Other contenders in a novel class of glucose-lowering agents are waiting in the wings, despite a negative reception by the Food and Drug Administration on dapagliflozin – the first in that class of agents – presumably because of concerns noted by an FDA advisory panel about potential increases in the risk of bladder and breast cancers associated with the drug.
On Jan. 19, the drug’s joint developers, Bristol-Myers Squibb and AstraZeneca, announced that it received a complete response from the FDA that asked for still more clinical data on dapagliflozin. Although the companies offered no specifics about the request, they said in a statement that they are working "closely with the FDA to determine the appropriate next steps for the dapagliflozin application."
Dapagliflozin lowers glucose by selectively inhibiting renal glucose reabsorption via inhibition of sodium-glucose cotransporter 2 (SGLT2). It was developed as an insulin-independent treatment approach for type 2 diabetes mellitus, as an adjunct to diet and exercise, as monotherapy, or in combination with other diabetes drugs. Despite the initial FDA panel vote, interest in the drug persists, as it is believed to address a pathogenic defect that has yet to be addressed in diabetes.
Bristol-Myers Squibb and AstraZeneca submitted data from recently completed and ongoing phase III clinical trials of dapagliflozin in response to an FDA request for clarification on the drug’s cancer and hepatic risks, along with further data on efficacy and safety in special populations, including the elderly, minorities, and patients with moderate renal impairment.
"This data submission constitutes a major amendment to the original new drug application (NDA) for dapagliflozin," Dr. Brian Daniels, senior vice president of global development and medical affairs at Bristol-Myers Squibb, explained in a statement last fall.
In July 2011, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee recommended against its approval in a 9-6 vote. Despite the drug’s associated cardiovascular and weight-loss benefits, panel members were troubled by nine cases each of bladder and breast cancer among dapagliflozin-treated patients, compared with one of each type in control patients. Using these numbers, the FDA calculated risk ratios of 5.08 for the incidence of bladder cancer in dapagliflozin-treated men, compared with controls, and 4.04 for the incidence of breast cancer in women. The agency’s decision to deny marketing approval for dapagliflozin was widely expected.
Nevertheless, the pipeline of SGLT2-based drugs is full. At the European Association for the Study of Diabetes (EASD) meeting in September, data were presented on Boehringer Ingelheim’s empagliflozin, Astellas Pharma’s ipragliflozin, Taisho Pharmaceuticals’ TS-071, and Lexicon Pharmaceuticals’ LX4211, which is a dual inhibitor of both SGLT1 and SGLT2. All of these agents showed that they can successfully lower glucose levels and improve other metabolic parameters, with generally good short-term safety profiles. The largest of the study populations was 495 patients (for empagliflozin), and the longest of the study periods was 16 weeks (for ipragliflozin).
In an interview, Dr. Pablo Lapuerta, senior vice president and chief medical officer at Lexicon, noted that as a dual SGLT1/SGLT2 inhibitor, LX4211 is actually in a distinct class from dapagliflozin.
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