"The Big GLP" - Should We Be Excited About Novo's Liraglutide?

Implications: The results of two Phase III trials conducted by Novo Nordisk on liraglutide, a once-daily dosed GLP-1 analog, indicate significant glucose lowering efficacy and weight loss. On a positive note, Novo has to be relieved that they are seeing the same magnitude of HbA1c reduction and weight loss as exenatide (Byetta) with less-frequent dosing. However, given the ADA's refusal to include exenatide (and by inference, other GLP-1 analogs) in first-line therapy, it's hard to get too enthusiastic over this incremental improvement to Byetta, especially since the once-weekly form of Amylin's therapy (Byetta LAR) is roughly a year away from the market.

Analysis: Novo Norodisk has released data from two Phase III studies that examine the glucose and body weight lowering efficacy of their GLP-1 analog liraglutide. In the first study (LEAD 1), liraglutide was added to a sulfonylurea (glimepiride) regimen and compared to glimepiride alone or in combination with the TZD rosiglitazone. The second study (LEAD 2) compared the combination of liraglutide and metformin against a metformin only or metformin/glimepiride combination. Each study ran for 26 weeks and enrolled Type 2 Diabetics (mean initial HbA1c of about 8.5%) that had previously failed one or two oral antidiabetic therapies.

The data indicate that liraglutide provided superior blood glucose control to rosiglitazone in the patient population tested. In patients that had failed one prior oral therapy, the effect was more pronounced, with approximately 50% of liraglutide treated subjects achieving an HbA1c level of 7% or lower. When compared to the metformin regimen, comparable reductions in HbA1c were noted. In both studies, patients on liraglutide lost between 2 and 4 kg compared to placebo.

While encouraging, the results are very similar to those obtained with exenatide (Byetta), Amylin's already-approved GLP-1 analog. From a compliance standpoint, the knock on Byetta has been the need for thrice-daily injections, and Amylin is currently running a 30-week equivalence study using a new once-weekly formulation (Byetta LAR). This study is expected to complete by the end of 2007, and given favorable results, the long-acting form of the drug could be on the market in late 2008. Perhaps more importantly, the ADA's recently issued Clinical Practice Recommendations do not recommend a GLP-1 analog as part of first-line pharmacologic therapy for Type 2 Diabetes. The weight loss is meaningful, but not overwhelming, especially given Byetta's already proven efficacy in this area. Diabetics are going to have to make significant lifestyle changes to make a significant impact on their conditions no matter what pharmacologic therapies they use. The GLP-1 analogs at least avoid the weight gain seen with other oral medications for Type 2 Diabetes.

Given the current situation, it's not unreasonable to expect that Novo Nordisk will sell a few hundred million dollars worth of liraglutide in 2008 and beyond. I would be quite surprised, however, if the drug ever reaches any type of significant sales. Remember, there are many new oral therapies (notably DPP-IV, but others to come) for diabetes that may confer additional benefit around beta cell health, cardiovascular protection, etc., and these are the potential blockbusters. If nothing else, I'd like to see an oral GLP-1 analog hit the market in order to give patients and doctors something to be excited about in the relatively near term.

Stay tuned...