DPP IV inhibitor clears Phase II study in diabetes
diabetes - Novartis' LAF-237 - seems to improve glucose control
without the weight gain associated with other orally-active drugs
for this common disease, reports Phil Taylor.
Clinical results presented at the European Association for the Study of Diabetes (EASD) meeting in Munich last week suggest that LAF-237 given in combination with metformin, one of the most widely prescribed oral antidiabetic agents worldwide, improves control of glucose as measured by haemoglobin A1C (HbA1c) levels.
This is crucial, because while most oral antidiabetic agents are initially effective at achieving acceptable glycemic control in patients with type 2 diabetes, it is well-known that HbA1c levels increase as the disease progresses and good glycemic control is seldom maintained in the long-term, even with combination therapy. And poor glucose control is intrinsically linked to the development of the damaging consequences of diabetes, such as nerve, eye and heart disease.
LAF-237 is an inhibitor of dipeptidyl peptidase (DPP)-IV, an enzyme involved in the breakdown of two hormones, glucagons-like peptide (GLP-1) and gastric polypeptide (GIP), that are involved in boosting insulin activity after a meal .
The 12-month, Phase II study compared the addition of placebo versus once daily LAF-237 to patients' regular dose of metformin. The results showed that the increase in HbA1c each month was less in patients treated with LAF-237 than those on placebo and that by 12 months the overall difference in HbA1c was 1.1 per cent.
An HbA1c reduction of 1.1 per cent seems small, but is impressive for an oral antidiabetic agent, particularly as it was achieved on top of existing treatment with metformin. Moreover, the reduction in HbA1c was maintained to one year, whereas often early treatment benefits diminish over time with oral antidiabetic drugs.
There was also no reported weight gain with LAF-237, a side effect observed with almost all existing oral therapies and one of the biggest challenges faced by diabetologists. This increase in weight is thought to contribute to the already elevated risk for diabetics of going onto develop heart disease.
According to the EASD, the DPP IV inhibitors are among the more promising new therapies in the pipeline for the treatment of type 2 diabetes, which currently affects 37 million people in the top seven markets and is expected to grow to 50 million people by 2012.
Physicians have been disappointed by the lack of successful new therapies for type 2 diabetes in the last 20 years, but if Phase III results, which are expected in Q3 2005, mirror the results to date, LAF-237 could become a useful new tool to diabetologists from 2006.
Meanwhile, Merck & Co has also been working on DPP IV inhibitors and was scheduled to start Phase III trials of a lead candidate - MK-0431 - in the middle of this year. Bristol-Myers Squibb has an unnamed candidate in Phase II, while Novo Nordisk is very active in this area. Researchers from the latter company published an article detailing the structure of DPP IV bound to a substrate in the January 2003 issue of Nature Structural & Molecular Biology.
Other companies working on DPP IV inhibitors includes GlaxoSmithKline, with three compounds in Phase I, and Germany's Probiodrug (which sold its DPP IV platform to UK firm Prosidion in June).
