In an interview with PharmaShots, Dr. Saoirse O'Sullivan, Ph.D., Scientific Advisor to Artelo Bio shares insights on new cannabinoids, their relevancy, and the other opportunities that can arise from modulating the ECS.

Shots:

• The endocannabinoid system is a network of neurotransmitters and receptors throughout the body that can have a significant impact on improving human health when affected or modulated with therapies
• Artelo has developed a unique cannabinoid that can't be found in the plant. It is being examined to treat cancer-related anorexia
• In addition to ART27.13, Artelo Biosciences has two other endocannabinoid-modulating drugs in development. The company is evaluating ART27.13 in a P-I/II CAReS study for cancer patients experiencing anorexia

Tuba: Put lights on synthetic cannabinoids, their relevancy, and the other opportunities that can arise from modulating the ECS.

Saoirse O'Sullivan: Nature has provided us with hundreds of molecules in the phytocannabinoid (plant-derived) and endocannabinoid (made in our bodies) family. Research tells us that these compounds can be very useful in treating a wide range of diseases and disorders from epilepsy to anxiety to cancer. However, these molecules are not perfectly adapted for improving human health; many are very insoluble and poorly absorbed in the body, some are not very potent, many are found in tiny quantities. Producing these molecules synthetically, or improving their physical, chemical, and biological properties through medicinal chemistry programs allows us to harness the best of what nature provides us. Commercially, this also allows for the creation of Intellectual Property (IP) which is crucial to attracting investment for the expensive development of new medicines.

Tuba: What motivates you to develop an entirely synthetic cannabinoid for Cancer Anorexia?

Saoirse O'Sullivan: There is already good clinical evidence that the plant-derived CB1 agonist THC can be a useful tool for stimulating appetite and maintaining body weight in a number of diseases where wasting is a significant problem, including cancer. However, for some patients, the psychotropic and central nervous system (CNS) side effects that are associated with THC are not desired or tolerable. ART27.13 has the advantage of being peripherally restricted, meaning that it doesn't easily cross the blood barrier and activate CB1 receptors in the brain. The effect of peripheral CB1 activation is also believed to promote appetite, and energy storage, and preservation, so CNS penetration is not required when treating cancer anorexia. ART27.13 is also more potent at CB1 than THC and acts as a full agonist at the CB1 receptor (THC is only a partial agonist). THC and its metabolites also activate another receptor called GPR119, which suppresses appetite, so weight loss can actually be observed with chronic THC use. Together, these factors make us believe that the synthetic, potent, peripherally restricted full CB1 agonist ART27.13 will be more efficacious than THC for cancer anorexia.

Source: Artelo

Tuba: Discuss the role of the endocannabinoid system in modulating therapies.

Saoirse O'Sullivan: The endocannabinoid system is a network of neurotransmitters and receptors throughout the body that, when affected or modulated with therapies, can have a significant impact on improving human health.

Tuba: Highlight the different programs that are currently in development in your pipeline.

Source: Artelo

Saoirse O'Sullivan: In addition to ART27.13, Artelo Biosciences has two other endocannabinoid-modulating drugs in development.  Firstly, Artelo developed a patented novel CBD cocrystal called ART12.11. Cocrystallization is a proven pharmaceutical development strategy to address solid polymorphism and follows FDA guidance for chemicals with properties similar to CBD with poor physicochemical properties (see cbdcocrystal.com). ART12.11 uses TMP (tetramethylpyrazine) as the coformer (to form the cocrystal). TMP is a plant-derived compound that has been used in medicine and food flavoring applications for several decades. A CBD cocrystal has the potential to have better consistency, bioavailability, improved stability, and is free of any THC. ART12.11 is the first and only CBD cocrystal to have an issued composition of matter patent from the US Patent and Trademark Office.

