Today, the FDA Endocrinologic and Metabolic Drugs Advisory Committee voted 10-4 in favor of the updated cardiovascular risk profile of the investigational sodium-glucose co-transporter 2 inhibitor, dapagliflozin. The committee also voted 13-1 in favor of the agent as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes (see here).
“We found no evidence of increased CV risk in the pre-specified meta-analysis,” Eugenio Andraca-Carrera, PhD, a mathematical statistician at FDA, said during the meeting.
Dapagliflozin (Bristol-Myers Squibb/AstraZeneca) was denied approval by the FDA in the United States in January 2012. Six months prior, the advisory committee recommended against the approval of the drug at a July 2011 meeting by a 9-6 vote due to concerns of potential breast or bladder cancer risks found in the 11 phase-3 clinical trials (see here).
Recent studies and additional long-term cardiovascular data compared with previously submitted studies were included in the resubmission, according to briefing documents.
“Diabetes remains an epidemic with significant morbidity and mortality. Improvements in metabolic parameters are associated with improved outcomes. Numerous treatment options are available but each has its limitations; a need remains for new therapeutic options,” Harold E. Bays, MD, FTOS, FACE, FNLA, medical director and president of the Louisville Metabolic and Atherosclerosis Research Center Inc., said during the meeting.
Dapagliflozin is currently approved for the treatment of type 2 diabetes in the European Union, Australia, Brazil, Mexico and New Zealand.
The renal sodium- glucose cotransporter or SGLT-2 is an interesting target for treatment of diabetes. Inhibition of this transporter blocks glucose reabsorption and increases urinary glucose excretion. This leads to lowering of blood glucose levels with a lower risk of hypoglycemia than sulfonylureas (see here). The loss of glucose is also associated with weight loss, which by itself may improve insulin sensitivity. The clinical experience to date shows that dapagliflozin is well-tolerated. There is an increased risk of genital infections and urinary tract infections (see here). The previous experience with other antidiabetic drugs, mainly those belonging to thiazolidinedione (TZD) class, has led to a very cautious approach by regulatory agencies and to a recent FDA Guidance FDA Guidance that mandates large cardiovascular outcome studies for new anti-diabetic drugs. Furthermore, as stated above, the possible increased risk of bladder and breast cancer during dapagliflozin trials had led the FDA panel to recommend against approval of this agent in January 2012. Additional data provided by the sponsors has now convinced the Advisory Committee to recommend for approval of dapagliflozin. If approved, which is likely, dapagliflozin will be the second SGLT-2 inhibitor to be approved by the US FDA for the treatment of type 2 diabetes. The first agent from this class, canagliflozin (Invokana, Janssen Pharmaceuticals), was approved by the FDA on March 29, 2013 (see here and here).