FDA Panel Backs Somatostatin Analogue for Cushing's

SILVER SPRING, MD.  – The clinically meaningful response to pasireotide in patients with Cushing’s disease convinced an expert committee to endorse the novel drug for approval, albeit with recommendations that include following the long-term adverse effects of hyperglycemia and diabetes associated with the drug in a postmarketing study.

At a meeting on Nov. 7, the FDA’s Endocrinologic and Metabolic Advisory Committee voted 10-0 that the data on the efficacy and safety of the drug supported the approval for treatment of patients with Cushing’s disease who require medical intervention – the proposed indication – despite concerns about the marked hyperglycemia-associated effects, including increased hemoglobin A_1c levels and diabetes in treated patients, as well as abnormal liver enzymes in some patients treated with the drug.

The panel agreed that the reduction in urinary free cortisol levels in patients treated with the drug in the pivotal clinical trial sponsored by the manufacturer, Novartis, was associated with meaningful changes in clinical signs and symptoms of the disease, including weight loss, although this was not a universal effect.

Pasireotide, administered subcutaneously twice a day, binds to somatostatin receptors 1, 2, 3, and 5, with enhanced binding to somatostatin receptor 5, which is expressed in the corticotroph cells of pituitary adenomas. The two approved somatostatin analogues, lanreotide and octreotide, which are approved for acromegaly, bind primarily to somatostatin receptor 2, and pasireotide was studied in Cushing’s disease because of its "broader binding profile," according to the FDA. Treatment lowers the mean blood adrenocorticotropic hormone (ACTH) and mean urinary cortisol levels. As with other somatostatin analogues, the drug is associated with GI-related effects, QTc prolongation and bradycardia, cholestasis and cholelithiasis, and glucose intolerance.

The pivotal study was an uncontrolled international phase III study comparing two doses of pasireotide in 162 patients diagnosed with Cushing’s disease for a mean of 5 years; their mean urinary cortisol levels were at least 1.5 times the upper limit of normal (ULN), their mean age was 40 years, and about a third were males (N. Engl. J. Med. 2012;366:914-24).

At 6 months, 12 (15%) of the 82 patients treated with 600 mcg twice a day and 21 (26%) of the 80 patients treated with 900 mcg twice a day met the primary end point, urinary free cortisol level at or below the ULN. Treatment was also associated with improvements in mean blood pressure, although the use of antihypertensive drugs increased in both groups, and in clinical signs and symptoms of Cushing’s disease.

The adverse events were similar to those of other somatostatin analogues (including diarrhea in 58%, and nausea in 52%). But treatment was also associated with an increased rate of hyperglycemia (13%) and diabetes mellitus (7%); 118 (73%) of the patients had a hyperglycemia-related event. Several patents in the study had elevations in hepatic transaminases, with a pronounced increase in bilirubin levels early in treatment; and four patients not in the trial, including three healthy volunteers, developed elevated liver enzymes; but the patients recovered with no serious effects.

The panel members were not overly concerned about the hepatic risks, but the mechanism for this effect was not clear and the panel recommended that patients have baseline liver function tests, which should be repeated periodically during treatment.

While they were concerned about the hyperglycemic effects, panelists pointed out that there are not many options for these patients. "As clinicians, we are very frustrated by the very limited armamentarium" available for Cushing’s disease, said panelist Dr. Ellen Seely, director of clinical research in the endocrinology, diabetes, and hypertension division at Brigham and Women’s Hospital, Boston.

She and other panelists stressed the importance of labeling for prescribers that includes the risk of hyperglycemia and diabetes with treatment, and counseling patients about these risks. Panelists agreed that the study planned by Novartis to evaluate the most effective classes of medications for treatment of pasireotide-induced hyperglycemia and diabetes was important and would provide helpful information for prescribers.

If approved, pasireotide would be the second drug approved for treatment of endogenous Cushing’s disease. In February 2012, mifepristone, a glucocorticoid receptor antagonist, was approved for the treatment of hypercortisolism in patients with Cushing’s disease who have failed surgery or are not candidates for surgery and have concomitant manifestations of glucose intolerance or type 2 diabetes.

If approved, the drug will be available only through a central pharmacy, which will deliver the drug directly to patients with updated informational materials, according to Novartis. Pasireotide was approved for Cushing’s disease in Europe in April.

If the drug is approved, Novartis plans to market pasireotide as Signifor. 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 not at this meeting.

