FDA Advisory Committee Meeting

SILVER SPRING, MD. – Reassured by the data on the risks of bladder cancer and liver injury and on cardiovascular safety, a Food and Drug Administration advisory panel supported the approval of the sodium glucose co-transporter 2 inhibitor dapagliflozin as a treatment for type 2 diabetes at a meeting on Dec. 12.

Voting 13-1, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee agreed that the benefits of dapagliflozin outweighed its risks for the proposed indication: to improve glycemic control in adults with type 2 diabetes mellitus as an adjunct to diet and exercise. The recommended dose is 5 mg or 10 mg/day, at any time of the day regardless of meals. It is not recommended for patients with moderate renal impairment, and the 5-mg dose is recommended for people at risk for volume depletion related to a coexisting condition.

Panelists, however, strongly recommended that cardiovascular safety, bladder cancer, and hepatotoxicity in patients treated with dapagliflozin should be closely monitored after approval.

The risks "appear to be low enough to go ahead, but there is surveillance that is needed to make sure we’re not missing something," said panelist Dr. Peter Savage, senior advisor for clinical research in the division of diabetes, endocrinology, and metabolism at the National Institute of Diabetes, Digestive, and Kidney Diseases.

One of the two oncologists on the panel, Dr. Wyndham Wilson of the lymphoid malignancy branch at the National Cancer Institute’s Center for Cancer Research, said that, based on the effects of the drug on surrogate endpoints, he believed it was useful for treating type 2 diabetes and that the cancer and hepatic findings "did not rise to the level of nonapproval for me." He emphasized, however, the importance of the postmarketing studies that are being planned or are underway that are addressing the cancer and cardiac risks further.

This was the second time the panel has met to review dapagliflozin, which, by inhibiting sodium glucose co-transporter 2 (SGLT2) that is expressed in the kidney, reduces renal glucose reabsorption, increasing urinary excretion of glucose and reducing plasma glucose levels. If approved, dapagliflozin would be the second SGLT2-inhbitor on the U.S. market. In March 2013, canagliflozin (Invokana), another SGLT2 inhibitor, was approved.

Because of a numerical increase in bladder and breast cancers and a possible drug-induced liver injury case, the majority of the same panel voted against approval at a July 2011 meeting. In January 2012, the FDA issued a complete response letter to the company, requesting more data and analyses on hepatic safety, bladder cancer, and cardiovascular safety. Bristol-Myers Squibb and AstraZeneca resubmitted the application for approval in July 2013, with data from additional studies, for a total of more than 11,000 patients (with more than 6,000 treated with dapagliflozin),which included updated safety information on hepatic safety, bladder cancers, and CV safety analyses.

In the updated meta-analysis of these studies, the hazard ratio for the cardiovascular composite endpoint of CV death, MI, stroke, and hospitalization for unstable angina was 0.81. For the stricter major adverse cardiovascular event (MACE, comprising CV death, MI, and stroke) endpoint, it was 0.78. In two 24-week studies that randomized almost 2,000 patients with established cardiovascular disease to dapagliflozin or placebo, who were followed for up to two years, the hazard ratio for the primary composite endpoint was 0.98 and for the MACE endpoint, it was 1.11.

Based on these analyses, the panel voted 10-4 that the company had provided sufficient evidence that dapagliflozin has an acceptable cardiovascular profile based on the FDA’s guidance document for industry, which states that an estimated cardiovascular risk of 1.8 or more for a new type 2 diabetes drug should be ruled out.

"Overall, it looks fairly neutral," and "the overall effect does not appear to be adverse," even when adding the two studies in patients with established CV disease, said panelist Dr. Peter Wilson, professor of cardiology at Emory University, Atlanta. Those who voted no on this question said that there were not enough data to make a conclusion about cardiovascular safety.

The panelists agreed that they were reassured by aspects of the 10 bladder cancer cases reported among patients treated with dapagliflozin in clinical trials (a rate of 0.16%), compared with one case (0.03%) among those on comparator arms. Of the 10 cases, 6 were detected within 6 months of treatment (while tumorigenesis can take years) and 8 were noninvasive. In seven cases, the patient had hematuria before starting dapagliflozin, although hematuria is more common among people with diabetes, they pointed out. The panelists, though, did not think the bladder cancer issue could be entirely dismissed and agreed that this issue should be monitored after approval.

The panel did not have substantial concerns about the risk of liver disease associated with the drug and agreed the data did not indicate a significant signal for hepatoxicity, but that hepatic adverse events should be monitored after approval. The one case of what was thought to be probable drug-induced liver injury in clinical trials was later considered more likely to be autoimmune hepatitis, provided "substantial reassurance" that this was not drug-related, although it could not be completely ruled out, they said.

