EASD 2009: post-marketing data disappoints

At the European Association for the Study of Diabetes 2009 conference (EASD 2009), a retrospective analysis of a US insurance claims database of the absolute and relative risks of acute pancreatitis in patients initiated on Byetta (exenatide; Amylin/Eli Lilly) was conducted, with comparisons made to other antidiabetic therapies. The Byetta cohort demonstrated a slight gender bias towards women and a higher prevalence of baseline claims for type 2 diabetes. The data represented an interim analysis and Eli Lilly has suggested that Byetta is not associated with an increased rate of acute pancreatitis. However, during the questions after the oral presentation, the company admitted that the limitations of the study meant that a casual link between Byetta and acute pancreatitis could be neither proved nor disproved.

During the conference, Novo Nordisk published surprising data from the LEAD-3 extension trial demonstrating a 2.5mmHg reduction in systolic blood pressure up to 26 weeks and a 2.2mmHg drop after 40 weeks with Victoza (liraglutide) therapy. Reductions in diastolic blood pressure were small and non-significant. Novo Nordisk was also able to demonstrate that the blood pressure drop was independent of the weight lost during Victoza therapy. Amylin and Eli Lilly have also been able to demonstrate systolic blood pressure reductions with the weekly dosed Byetta LAR (exenatide LAR), leading to the suggestion that the impact on blood pressure is a class effect. However, despite launching in the US in 2005 and their publishing data in 2008, the companies have not included the impact of Byetta on systolic blood pressure within their marketing messages.

Further criticism was leveled at Amylin and Eli Lilly after the presentation of Byetta safety data in a poster session. The companies presented a Kaplan-Meier plot of major adverse cardiovascular endpoints (MACE) and a broad cardiovascular endpoint. The data showed that Byetta did not cause an increase in cardiovascular events in line with the FDA stipulations on cardiovascular safety. However, the moderator for the poster session pointed out the low level of cardiovascular events meant that the data presented were all but meaningless. A company representative countered that the analysis had been completed to the FDA's predetermined standards, calling into question the applicability of the FDA's cardiovascular safety test when applied to marketed products.

Galvus (vildagliptin; Novartis) was the second dipeptidyl peptidase-IV (DPP-IV) inhibitor to reach the market in Europe in April 2008. The drug had encountered well documented problems during its development and launch, with a liver safety signal seen in a withdrawn higher dose formulation and skin lesions observed in animal models. Within the product information published by Novartis, the company highlighted the need to test a patient's baseline liver function prior to commencement of therapy and thereafter tests would need to be conducted at three month intervals for the first year and at regular intervals after this point. This need for liver testing is another disadvantage for the drug compared to the market leader Januvia (sitagliptin; Merck & Co) and recently approved Onglyza (saxagliptin; AstraZeneca/Bristol-Myers Squibb), with questions raised in physicians' and patients' minds regarding the safety of the drug, while significantly increasing the input needed from the physician and patient for what was originally aimed to be a simple, low maintenance drug. Datamonitor expects this data publication to lead to the further marginalization of Galvus and Eucreas (vildagliptin + metformin; Novartis).

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