Diabetes drug safety controversy grows with new analysis

The safety scrutiny of the diabetes drugs called incretin mimetics is likely to grow with analysis of adverse event data linking the class to a pancreatic cancer signal. While any action, if it is to come at all, is probably some time off and will require additional investigation, the emerging evidence should amplify calls for regulators to conduct a new risk-benefit inquiry.

Twelve months of data reported to the FDA are likely to put GLP-1 agonists such as Novo Nordisk’s Victoza and Bristol-Myers Squibb and AstraZeneca’s Bydureon under particular pressure, as the most pronounced signal could be seen with those products. With sales in this class expected to rocket, new safety worries will be harmful to several companies’ growth plans.

Heightened risk ...

The data reported to the FDA’s Adverse Event Reporting System and analysed by the Institute for Safe Medical Practice clarified an earlier report based on tissue samples from diabetic patients who had died of unspecified causes (FDA cancer scrutiny casts shadow on diabetes drug development, March 15, 2013). Patients taking GLP-1 agonists were 23.3 times as likely to have developed pancreatic cancer as those taking sulfonylureas or metformin.

DPP-IV inhibitor drugs like Merck & Co’s Januvia, Bristol-Myers Squibb’s Onglyza and Boehringer Ingelheim’s Tradjenta also had a link – diabetics taking these compounds were 13.5 times as likely to develop pancreatic cancer, although all but two of the 20 cases were reported in Januvia patients. A higher risk of pancreatitis was identified for all agents, while thyroid cancer was associated with use of the GLP-1 agonists.

Behind the numbers is how both drugs affect the hormone GLP-1 (glucagon-like peptide-1), which is stimulated by the digestive system in the presence of food to stimulate production of insulin, which in turn modulates blood-sugar levels. GLP-1 agonists behave like the hormone but are not affected by the enzyme dipeptidyl peptidase IV (DPP-IV), which in normal metabolism breaks down GLP-1 quickly.

The belief is that both drugs make GLP-1 more available in tissues throughout the body. Given that the hormone stimulates cellular growth and slows programmed cell death, its more ready availability was feared to be a cancer promoter; pancreatic lesions, for example, have GLP-1 receptors. Moreover, both Victoza and Bydureon labels have black box warnings of thyroid tumours.

The institute was careful to point out that the FDA does not collect data systematically, nor does the correlation conclusively establish a cause. In response to the findings, the manufacturers write that their own data did not identify the pancreatic cancer link, and note that voluntary reporting is not reliable enough to estimate the actual frequency of adverse events.

... and heightened risk

So far the agency has not responded to the findings. However, it is safe to say that the latest findings affirm that regulators were right to raise concerns earlier. And given the role diabetes drugs play in driving sales growth for a number of companies it has to be worrisome news.

Take Merck, for example. Januvia and its metformin combination Janumet will be vying to be one of the biggest-selling franchises in the world, and will drive half the company’s sales growth between now and 2018, according to EvaluatePharma estimates. For a company forecast to have flat sales over the next few years the news has to be a source of some nervousness.

Or Novo Nordisk. The Danish company looked to have a balanced attack in diabetes until its long-acting insulin Tresiba stumbled at the FDA, and now is much more dependent on keeping sales of Victoza humming (Dizzy day for Novo as FDA rejects Tresiba, February 11, 2013).

Even Sanofi, with its top-selling long-acting insulin, Lantus – forecast to become the second-biggest selling product in the world in 2018 – is hopeful that its GLP-1 agonist Lyxumia will help protect the insulin franchise as a combination therapy with Lantus (Event – Lyxumia decision key to Sanofi’s diabetes defence, October 11, 2013).

Lilly, meanwhile, has to be feeling a bit rueful over the timing, as its own GLP-1, dulaglutide, just reported positive data this week (Clean superiority sweep for dulaglutide could reshape diabetes market, April 17, 2013).

It is not at all certain that the FDA or other national agencies will decide that any confirmed risk is sufficient to take action on the two drug classes. However, with new evidence it becomes clear that there is additional risk to any companies whose strategies centre on GLP-1-related drugs.

To contact the writer of this story email Jonathan Gardner in London at JonathanG@EPVantage.com or follow @JonEPVantage on Twitter

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