FDA panel backs approval of canagliflozin for type 2 diabetes

SILVER SPRING, MD. – The majority of a Food and Drug Administration advisory panel supported the approval of canagliflozin for the treatment of type 2 diabetes with caveats, including precautions about its use in patients with moderately impaired renal function and recommendations to continue to evaluate cardiovascular safety after approval.

At a meeting on Jan. 10, FDA’s Endocrinologic and Metabolic Drugs Advisory voted 10-5 to recommend approval of the selective sodium glucose cotransporter 2 (SGLT2) inhibitor for treating type 2 diabetes, based on the available safety and efficacy data on canagliflozin, which blocks the reabsorption of glucose by the kidney, increasing glucose excretion and lowering blood glucose levels.

The proposed indication is as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes, taken by mouth at a dose of 100 mg or 300 mg once a day, before the first meal of the day. If approved, the drug would be the first SGLT2 inhibitor to be approved by the FDA. Primarily expressed by the kidney, SGLT2 is responsible for the majority of renal glucose reabsorption.

The manufacturer, Janssen Pharmaceuticals, submitted the results of nine phase III international studies in almost 10,300 patients with type 2 diabetes, comparing the drug with placebo or active controls, as monotherapy and as add-on therapy to other antihyperglycemic drugs; and the interim results of a cardiovascular outcomes study, required by the FDA for all new type 2 diabetes drugs. In the outcomes study, there was an imbalance in the rate of major adverse cardiovascular events (mostly strokes), with more cases among the canagliflozin-treated patients in the first 30 days, but the risk dropped after 30 days to below the threshold – a hazard ratio of 1.8 – set by the FDA as an acceptable CV risk for a new type 2 diabetes treatment.

Panelists voting on both sides noted that the risk-benefit profile was less clear-cut in patients with impaired renal function, since canagliflozin was less effective and was associated with more adverse events as renal function decreased. Those voting in favor of approval said that, although they were uncertain about the imbalance in CV events during the first 30 days of treatment, they were reassured by the available data available so far. In another vote, 8 of the 15 panel members, including several who supported approval, said they still had concerns about whether the risk had been excluded for the drug and agreed that more data were needed.

Other safety issues that panelists said should be monitored after approval included the potential long-term effects of the dose dependent increase in LDL cholesterol associated with canagliflozin treatment, and the impact of treatment on bone density and fractures. In the studies, there were more fractures among patients treated with canagliflozin – mostly low trauma upper limb fracture, but the difference was not statistically significant.

The panel chair, Dr. Abraham Thomas, the head of the division of endocrinology, diabetes, bone, and mineral disorders at Henry Ford Hospital in Detroit, voted in favor of approval, citing the "definite benefits" of the drug, but added that he, like other panelists, still had concerns regarding safety. More data are needed to determine whether the increase in adverse cardiovascular outcomes –stroke in particular – is a real issue or "a red herring," he said. Once approved, long-term follow-up of safety issues such as the effects of treatment on cardiovascular risk and bone should be evaluated in long-term registry studies, since they can be difficult to identify in clinical trials, he added.

Voting against approval, Dr. William Knowler, chief of the diabetes epidemiology and clinical research section at the Phoenix branch of the National Institute of Diabetes and Digestive and Kidney Diseases, said that he would support approval of the drug as an add-on therapy but not as an initial treatment because there were no data comparing canagliflozin to metformin, the standard initial therapy recommended by American Diabetes Association/European Association for the Study of Diabetes treatment guidelines. "I think the drug would be acceptable as add-on therapy for some patients, but for a general indication including monotherapy, I cannot recommend it," he said.

Cardiologist William Hiatt, professor of medicine at the University of Colorado, Denver, said that he voted against approval because the cardiovascular risks had not been fully evaluated and that his residual concerns about safety could be resolved once the cardiovascular outcomes study was completed.

In the phase III studies, treatment with canagliflozin resulted in significant improvements in glycemic control, based on the primary endpoint, changes in hemoglobin A_1c from baseline to the end of the study, with sustained responses over 52 weeks and a large proportion of patients achieving glycemic goals, according to Janssen. Treatment in patients with renal impairment was also associated with reductions in HbA_1c, which were of less magnitude than the reductions seen in patients with normal kidney function. Other favorable effects associated with canagliflozin included decreased body weight and reductions in systolic blood pressure.

