those that were untreated.³ In various prostate cancer cell lines, the Stony Brook researchers also found that, when ART26.12 was combined with low-dose taxanes — the standard of care in prostate cancer — cancer cells were completely eradicated, which was not achieved with taxanes alone.^4,5 In combination with other standard-of-care medicines, we believe that modulation of lipid signaling has the potential to be the next revolution in cancer therapeutics. 

Artelo is working with Stony Brook to optimize a FABP5 inhibitor for the treatment of both breast and prostate cancer. The program was initially supported by $3.8 million in NIH funding. Recently, the National Cancer Institute awarded the program an additional $4.2 million grant for development in prostate cancer. We are working to get ART26.12 approved for clinical studies and have high hopes that its ability to address both pain and cancer growth will bring tremendous benefit to patients.

Proprietary Cocrystal

Our third candidate, ART12.11, was developed at Artelo. It is a novel cocrystal composition of cannabidiol (CBD) with potential to treat multiple indications, including posttraumatic stress disorder (PTSD), inflammatory bowel diseases (e.g., colitis and Crohn’s), and some rare diseases. 

PTSD is a significant health problem, which affected 7–8% of American adults before the COVID-19 pandemic —that has only worsened as this global health and economic crisis has continued. There are currently only two FDA-approved drugs for PTSD, both of which are selective serotonin reuptake inhibitors. Many people self-medicate using antidepressants, anxiolytics, CBD-rich cannabis, sleep medications, mood stabilizers, narcotics, and non-narcotic pain drugs. There is an urgent need to find additional effective pharmacologic treatments for PTSD.

CBD alone has been shown to block anxiety-related REM sleep alterations. Artelo’s proprietary CBD cocrystal offers enhanced pharmaceutical properties compared with conventional CBD. Formation of a cocrystal with tetramethylpyrazine (TMP) successfully addresses the issues associated with the solid polymorphism of CBD and enables synthetic manufacture of a solid dosage form. In addition, TMP on its own has been shown in preclinical research to exhibit activity in PTSD models; thus, the cocrystal potentially offers the combination of two therapeutic agents. The greater consistency of exposure offered by the cocrystal is also expected to improve safety and efficacy.

Artelo has recently been awarded a U.S. composition of matter patent with a term through December 2038, offering an unprecedented and advantageous market exclusivity protection position. Our initial target is the treatment of symptoms of PTSD, particularly associated anxiety and sleep disturbances. The CBD cocrystal enables federally regulated drug development in major diseases and medical conditions with an approach aligned with FDA Guidance to Industry for compounds exhibiting solid state polymorphism. 

Opportunity to Penetrate the Industry

Although modulating the endocannabinoid system is not yet mainstream, we are excited by the opportunity to discuss the importance of the ECS and the real potential it provides to drug developers and ultimately patients. All of our programs target multibillion-dollar opportunities and have the potential for widespread benefit.

Within the next 18 months, we could very well have three product candidates in the clinic — a tremendous achievement within the short span since our inception. Five or six years from now, we anticipate that one or more of those compounds will have completed the regulated drug development process and be on the market serving patient needs. 

While Artelo is one of about a half dozen publicly traded companies on Nasdaq targeting the ECS, we are unique in that we are taking a full-spectrum approach across three methods to modulate the ECS — leveraging chemicals found in nature, developing rationally designed synthetic chemicals, and inhibiting proteins that impact fatty acid signaling. All other companies with ECS targeting therapeutics are focusing on a single approach or mechanism of action. We believe our portfolio strategy exemplifies a leading commitment to harnessing the vast potential of the ECS. 

References

1. Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland, May. 2013. Web. 

2. Zilbermint, Mihail F. and Adrian S. Dobs. “Nonsteroidal selective androgen receptor modulator Ostarine in cancer cachexia.” Future Oncol. 5: 1211–1220 (2009).

3. Advani, Shailesh M. et al. “Pharmacological management of cachexia in adult cancer patients: a systematic review of clinical trials.” BMC Cancer. 18:1174 (2018). 

4. Al-Jameel, W. “Inhibitor SBFI26 suppresses the malignant progression of castration-resistant PC3-M cells by competitively binding to oncogenic FABP5.” Oncotarget. 8: 31041-31056 (2017).

5. Su Yan et al. “SAR studies on truxillic acid mono esters as a new class of antinociceptive agents targeting fatty acid binding proteins.” European Journal of Medicinal Chemistry. 154: 233–252 (2018).

6. Carbonetti, G. et al. “Docetaxel/cabazitaxel and fatty acid binding protein 5 inhibitors produce synergistic inhibition of prostate cancer growth.” The Prostate. 9 Oct. 2019. Web.