Worries over incretin mimetics’ potential to cause pancreatic cancer in diabetics are not going away, but it looks for now as if there is no immediate threat of regulatory action. Although adverse event reporting in the US has detected some troubling signals, FDA officials believe that the data should be considered weak given that it provides no way to measure the magnitude of risk (FDA cancer scrutiny casts shadow on diabetes drug development, March 15, 2013).
Big pharma is now backing a more detailed review proposed by the American Diabetes Association earlier this week, which should make the incidence of pancreatic disease – a known risk of these medicines – much clearer. The meta-analysis of patient data theoretically should settle the question of whether there is a link to GLP-1 agonists and DPP-IV inhibitors; no doubt this will be a burning discussion at next week’s American Diabetes Association scientific meeting.
For now, a hypothesis
A workshop convened by the US National Institutes of Health this week is hashing out the issues facing regulators in establishing a link, if indeed there is one, between use of the diabetes treatments and pancreatic cancer. The incretin mimetics – the dipeptyl peptidase IV inhibitors (DPP-IV) and glucagon-like peptide-1 (GLP-1) agonists – help lower blood sugar by enhancing release of insulin, DPP-IVs by inhibiting an enzyme that inactivates GLP-1, while the GLP-1 agonists directly stimulates the pancreas’s release of insulin.
Drugs in the GLP-1 class include Novo Nordisk’s Victoza and Bristol-Myers Squibb and AstraZeneca’s Bydureon, while the DPP-IV class includes Merck & Co’s Januvia and Bristol-Myers’s Onglyza. All of the drugs carry warnings of pancreatitis, itself a risk factor in pancreatic cancer. Confounding the analysis is the heightened risk of pancreatic cancer from diabetes, and with growth in the prevalence of the endocrine disease, an increase in the background incidence of cancer.
Thus it is not a simple analysis, as stated in the synopsis of an FDA presentation today at the two-day meeting. The news that alarmed regulators had emerged from the FDA’s adverse event reporting system (AERS), a database that probably under-reports cases because it is voluntary. Without an accurate population denominator and little documentation of other risk factors, it is difficult to calculate an incidence rate – and as there is no control population, it is difficult to establish even a causal link.
AERS should be considered “hypothesis generating” rather than anything approaching the last word on incretin mimetics, according to the FDA.
As the workshop approached earlier this week, the ADA called on the makers of GLP-1 agonists and DPP-IV inhibitors to release patient-level data from clinical trials to allow for a better assessment of risk, an analysis that could be conducted by a university or research institution.
Bristol-Myers, AstraZeneca and Merck released statements expressing support for an independent review; Merck and Novo are both scheduled to present data at the NIH meeting. The joint Bristol-Myers/Astra statement stopped short of explicitly volunteering the companies' own trial outcomes for the analysis of pooled patient data.
Given the pressure on big pharma to be more transparent about safety, it would be unwise for any of the makers of incretin mimetics to resist a call for patient data. They can rest a little easier knowing that the immediate pressure is off – although the peril is lingering in the background.
|Outlook for incretin mimetics ranked on 2018 WW sales|
|WW sales ($m)|
|Product||Generic name||Company||2013||2014||2016||2018||WW status|
|Glucagon-like peptide 1 (GLP-1) agonist||Victoza||liraglutide||Novo Nordisk||2,165||2,626||3,419||4,067||Marketed|
|Bydureon||exenatide synthetic||Bristol-Myers Squibb/AstraZeneca||381||627||1,081||1,458||Marketed|
|Dulaglutide||dulaglutide||Eli Lilly||-||75||355||609||Phase III|
|Dipeptidyl peptidase IV (DPP-IV) inhibitor||Januvia/Glactiv/Tesavel||sitagliptin phosphate||Merck & Co/Ono Pharmaceutical/Almirall/Daewoong Pharmaceutical/Sigma Tau Group||4,959||5,495||6,417||7,118||Marketed|
|Galvus (no US sales)||vildagliptin||Novartis||1,149||1,381||1,741||1,989||Marketed|
|Onglyza||saxagliptin hydrochloride||Bristol-Myers Squibb/Kyowa Hakko Kirin/Otsuka Holdings||626||766||1,042||1,274||Marketed|
|Tenelia||teneligliptin hydrobromide||Mitsubishi Tanabe Pharma||43||76||168||250||Marketed|
|MK-3102||-||Merck & Co||-||-||46||226||Phase III|
|SYR-472||trelagliptin succinate||Takeda||-||9||18||22||Phase III|
All data sourced to EvaluatePharma