Adverse effects associated with canagliflozin included genital mycotic infections in both men and women. Urinary tract infections, urinary frequency or thirst, and other adverse events related to osmotic diuresis, and adverse events related to reductions in intravascular volume, such as postural hypotension, were also higher among those on canagliflozin. However, the discontinuation rate from adverse events was low, and the incidence of serious adverse events and deaths were similar among those on canagliflozin and controls. There was also a "modest" dose-dependent increase in bone resorption associated with the drug in studies, which the company said could be caused by weight loss. Renal adverse events were higher among those on canagliflozin, compared with placebo, and led to a higher discontinuation rate among those on 300 mg.

The cardiovascular outcome study CANVAS, is comparing the rate of a composite major adverse cardiovascular event (MACE) endpoint (cardiovascular death, nonfatal MI, nonfatal stroke, and hospitalization for unstable angina) in about 4,300 patients at high risk of CV disease, with a 2:1 randomization. In the first 30 days of treatment, there were 13 events among those on canagliflozin (including six strokes, one of which was a fatal ischemic stroke), and one event in placebo patients in the first 30 days of treatment, an imbalance the company said reflected the month-to month variability and was not associated with adverse events related to volume depletion. The hazard ratio for MACE-plus events in the first 30 days of the cardiovascular outcomes study was 6.49, dropping to 0.89 after 30 days, and was 0.64 in other studies, according to the FDA.

Janssen is recommending a starting dose of 100 mg for patients on a loop diuretic, patients with moderate renal impairment (eGFR 30 to less than 60 mL/min per 1.73m²), or those who are aged 75 years and older, because these groups of patients were at higher risk of adverse reactions related to volume depletion in the studies. Because it would not be effective, canagliflozin would not be used in patients with severe renal impairment (eGFR less than 30 mL/min per 1.73m²), end stage renal disease, or in patients on dialysis.

Another SGLT2 inhibitor, dapagliflozin, was not approved by the FDA, presumably because of potential increases in the risk of bladder and breast cancers associated with the drug. If approved, Janssen plans to market canagliflozin as Invokana.* In December 2012, the company submitted an application for approval of a combined fixed dose formulation of canagliflozin with immediate-release metformin.

Canagliflozin, which is also under review for approval in the European Union, has not yet been approved anywhere. The FDA’s deadline for making a decision on approval is the end of March. The FDA usually follows the recommendations of its advisory panels, which are not binding. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting, although a panelist may be given a waiver, but none were granted at this meeting.

e.mechcatie@elsevier.com

*Correction, 1/15/13: An earlier version of  this story misspelled Invokana.

SILVER SPRING, MD. – The majority of a Food and Drug Administration advisory panel supported the approval of canagliflozin for the treatment of type 2 diabetes with caveats, including precautions about its use in patients with moderately impaired renal function and recommendations to continue to evaluate cardiovascular safety after approval.

At a meeting on Jan. 10, FDA’s Endocrinologic and Metabolic Drugs Advisory voted 10-5 to recommend approval of the selective sodium glucose cotransporter 2 (SGLT2) inhibitor for treating type 2 diabetes, based on the available safety and efficacy data on canagliflozin, which blocks the reabsorption of glucose by the kidney, increasing glucose excretion and lowering blood glucose levels.

The proposed indication is as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes, taken by mouth at a dose of 100 mg or 300 mg once a day, before the first meal of the day. If approved, the drug would be the first SGLT2 inhibitor to be approved by the FDA. Primarily expressed by the kidney, SGLT2 is responsible for the majority of renal glucose reabsorption.

The manufacturer, Janssen Pharmaceuticals, submitted the results of nine phase III international studies in almost 10,300 patients with type 2 diabetes, comparing the drug with placebo or active controls, as monotherapy and as add-on therapy to other antihyperglycemic drugs; and the interim results of a cardiovascular outcomes study, required by the FDA for all new type 2 diabetes drugs. In the outcomes study, there was an imbalance in the rate of major adverse cardiovascular events (mostly strokes), with more cases among the canagliflozin-treated patients in the first 30 days, but the risk dropped after 30 days to below the threshold – a hazard ratio of 1.8 – set by the FDA as an acceptable CV risk for a new type 2 diabetes treatment.

