RESEARCH & DEVELOPMENT
Fatty liver is the accumulation of fat in the liver cells. Non-alcoholic fatty liver disease (NAFLD) is caused by excessive nutrient intake and sedentary life style. Advanced fatty liver disease is associated with inflammation of the liver so called steatohepatitis (NASH) which may progress to cirrhosis, liver failure and hepatocellular carcinoma. Steatohepatitis is most frequently caused by or associated with diabetes and obesity.
Current treatment options of fatty liver disease and steatohepatitis consist of addressing the underlying disease by diet, exercise, and antidiabetic drugs and ultimately liver transplantation. There is currently no established pharmacological treatment for non-alcoholic fatty liver disease (NAFLD).
Obesity is a medical condition in which patients have very high amount of body fat in relation to lean body mass causing a body mass index greater than 30. More than 10% of all adults worldwide are affected with up to 40% in some geographical regions. This condition is very often caused by excessive nutrient intake and sedentary lifestyle. However, recent studies identified gene mutations which increase the risk of obesity.
There are many serious complications caused by obesity like high blood pressure, diabetes, coronary artery disease, stroke, osteoarthritis, fertility & pregnancy problems and many others. So far the main treatment option is the reduction of nutrient intake by energy-limited diet combined with increased exercise. There are only some limited pharmacological treatment options with only modest success and side effects. The only effective treatments today are bariatric surgeries reducing the size of the stomach.
Diabetes mellitus is a group of complex metabolic disorders sharing the common underlying feature of hyperglycemia. Hyperglycemia results from defects in insulin secretion, insulin action or both. There are many serious complications of diabetes causing damages in multiple organ systems particularly in kidney, eyes, nerves and blood vessels. Diabetes affects app. 16m people in the US with additional 800,000 individuals developing diabetes each year.
Diabetes is the leading cause of end-stage renal disease, blindness in people below the age of 55, and non-traumatic lower extremity amputations in the US. Current standard of care focuses on normalization of blood sugar levels by diet, exercise, and different pharmacological therapies with insulin or oral medications for insulin sensitization, drugs that stimulate Insulin release or inhibit Glucagon release. However all these treatments have significant side effects and need lifelong treatment.
Chronic Kidney Disease (CKD) is a long-term medical condition with a gradual loss of kidney function over time. CKD is rapidly emerging as one of the world’s most common noncommunicable chronic diseases (Borg et al. 2023 Int J Nephrol). Causes of CKD are multifactorial and diverse and progression rates are highly variable, but patients encounter both an increased risk for end-stage kidney disease as well as increased cardiovascular risk. So far, the treatment options are still limited and rarely curative, but instead aims at slowing the progression of the disease and delaying kidney failure. Current standard of care targets blood pressure control and employment of blockers of the renin-angiotensin system (RAS). Additionally, new sodium-glucose cotransporter 2 inhibitor (SGLT2i) drugs which are approved for type 2 diabetes (T2D) showed very promising results and were recently added to the treatment guidelines for patients with T2D and CKD (DeBoer et al. 2020 Kidney Int).
NaCT, also known as PMCT or SLC13A5, is a sodium coupled citrate transporter which is predominantly expressed in liver cells and the mammalian homolog of the INDY (“I am not dead yet”) gene in Drosophila. In mouse studies it was shown that NaCT knock out protects from adiposity and insulin resistance induced by aging and high-fat diet (Cell Metabolism 14, 184, 2011). Further analysis in human liver samples showed the direct link of NaCT to the pathogenesis of Non-alcoholic fatty liver disease (NAFLD) and Steatohepatitis (NASH) and could elucidate NaCT gene regulation (Hepatology 66, 616, 2017). Therefore NaCT is an attractive therapeutic target for the treatment of nonalcoholic fatty liver disease, obesity, and type 2 diabetes by influencing the mammalian energy metabolism. Recent studies have been shown human genetic evidence that NaCT is linked to the regulation of plasma citrate concentration and affecting kidney and liver function as well as bone stability (Gill et al. 2023 BMC Med, Zahn et al. Metabolite 2023).
Eternygen is developing novel small molecule inhibitors against the sodium coupled citrate transporter NaCT. The proof of concept of this therapeutic approach was already shown in knock out animals but also with small molecule development candidates. Thus, Eternygen´s proprietary molecules have been shown a therapeutic effect on glucose metabolism and hepatic lipid oxidation in a diet induced obesity model in mice. Furthermore, human genetic data analyses of single nucleotide polymorphisms (SNPs) corroborates evidence from various animal models to support effects of NaCT inhibition on improving kidney function. Eternygen has a drug development collaboration with Evotec AG covering a broad expertise in drug discovery and pre-clinical development in the field of metabolic and kidney diseases. Eternygen´s NaCT inhibitors are currently in pre-clinical development phase.