Memorandum

EMA’s CHMP concludes its investigation into incretin therapies: no new concerns based on current evidence though access an ongoing issue – July 30, 2013

Executive Highlights

  • The EMA’s Committee for Medicinal Products for Human Use concluded that presently available data for incretin-based therapies do not adequately support concerns about pancreatic adverse events.
  • Merck issued a response statement emphasizing its intention to continue Januvia safety monitoring.
  • This is positive news regarding safety though ongoing access in the EU for DPP-4 inhibitors remains a major concern.

The EMA’s Committee for Medicinal Products for Human Use (CHMP) has released the conclusions of its review of incretin-based diabetes therapies (which include GLP-1 agonists and DPP-4 inhibitors). The conclusion states that available evidence does not adequately support any new safety concerns, including pancreatic adverse events. Importantly, the statement highlighted incretins’ benefits for ameliorating the “major public health challenge” of type 2 diabetes, suggesting that the CHMP has considered both the potential harm of possible pancreatic effects as well as the potential harm that restricting incretins’ use would have on patients’ glycemic control. The CHMP notice emphasized that its conclusion was based only on presently available data, and that the committee supports continued monitoring of pancreatic adverse events for patients on incretin therapies. It notes that the several large cardiovascular outcomes studies that are being planned or are in progress may further elucidate the risk profiles of incretin therapies. As a sidenote, we will be interested to watch this, since we have also heard that the pancreatitis event rate may be so low that even CVOTs may not pick up a signal – which begs the question how big the potential concern would be if multiple CVOTs won’t further elucidate the problem. Additionally, the European Commission’s SAFEGUARD Consortium expects to release data in 2014 on the safety of a broad range of diabetes therapies, including incretins. The CHMP statement further suggests that safety labels on incretin therapies should be “harmonized” in order to provide patients and providers with consistent advice – this was positive to hear since it should promote greater understanding among a group of harried, busy HCPs.

In a press release issued on Friday in response to the CHMP’s announcement, Merck emphasized in a straightforward release that it will continue monitoring the safety of sitagliptin (the company’s DPP-4 inhibitor Januvia) in close collaboration with researchers and regulatory agencies. We do believe that in the EU access to DPP-4 inhibitors rather than safety is a larger concern though of course if the CHMP had decided safety was a concern, this would have been a big problem for Merck, Novartis, BI/Lilly, BMS/AZ, and Takeda. During Merck’s 2Q13 financial update today, management remarked, “the [reimbursement] environment in Europe is tough and I think it will continue to be tough.” However, Merck expressed confidence that European governments see the implications of not treating diabetes and that Januvia has “strong potential” in Europe as a second-line to metformin, particularly if a person has side effect issues with a sulfonylurea.

The CHMP review was initiated following the widely publicized findings of Dr. Peter Butler’s morphological study of pancreata obtained from deceased organ donors – read the publication at http://diabetes.diabetesjournals.org/content/early/2013/03/17/db12-1686.long. You can also read our coverage of Dr. Steven Kahn’s critical review of the study (http://www.closeconcerns.com/knowledgebase/r/b03ed6a2) and our report on a debate between Dr. Butler and Dr. Michael Nauck on incretins and pancreatitis in Diabetes Care (http://www.closeconcerns.com/knowledgebase/r/6d3e6d53). In the morphological study, Dr. Butler’s group found an increased incidence of pancreatitis and pancreatic duct metaplasia in samples from type 2 diabetes patients treated with incretins. In its announcement, the CHMP stated that a number of methodological limitations and potential biases interfere with meaningful interpretation of the study’s results. Dr. Robert Ratner (ADA, Alexandria, VA) discussed some of these limitations in depth during a recent presentation at Keystone 2013 – see pages 10-12 of our Keystone Day 1 Report at http://www.closeconcerns.com/knowledgebase/r/95c2cb96. He noted that the two study groups were poorly matched by age and diabetes duration. Some of the pancreata came from patients who died of ketoacidosis, indicating that they may have had type 1 rather than type 2 diabetes. Furthermore, a polyclonal anti-GLP-1R antibody used in the study was also shown to bind nonspecifically.

Friday’s announcement was the latest in a series of recent high-profile announcements allaying concerns about incretins, pancreatitis, and pancreatic carcinoma. In March, the FDA issued a communication to that effect, which was followed by an ADA/EASD/IDF joint statement in June. Also in June was the NIDDK’s two-day summit on incretins and pancreatitis – read our day one (http://www.closeconcerns.com/knowledgebase/r/8326d0dd) and day two (http://closeconcerns.com/knowledgebase/r/e90a832d) coverage for more information on that illuminating meeting, or see page 23 of our ADA 2013 Incretins Report (http://www.closeconcerns.com/knowledgebase/r/6001b62d) for Dr. Vanita Aroda’s recap of the meeting. For an overview of the controversy up until the NIDDK summit (along with many informative links), see our NIDDK Summit Preview (http://www.closeconcerns.com/knowledgebase/r/9be41df8).

-- by Manu Venkat, Jessica Dong, and Kelly Close