Panelists voting on both sides noted that the risk-benefit profile was less clear-cut in patients with impaired renal function, since canagliflozin was less effective and was associated with more adverse events as renal function decreased. Those voting in favor of approval said that, although they were uncertain about the imbalance in CV events during the first 30 days of treatment, they were reassured by the available data available so far. In another vote, 8 of the 15 panel members, including several who supported approval, said they still had concerns about whether the risk had been excluded for the drug and agreed that more data were needed.

Other safety issues that panelists said should be monitored after approval included the potential long-term effects of the dose dependent increase in LDL cholesterol associated with canagliflozin treatment, and the impact of treatment on bone density and fractures. In the studies, there were more fractures among patients treated with canagliflozin – mostly low trauma upper limb fracture, but the difference was not statistically significant.

The panel chair, Dr. Abraham Thomas, the head of the division of endocrinology, diabetes, bone, and mineral disorders at Henry Ford Hospital in Detroit, voted in favor of approval, citing the "definite benefits" of the drug, but added that he, like other panelists, still had concerns regarding safety. More data are needed to determine whether the increase in adverse cardiovascular outcomes –stroke in particular – is a real issue or "a red herring," he said. Once approved, long-term follow-up of safety issues such as the effects of treatment on cardiovascular risk and bone should be evaluated in long-term registry studies, since they can be difficult to identify in clinical trials, he added.

Voting against approval, Dr. William Knowler, chief of the diabetes epidemiology and clinical research section at the Phoenix branch of the National Institute of Diabetes and Digestive and Kidney Diseases, said that he would support approval of the drug as an add-on therapy but not as an initial treatment because there were no data comparing canagliflozin to metformin, the standard initial therapy recommended by American Diabetes Association/European Association for the Study of Diabetes treatment guidelines. "I think the drug would be acceptable as add-on therapy for some patients, but for a general indication including monotherapy, I cannot recommend it," he said.

Cardiologist William Hiatt, professor of medicine at the University of Colorado, Denver, said that he voted against approval because the cardiovascular risks had not been fully evaluated and that his residual concerns about safety could be resolved once the cardiovascular outcomes study was completed.

In the phase III studies, treatment with canagliflozin resulted in significant improvements in glycemic control, based on the primary endpoint, changes in hemoglobin A_1c from baseline to the end of the study, with sustained responses over 52 weeks and a large proportion of patients achieving glycemic goals, according to Janssen. Treatment in patients with renal impairment was also associated with reductions in HbA_1c, which were of less magnitude than the reductions seen in patients with normal kidney function. Other favorable effects associated with canagliflozin included decreased body weight and reductions in systolic blood pressure.

Adverse effects associated with canagliflozin included genital mycotic infections in both men and women. Urinary tract infections, urinary frequency or thirst, and other adverse events related to osmotic diuresis, and adverse events related to reductions in intravascular volume, such as postural hypotension, were also higher among those on canagliflozin. However, the discontinuation rate from adverse events was low, and the incidence of serious adverse events and deaths were similar among those on canagliflozin and controls. There was also a "modest" dose-dependent increase in bone resorption associated with the drug in studies, which the company said could be caused by weight loss. Renal adverse events were higher among those on canagliflozin, compared with placebo, and led to a higher discontinuation rate among those on 300 mg.

The cardiovascular outcome study CANVAS, is comparing the rate of a composite major adverse cardiovascular event (MACE) endpoint (cardiovascular death, nonfatal MI, nonfatal stroke, and hospitalization for unstable angina) in about 4,300 patients at high risk of CV disease, with a 2:1 randomization. In the first 30 days of treatment, there were 13 events among those on canagliflozin (including six strokes, one of which was a fatal ischemic stroke), and one event in placebo patients in the first 30 days of treatment, an imbalance the company said reflected the month-to month variability and was not associated with adverse events related to volume depletion. The hazard ratio for MACE-plus events in the first 30 days of the cardiovascular outcomes study was 6.49, dropping to 0.89 after 30 days, and was 0.64 in other studies, according to the FDA.

