Unmet Medical Need: Gluconeogenesis

Gluconeogenesis is a metabolic pathway that synthesizes glucose from non-carbohydrate precursors, primarily occurring in the liver and kidneys. It plays a crucial role in maintaining blood glucose levels, especially during fasting or intense exercise. However, excessive gluconeogenesis is a significant contributor to hyperglycemia in conditions such as type 2 diabetes (T2D) and non-alcoholic steatohepatitis (NASH). In T2D, the overproduction of glucose via gluconeogenesis leads to elevated blood sugar levels, which can result in severe complications if not managed effectively. NASH, a progressive form of non-alcoholic fatty liver disease, is characterized by liver inflammation and damage, with gluconeogenesis contributing to the metabolic dysregulation observed in these patients.

The global prevalence of type 2 diabetes is alarming, with estimates suggesting that over 537 million adults were living with diabetes in 2021, a number projected to rise to 643 million by 2030 (International Diabetes Federation, IDF). The economic burden of diabetes is substantial, with global healthcare expenditures related to diabetes estimated at $966 billion in 2021. NASH is also on the rise, with a prevalence of approximately 25% in the general population and up to 70% in individuals with obesity or diabetes. The economic impact of NASH is significant, as it is associated with increased healthcare costs due to complications such as cirrhosis and liver cancer, which can lead to liver transplantation.

There is a critical unmet medical need for effective therapies targeting gluconeogenesis, particularly in the context of T2D and NASH. Current antidiabetic medications primarily focus on improving insulin sensitivity or increasing insulin secretion, but they do not directly address the excessive glucose production from gluconeogenesis. This gap in treatment options leaves many patients with poorly controlled blood glucose levels, leading to long-term complications such as cardiovascular disease, neuropathy, and kidney damage.

In the case of NASH, the lack of approved pharmacological treatments exacerbates the unmet need. NASH is associated with significant morbidity and mortality, and the absence of effective therapies highlights the urgent requirement for novel approaches that can target the underlying metabolic dysregulation, including gluconeogenesis. The development of fructose-1,6-bisphosphatase (FBPase) inhibitors represents a promising avenue to address this unmet need, as these agents can directly inhibit gluconeogenesis and potentially improve glycemic control in T2D and metabolic health in NASH patients.

Current treatment options for type 2 diabetes include lifestyle modifications, oral hypoglycemic agents (such as metformin, sulfonylureas, and DPP-4 inhibitors), and injectable therapies (such as GLP-1 receptor agonists and insulin). However, these treatments often do not effectively reduce gluconeogenesis, which remains a significant contributor to hyperglycemia. For NASH, there are currently no FDA-approved pharmacological therapies, and management primarily focuses on lifestyle changes, weight loss, and controlling associated conditions such as diabetes and hyperlipidemia.

The limitations of existing treatments include:

Several clinical trials are currently investigating FBPase inhibitors as potential treatments for T2D and NASH. For example, CS-917, a well-characterized FBPase inhibitor, has shown promise in reducing gluconeogenesis and improving glycemic control in diabetic rodents and has favorable safety profiles in early clinical evaluations. Future trials of second-generation FBPase inhibitors, such as MB07803, are anticipated to provide further insights into their efficacy and safety in managing hyperglycemia and addressing the unmet needs in both T2D and NASH.

The increasing prevalence of T2D and NASH, coupled with the limitations of current treatment options, underscores the urgent need for innovative therapies targeting gluconeogenesis. The development of FBPase inhibitors and other novel agents could significantly improve patient outcomes and reduce the economic burden associated with these metabolic disorders. Addressing the unmet medical needs in gluconeogenesis not only has the potential to enhance glycemic control but also to mitigate the long-term complications associated with diabetes and liver disease, ultimately improving the quality of life for affected individuals.

In conclusion, the unmet medical need for gluconeogenesis is significant, particularly in the context of T2D and NASH, where current treatment options are inadequate. The development of targeted therapies, such as FBPase inhibitors, represents a promising approach to address these challenges and improve patient outcomes.