The investigational drug LAF237, the first in a new class of oral anti-diabetes agents, significantly improved glycemic control in patients with type 2 diabetes who were not adequately controlled by metformin alone, an improvement that was sustained for up to a year while taking LAF237, according to data presented at the European Association for the Study of Diabetes (EASD) annual meeting.
According to the company release, in a 28-day, randomized, placebo-controlled, double-blind crossover trial of 12 patients with type 1 diabetes treated by insulin pump therapy, LAF237 suppressed glucagon secretion following a meal, indicating that GLP-1 acts on glucagon secretion independent of insulin effects. In a separate double-blind four-way crossover study involving 16 healthy male subjects, LAF237 reduced GLP-1 and GIP secretion in response to glucose administration. Larger follow-up studies to confirm these findings are ongoing.
Several other studies presented during the meeting suggest that LAF237, a member of an innovative class of diabetes treatments known as DPP-4 inhibitors, works to address the insulin/glucose imbalance that is the underlying defect of type 2 diabetes. Researchers reported that LAF237 increases insulin secretion while suppressing the release of glucagon in patients with diabetes. Additionally, researchers in a small study of people with type 2 diabetes concluded that the compound improved function of the insulin-producing beta cells in the pancreas.
LAF237 works in a different manner than other therapies used to treat type 2 diabetes. It increases levels of specific hormones found in the gut (incretin hormones) called glucagon-like peptide (GLP)-1 and gastric inhibitory polypeptide (GIP), by blocking the action of dipeptidyl peptidase (DPP)-4, an enzyme that normally inactivates them. GLP-1 and GIP are secreted from the intestine in response to food and stimulates insulin production by the beta cells of the pancreas. GLP-1 also reduces the secretion of glucagon, a hormone that signals the liver to produce glucose. In this way, LAF237 helps to address the imbalance between insulin supply and demand, one of the underlying causes of type 2 diabetes.
"Although most oral antidiabetic agents are initially effective in achieving acceptable glycemic control in patients with type 2 diabetes, control is seldom maintained in the long term, even with combination therapy," explained study author Professor Bo Ahrén of Lund University, Sweden. He added, "The finding that LAF237 can achieve acceptable hemoglobin A1c reduction and maintain it for up to a year is very encouraging."
The long-term study results reveal that the phase II study, 42 patients were given oral LAF237 plus metformin once daily and 29 patients received placebo plus metformin. Haemoglobin A1c (HbA1c) levels were measured over the course of 52 weeks. In patients treated with LAF237 plus metformin, the HbA1c levels decreased significantly and those levels were maintained up to 52 weeks. In the patients who continued on metformin alone, glycemia control deteriorated over time. At study end, there was an average difference of 1.1 per cent between the two groups (p<0.0001). Glucose levels measured after 8-12 hours of fasting and 1-2 hours after eating a meal were also reduced in patients taking metformin plus LAF237 versus continued therapy with metformin alone.
"The more we learn about LAF237, the more promise this treatment appears to hold," Dr. Jorg Reinhardt, head of Development, Novartis Pharma AG said adding, "Clinically, we're seeing meaningful endpoints in sustainable reductions of haemoglobin A1c levels, and when we closely examine how the drug works, we see it closely mirrors the body's own natural, physiological mechanism to balance out insulin supply and demand. This effect, combined with LAF237's oral administration, good tolerability, and the lack of weight gain seen among patients is exciting and encouraging to the Novartis research team as we continue the compound's phase III development programme."
The development of new diabetes treatments like DPP-4 inhibitors is critically important given the World Health Organization's estimate that the number of people with diabetes in Europe will rise from approximately 33.3 million in 2000 to more than 48 million in 2030. In 2000 alone, approximately 609,000 deaths in Europe were attributed to diabetes.
The phase III clinical trial programme of LAF237 is currently ongoing, with first regulatory submissions expected in 2006. The development of LAF237 is driven by Novartis' cardiovascular and metabolic business franchise.