Janssen is recommending a starting dose of 100 mg for patients on a loop diuretic, patients with moderate renal impairment (eGFR 30 to less than 60 mL/min per 1.73m²), or those who are aged 75 years and older, because these groups of patients were at higher risk of adverse reactions related to volume depletion in the studies. Because it would not be effective, canagliflozin would not be used in patients with severe renal impairment (eGFR less than 30 mL/min per 1.73m²), end stage renal disease, or in patients on dialysis.

Another SGLT2 inhibitor, dapagliflozin, was not approved by the FDA, presumably because of potential increases in the risk of bladder and breast cancers associated with the drug. If approved, Janssen plans to market canagliflozin as Invokana.* In December 2012, the company submitted an application for approval of a combined fixed dose formulation of canagliflozin with immediate-release metformin.

Canagliflozin, which is also under review for approval in the European Union, has not yet been approved anywhere. The FDA’s deadline for making a decision on approval is the end of March. The FDA usually follows the recommendations of its advisory panels, which are not binding. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting, although a panelist may be given a waiver, but none were granted at this meeting.

e.mechcatie@elsevier.com

*Correction, 1/15/13: An earlier version of  this story misspelled Invokana.

SILVER SPRING, MD. – The majority of a Food and Drug Administration advisory panel supported the approval of canagliflozin for the treatment of type 2 diabetes with caveats, including precautions about its use in patients with moderately impaired renal function and recommendations to continue to evaluate cardiovascular safety after approval.

At a meeting on Jan. 10, FDA’s Endocrinologic and Metabolic Drugs Advisory voted 10-5 to recommend approval of the selective sodium glucose cotransporter 2 (SGLT2) inhibitor for treating type 2 diabetes, based on the available safety and efficacy data on canagliflozin, which blocks the reabsorption of glucose by the kidney, increasing glucose excretion and lowering blood glucose levels.

The proposed indication is as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes, taken by mouth at a dose of 100 mg or 300 mg once a day, before the first meal of the day. If approved, the drug would be the first SGLT2 inhibitor to be approved by the FDA. Primarily expressed by the kidney, SGLT2 is responsible for the majority of renal glucose reabsorption.

The manufacturer, Janssen Pharmaceuticals, submitted the results of nine phase III international studies in almost 10,300 patients with type 2 diabetes, comparing the drug with placebo or active controls, as monotherapy and as add-on therapy to other antihyperglycemic drugs; and the interim results of a cardiovascular outcomes study, required by the FDA for all new type 2 diabetes drugs. In the outcomes study, there was an imbalance in the rate of major adverse cardiovascular events (mostly strokes), with more cases among the canagliflozin-treated patients in the first 30 days, but the risk dropped after 30 days to below the threshold – a hazard ratio of 1.8 – set by the FDA as an acceptable CV risk for a new type 2 diabetes treatment.

Panelists voting on both sides noted that the risk-benefit profile was less clear-cut in patients with impaired renal function, since canagliflozin was less effective and was associated with more adverse events as renal function decreased. Those voting in favor of approval said that, although they were uncertain about the imbalance in CV events during the first 30 days of treatment, they were reassured by the available data available so far. In another vote, 8 of the 15 panel members, including several who supported approval, said they still had concerns about whether the risk had been excluded for the drug and agreed that more data were needed.

Other safety issues that panelists said should be monitored after approval included the potential long-term effects of the dose dependent increase in LDL cholesterol associated with canagliflozin treatment, and the impact of treatment on bone density and fractures. In the studies, there were more fractures among patients treated with canagliflozin – mostly low trauma upper limb fracture, but the difference was not statistically significant.

The panel chair, Dr. Abraham Thomas, the head of the division of endocrinology, diabetes, bone, and mineral disorders at Henry Ford Hospital in Detroit, voted in favor of approval, citing the "definite benefits" of the drug, but added that he, like other panelists, still had concerns regarding safety. More data are needed to determine whether the increase in adverse cardiovascular outcomes –stroke in particular – is a real issue or "a red herring," he said. Once approved, long-term follow-up of safety issues such as the effects of treatment on cardiovascular risk and bone should be evaluated in long-term registry studies, since they can be difficult to identify in clinical trials, he added.

