Inversago Pharma Inc. is focused on the development of peripherally-restricted CB1 receptor (CB1) 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.
- Cinar et al., Hybrid inhibitor of peripheral cannabinoid-1 receptors and inducible nitric oxide synthase mitigates liver fibrosis. JCI Insight. 2016;1(11):e87336. http://dx.doi.org/10.1172/jci.insight.87336
- Cinar et al., Cannabinoid CB1 receptor overactivity contributes to the pathogenesis of idiopathic pulmonary fibrosis. JCI Insight. 2017;2(8):e92281. https://doi.org/10.1172/jci.insight.92281
- Knani et al., Targeting the endocannabinoid/CB1 receptor system for treating obesity in Prader-Willi syndrome, Mol. Met., (2016) 5 1187-1199.
- Motaghedi et al. Psychiatric adverse effects of rimonabant in adults with Prader Willi syndrome. European Journal of Medical Genetics 54 (2011) 14-18