Secondly, Artelo's research team is also working with scientists at Stony Brook University, who are pioneers in developing fatty acid-binding protein five (FABP5) inhibitors, to advance their lipid signaling program towards first-in-human trials. At Artelo, this program is called ART26.12 and covers a library of unique small molecules that have been designed to selectively and potently inhibit FABPs.  Preclinical studies have shown that molecules that inhibit FABP5 show considerable promise in animal models of cancer, pain, inflammation, and anxiety.

Tuba: Discuss the design of the P-I/II CAReS study of ART27.13.

Saoirse O'Sullivan: CAReS is a two-stage randomized, double-blind, placebo-controlled clinical trial with the synthetic cannabinoid, ART27.13 for cancer patients experiencing anorexia. Stage 1 of the study will determine the optimal dose of ART27.13 to be used in the second stage of the study. CAReS is recruiting adult patients of all cancers (except brain cancer or brain metastases) not on any active treatment for their cancer or on maintenance/stable anti-cancer therapy who have documented weight loss of >5% body weight in the prior 6 months from enrolment. The endpoints of the trial are safety and pharmacokinetics, and measurements of lean body mass, weight gain, appetite, quality of Life (QoL), and activity. Exploratory endpoints will assess the anti-inflammatory and hormonal effects, physical activity, abuse potential, and any opioid-sparing effects of ART27.13.

Tuba: When we can expect the results of this study?

Saoirse O'Sullivan: We are planning to be able to share data on the CAReS trial later in 2021.

Tuba: Can you shed light for our readers on the working of ART27.13? How does it help people with Cancer Anorexia?

Saoirse O'Sullivan: The CB1 receptor is well known to regulate appetite and body weight, however, unwanted central side effects of either agonist (in wasting disorders) or antagonists (in obesity and diabetes) have limited their use. The next generation of these potential medicines has been peripherally restricted to reduce these CNS issues. ART27.13 is a clinical development stage CB1/CB2 receptor agonist with reduced brain penetration. In otherwise healthy subjects who participated in a Phase 1 pain study, it was observed that low doses of ART27.13 rapidly increased body weight of more than 3% that was not explained by fluid retention and without serious or persistent side effects.

At the peripheral level, CB1 receptor activation impacts the overall energy balance of mammals in a number of different ways; inhibiting satiety (feeling full) and nausea, increasing food intake, altering the levels of the hormone that controls appetite, altering taste sensation, slowing gastrointestinal motility, decreasing lipolysis (fat break down) and increasing lipogenesis (fat generation). The combined effect of peripheral CB1 activation is to promote appetite, and energy storage, and preservation.

Tuba: Are you interested in collaborating with other companies to advance your pre clinical therapies?

Saoirse O'Sullivan: We are welcome to discuss mutually beneficial collaborations with partners to advance our science related to our clinical and preclinical programs.

Tuba: Share something specific with our readers about the therapeutic aspects of the Endocannabinoid System (ECS) for cancer.

Saoirse O'Sullivan: Activation of the endocannabinoid system may have therapeutic potential in many aspects of symptom management and even anti-cancer effects.  There is good clinical evidence to support the use of CB1 receptor agonists (usually in the form of THC or cannabis medicines) to treat nausea and appetite stimulation, cancer-related pain, sleep & fatigue, mental health (anxiety, depression, and mood), and quality of life. Preclinically (i.e. in cell and animal research) there is evidence that both CB1 and CB2 receptor agonists, and compounds that increase endocannabinoid tone, have anti-tumoral effects (reduce cancer cell growth and spread), reduce new vessel growth to tumors (angiogenesis), and reduce cancer-related pain.

Main Source: Freepik

About Author:

Dr. Saoirse O'Sullivan is a Scientific Advisor to Artelo Bio. She has over 26 original research articles, 6 reviews, and 3 book chapters on the topic of cannabinoid pharmacology, with specific interests in the cardiovascular and gastrointestinal effects of cannabinoids and the therapeutic potential of cannabis-based medicines.

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