The panel also recommended that rates of breast cancer in women be monitored after approval. A numerical increase in breast cancers among those on dapagliflozin was a concern at the first meeting, although the FDA concluded that the data on the breast cancer risk associated with dapagliflozin were inconclusive and insufficient.

The companies are planning to follow these safety issues in studies that include pharmacoepidemiology studies underway in Europe – which are monitoring for cancer, acute liver injury, and severe urinary tract infection complications – and a cardiovascular outcomes study with a planned enrollment of 17,150 patients with type 2 diabetes and established CV disease or at least two CV risk factors. Enrollment for the latter study – the Dapagliflozin Effect on Cardiovascular Events (DECLARE-TIMI-58) study – in Europe has already begun.

The FDA usually follows the recommendations of its advisory panels. Members of FDA panels have usually been cleared of conflicts related to the product under review; occasionally, a panelist is given a waiver, but not at this meeting.

In studies, dapagliflozin lowered hemoglobin A_1c at the 5-mg and 10-mg once-daily doses and also was associated with decreases in fasting blood sugar, small decreases in systolic blood pressure (in hypertensive patients) and body weight, and LDL-cholesterol elevation. Adverse events associated with treatment include a higher rate of genital infections, volume depletion, and polyuria.

Since November 2012, dapagliflozin has been approved in the European Union, Australia, Mexico, New Zealand, Brazil, and Argentina. To date, over 35,000 people worldwide have been treated with dapagliflozin, according to Bristol-Myers Squibb. If approved, BMS and AstraZeneca plan to market dapagliflozin as Forxiga. A decision on approval is expected by Jan. 11, 2014.

[email protected]

SILVER SPRING, MD. – Reassured by the data on the risks of bladder cancer and liver injury and on cardiovascular safety, a Food and Drug Administration advisory panel supported the approval of the sodium glucose co-transporter 2 inhibitor dapagliflozin as a treatment for type 2 diabetes at a meeting on Dec. 12.

Voting 13-1, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee agreed that the benefits of dapagliflozin outweighed its risks for the proposed indication: to improve glycemic control in adults with type 2 diabetes mellitus as an adjunct to diet and exercise. The recommended dose is 5 mg or 10 mg/day, at any time of the day regardless of meals. It is not recommended for patients with moderate renal impairment, and the 5-mg dose is recommended for people at risk for volume depletion related to a coexisting condition.

Panelists, however, strongly recommended that cardiovascular safety, bladder cancer, and hepatotoxicity in patients treated with dapagliflozin should be closely monitored after approval.

The risks "appear to be low enough to go ahead, but there is surveillance that is needed to make sure we’re not missing something," said panelist Dr. Peter Savage, senior advisor for clinical research in the division of diabetes, endocrinology, and metabolism at the National Institute of Diabetes, Digestive, and Kidney Diseases.

One of the two oncologists on the panel, Dr. Wyndham Wilson of the lymphoid malignancy branch at the National Cancer Institute’s Center for Cancer Research, said that, based on the effects of the drug on surrogate endpoints, he believed it was useful for treating type 2 diabetes and that the cancer and hepatic findings "did not rise to the level of nonapproval for me." He emphasized, however, the importance of the postmarketing studies that are being planned or are underway that are addressing the cancer and cardiac risks further.

This was the second time the panel has met to review dapagliflozin, which, by inhibiting sodium glucose co-transporter 2 (SGLT2) that is expressed in the kidney, reduces renal glucose reabsorption, increasing urinary excretion of glucose and reducing plasma glucose levels. If approved, dapagliflozin would be the second SGLT2-inhbitor on the U.S. market. In March 2013, canagliflozin (Invokana), another SGLT2 inhibitor, was approved.

Because of a numerical increase in bladder and breast cancers and a possible drug-induced liver injury case, the majority of the same panel voted against approval at a July 2011 meeting. In January 2012, the FDA issued a complete response letter to the company, requesting more data and analyses on hepatic safety, bladder cancer, and cardiovascular safety. Bristol-Myers Squibb and AstraZeneca resubmitted the application for approval in July 2013, with data from additional studies, for a total of more than 11,000 patients (with more than 6,000 treated with dapagliflozin),which included updated safety information on hepatic safety, bladder cancers, and CV safety analyses.

In the updated meta-analysis of these studies, the hazard ratio for the cardiovascular composite endpoint of CV death, MI, stroke, and hospitalization for unstable angina was 0.81. For the stricter major adverse cardiovascular event (MACE, comprising CV death, MI, and stroke) endpoint, it was 0.78. In two 24-week studies that randomized almost 2,000 patients with established cardiovascular disease to dapagliflozin or placebo, who were followed for up to two years, the hazard ratio for the primary composite endpoint was 0.98 and for the MACE endpoint, it was 1.11.