Voting against approval, Dr. William Knowler, chief of the diabetes epidemiology and clinical research section at the Phoenix branch of the National Institute of Diabetes and Digestive and Kidney Diseases, said that he would support approval of the drug as an add-on therapy but not as an initial treatment because there were no data comparing canagliflozin to metformin, the standard initial therapy recommended by American Diabetes Association/European Association for the Study of Diabetes treatment guidelines. "I think the drug would be acceptable as add-on therapy for some patients, but for a general indication including monotherapy, I cannot recommend it," he said.

Cardiologist William Hiatt, professor of medicine at the University of Colorado, Denver, said that he voted against approval because the cardiovascular risks had not been fully evaluated and that his residual concerns about safety could be resolved once the cardiovascular outcomes study was completed.

In the phase III studies, treatment with canagliflozin resulted in significant improvements in glycemic control, based on the primary endpoint, changes in hemoglobin A_1c from baseline to the end of the study, with sustained responses over 52 weeks and a large proportion of patients achieving glycemic goals, according to Janssen. Treatment in patients with renal impairment was also associated with reductions in HbA_1c, which were of less magnitude than the reductions seen in patients with normal kidney function. Other favorable effects associated with canagliflozin included decreased body weight and reductions in systolic blood pressure.

Adverse effects associated with canagliflozin included genital mycotic infections in both men and women. Urinary tract infections, urinary frequency or thirst, and other adverse events related to osmotic diuresis, and adverse events related to reductions in intravascular volume, such as postural hypotension, were also higher among those on canagliflozin. However, the discontinuation rate from adverse events was low, and the incidence of serious adverse events and deaths were similar among those on canagliflozin and controls. There was also a "modest" dose-dependent increase in bone resorption associated with the drug in studies, which the company said could be caused by weight loss. Renal adverse events were higher among those on canagliflozin, compared with placebo, and led to a higher discontinuation rate among those on 300 mg.

The cardiovascular outcome study CANVAS, is comparing the rate of a composite major adverse cardiovascular event (MACE) endpoint (cardiovascular death, nonfatal MI, nonfatal stroke, and hospitalization for unstable angina) in about 4,300 patients at high risk of CV disease, with a 2:1 randomization. In the first 30 days of treatment, there were 13 events among those on canagliflozin (including six strokes, one of which was a fatal ischemic stroke), and one event in placebo patients in the first 30 days of treatment, an imbalance the company said reflected the month-to month variability and was not associated with adverse events related to volume depletion. The hazard ratio for MACE-plus events in the first 30 days of the cardiovascular outcomes study was 6.49, dropping to 0.89 after 30 days, and was 0.64 in other studies, according to the FDA.

Janssen is recommending a starting dose of 100 mg for patients on a loop diuretic, patients with moderate renal impairment (eGFR 30 to less than 60 mL/min per 1.73m²), or those who are aged 75 years and older, because these groups of patients were at higher risk of adverse reactions related to volume depletion in the studies. Because it would not be effective, canagliflozin would not be used in patients with severe renal impairment (eGFR less than 30 mL/min per 1.73m²), end stage renal disease, or in patients on dialysis.

Another SGLT2 inhibitor, dapagliflozin, was not approved by the FDA, presumably because of potential increases in the risk of bladder and breast cancers associated with the drug. If approved, Janssen plans to market canagliflozin as Invokana.* In December 2012, the company submitted an application for approval of a combined fixed dose formulation of canagliflozin with immediate-release metformin.

Canagliflozin, which is also under review for approval in the European Union, has not yet been approved anywhere. The FDA’s deadline for making a decision on approval is the end of March. The FDA usually follows the recommendations of its advisory panels, which are not binding. Panelists have been cleared of potential conflicts of interest related to the topic of the meeting, although a panelist may be given a waiver, but none were granted at this meeting.

e.mechcatie@elsevier.com

*Correction, 1/15/13: An earlier version of  this story misspelled Invokana.