The Endocannabinoid System
Haspula, et al. Cannabinoid Receptors: An Update on Cell Signaling, Pathophysiological Roles and Therapeutic Opportunities in Neurological, Cardiovascular, and Inflammatory Diseases, International Journal of Molecular Sciences. 2020;21:5.
The endocannabinoid system regulates multiple processes in the body to restore homeostasis through the interplay of its receptors and their ligands. This system is in many animals (including humans), and its role extends to the central nervous system, the immune system, metabolism and more. It is involved in inflammation, fibrosis, wound healing, energy regulation, behavior, memory, pain, reproduction and cell growth and differentiation. The extensive involvement of the endocannabinoid system in regulating vital processes in the body is the basis for new opportunities to develop medicines to treat human illnesses.
At Corbus, we are targeting the two main cannabinoid G-protein-coupled receptors (GPCRs): the cannabinoid receptor type 1 (CB1) is widely expressed throughout the body and especially in the nervous system while the cannabinoid receptor type 2 (CB2) is highly expressed in activated cells of the immune system. By rationally designing novel small molecules that bind to these receptors and modulate their activity, Corbus is developing compounds that could treat cancer, and inflammatory, fibrotic, and metabolic disorders.
Research demonstrates that targeting CB2 in the immune system reduces inflammation and inhibits or halts fibrosis. CB2 is preferentially expressed on activated immune cells and found on other cell types, such as fibroblasts, muscle cells, endothelial cells, and cancer cells.
Lenabasum
Corbus’ most advanced compound lenabasum is an oral, small molecule that selectively activates CB2. Biologic activities of lenabasum have been shown in animal models and humans, and include activation of the resolution of inflammation, reducing inflammatory mediators, and limiting fibrosis. Lenabasum has had an acceptable safety profile in studies to date. Approximately 1,300 subjects have received lenabasum. The most common adverse events related to lenabasum are dizziness, headache and fatigue.
Lenabasum is not approved for the treatment of any indication.
Key Lenabasum Studies
| Target (Program) | Phase | Number Dosed | Status |
|---|---|---|---|
| Dermatomyositis | 3 | 175 | • Primary efficacy endpoint (Total Improvement Score) not met • Additional data analyses being completed and working on gaining clarity from FDA on potential path forward |
| SLE | 2 | 102 | • Ongoing, topline data expected Q4 2021 |
| Systemic Sclerosis | 3 | 363 | • Primary efficacy endpoint (ACR CRISS score) not met • FVC changes seen in sub-population in post-hoc analysis • Acceptable safety profile •Analyzing data on FVC in conjunction with dermatomyositis data on FVC |
| Cystic Fibrosis | 2b | 525 | • Primary efficacy endpoint (pulmonary exacerbation rate) was not met Acceptable safety profile • Not planning additional studies in CF |
Obesity is a Growing Health Crisis in the U.S.
Obese patients are greater than
2X More Likely
to develop hypertension, dementia and certain cancers
Obese patients are over
3X More Likely
to develop diabetes, osteoarthritis and end stage renal disease1
1. Milkin Institute, October 2018
CB1 activation contributes to “diabesity.”
Cannabinoid type 1 receptor (CB1) activation increases appetite, food intake, fat production and storage, glucose intolerance, insulin resistance, inflammation and fibrosis. CB1 activation decreases insulin secretion, metabolism of fat, and energy expenditure.
First-generation CB1 inverse agonists showed efficacy in late-stage clinical trials in obesity and related metabolic disorders. For example, rimonabant (Acomplia) was approved in Europe for treatment of obesity in combination with a program of diet and exercise. Rimonabant was withdrawn in 2008 due to psychiatric safety concerns with increased anxiety, depression, and suicidality, linked to inhibiting CB1 in the brain. These safety issues halted further development of CB1 inverse agonists despite their demonstrated efficacy in multiple metabolic disorders with several different CB1 inhibitors.
Deeba, et al. Targeting the endocannabinoid system in diabesity: Fact or fiction?, Drug Discovery Today. 2021;in press:2.
CB1 inverse agonists provide opportunities to treat multiple metabolic and related fibrotic diseases, if the safety concerns could be addressed.
To minimize psychiatric side effects, Corbus is developing small molecule CB1 inverse agonists designed to minimize CB1 binding in the brain. We believe these CB1 inverse agonists have the potential to treat obesity and related metabolic diseases. Importantly, we believe these CB1 inverse agonists may augment effects of standard treatments for these diseases, such as GLP-1R agonists in diabetes and obesity. Our experimental CB1 inverse agonists induced weight loss both as a monotherapy and in combination with a GLP-1 agonist in preclinical models of diet-induced obesity. The program is progressing through preclinical studies and regulatory pathway evaluation.
Cancer is a leading cause of death worldwide
Currently, only
44%
of cancer patients are eligible for checkpoint inhibitors
(drugs that block proteins called checkpoints that are made by some immune system and cancer cells).
Only,
12.5%
of all treated cancer
patients respond.
Haslam et al., Estimation of the Percentage of US Patients With Cancer Who Are Eligible for and Respond to Checkpoint Inhibitor Immunotherapy Drugs, JAMA 2019
Among patients who respond to CPIs, disease progression often occurs due to resistance mechanisms. Significant unmet need remains for greater and more durable responses to CPIs.
There is a growing body of published data demonstrating the complex role the endocannabinoid system plays in cancer.
CB2 is expressed by cancer cells themselves and activated immune cell, fibroblasts, and endothelial cells in the tumor microenvironment (TME). CB2-dependent pathways can inhibit the ability of cancers to grow and metastasize, providing beneficial effects on the immune system and the tumor stroma. Results from cell and animal studies demonstrate that activating CB2 counteracts tumor growth, promotes tumor apoptosis and reduces the ability of tumors to evade the immune system.
Kiskova, et al. Future Aspects for Cannabinoids in Breast Cancer Therapy, International Journal of Molecular Sciences. 2019;20:5.
Corbus’ CB2 agonists have demonstrated activity against tumor cells in vitro, and several show activity as monotherapy in animal models of solid tumors. We are currently exploring development pathways for this program.