FDA Turns Down Novel Antidiabetes Drug

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.

"This differentiates LX4211 from the SGLT2-specific inhibitors in several ways. For example, in patients with type 2 diabetes, LX4211 has been shown to cause a rapid reduction in blood sugar levels after meals, and an increase in GLP-1 [glucagonlike peptide–1] and the increase in PYY [peptide YY], effects that are associated with SGLT1 inhibition by LX4211 in the gastrointestinal tract. Also, recent studies in healthy subjects have shown that LX4211 substantially decreases postprandial glucose levels without hypoglycemia, and in both diabetic patients and healthy subjects, LX4211 can substantially reduce triglycerides. These results have not been reported for SGLT2-selective inhibitors," he said.

With regard to safety, Dr. Lapuerta noted that the "issue for the FDA advisory committee had to do with the overall benefit/risk profile of dapagliflozin. We believe the solution will involve addressing both benefits and risks. On the benefit side, we believe that LX4211 is a cardiovascular drug, not just a diabetes drug. Dual inhibition of SGLT1/2 with LX4211 offers the potential benefit to combine strong [hemoglobin] A_1c reduction with benefits in blood pressure, uric acid, weight loss, and triglycerides. Cardiovascular benefits will be relevant to approval," he said.

"On the risk side, there is the potential that reports of bladder cancer on dapagliflozin reflected an ascertainment bias. We can address this in the LX4211 clinical program by ensuring that we carefully document physician referral patterns and take steps to ensure [that] our studies identify as much as possible new conditions instead of preexisting ones."

Susan Holz, public relations manager at Boehringer Ingelheim Pharmaceuticals, said in an earlier interview, "We are aware of the advisory committee’s concerns with dapagliflozin and are working with the FDA to ensure [that] our filing package for empagliflozin is robust and comprehensive. Phase III trials for empagliflozin are underway, and we are continuing to evaluate the drug’s safety profile." Currently, there are 11 ongoing, multinational, phase III clinical trials, including a large cardiovascular outcomes safety trial, she said.

At the EASD meeting in September, Dr. Michaela Diamant, scientific director of the diabetes center at Free University Medical Center in Amsterdam, commented that SGLT2 inhibitors have "an interesting mechanism that addresses, to a certain extent, a pathogenic defect that has been largely overlooked in diabetes. ... I’m sure there is a huge group of patients who can profit from these novel agents."

Regarding the safety issue, she asked, "If you would have a trial of 2-5 years, would you definitely address causality of cancer? We know that cancer development takes 20 years. It’s very unlikely that the drug caused cancer. We have to do what is feasible. The industry is not going to develop any more of these drugs if they are required to do a trial of 10 years. It’s difficult to tease out [contributors] to the development of cancer," Dr. Diamant continued.

Dr. Diamant has been a board member, advisory panel member, consultant, research support recipient, and/or speakers bureau participant for Eli Lilly, Merck Sharp & Dohme, Novo Nordisk, Abbott, AstraZeneca/BMS, Boehringer Ingelheim, Poxel Pharma, Sanofi-Aventis, Amylin Pharmaceuticals, Novartis, and Takeda.

Sue Sutter of "The Pink Sheet" contributed to this story. "The Pink Sheet" and this publication are both owned by Elsevier.

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.

"This differentiates LX4211 from the SGLT2-specific inhibitors in several ways. For example, in patients with type 2 diabetes, LX4211 has been shown to cause a rapid reduction in blood sugar levels after meals, and an increase in GLP-1 [glucagonlike peptide–1] and the increase in PYY [peptide YY], effects that are associated with SGLT1 inhibition by LX4211 in the gastrointestinal tract. Also, recent studies in healthy subjects have shown that LX4211 substantially decreases postprandial glucose levels without hypoglycemia, and in both diabetic patients and healthy subjects, LX4211 can substantially reduce triglycerides. These results have not been reported for SGLT2-selective inhibitors," he said.

With regard to safety, Dr. Lapuerta noted that the "issue for the FDA advisory committee had to do with the overall benefit/risk profile of dapagliflozin. We believe the solution will involve addressing both benefits and risks. On the benefit side, we believe that LX4211 is a cardiovascular drug, not just a diabetes drug. Dual inhibition of SGLT1/2 with LX4211 offers the potential benefit to combine strong [hemoglobin] A_1c reduction with benefits in blood pressure, uric acid, weight loss, and triglycerides. Cardiovascular benefits will be relevant to approval," he said.

"On the risk side, there is the potential that reports of bladder cancer on dapagliflozin reflected an ascertainment bias. We can address this in the LX4211 clinical program by ensuring that we carefully document physician referral patterns and take steps to ensure [that] our studies identify as much as possible new conditions instead of preexisting ones."