Based on these analyses, the panel voted 10-4 that the company had provided sufficient evidence that dapagliflozin has an acceptable cardiovascular profile based on the FDA’s guidance document for industry, which states that an estimated cardiovascular risk of 1.8 or more for a new type 2 diabetes drug should be ruled out.

"Overall, it looks fairly neutral," and "the overall effect does not appear to be adverse," even when adding the two studies in patients with established CV disease, said panelist Dr. Peter Wilson, professor of cardiology at Emory University, Atlanta. Those who voted no on this question said that there were not enough data to make a conclusion about cardiovascular safety.

The panelists agreed that they were reassured by aspects of the 10 bladder cancer cases reported among patients treated with dapagliflozin in clinical trials (a rate of 0.16%), compared with one case (0.03%) among those on comparator arms. Of the 10 cases, 6 were detected within 6 months of treatment (while tumorigenesis can take years) and 8 were noninvasive. In seven cases, the patient had hematuria before starting dapagliflozin, although hematuria is more common among people with diabetes, they pointed out. The panelists, though, did not think the bladder cancer issue could be entirely dismissed and agreed that this issue should be monitored after approval.

The panel did not have substantial concerns about the risk of liver disease associated with the drug and agreed the data did not indicate a significant signal for hepatoxicity, but that hepatic adverse events should be monitored after approval. The one case of what was thought to be probable drug-induced liver injury in clinical trials was later considered more likely to be autoimmune hepatitis, provided "substantial reassurance" that this was not drug-related, although it could not be completely ruled out, they said.

The panel also recommended that rates of breast cancer in women be monitored after approval. A numerical increase in breast cancers among those on dapagliflozin was a concern at the first meeting, although the FDA concluded that the data on the breast cancer risk associated with dapagliflozin were inconclusive and insufficient.

The companies are planning to follow these safety issues in studies that include pharmacoepidemiology studies underway in Europe – which are monitoring for cancer, acute liver injury, and severe urinary tract infection complications – and a cardiovascular outcomes study with a planned enrollment of 17,150 patients with type 2 diabetes and established CV disease or at least two CV risk factors. Enrollment for the latter study – the Dapagliflozin Effect on Cardiovascular Events (DECLARE-TIMI-58) study – in Europe has already begun.

The FDA usually follows the recommendations of its advisory panels. Members of FDA panels have usually been cleared of conflicts related to the product under review; occasionally, a panelist is given a waiver, but not at this meeting.

In studies, dapagliflozin lowered hemoglobin A_1c at the 5-mg and 10-mg once-daily doses and also was associated with decreases in fasting blood sugar, small decreases in systolic blood pressure (in hypertensive patients) and body weight, and LDL-cholesterol elevation. Adverse events associated with treatment include a higher rate of genital infections, volume depletion, and polyuria.

Since November 2012, dapagliflozin has been approved in the European Union, Australia, Mexico, New Zealand, Brazil, and Argentina. To date, over 35,000 people worldwide have been treated with dapagliflozin, according to Bristol-Myers Squibb. If approved, BMS and AstraZeneca plan to market dapagliflozin as Forxiga. A decision on approval is expected by Jan. 11, 2014.

[email protected]

SILVER SPRING, MD. – Reassured by the data on the risks of bladder cancer and liver injury and on cardiovascular safety, a Food and Drug Administration advisory panel supported the approval of the sodium glucose co-transporter 2 inhibitor dapagliflozin as a treatment for type 2 diabetes at a meeting on Dec. 12.

Voting 13-1, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee agreed that the benefits of dapagliflozin outweighed its risks for the proposed indication: to improve glycemic control in adults with type 2 diabetes mellitus as an adjunct to diet and exercise. The recommended dose is 5 mg or 10 mg/day, at any time of the day regardless of meals. It is not recommended for patients with moderate renal impairment, and the 5-mg dose is recommended for people at risk for volume depletion related to a coexisting condition.

Panelists, however, strongly recommended that cardiovascular safety, bladder cancer, and hepatotoxicity in patients treated with dapagliflozin should be closely monitored after approval.

The risks "appear to be low enough to go ahead, but there is surveillance that is needed to make sure we’re not missing something," said panelist Dr. Peter Savage, senior advisor for clinical research in the division of diabetes, endocrinology, and metabolism at the National Institute of Diabetes, Digestive, and Kidney Diseases.

One of the two oncologists on the panel, Dr. Wyndham Wilson of the lymphoid malignancy branch at the National Cancer Institute’s Center for Cancer Research, said that, based on the effects of the drug on surrogate endpoints, he believed it was useful for treating type 2 diabetes and that the cancer and hepatic findings "did not rise to the level of nonapproval for me." He emphasized, however, the importance of the postmarketing studies that are being planned or are underway that are addressing the cancer and cardiac risks further.

