FDA rejection of Dapagliflozin creates uncertainty for other SGLT-2 inhibitors
This article was originally published in Scrip
Executive Summary
Dapagliflozin, the most advanced candidate in the novel SGLT-2 inhibitor antidiabetic class, was the subject of a complete response letter from the FDA, co-developers Bristol-Myers Squibb and AstraZeneca announced on 19 January 2012. The letter was not unexpected, given a negative 9-6 vote from an FDA Advisory Committee in July 2011 which revealed concerns about possible increased risks of breast and bladder cancers seen in the aggregated Phase II and Phase III trial data, as well as a case of probable drug-induced liver injury (scripintelligence.com, 21 July 2011).
Dapagliflozin, the most advanced candidate in the novel SGLT-2 inhibitor antidiabetic class, was the subject of a complete response letter from the FDA, co-developers Bristol-Myers Squibb and AstraZeneca announced on 19 January 2012. The letter was not unexpected, given a negative 9-6 vote from an FDA Advisory Committee in July 2011 which revealed concerns about possible increased risks of breast and bladder cancers seen in the aggregated Phase II and Phase III trial data, as well as a case of probable drug-induced liver injury (scripintelligence.com, 21 July 2011).
The companies are unsure that the FDA will require additional trials, although this seems likely. If extra studies are required, and the companies conduct them, the delay may enable other SGLT-2 inhibitors to overtake dapagliflozin and gain the advantage of first-to-market status.
The most advanced rivals in the US are canagliflozin (Johnson & Johnson/Mitusbishi Tanabe) and empagliflozin (Boehringer Ingelheim/Eli Lilly), both in Phase III development. These drugs do not yet have published data for the cancer and liver toxicity risk concerns observed with dapagliflozin, and it is not known if the risks will be class-wide or drug-specific.
Dapagliflozin is the first of a new class of type 2 diabetes drugs, the SGLT-2 inhibitors. They work by preventing glucose reabsorption in the kidneys, and increasing excretion in the urine. This novel mechanism has a moderate effect on blood sugar, and is potentially a useful add-on to other treatments. Because glucose is excreted, not as many calories are taken up by the body and so these drugs have a beneficial side-effect of weight loss. However, higher glucose concentrations in the urine can also increase the risk of urogenital infections.
Dapagliflozin had a very large Phase II and Phase III trial program, with over 8000 patients treated with the drug or comparators. This is increasingly the norm for novel antidiabetic therapies as developers need to establish cardiovascular safety, in line with FDA Guidelines. This can lead to the observation of low-probability risk events, with uncertainty as to whether an association with the drug is real (and will reappear in a much larger post-approval patient population) or due to chance.
Any new trials would have to have large patient numbers and have a long duration to address safety concerns that occur at very low rates (for instance, in the pooled trial data there were 9 cases of breast cancer seen in 4,287 dapagliflozin-treated patients, and 0 cases in the 1,941 comparator-treated patients). That would require additional resources from the developers, and the studies might only serve to confirm the safety concerns.
While the overall diabetes market potential is large, the treatment algorithm is crowded, and the market for a new drug class with moderate efficacy and some side-effect concerns is uncertain. Datamonitor believes that there is a possibility that Bristol-Myers Squibb and AstraZeneca would decide not to pursue additional lengthy studies.
Bristol-Myers Squibb and AstraZeneca have also submitted dapagliflozin in Europe, and are awaiting an opinion from the CHMP. It is possible that there will be a different outcome in Europe, as seen in the recent example of Bydureon (exenatide once-weekly; Amylin) which was approved in Europe while the developers were still responding to an FDA request for more data in the US. While there are many antidiabetic products available for type 2 diabetes patients, many patients still have poorly controlled blood sugar and physicians see the disease as having a lot of variation in patient responses to medication, based on individual response, lifestyle and co-morbidities.
The new SGLT-2 class will be a potentially valuable option for some type 2 diabetes patients, and Datamonitor believes that there is a chance for the novel products to gain some patient share, if safety concerns can be overcome.
Christine Henry is an analyst with Datamonitor specialising in cardiovascular disease and diabetes