On July 26, the European Medicines Agency (EMA) announced that there was not enough evidence to confirm a link between glucagon-like peptide 1 (GLP-1) receptor agonists and increased risk of pancreatitis or pancreatic cancer. There has been a longstanding awareness of such a link, but the discussion was brought back to the fore recently following publication of a study by Butler et al. in Diabetes. This potential safety issue could prove fatal for GLP-1 receptor agonists like AstraZeneca & Bristol-Myers Squibbs. Byetta (exenatide; over $500 million sales in 2012) and Bydureon (long-acting exenatide; over $100 million sales in 2012) and Novo Nordisk's Victoza (liraglutide; over $1.5 billion sales in 2012), should an increase in pancreatitis and pancreatic cancer be conclusively proven due to GLP-1 receptor agonist use. An example of safety issues impacting drug sales has previously been seen with the peroxisome proliferator-activated receptor (PPAR-) gamma agonist drug class. Both GlaxoSmithKline's Avandia (rosiglitazone) and Takeda's Actos (pioglitazone) suffered drastic declines in sales following safety concerns surrounding these agents. But, does the positive news for the GLP-1 receptor agonists really change anything.
The GLP-1 receptor agonists mimic the hormone GLP-1, which stimulates natural insulin production in the pancreas. Byetta was the first of this class to launch in 2005; however, due to an unfavorable dosing profile (Byetta requires twice-daily injections), uptake has been limited. Victoza, which launched in 2009 and has a once-daily administration, is now the market leader in its class. Decision Resources believes that GLP-1 receptor agonists in development requiring only once-weekly injections will overtake Victoza as the market leader. For information on these emerging agents, see our Pharmacor report on type 2 diabetes. Overall we predict growth in the sales of this drug class, mainly due to their strong efficacy profile and promising emerging therapies. However, that growth could potentially be hampered by the possible link to pancreatitis and pancreatic cancer.
The safety concerns surrounding the GLP-1 receptor agonists returned to prominence in part due to another recently published Diabetes study by Butler et al., which analyzed post-mortem tissue from type 2 diabetes patients. Another study published in JAMA in February this year states that investigators found patients who were hospitalized with pancreatitis were twice as likely to be using either the dipeptidyl peptide IV (DPP-IV) inhibitor Januvia or Byetta, when compared with type 2 diabetes patients who didn't have pancreatitis. Concerns first emerged in 2007, when the FDA identified a high incidence of pancreatitis in Victoza- and Byetta-treated patients, after reviewing 30 postmarketing reports, leading to a warning on its label.
The FDA has announced its agreement with the findings of the EMA and doesn't believe that there is enough evidence to support a link between the GLP-1 receptor agonists and pancreatitis or pancreatic cancer. The EMA's conclusion is based on a review of all available data for the drug class, in addition to the Diabetes study. The organization raised questions about the design of the study, citing a number of methodological limitations and potential sources of bias. These include differences in the studied groups in terms of age, gender, duration of the disease and treatments, which are important factors considering the interpretation of the results.
The EMA did admit that the number of events was too small to draw final conclusions; and results from two large, independent investigations funded by the European Commission are not expected to be seen until spring 2014. Additional large outcome trials have been started by the companies in question, and we await with interest the results from these studies to shed some light on the risks associated with these medicines. For now, the announcements from the EMA and FDA should ensure that the strong sales generated by the GLP-1 receptor agonists should continue. However, the devil is in the detail of these announcements. Rather than demonstrating the safety of these agents, all we can infer is that we don't have enough evidence to definitively state if the risk of pancreatic adverse events with the GLP-1 receptor agonists exists or not. Until this evidence becomes available, a question mark will hang over the long-term future of this drug class.
Stefanie Matlok is a data analyst with the Cardiovascular, Metabolic and Renal Disorders team at Decision Resources.