Metabolism, which refers to all life-sustaining processes occurring at chemical level within living organisms, fulfills three purposes: converting food to energy to fuel cellular activity, using that energy to elaborate key components (proteins, lipids, nucleic acids, carbohydrates), and eliminating nitrogen (ammonia, urea, uric acid and creatinine).
In optimal conditions, metabolism functions in a state of balance, or homeostasis, regulating various parameters such as body temperature, energy intake and expenditure, glucose, appetite and energy-related levels, etc. The peripheral endocannabinoid system is believed to contribute to homeostasis by controlling appetite, food intake and energy balance.
Any medical condition disrupting homeostasis, such as obesity, type 2 diabetes or various genetic conditions (e.g.: Prader-Willi Syndrome), is called a metabolic disorder. In order to address these indications, Inversago focuses its research on the peripheral endocannabinoid system, more precisely the CB1 receptor activity, whose regulation is recognized to be involved in many conditions.
Prader-Willi syndrome (PWS) is a genetic disorder affecting equally male and female newborns, notwithstanding geographical origin, and occuring in about one out of 15,000 births. PWS is considered as the most common genetic cause of life-threatening childhood obesity.
Prader-Willi syndrome is a complex genetic condition that affects the body in many ways. In its early stage, PWS is characterized by weak muscle tone (hypotonia), feeding difficulties, poor growth, and delayed development. Then, affected children develop an insatiable appetite, which leads to chronic overeating (hyperphagia) and obesity, among other symptoms. Some people with Prader-Willi syndrome, particularly those with obesity, also develop type 2 diabetes (the most common form of diabetes).
The treatment of PWS is currently based on addressing the symptoms of the disorder as they arise, as there is currently no cure for this genetic disease. The inability to control food intake is often the biggest challenge facing PWS patients and preventing them from living as independent individuals. To date, no medications have proven effective in regulating appetite in PWS, and therefore, strict environmental control and constant supervision are the only ways to prevent life-threatening overeating and extreme obesity at present.
In this context, Inversago’s focus on PWS with INV-101, the company’s lead compound currently under investigation, is an opportunity to validate the relevance of our approach in the years to come, while potentially addressing a significant unmet medical need.
Insulin, a hormone produced by the pancreas, regulates the amount of glucose (sugar) present in the blood stream. Blood sugar must be carefully balanced to ensure that the body functions properly. Too much blood sugar can cause damage to organs, blood vessels, and nerves. The human body also needs insulin to convert sugar into energy.
Diabetes is a metabolic disease caused by either the unability of the human body to produce insulin or to properly use the insulin it produces. Global prevalence of diabetes among adults over 18 years of age has risen from 4.7% in 1980 to 8.5% in 2014. It is estimated that 30 million Americans and 11 million Canadians are living with diabetes or prediabetes.
Type 1 diabetes is an autoimmune disease, also referred-to as insulin-dependent diabetes. People with type 1 diabetes aren’t able to produce insulin, because their immune system considers the pancreas as a threat, hence attacking it. About 90 per cent of people live with type 2 diabetes, whereas 10 per cent have type 1 diabetes. People with type 2 diabetes can’t properly use the insulin made by their bodies, or their bodies aren’t able to produce enough insulin.
Diabetes can affect almost every part of the body, which is the reason why patients need to manage their blood glucose levels appropriately. Inversago believes that appropriate CB1 receptor blockade could increase insuline production and help manage insuline resistance. Since previous generations of CB1 blockers have shown great promise in the field of type-2 diabetes, supported by solid clinical efficacy data, Inversago believes that its safer versions of CB1 blockers will allow the company to leverage the full medical potential of this class of drugs, for the benefit of the diabetic population.
Certain health conditions—including obesity, metabolic syndrome, and type 2 diabetes—make people more likely to develop Nonalcoholic steatohepatitis (NASH), a subcategory of Nonalcoholic fatty liver disease (NAFLD). NASH is defined as the presence of hepatic steatosis and inflammation with hepatocyte (liver cells) injury and ﬁbrosis. The presence of liver ﬁbrosis (LF) confers an increased risk of disease progression to cirrhosis, liver failure, and hepatocellular carcinoma, with a higher mortality. Therefore, reducing LF is expected to improve the long-term clinical outcomes of patients with NASH.
Approximately one-quarter of the world’s population has NAFLD, with estimates of the prevalence of NASH ranging from 1.5% to 6.45%. NASH is currently the second leading cause of cirrhosis among adults awaiting liver transplantation in the USA, and is expected to soon represent the leading indication for liver transplantation. There are currently no approved medications in the US for the treatment of NASH. Current disease management is primarily focused on promoting weight loss through lifestyle interventions.
First generation CB1 blockers have already demonstrated a clear therapeutic potential to treat NASH, with strong clinical efficacy data suggesting a broad impact through multiple pathways downstream to the CB1 receptor, suggesting a possible combination of steatosis reduction, fibrogenesis reduction and reversal, insulin and leptin resistance management, as well as body weight reduction. In this context, Inversago’s new peripheral CB1 blockers could represent a potential treatment for this multicomponent condition, exploiting the CB1 receptor’s full therapeutic potential.
Inversago believes that peripheral CB1 blockade represents a promising therapeutic avenue for other metabolic disorders, such as primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC), two major types of chronic cholestatic liver diseases (conditions preventing bile to flow from the liver to the duodenum).
PBC is a rare autoimmune liver disease characterized by biliary destruction, progressive cholestasis, and, ultimately, the development of fibrosis, cirrhosis, and hepatocellular carcinoma. Forty per cent of patients have an insufficient response to the primary medical treatment for PBC, putting them at risk of potentially life-threatening complications. Several studies have shown that CB1 receptors are markedly expressed in hepatocytes and biliary epithelial cells in the livers of patients with PBC. Moreover, PBC features liver inflammation and fibrosis, which can be reduced by the administration of CB1 antagonists.
PSC is characterized by chronic inflammation, progressive fibrosis, and stricturing of bile ducts.
In a context where no cure exists for either indication and available medications can only help slowing the progression of the diseases, exploring the anti-fibrotic benefit of the peripheral CB1 blockade represents an opportunity to address unmet medical needs.