A Shocker From The FDA: BydureonPosted October 21, 2010 by John L. Leahy, MD
This was supposed to be an important week for the diabetes world, with approval of the first long-acting incretin therapy (exenatide LAR, Bydureon®). In a bit of a stunner, on October 19th the FDA issued a complete response letter to the manufacturers of the once weekly exenatide requesting additional studies before considering approval. Specifically, the FDA expressed concerns over cardiac toxicity, and requested a "thorough QT (tQT) study with exposures of exenatide higher than typical therapeutic levels of Bydureon." That was totally unexpected, as there had been no cardiac toxicity signal in any of the research studies on exenatide LAR (long-acting release formulation). So, to the average guy (me), the FDA statement sounds pretty arbitrary, overly cautious, and continues the feeling that the FDA approach to diabetes drugs is a moving target that pharma still can’t figure out.
DURATION-1 and the Promise of Weekly Treatment
Review of the published clinical trials from the manufacturer (the so-called DURATION series) shows why this decision was eagerly awaited. DURATION-1 did a 30-week head-to-head comparison of twice daily exenatide (currently have on the market) and the weekly preparation involving 295 patients naïve to therapy or on various oral agents, with starting average A1C of 8.3%. The weekly preparation did much better at improving the A1C (-1.9% versus -1.5%—in other words, to an average below 6.5% in the patients given the weekly preparation). This drug class’s well-recognized effects of modest weight loss and nausea was seen with both treatments. An open-label continuation of the study groups carried out a full year, with the twice daily exenatide group switched to the weekly preparation, showed continuing benefits, including an average A1C of 6.6% of the whole group, a 4 kg weight loss, and quite modest hypoglycemia. So the weekly preparation was not only attractive from a presumed patient acceptance point of view: it was more effective than taking exenatide twice daily.
These studies did provide one surprise. A head-to-head comparison between twice daily exenatide and the once daily agent liraglutide had shown the longer-acting agent was better at controlling fasting blood glucose. Indeed, a principle has evolved whereby longer-acting agents are expected to control fasting blood glucose better than twice daily exenatide, ergo better lowering of A1C. On the other hand, twice daily exenatide was much better at controlling postprandial glucose than the once daily liraglutide. We assumed that was a characteristic of the exenatide molecule, and it was thus a bit of a shocker when the DURATION 1 trial showed better fasting blood glucose with LAR versus the twice daily preparation (expected), but less postprandial control (unexpected, and still not sure what that means).
More Promise From DURATION-2 and DURATION-3
DURATION-2 compared exenatide LAR to sitagliptin or pioglitazone for 26 weeks in persons failing metformin therapy with a mean baseline A1C of 8.5%. A1C-lowering was better with exenatide LAR (average 1.5% versus 0.9% and 1.2%, respectively). Also, there was significantly greater weight loss with LAR (average 2.3 kg), little to no hypoglycemia, and modest nausea and diarrhea.
DURATION-3 compared exenatide LAR to glargine insulin for 26 weeks in persons failing maximal metformin or combination metformin sulfonylurea therapy. Once again, A1C-lowering was better with exenatide LAR (average 1.5% versus 1.3%). Also, as expected, there was weight loss (average 5.8 lb reduction versus 3.1 lb increase with glargine) and considerably less hypoglycemia than glargine.
Now, exenatide LAR is not perfect. It has distinct drawbacks, including requiring reconstitution before use, and a 23 gauge needle versus the standard sized insulin needles that we advertise to patients as a non-event when the GLP-1 injection therapies are discussed. Still, the diabetes world is interested in exenatide LAR. Most of us agree that it’s time for approval to see exactly how good it is. Also, there’s a bit of voyeurism, with some interested in watching Novo Nordisk and Amylin/Eli Lilly slug it out.
The FDA’s Take
Unfortunately, it’s not to be, at least for now. Before approval, the FDA now says it wants the results of the DURATION-5 study "to evaluate the efficacy, and the labeling of the safety and effectiveness, of the commercial formulation of Bydureon." This one is harder to critique. DURATION-5 is essentially a repeat of DURATION-1, a head-to-head comparison of twice daily exenatide and exenatide LAR. However, since DURATION-1, there have been subtle changes in the Bydureon clinical product, and it looks like the FDA wants safety and efficacy data with the actual product. Whether that is justified and should hold up approval is in the eyes of the beholder.
Where We Go From Here
So we will have to wait a couple years longer for a long-acting GLP-1 agent. Many compounds are in development, and we eventually expect to have several to choose from in the marketplace. One recent wrinkle is that Roche recently announced it was slowing development of taspoglutide because of hypersensitivity issues, mostly rashes and digestive problems. Whether problems with these long-acting compounds will start to appear, and various development programs drop out is hard to predict. So far the published data from these agents is exciting–good to great lowering of A1C with few problems, possibly including less nausea than the agents we have. The diabetes field wants one of these agents to explore its potential, and the recent FDA decision feels like a major setback.