CC-66 in Acute Diseases
CC-66 in Transplantation
Ischaemia/Reperfusion Injury (IRI)
IRI is an unavoidable consequence of kidney transplantation and influences short-term as well as long-term graft outcome. Ischaemia and reinstitution of blood flow in oxygen-deprived kidneys activate a complex sequence of events that cause renal injury and play a pivotal role in the development of delayed graft function, acute graft rejection, chronic rejection and chronic graft dysfunction. The inflammatory cascade triggered by IRI also affects many other regulatory systems in the body, including the CNS, and can lead to severe complications. Suppression of this inflammatory cascade, along with protection of the kidney from damage, would offer a significant advance in kidney transplantation.
Cypralis’ drug candidate is an intravenously administered small molecule scheduled to enter human trials in Q1 2020 to prevent and/or treat acute kidney injury associated with transplantation (kidney, liver, other organs). The compound has been shown to provide excellent protection against AKI induced by ischaemia, LPS or toxins in a number of preclinical animal models.
CC-66 in organ preservation
Organ transplantation involves the distinct phases of organ procurement (including storage and transportation) and implantation surgery. The main determinant of the long-term patient survival is the quality of the transplanted organ, which depends to some extent on the quality of the organ. However, the main enemy is time, the length of the period between removal of the organ from the donor to the moment of post-transplantation resuscitation of the recipient being a strong predictor of successful transplantation. During this period of storage and transport the organ is exposed to significant stress due to hypoxia and nutrient deprivation, leading to progressive deterioration of the functional capability of the organ and triggering the onset of inflammation.
Cypralis’ drug candidate is a water-soluble small molecule scheduled to enter first in human trials in Q1 2020. In animal experiments of organ protection use of the drug in conjunction with current preservation protocols has been shown by histopathology and immunohistochemistry to result in significantly reduced tissue damage and inflammation. This drug has the potential to significantly prolong organ storage times and improve the quality of transplanted organs with the overall benefit of reduced organ supply pressure, better long-term outcomes and significant cost savings. Clinical studies will begin early in 2020 with the goal to define the best positioning of this drug in organ preservation and transplantation.
CC-66 in Acute Pancreatitis
Acute pancreatitis (AP) is a sudden severe inflammation of the pancreas gland that begins in the pancreatic acinar cells that produce digestive enzymes. Pancreatic necrosis, systemic inﬂammatory response syndrome, multiple organ failure and sepsis are characteristic of the disease which results in significant mortality and is currently without disease-modifying therapy. The disease is extremely painful requiring hospitalisation of between 5 – 30 days duration. In most cases the disease is caused either by gallstones blocking drainage of the bile duct and exposing the acinar cells to the toxic effects of bile acid or by excessive alcohol consumption. Both factors cause necrosis of acinar cells by either direct toxicity (bile acids) or by amplifying physiological Ca2+ signals leading to necrotic cell death (alcohol).
Therapeutic efficacy of CC-66 has been demonstrated in rodent models of AP where the disease is induced by bile acid salts, fatty acid ethyl esters (a physiological product of alcohol metabolism) or supraphysiological doses of cerulein, a secretagogue mimicking the activity of cholecystokinine.
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