Peripherally-restricted CB1 Blockade
Inversago Pharma Inc. is focused on the development of peripherally-restricted CB1 receptor (CB1) antagonists / inverse agonists for the treatment of Prader-Willi Syndrome, type 1 diabetes and metabolic disorders in general.
The CB1 receptor is a clinically validated target for the treatment of a series of metabolic disorders such as obesity, type-2 diabetes, NAFLD, NASH and liver fibrosis.
First generation CB1 blockers were permeable to the Blood-Brain Barrier (BBB) and targeted brain CB1 receptors, occupying 30-40% of the central CB1 receptors. This brain occupancy, believed essential for appetite suppression, led to psychiatric adverse events which would eventually cause the termination of all CB1 inverse agonist programs led by multinational pharma companies.
Ten years after this debacle, CB1 receptor world expert George Kunos has demonstrated that peripherally restricted CB1 blockade provides an equivalent therapeutic potential to treat obesity/NASH/T2D and fibrosis (liver and lung), without causing CNS/behavioral effects in mice, predictive of neuropsychiatric side effects in humans.
Prader-Willi Syndrome has an important endocannabinoid/CB1 component
Recent clinical data shows that individuals with PWS have elevated 2-arachidonoylglycerol (2-AG) serum levels, an endogenous CB1 agonist, which establishes a clear link with many of the symptoms they live with (e.g. hyperphagia, obesity, slow GI transit/chronic-severe constipation, low energy expenditure) and with the therapeutic potential of CB1 inverse agonists to treat them. More clinical data also indicate that individuals with PWS are more sensitive to the central effects (brain occupancy) of 1st generation CB1 blockers (rimonabant has clinical data in PWS). This indication is therefore a perfect fit in terms of rapid demonstration of therapeutic potential and safety.
The Endocannabinoid System
CB1 Receptors: Signaling the Brain from the Periphery
The endocannabinoid system is responsible for both homeostasis and equilibrium of the human metabolism. It is involved in regulating several pathways linked to energy intake, reserves and overall expenditure. To do so, the cannabinoid-1 receptor (CB1) may be activated and deactivated such that it impacts many metabolic pathways involving several enzymes and proteins, e.g. leptin, insulin and ghrelin.
While the highest density of CB1 receptors are located in the brain, most cells outside of the central nervous system (hepatocytes, β-cells, adipocytes, myocytes, epithelial cells of the GI tract, etc.) also express the CB1 receptor.
The peripheral endocannabinoid system is now recognized as an important driver in the multi-indication efficacy observed with first generation CB1 antagonists like rimonabant. As such, a potent CB1 blocker has the potential to block or reverse (inverse agonize) the biological processes induced by their activation and treat several metabolic indications.
CB1 Inverse Agonist/Antagonist
A molecule binding to the CB1 receptor and activating a biological response (e.g.: seek food (increased appetite), slow down metabolism / gastric transit and reduce energy expenditure). Activation of the CB1 receptors is also involved in fibrogenesis.
CB1 Inverse Agonist
These types of molecules inhibit the signal induced by the CB1 receptor, and even reverse its biological response (e.g.: no signal to seek food, signal to increase energy expenditure and speed up metabolism at rest, no fibrogenesis or even reverse fibrogenesis).