Cushing’s Syndrome is a rare disease caused by prolonged exposure to elevated levels of either endogenous glucocorticoids or exogenous glucocorticoids. ST-002 is uniquely well-suited to address the hyperglycemia and NASH that characterize Cushing’s Syndrome. Despite the apparently benign character of the disease, Cushing’s syndrome is associated with increased mortality and multisystem morbidity. Cushing’s Syndrome patients also suffer from other severe conditions like diabetes, obesity, and NASH/NAFL.
Mechanism of Action of ST-002
ST-002 exhibits pharmacological effects including glucocorticoid inhibition, anti-inflammatory, and anti-diabetic effects. ST-002 suppresses the activity of glucocorticoids but not the glucocorticoids themselves, thus there is no adrenal insufficiency with ST-002 as seen in other anti-glucocorticoid drugs.
Primary Sclerosing Cholangitis (PSC)
Primary sclerosing cholangitis (PSC) is a rare, heterogeneous, idiopathic, inflammatory disorder of the bile ducts resulting in strictures of the intrahepatic and /or extrahepatic bile ducts. Although the great majority of PSC patients have inflammatory bowel disease (IBD), only ~ 5% of IBD patients will develop PSC, the underlying causes of the association remains poorly understood. PSC affects all age groups and has been described in a variety of ethnic and racial groups but is best characterized in populations of Northern European descent. PSC has a male predominance (2:1); and although it may occur at any age, it has a diagnostic peak at 30–40 years. Women tend to be diagnosed later at an average age of approximately 45 years.
PSC and Galanin
Galanin was first isolated in 1983 and is relatively new with an evolving understanding of its functions in humans. Galanin’s central nervous system (CNS) actions—and in particular its proposed role in Alzheimer's disease—have helped to fuel interest in galanin. The late introduction of specific, high-affinity galanin antagonists in 1991 made it possible to study the role of endogenous galanin—which often appears as a strong tonic inhibitor of neuronal actions, a feature studied best by use of antagonists. Within the central nervous system, the highest concentrations are found in the hypothalamus, with lower levels in the cortex and brainstem. It is widely distributed in the gastrointestinal system, particularly in the liver and intestines.
Galanin receptor inhibitor (ST-003) in treating PSC
The goals of PSC treatment are to halt the impact of excessive galanin concentrations that increase cholangiocyte proliferation and fibrogenesis as is found in humans as well as in the Mdr2KO murine model. Gal1 and Gal2 antagonism in the Mdr2KO has resulted in reduced bile duct mass and hepatic fibrosis. ST-003 portends to be an important treatment as it has the ability to meet the treatment goals by addressing a host of disease factors found in the PSC complex, multifactorial disease state.
Sterotherapeutics’ ST004 is a highly selective novel matrix metallaoproteinase-13 (MMP-13) inhibitor licensed from the Moffitt Cancer Center/ FAU with no apparent off-target MMP inhibition thereby solving the foremost problem with the class of drugs. It is also noteworthy that ST004 exhibits no collagenolysis and no MSS.
Matrix Metallaoproteinase-13 overexpression has been strongly correlated to multiple myeloma through the promotion of osteoclastogenesis. Due to MMP-13 over activity in the number of osteoclasts (bone destruction) increases whilst the number of osteoblasts (bone formation) decreases. In addition to the Increase in the number of osteoclasts the destructive activity is enhanced due to an increase in osteoclast polynucelation. It is also noteworthy that the number of abnormal (malignant) plasma cells is reduced. This has made MMP-13 inhibition a prime target for the treatment of multiple myeloma.
Efforts to develop MMP-13 inhibitor have met with failure, primarily due to off-target adverse events (AE) due to the lack of selectivity for other MMPs. Muscle skeletal syndrome (MSS) has been the most frequently reported AE due in part to a breakdown of collagen. Other issues have plagued MMP-13 inhibitors such as stability, bioavailability, and cell permeability.