Susan Holz, public relations manager at Boehringer Ingelheim Pharmaceuticals, said in an earlier interview, "We are aware of the advisory committee’s concerns with dapagliflozin and are working with the FDA to ensure [that] our filing package for empagliflozin is robust and comprehensive. Phase III trials for empagliflozin are underway, and we are continuing to evaluate the drug’s safety profile." Currently, there are 11 ongoing, multinational, phase III clinical trials, including a large cardiovascular outcomes safety trial, she said.

At the EASD meeting in September, Dr. Michaela Diamant, scientific director of the diabetes center at Free University Medical Center in Amsterdam, commented that SGLT2 inhibitors have "an interesting mechanism that addresses, to a certain extent, a pathogenic defect that has been largely overlooked in diabetes. ... I’m sure there is a huge group of patients who can profit from these novel agents."

Regarding the safety issue, she asked, "If you would have a trial of 2-5 years, would you definitely address causality of cancer? We know that cancer development takes 20 years. It’s very unlikely that the drug caused cancer. We have to do what is feasible. The industry is not going to develop any more of these drugs if they are required to do a trial of 10 years. It’s difficult to tease out [contributors] to the development of cancer," Dr. Diamant continued.

Dr. Diamant has been a board member, advisory panel member, consultant, research support recipient, and/or speakers bureau participant for Eli Lilly, Merck Sharp & Dohme, Novo Nordisk, Abbott, AstraZeneca/BMS, Boehringer Ingelheim, Poxel Pharma, Sanofi-Aventis, Amylin Pharmaceuticals, Novartis, and Takeda.

Sue Sutter of "The Pink Sheet" contributed to this story. "The Pink Sheet" and this publication are both owned by Elsevier.

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.

"This differentiates LX4211 from the SGLT2-specific inhibitors in several ways. For example, in patients with type 2 diabetes, LX4211 has been shown to cause a rapid reduction in blood sugar levels after meals, and an increase in GLP-1 [glucagonlike peptide–1] and the increase in PYY [peptide YY], effects that are associated with SGLT1 inhibition by LX4211 in the gastrointestinal tract. Also, recent studies in healthy subjects have shown that LX4211 substantially decreases postprandial glucose levels without hypoglycemia, and in both diabetic patients and healthy subjects, LX4211 can substantially reduce triglycerides. These results have not been reported for SGLT2-selective inhibitors," he said.

With regard to safety, Dr. Lapuerta noted that the "issue for the FDA advisory committee had to do with the overall benefit/risk profile of dapagliflozin. We believe the solution will involve addressing both benefits and risks. On the benefit side, we believe that LX4211 is a cardiovascular drug, not just a diabetes drug. Dual inhibition of SGLT1/2 with LX4211 offers the potential benefit to combine strong [hemoglobin] A_1c reduction with benefits in blood pressure, uric acid, weight loss, and triglycerides. Cardiovascular benefits will be relevant to approval," he said.

"On the risk side, there is the potential that reports of bladder cancer on dapagliflozin reflected an ascertainment bias. We can address this in the LX4211 clinical program by ensuring that we carefully document physician referral patterns and take steps to ensure [that] our studies identify as much as possible new conditions instead of preexisting ones."

Susan Holz, public relations manager at Boehringer Ingelheim Pharmaceuticals, said in an earlier interview, "We are aware of the advisory committee’s concerns with dapagliflozin and are working with the FDA to ensure [that] our filing package for empagliflozin is robust and comprehensive. Phase III trials for empagliflozin are underway, and we are continuing to evaluate the drug’s safety profile." Currently, there are 11 ongoing, multinational, phase III clinical trials, including a large cardiovascular outcomes safety trial, she said.

At the EASD meeting in September, Dr. Michaela Diamant, scientific director of the diabetes center at Free University Medical Center in Amsterdam, commented that SGLT2 inhibitors have "an interesting mechanism that addresses, to a certain extent, a pathogenic defect that has been largely overlooked in diabetes. ... I’m sure there is a huge group of patients who can profit from these novel agents."

Regarding the safety issue, she asked, "If you would have a trial of 2-5 years, would you definitely address causality of cancer? We know that cancer development takes 20 years. It’s very unlikely that the drug caused cancer. We have to do what is feasible. The industry is not going to develop any more of these drugs if they are required to do a trial of 10 years. It’s difficult to tease out [contributors] to the development of cancer," Dr. Diamant continued.

Dr. Diamant has been a board member, advisory panel member, consultant, research support recipient, and/or speakers bureau participant for Eli Lilly, Merck Sharp & Dohme, Novo Nordisk, Abbott, AstraZeneca/BMS, Boehringer Ingelheim, Poxel Pharma, Sanofi-Aventis, Amylin Pharmaceuticals, Novartis, and Takeda.

Sue Sutter of "The Pink Sheet" contributed to this story. "The Pink Sheet" and this publication are both owned by Elsevier.