This excerpt taken from the NVS 6-K filed Sep 21, 2005.
LAF237 (vildagliptin), a potentially first-in-class oral DPP-IV inhibitor for the treatment of type 2 diabetes, is planned to be filed with regulatory authorities in the US in the first half of 2006. New Phase IIb/III studies showed sustained efficacy and good tolerability in treating patients with type 2 diabetes.
Phase IIb/III trial results presented at the event demonstrated strong efficacy in lowering HbA1c levels (a measure of average blood sugar levels over a two- to three-month period) and excellent tolerability without weight gain. The results also indicated the ability of LAF237 to improve and sustain pancreatic islet cell function and insulin sensitivity over a one-year period.
Consistent with earlier studies, LAF237 showed in a 12-week trial the ability to achieve in a dose-proportional manner clinically meaningful and sustained reductions of HbA1c by up to 1.6 percentage points. The trial used pioglitazone as a non-comparator positive control.
In another trial presented at the event, initial 52-week data showed a sustained reduction in HbA1c of 1.0 percentage points as a monotherapy, but narrowly missed the primary endpoint of non-inferiority versus metformin. However, the interim data from this two-year trial showed LAF237 was better tolerated than metformin, particularly with a superior gastro-intestinal tolerability profile.
LAF237 has the potential to become a first-line treatment, either as a monotherapy or in combination with other agents, for patients with type 2 diabetes, which comprises about 90% of the ever growing number of patients, estimated at currently 150 million worldwide suffering from this disease. LAF237 has demonstrated the ability to reduce HbA1c on a sustainable basis in a wide range of patients. It also showed neutral effect on body weight, good tolerability and a low incidence of hypoglycemia (low blood sugar), especially in combination with insulin.
An extensive clinical trial program is currently underway for LAF237 that aims to define the role of pancreatic islet cell protection in delaying the onset of type 2 diabetes, slowing progression and maintaining control in diabetes management and reducing cardiovascular complications. LAF237 has the potential to modify disease progression due to its positive effect on pancreatic islet cells, which produce insulin and are damaged in patients with type 2 diabetes.
This excerpt taken from the NVS 6-K filed Feb 4, 2005.
LAF237 is the first of a new class of "incretin enhancers"oral antidiabetic agents that act by inhibiting an enzyme called dipeptidyl peptidase-4 or DPP-4. Now undergoing Phase III trials for the treatment of type 2 diabetes, LAF237 has the potential to modify the disease.
Already considered an epidemic in the US, diabetes is on the rise globally among men and women of all ages, ethnic groups and levels of education. The World Health Organization estimates that 170 million people currently suffer from diabetes. Prevalence is expected to double, to 366 million people, by 2030.
Type 2 diabetes is a disorder leading to elevated levels of glucose in the blood. Glucose is the principal source of energy for cellular metabolism. Normally, as blood glucose levels climb after a meal, insulin is secreted by pancreatic beta cells to absorb glucose into cells and return levels in blood to the normal range. In people with type 2 diabetes, this uptake of glucose into cells is impairedeither as a result of insufficient insulin production, or because tissue in muscle develops abnormal resistance to insulin.
Incretins are hormones that play a critical role in regulation of insulinand hence blood glucose. Following a meal, the incretin hormones GLP-1 (glucagon-like peptide 1) and GIP (gastric inhibitor polypeptide) are secreted from the intestine and stimulate secretion of insulin by beta cells. In healthy people, GLP-1 triggers the release of enough insulin to restore blood sugar levels to normal. The feedback system controlling insulin release is exquisitely sensitiveafter a half-life of only 90 seconds, GLP-1 is degraded by the DPP-4 enzyme.
However, people with type 2 diabetes need GLP-1 and insulin to last longer to decrease elevated glucose levels in their blood. LAF237 works by inhibiting DPP-4, to delay degradation of GLP-1, and extend the action of insulin.
Phase II data presented at last year's annual meeting of the American Diabetes Association showed that LAF237 significantly improved blood glucose control when added to metformin, a standard treatment for type 2 diabetes. The significant decrease in HbA1c, the primary measure of blood glucose control, was maintained for one year.
Phase III trials are studying LAF237 as both monotherapy and in combinations. Initial data from the Phase III studies are expected during the latter part of 2005.
LAF237 also has a disease-modifying potential through its beneficial effects on pancreatic beta cells. In animal studies, LAF237 has shown a positive effect on insulin secretion by increasing the genesis, proliferation and differentiation of beta cells, while inhibiting apoptosis, or programmed death, of these cells.
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