Robin Custeau, M.S., Analyst, Cardiovascular & Metabolic/Endocrinology, Citeline
Whenever a new mechanism of action with blockbuster potential is discovered, the pharmaceutical industry sits up, takes notice, and starts researching it. Every company involved in this research ultimately hopes to find the perfect drug candidate, move it into clinical trials, file for approval, and be the first to be granted approval. The competition is fierce and there can be several companies with compounds in Phase III development at the same time with the same mechanism. With financial stakes this high, timing is everything.
The Citeline Analysts on the Cardiovascular & Metabolic/Endocrinology Team are very familiar with this drug approval race due to their extensive coverage of type 2 diabetes clinical trials. They have followed the DDP-IV inhibitor and GLP-1 agonist clinical trial programs, and have witnessed the approvals of the first drugs in both of these classes. Clinical trials that involve drugs with these mechanisms are ongoing, but the hot topic in the world of diabetes today is the SGLT-2 inhibitors and who will get the first one approved. At this moment, AstraZeneca and Bristol-Myers Squibb are the frontrunners and are likely to accomplish this goal.
AstraZeneca and Bristol-Myers Squibb have a worldwide licensing partnership for co-development of dapagliflozin, which is emerging as the ‘first in class’ drug for this novel mechanism. Through a mechanism independent of insulin action, the SGLT-2 inhibitors block glucose reabsorption by the kidney. Dapagliflozin has been shown to significantly lower HbA1c levels and other measures of glucose control in type 2 diabetes patients across various stages of the disease and in different therapeutic regimens. Due to the success of their Phase III clinical trials program, the companies filed the NDA and MAA submissions for dapagliflozin in December 2010. The companies reported that the MAA filing had been validated in a January 27, 2011 press release. A press release dated March 8, 2011 also indicated that the NDA filing was accepted and that the PDUFA date had been set for October 28, 2011. This news bodes well for AstraZeneca and Bristol-Myers Squibb, but there is no guarantee that dapagliflozin will be the first SGLT-2 inhibitor to receive approval.
The safety of dapagliflozin will definitely be on the minds of the EMEA and FDA when they consider whether or not to approve it. Cardiovascular safety is a major concern for potential new diabetes drugs and the FDA is extremely cautious when it comes to putting patients at risk. It will be interesting to see how the FDA and EMEA react to the cardiovascular safety data, and whether or not additional safety data will be requested. Another safety concern with dapagliflozin is the risk of urinary and genital infections as a result of increased glucose levels in the urine. These infections are inconvenient but treatable, and the benefits of dapagliflozin could prove to outweigh this risk in the eyes of the FDA and EMEA.
If dapagliflozin does not receive approval, Mitsubishi Tanabe Pharma and Johnson & Johnson are waiting in the wings with canagliflozin. The companies have indicated that they plan to file for approval of this drug in the US and EU in 2012. Tofogliflozin, BI-10773, and ASP1941 are also in Phase III clinical trials. Citeline Analysts are looking forward to seeing how the approvals play out, and whether or not dapagliflozin will be the first SGLT-2 inhibitor on the market.