SILVER SPRING, MD.  – The clinically meaningful response to pasireotide in patients with Cushing’s disease convinced an expert committee to endorse the novel drug for approval, albeit with recommendations that include following the long-term adverse effects of hyperglycemia and diabetes associated with the drug in a postmarketing study.

At a meeting on Nov. 7, the FDA’s Endocrinologic and Metabolic Advisory Committee voted 10-0 that the data on the efficacy and safety of the drug supported the approval for treatment of patients with Cushing’s disease who require medical intervention – the proposed indication – despite concerns about the marked hyperglycemia-associated effects, including increased hemoglobin A_1c levels and diabetes in treated patients, as well as abnormal liver enzymes in some patients treated with the drug.

The panel agreed that the reduction in urinary free cortisol levels in patients treated with the drug in the pivotal clinical trial sponsored by the manufacturer, Novartis, was associated with meaningful changes in clinical signs and symptoms of the disease, including weight loss, although this was not a universal effect.

Pasireotide, administered subcutaneously twice a day, binds to somatostatin receptors 1, 2, 3, and 5, with enhanced binding to somatostatin receptor 5, which is expressed in the corticotroph cells of pituitary adenomas. The two approved somatostatin analogues, lanreotide and octreotide, which are approved for acromegaly, bind primarily to somatostatin receptor 2, and pasireotide was studied in Cushing’s disease because of its "broader binding profile," according to the FDA. Treatment lowers the mean blood adrenocorticotropic hormone (ACTH) and mean urinary cortisol levels. As with other somatostatin analogues, the drug is associated with GI-related effects, QTc prolongation and bradycardia, cholestasis and cholelithiasis, and glucose intolerance.

The pivotal study was an uncontrolled international phase III study comparing two doses of pasireotide in 162 patients diagnosed with Cushing’s disease for a mean of 5 years; their mean urinary cortisol levels were at least 1.5 times the upper limit of normal (ULN), their mean age was 40 years, and about a third were males (N. Engl. J. Med. 2012;366:914-24).

At 6 months, 12 (15%) of the 82 patients treated with 600 mcg twice a day and 21 (26%) of the 80 patients treated with 900 mcg twice a day met the primary end point, urinary free cortisol level at or below the ULN. Treatment was also associated with improvements in mean blood pressure, although the use of antihypertensive drugs increased in both groups, and in clinical signs and symptoms of Cushing’s disease.

The adverse events were similar to those of other somatostatin analogues (including diarrhea in 58%, and nausea in 52%). But treatment was also associated with an increased rate of hyperglycemia (13%) and diabetes mellitus (7%); 118 (73%) of the patients had a hyperglycemia-related event. Several patents in the study had elevations in hepatic transaminases, with a pronounced increase in bilirubin levels early in treatment; and four patients not in the trial, including three healthy volunteers, developed elevated liver enzymes; but the patients recovered with no serious effects.

The panel members were not overly concerned about the hepatic risks, but the mechanism for this effect was not clear and the panel recommended that patients have baseline liver function tests, which should be repeated periodically during treatment.

While they were concerned about the hyperglycemic effects, panelists pointed out that there are not many options for these patients. "As clinicians, we are very frustrated by the very limited armamentarium" available for Cushing’s disease, said panelist Dr. Ellen Seely, director of clinical research in the endocrinology, diabetes, and hypertension division at Brigham and Women’s Hospital, Boston.

She and other panelists stressed the importance of labeling for prescribers that includes the risk of hyperglycemia and diabetes with treatment, and counseling patients about these risks. Panelists agreed that the study planned by Novartis to evaluate the most effective classes of medications for treatment of pasireotide-induced hyperglycemia and diabetes was important and would provide helpful information for prescribers.

If approved, pasireotide would be the second drug approved for treatment of endogenous Cushing’s disease. In February 2012, mifepristone, a glucocorticoid receptor antagonist, was approved for the treatment of hypercortisolism in patients with Cushing’s disease who have failed surgery or are not candidates for surgery and have concomitant manifestations of glucose intolerance or type 2 diabetes.

If approved, the drug will be available only through a central pharmacy, which will deliver the drug directly to patients with updated informational materials, according to Novartis. Pasireotide was approved for Cushing’s disease in Europe in April.

If the drug is approved, Novartis plans to market pasireotide as Signifor. 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 not at this meeting.

