EASD 2009: mixed data as the development pipeline matures

At this year's European Association for the Study of Diabetes conference (EASD 2009), AstraZeneca and Bristol-Myers Squibb presented data from two Phase III studies for their first-in-class sodium dependent glucose transport-2 (SGLT-2) inhibitor, dapagliflozin. The first study investigated the efficacy of the drug in type 2 diabetics failing on metformin therapy, with the drug reducing hemoglobin A1c (HbA1c) by 0.84% from a baseline of 7.92% with the 10mg dapagliflozin dose. Reductions in fasting plasma glucose (FPG) of 23.5 mg/dL and weight loss of 3.43kg were also recorded. A small rise in urinary tract and genital tract infections was seen but did not represent a significant side-effect problem. Blood pressure falls were also seen independently of a risk of hypotension. The second study investigated the impact of dapagliflozin in conjunction with insulin therapy in type 2 diabetics. HbA1c reductions of 0.61%, FPG reductions of 2.4mg/dL, and weight loss of 4.5kg were recorded. Low levels of hypoglycemia were seen, despite the continued use of insulin, and no changes in plasma sodium or calcium levels were detected.

Dr Julio Rosenstock presented data from Phase II clinical trials of the GLP-1 agonists Syncria (albiglutide; GlaxoSmithKline) and lixisenatide (Sanofi-Aventis). Despite positive data, the two drugs did not offer clinical advantages over their direct competitors, Byetta LAR (exenatide LAR; Amylin/Alkermes/Eli Lilly) and Victoza (liraglutide; Novo Nordisk), respectively. After a question from the conference floor, Dr Rosenstock was of the opinion that both companies would need to conduct head-to-head clinical trials with their direct competitors to demonstrate a clear clinical advantage, or be relegated to me-too drugs.

Data from the Phase II Syncria trial showed HbA1c reductions of 0.87%, 0.79% and 0.87% for the maximal doses at twice-weekly, weekly and monthly dosing regimens, respectively. Exenatide was used as the active comparator and reduced HbA1c by 0.54%. FPG was also monitored, fluctuations in which were closer related to albiglutide exposure. The high pharmacokinetic fluctuations in the plasma albiglutide with the monthly dosing schedule was correlated to the high incidence of nausea, leading to the identification of the twice-weekly and weekly dosing regimens as the most likely to have therapeutic benefit. In comparison, Phase III data from the DURATION-1 trial demonstrated an HbA1c reduction of 1.9% for Byetta LAR. However, questions have been raised over the DURATION-1 data as Byetta LAR recorded an HbA1c reduction of 1.5% compared to reductions of 0.8% at the maximal dose registered in the prescribing information.

Following the Syncria presentation, Dr Rosenstock presented data for the once-daily GLP-1 agonist lixisenatide. Previously presented data had demonstrated HbA1c reductions of between 0.5% and 0.8% from a baseline of 7.5%. Dr Rosenstock's presentation focused on two-hour post-meal glucose, area under the curve (AUC) of insulin, proinsulin and C-peptide and 2-hour glucagon levels. AUC for 2-hour glucose, insulin, proinsulin and C-peptide were all dose dependent with daily lixisenatide dosing, while glucagon levels were reduced but were not dose dependent. The data increased the depth of empirical evidence available for the drug but did not provide any clinical advantage over Victoza.

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