Clinical Application

Cannabinoids: Mental & Metabolic Health

Endogenous cannabinoid signals are responsible for a wide range of physiological responses centered around the consumption and storage of energy by the body and brain.

• They are heavily implicated in appetite, increasing circulating endocannabinoids is inversely correlated with leptin, a molecule which is largely thought to be responsible for preventing obesity and excess eating.
• They can potentially serve as a biomarker of the development of obesity.
• CB1 is significantly overactivated in a number of metabolic alterations making it an attractive therapeutic target.
  • First generation therapeutics such as Sanofi’s Rimonabant (Acomplia) and Merck’s Taranabant were originally developed for metabolic disorder, but later pulled due to off-target toxicity.
  • Inversago (a Novo Nordisk Company)’s INV-202, Corbus Pharmaceuticals’s CRB-913, and Skye Bioscience’s Nimacimab are some examples of next generation peripherally restricted CB1 antagonists in this space

• Major Depressive Disorder is correlated with a decrease in circulating endocannabinoids such as 2-Arachidonoylglycerol (2-AG) in untreated patients, while increases in 2-AG and another endocannabinoid, Oleoylethanolamide (OEA), is associated with SSRI therapy.
• Post-Traumatic Stress Disorder (PTSD) is also correlated with a decrease in the circulating endocannabinoid Anandamide (AEA) and reduction in severity associates with increases in AEA.
• Schizophrenia on the other hand is associated with an increase in circulating endocannabinoids like AEA, particularly during acute episodes and can serve as a biomarker for remission.
• Substance Use Disorder (SUD) associates with decreases in peripheral cannabinoid tone, as the endocannabinoid system is responsible for drug-reward memory. Resistance to SUD on the other hand can be predicted by increases in circulating cannabinoid levels.

The cross talk between mental and metabolic health has led to numerous failures to develop modulators of the endocannabinoid system. In all, better biomarkers, enabled by our platform, are required to ensure safe and effective treatment approaches to these conditions.

Incretins: Metabolic Health

The 3 primary signals, Glucagon-like Peptide-1 (GLP-1), Gastric Inhibitory Polypeptide (GIP), and Glucagon regulate glucose metabolism. They act quickly in response to hypo- and hyper-glycemic events. Looking beyond blood glucose and glycated hemoglobin (HbA1c), the incretin peptides can serve as important biomarkers of metabolic disease and response to treatment.

• GLP-1 is a short acting hormone which stimulates the release of insulin following a meal and functions as a satiety signal to the brain. Patients with impaired GLP-1 function are more likely to develop metabolic disease
  • Multiple treatment approaches are seeking to augment these signals by binding to and agonizing the GLP-1 receptor including Mounjaro®, Ozempic®, Wegovy®, and Zepbound®.
  • Monitoring levels of therapeutic drug is the single most important determinant of safety and efficacy.
    The endogenous peptides are rapidly degraded into shortened forms that are responsible for other beneficial effects in the brain.
• Glucagon acts on the opposite end of the spectrum and works to increase blood sugar during hypoglycemic events by stimulating release from the liver.
  • Analogs can be used in emergent hypoglycemic events to restore homeostasis, but are underutilized due to fears around dosing and potential toxicities.
• Gastric Inhibitory Polypeptide (GIP) increases glucagon and also insulin secretion in a glucose-dependent manner.
• More recent therapies in development have explored the utility of co-agonizing GLP-1 alongside other incretins such as GIP and Glucagon or even other GPCRs like Amylin.
  • GLP-1/GIP
    • Eli Lilly’s Tirzepatide
    • Roche’s CT-388
    • Viking Therapeutics’ VK2735
  • GLP-1/Amylin
    • Novo Nordisk CagriSema
  • GLP-1/Glucagon:
    • Boehringer Ingelheim’s Survodutide
    • Eli Lilly/Innovent’s Mazdutide
  • GLP-1/GIP/Glucagon
    • Eli Lilly’s Retratrutide

Our goal is to optimize care with current and future incretin therapies in development through analyzing patient endogenous response to glycemic events and determining which signals need to be further augmented. For example if a patient has insufficient GLP1 response to hyperglycemia, they may be a suitable candidate for exogenous GLP1 agonist therapy.

Amylins: Metabolic and Neurological Health

Amylin is a neuroendocrine hormone which is co-secreted with insulin from beta cells.

• In metabolic health, its function is to delay the release of glucose into circulation by sending a satiety signal, delaying gastric emptying, sensitizing the CNS to leptin, and inhibiting glucagon secretion.
  • One approved agent – AstraZeneca’s Samlyn (Pramlintide).
  • Explored as a co-agonist with GLP-1 (Novo Nordisk’s CagriSema) or calcitonin (Nordic Bioscience’s KBP-042).
• In neurological health, receptors for Amylin are well distributed in the CNS and are involved in memory and learning.
  • They are thought to be implicated in the development of Alzheimer’s disease should concentrations of Amylin reach too low or high, and can be detected as a biomarker in blood.
  • Pramlintide may hold some promise as a treatment for Alzheimer’s but stratification by baseline Amylin levels will likely be required.

• Chemokines; Immunology/Inflammation, Onco
  • Dopamine & Serotonin: Mental and Neuro Health