Cannabinoid-1 Receptor Blockade to Treat Hyperphagia, Obesity and Related Metabolic Disorders in PWS

Funding Summary

This grant supports the development of a new drug to tackle hunger and obesity with PWS. Inversago, a newly started, specialized biotech company, proposes that its CB1 blockers would treat a wider spectrum of symptoms than anything presently in development for PWS. The drug targets the endocannabinoid pathway, which is known to be altered in PWS.  Unlike previous drugs that targeted the same pathway, this modified version does not enter the brain – thus it is expected to have a beneficial effect on metabolism and weight without psychiatric side effects.  FPWR funding will help support this company's development of their drug for PWS by supporting the ‘preclinical’ studies needed to move the drug into human clinical trials.

FPWR thanks the Storr Family Foundation whose generous support made this grant possible.

Theresa Strong, Director of Research Programs, shares details on this project in this short video clip. 

Fall 2018 Inversago

 

Watch the full webinar describing the 11 research projects funded in this grant cycle here.


Lay Abstract

Inversago is developing novel Cannabinoid-1 Receptor (CB1) blockers. CB1 blockers is a class of drugs with proven efficacy in humans for appetite suppression, weight loss, insulin and leptin resistance as well as liver diseases. Inversago intends to test its lead molecule, a 3rd generation CB1 blocker, in monkeys to demonstrate its safety. This is a pivotal step in bringing back CB1 blockers in clinical development because 1st generation CB1 blockers had the propensity to cause psychiatric adverse events in humans and monkeys, even more so in individuals with PWS based on clinical data. The observed adverse psychiatric effects are known to be caused by CB1 blockers entering the brain and acting on central CB1 receptors, causing anxiety and depression. Inversago has novel molecules specifically designed to only hit peripheral CB1 receptors (GI tract, liver, pancreas, fat cells, muscles, lungs, etc.), avoiding the brain and its associated adverse events, while still providing the beneficial metabolic parameter balancing effect. Given individuals with PWS were recently shown to have chronically activated CB1 receptors, a peripherally-restricted CB1 blockade has the potential to reverse this over activation, known to drive appetite, lower energy expenditure and slow gastrointestinal transit rate (chronic constipation). If unsuccessful in preventing psychiatric adverse events in monkeys, and in establishing a safe therapeutic window for human trials, Inversago would test its follow-on molecule, a 4th generation CB1 blocker. However, if successful, this first step will establish a therapeutic window for the first-in-human clinical trials (Phase 1), providing hope for the first time since 2008 that a CB1 blocker could help PWS patients. It is expected that upon completion of a positive monkey study, first-in-human trials (Phase 1) could be launched within 18-24 months.  For the PWS community, if shown to be safe, this product is expected to provide appetite reduction (hyperphagia), but also provide the clinically-demonstrated beneficial metabolic effects  of CB1 blockers such as weight loss, reversing insulin (type-2 diabetes) and leptin resistance, reducing fat and fibrosis in the liver, increase energy expenditure, and increase in gastrointestinal transit rate, useful to treat chronic constipation. Overall, Inversago's CB1 blockers would cover a wider spectrum of symptoms than anything presently in development for PWS.

Research Outcomes: Project Summary

This comparative CNS safety pharmacology study in Non-Human Primates (monkeys) confirmed the results observed in rodents at the inventor's laboratory (George Kunos, NIH/NIAAA) and support further development. Peripheral restriction of our compounds is demonstrated by our capacity to reach supratherapeutic exposures without CNS clinical observations. This preclinical study in NHP allows the company to confirm the lead compound to take into clinic development for the treatment of PWS: INV-101. After more than a decade since rimonabant failed in treating PWS due to psychiatric adverse events kinked to rimonabant and its brain penetration, Inversago now has a solid option for the treatment of PWS symptoms like hyperphagia, low energy expenditure, chronic constipation and other metabolic disorders associated with this condition. With this study, Inversago is confident it can continue development of INV-101 for this indication and is able to use its funds to enter into further development, hoping to reach the clinic next year. 

Funded Year:

2018

Awarded to:

Francois Ravenelle, PhD.

Amount:

$108,000

Institution:

Inversago

Researcher:

Francois Ravenelle, PhD.

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