This was the second time the panel has met to review dapagliflozin, which, by inhibiting sodium glucose co-transporter 2 (SGLT2) that is expressed in the kidney, reduces renal glucose reabsorption, increasing urinary excretion of glucose and reducing plasma glucose levels. If approved, dapagliflozin would be the second SGLT2-inhbitor on the U.S. market. In March 2013, canagliflozin (Invokana), another SGLT2 inhibitor, was approved.

Because of a numerical increase in bladder and breast cancers and a possible drug-induced liver injury case, the majority of the same panel voted against approval at a July 2011 meeting. In January 2012, the FDA issued a complete response letter to the company, requesting more data and analyses on hepatic safety, bladder cancer, and cardiovascular safety. Bristol-Myers Squibb and AstraZeneca resubmitted the application for approval in July 2013, with data from additional studies, for a total of more than 11,000 patients (with more than 6,000 treated with dapagliflozin),which included updated safety information on hepatic safety, bladder cancers, and CV safety analyses.

In the updated meta-analysis of these studies, the hazard ratio for the cardiovascular composite endpoint of CV death, MI, stroke, and hospitalization for unstable angina was 0.81. For the stricter major adverse cardiovascular event (MACE, comprising CV death, MI, and stroke) endpoint, it was 0.78. In two 24-week studies that randomized almost 2,000 patients with established cardiovascular disease to dapagliflozin or placebo, who were followed for up to two years, the hazard ratio for the primary composite endpoint was 0.98 and for the MACE endpoint, it was 1.11.

Based on these analyses, the panel voted 10-4 that the company had provided sufficient evidence that dapagliflozin has an acceptable cardiovascular profile based on the FDA’s guidance document for industry, which states that an estimated cardiovascular risk of 1.8 or more for a new type 2 diabetes drug should be ruled out.

"Overall, it looks fairly neutral," and "the overall effect does not appear to be adverse," even when adding the two studies in patients with established CV disease, said panelist Dr. Peter Wilson, professor of cardiology at Emory University, Atlanta. Those who voted no on this question said that there were not enough data to make a conclusion about cardiovascular safety.

The panelists agreed that they were reassured by aspects of the 10 bladder cancer cases reported among patients treated with dapagliflozin in clinical trials (a rate of 0.16%), compared with one case (0.03%) among those on comparator arms. Of the 10 cases, 6 were detected within 6 months of treatment (while tumorigenesis can take years) and 8 were noninvasive. In seven cases, the patient had hematuria before starting dapagliflozin, although hematuria is more common among people with diabetes, they pointed out. The panelists, though, did not think the bladder cancer issue could be entirely dismissed and agreed that this issue should be monitored after approval.

The panel did not have substantial concerns about the risk of liver disease associated with the drug and agreed the data did not indicate a significant signal for hepatoxicity, but that hepatic adverse events should be monitored after approval. The one case of what was thought to be probable drug-induced liver injury in clinical trials was later considered more likely to be autoimmune hepatitis, provided "substantial reassurance" that this was not drug-related, although it could not be completely ruled out, they said.

The panel also recommended that rates of breast cancer in women be monitored after approval. A numerical increase in breast cancers among those on dapagliflozin was a concern at the first meeting, although the FDA concluded that the data on the breast cancer risk associated with dapagliflozin were inconclusive and insufficient.

The companies are planning to follow these safety issues in studies that include pharmacoepidemiology studies underway in Europe – which are monitoring for cancer, acute liver injury, and severe urinary tract infection complications – and a cardiovascular outcomes study with a planned enrollment of 17,150 patients with type 2 diabetes and established CV disease or at least two CV risk factors. Enrollment for the latter study – the Dapagliflozin Effect on Cardiovascular Events (DECLARE-TIMI-58) study – in Europe has already begun.

The FDA usually follows the recommendations of its advisory panels. Members of FDA panels have usually been cleared of conflicts related to the product under review; occasionally, a panelist is given a waiver, but not at this meeting.

In studies, dapagliflozin lowered hemoglobin A_1c at the 5-mg and 10-mg once-daily doses and also was associated with decreases in fasting blood sugar, small decreases in systolic blood pressure (in hypertensive patients) and body weight, and LDL-cholesterol elevation. Adverse events associated with treatment include a higher rate of genital infections, volume depletion, and polyuria.

Since November 2012, dapagliflozin has been approved in the European Union, Australia, Mexico, New Zealand, Brazil, and Argentina. To date, over 35,000 people worldwide have been treated with dapagliflozin, according to Bristol-Myers Squibb. If approved, BMS and AstraZeneca plan to market dapagliflozin as Forxiga. A decision on approval is expected by Jan. 11, 2014.

[email protected]