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 endocannabinoid system, via its cannabinoid receptors type 1 (CB1), is contributing to homeostasis by influencing appetite, lipid metabolism, glycemic control and the overall energy balance.
Any medical condition leading to a disruption in 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 the pathophysiology of these indications, Inversago focuses its research and development on the peripheral CB1 receptors, whose regulation is clinically recognized to be involved in many of these conditions.
Diabetic Kidney Disease
Diabetic Kidney Disease (DKD), including Diabetic Nephropathy (DN), occurs when diabetes causes damages to blood vessel clusters in the kidneys (glomeruli) that are essential to blood filtering and waste elimination. Over time, severe damage to glomeruli can lead to kidney damage and high blood pressure, which in turn can cause further damage to the kidneys’ fragile filtering function.
As a complication of type 1 and type 2 diabetes, diabetic nephropathy affects approximately 1 in 3 people living with diabetes in the United States. Poorly controlled diabetes can induce diabetic nephropathy, leading to chronic kidney disease and requiring either dialysis or transplant in late stage.
DN is detected when abnormal levels of urinary albumin are measured with diabetic patients. This metabolic condition makes blood glucose levels difficult to control over time. No cure exists for this indication and available medications only help slowing the progression of the disease and control related complications.
Overactivity of peripheral CB1 receptors plays a key role in diabetic nephropathy and research in preclinical models has shown that the inhibition of CB1 signaling has the potential to prevent the impairment of kidney function.
Inversago believes that the development of peripheral CB1 inhibitors represents a promising therapeutic avenue for such a metabolic disorder. Leveraging the benefit of a safe and potent peripheral CB1 blockade represents an opportunity to address a significant unmet medical need affecting a growing number of patients globally.
Cannabinoid Receptor 1
Inhibition in Chronic
A New Therapeutic
Type 1 and Type 2 Diabetes
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. This condition can affect almost every part of the body, which is the reason why patients need to manage their blood glucose levels appropriately. Most common comorbid conditions include hypertension, obesity, hyperlipidemia, chronic kidney disease and cardiovascular disease. 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.
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.
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% of diabetics 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.
Inversago believes that appropriate peripheral CB1 receptor blockade could increase insulin production and help manage insulin resistance. Since previous generations of centrally-acting CB1 blockers have shown great promise in the field of type-2 diabetes, supported by solid clinical efficacy data, Inversago believes that developing safe and potent peripherally-acting CB1 blockers will allow the company to leverage the full medical potential of this class of drugs, for the benefit of the diabetic population in general and especially patients affected by type 1 diabetes, since no cure currently exists for their condition.
Certain health conditions—including obesity, metabolic syndrome, and type 2 diabetes—make people more likely to develop non-alcoholic steatohepatitis (NASH), a subcategory of non-alcoholic 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 without the safety challenges of the centrally-acting compounds.
Fibrosis is characterized by an excessive deposition of extracellular matrix components interfering with normal organ function. In the lung, fibrosis interferes with normal gas exchange and reduces lung volumes, leading to shortness of breath. When fibrosis occurs in the lung and gets worse, it is generally referred to as Progressive fibrosing – interstitial lung disease (PF-ILD). Progressive lung fibrosis may occur for many reasons, but inflammation or immune injury are common causes. Sometimes the cause is not clear, and these cases are called Idiopathic pulmonary fibrosis (IPF).
Despite having diverse causes, progressive lung fibroses share a common clinical course with worsening shortness of breath and loss of lung volume. They typically have a poor prognosis with a median life expectancy of only 2.5–3.5 years after diagnosis. As such, there is a high unmet need for anti-fibrotic therapies that could slow down fibrosis progression.
Numerous studies have shown that many mediators contribute to fibrogenesis. Recent studies have demonstrated that CB1 receptors are unregulated in the lungs of patients with pulmonary fibrosis, and in pre-clinical models, blocking the CB1 receptor can lead to a slowing of the progression of IPF. Similarly, CB1 receptor blockade has shown reductions in fibrosis in other organs, including models of fibrosis in the liver, kidneys and skin.
Based on these studies, Inversago believes that an effective peripheral CB1 blockade represents a novel therapeutic approach against pulmonary fibrosis.
Prader-Willi syndrome (PWS) is a genetic disorder affecting equally male and female newborns, notwithstanding geographical origin, and occurring 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 a recent clinical observation study, it was shown that people suffering from PWS have an overactivated endocannabinoid system as a consequence of this genetic disorder. As such, Inversago’s approach of blocking peripheral CB1 receptors is therapeutically aligned.