SILVER SPRING, MD.  – The clinically meaningful response to pasireotide in patients with Cushing’s disease convinced an expert committee to endorse the novel drug for approval, albeit with recommendations that include following the long-term adverse effects of hyperglycemia and diabetes associated with the drug in a postmarketing study.

At a meeting on Nov. 7, the FDA’s Endocrinologic and Metabolic Advisory Committee voted 10-0 that the data on the efficacy and safety of the drug supported the approval for treatment of patients with Cushing’s disease who require medical intervention – the proposed indication – despite concerns about the marked hyperglycemia-associated effects, including increased hemoglobin A_1c levels and diabetes in treated patients, as well as abnormal liver enzymes in some patients treated with the drug.

The panel agreed that the reduction in urinary free cortisol levels in patients treated with the drug in the pivotal clinical trial sponsored by the manufacturer, Novartis, was associated with meaningful changes in clinical signs and symptoms of the disease, including weight loss, although this was not a universal effect.

Pasireotide, administered subcutaneously twice a day, binds to somatostatin receptors 1, 2, 3, and 5, with enhanced binding to somatostatin receptor 5, which is expressed in the corticotroph cells of pituitary adenomas. The two approved somatostatin analogues, lanreotide and octreotide, which are approved for acromegaly, bind primarily to somatostatin receptor 2, and pasireotide was studied in Cushing’s disease because of its "broader binding profile," according to the FDA. Treatment lowers the mean blood adrenocorticotropic hormone (ACTH) and mean urinary cortisol levels. As with other somatostatin analogues, the drug is associated with GI-related effects, QTc prolongation and bradycardia, cholestasis and cholelithiasis, and glucose intolerance.

The pivotal study was an uncontrolled international phase III study comparing two doses of pasireotide in 162 patients diagnosed with Cushing’s disease for a mean of 5 years; their mean urinary cortisol levels were at least 1.5 times the upper limit of normal (ULN), their mean age was 40 years, and about a third were males (N. Engl. J. Med. 2012;366:914-24).

At 6 months, 12 (15%) of the 82 patients treated with 600 mcg twice a day and 21 (26%) of the 80 patients treated with 900 mcg twice a day met the primary end point, urinary free cortisol level at or below the ULN. Treatment was also associated with improvements in mean blood pressure, although the use of antihypertensive drugs increased in both groups, and in clinical signs and symptoms of Cushing’s disease.

The adverse events were similar to those of other somatostatin analogues (including diarrhea in 58%, and nausea in 52%). But treatment was also associated with an increased rate of hyperglycemia (13%) and diabetes mellitus (7%); 118 (73%) of the patients had a hyperglycemia-related event. Several patents in the study had elevations in hepatic transaminases, with a pronounced increase in bilirubin levels early in treatment; and four patients not in the trial, including three healthy volunteers, developed elevated liver enzymes; but the patients recovered with no serious effects.

The panel members were not overly concerned about the hepatic risks, but the mechanism for this effect was not clear and the panel recommended that patients have baseline liver function tests, which should be repeated periodically during treatment.

While they were concerned about the hyperglycemic effects, panelists pointed out that there are not many options for these patients. "As clinicians, we are very frustrated by the very limited armamentarium" available for Cushing’s disease, said panelist Dr. Ellen Seely, director of clinical research in the endocrinology, diabetes, and hypertension division at Brigham and Women’s Hospital, Boston.

She and other panelists stressed the importance of labeling for prescribers that includes the risk of hyperglycemia and diabetes with treatment, and counseling patients about these risks. Panelists agreed that the study planned by Novartis to evaluate the most effective classes of medications for treatment of pasireotide-induced hyperglycemia and diabetes was important and would provide helpful information for prescribers.

If approved, pasireotide would be the second drug approved for treatment of endogenous Cushing’s disease. In February 2012, mifepristone, a glucocorticoid receptor antagonist, was approved for the treatment of hypercortisolism in patients with Cushing’s disease who have failed surgery or are not candidates for surgery and have concomitant manifestations of glucose intolerance or type 2 diabetes.

If approved, the drug will be available only through a central pharmacy, which will deliver the drug directly to patients with updated informational materials, according to Novartis. Pasireotide was approved for Cushing’s disease in Europe in April.

If the drug is approved, Novartis plans to market pasireotide as Signifor. 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 not at this meeting.