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Diabetology

Diabetes

Diabetes is a condition where blood sugar levels increase: this is known as hyperglycaemia. This increase occurs because insulin, a hormone secreted by the pancreas and responsible for regulating blood sugar levels, is not produced in sufficient quantities or does not function properly. There are different forms of diabetes. The most common form is type 2 diabetes, which develops mainly in adults, while type 1 diabetes is an autoimmune condition and is the most frequent chronic disease in paediatric patients.
Type 2 diabetes is caused by the cells’ inability to respond to insulin. This mechanism results first in a progressive increase of the insulin produced by the pancreatic islet cells, and later leads to the weakening of these cells: the consequence is reduced insulin production, which, coupled with the onset of insulin resistance, induces an inability to control blood sugar levels.
Type 1 diabetes is caused by the autoimmune destruction of Langerhans islet cells that secrete insulin. In the vast majority of cases, the disease is caused by the release of antigens by pancreatic islet cells: these structures, located on the cell membrane, are recognized as “different” by the immune system, which starts producing antibodies. The result is virtually total lack of insulin production; this is treated by administering exogenous insulin and, in some selected cases, through pancreas or pancreatic islet transplant. In other circumstances, type 1 diabetes may develop as a result of a traumatic event that causes the destruction of Langerhans islet cells. In these cases, again, pancreatic islet transplant may represent a new frontier in the treatment of this disease.

Dompé’s commitment in diabetology

Dompé discovered and developed the first two drugs of a new class of inflammation modulators: Reparixin and Ladarixin. Both are inhibitors of interleukin-8 (IL-8), an essential factor in the pathogenesis of type 1 diabetes:

  • IL-8 is a key chemotactic factor for the inflammatory reaction immediately following pancreatic islet transplantation, and limits the efficacy of this therapy.
  • IL-8 is the main mediator of inflammation in the processes that trigger type 1 diabetes and the autoimmune destruction of Langerhans islet cells.

Pancreatic islet transplantation

Today, pancreatic islet transplantation provides a therapeutic approach also for cases of pancreatitis that cannot be controlled by other medical and surgical treatments (iatrogenic diabetes), enabling patients to undergo surgery while still being able to control blood glucose levels. Total pancreas removal may be associated with a series of long-term complications, related mainly to the onset of iatrogenic diabetes and a high risk of severe hypoglycaemia despite insulin treatment. In addition to absence of endogenous insulin, this procedure also causes a lack of other hormones that are important to maintain blood glucose regulation, for example glucagon. Independence from insulin treatment can be achieved by up to 40-45% of patients in the case of donor transplants1 and by 40% in the case of autologous transplant2. Langerhans islet graft, which is performed in local anaesthesia and requires a short postoperative hospitalization, is carried out by catheter injection of pancreatic islets through the abdominal wall into the portal vein that conveys blood to the liver. The Langerhans islet cells then flow into and lodge in the liver capillaries. From this time on, the islets start producing insulin in the liver.

Reparixin

Identified in Dompé’s Italian laboratories, Reparixin is a powerful and selective inhibitor of interleukin-8. The drug, currently at an advanced clinical development stage in the area of type 1 diabetes, is intended to improve the efficacy of autologous or allogeneic pancreatic islet transplantation.
Because of its innovative quality and potential ability to provide an effective response to the unmet need to reduce the risk of rejection in pancreatic islet transplantation (an extremely rare condition), Reparixin has been designated as orphan drug by the FDA and the EMA.

How Reparixin acts

Reparixin is an inhibitor of the CXCR1 receptor, activator of interleukin-8 (IL-8), an essential factor for the development of inflammatory response. Reparixin is the progenitor of a new class of low molecular weight inhibitors able to selectively regulate the receptor’s activity with an allosteric mechanism of action. More specifically, Reparixin acts through the interaction with IL-8 CXCR1 and CXCR2 receptors, a key factor in the inflammatory cascade able to “recall” and facilitate the action of specific white blood cells engaged in destroying whatever is recognized as “non-own” in the body (in this case, the transplanted islets).

The clinical trial process

On the basis of the results of a small phase II randomized clinical trial conducted in 9 patients, which demonstrated how treatment with Reparixin can significantly improve the efficacy of pancreatic islets transplantation in a selected population of patients with type 1 diabetes, two large clinical studies are currently in progress to evaluate the drug’s efficacy and safety in donor transplants, frequent in Italy and Europe, and in autologous transplants, more commonly performed in the United States.

  • Donor transplants. A phase III registration study is being conducted involving 8 centres in 5 Countries between Europe and the US and the enrolment of approximately 5 patients. The primary endpoint of the study is to evaluate the efficacy of Reparixin in improving the outcome of pancreatic islet transplantation; the secondary endpoints include the measurement of the percentage of patients who achieve independence from insulin and optimal blood glucose control after pancreatic islet transplantation.
  • Autologous transplantation. A phase II/III study is in progress in the United States to evaluate the efficacy and safety profile of Reparixin in autologous pancreatic islet transplantation. The study involves approximately 100 adult patients who are candidates for autologous pancreatic islet transplantation and have undergone total pancreatectomy, and have not previously received an islet transplantation. The endpoint of the study is to evaluate the efficacy of Reparixin in improving the function of transplanted cells, through the measurement of the percentage of patients who become independent from insulin as a result of autologous islet transplantation.

Ladarixin

Ladarixin is a drug resulting from Dompé research. It acts as inhibitor of IL-8, the main mediator of inflammation in the processes that lead to the progressive autoimmune destruction of Langerhans islet cells in type 1 diabetes. Currently in phase II clinical trials, the drug aims to control in an innovative manner the inflammatory reactions that characterize the initial stage of type 1 diabetes. The objective of treatment with Ladarixin is to limit the body’s “wrong” immune response that leads to the production of autoantibodies active against pancreatic islet cells and hence to the onset of type 1 diabetes.

Notes

1 Source: Barton FB et al., Improvement in outcomes of clinical islet transplantation: 1999-2010, Diabetes Care 2012, 35(7): 1436-1445

2 Source: Sutherland DE et al., Total Pancreatectomy and Islet Autotransplantation for Chronic Pancreatitis, J Am Coll Surg., 2012, 12(5): 580–586