FDA advisory panel decisions

FDA advisory committee approves Signifor to treat Cushing’s disease

The FDA Endocrinologic and Metabolic Drugs Advisory Committee has voted unanimously to approve pasireotide injection for the treatment of Cushing’s disease. This is the second drug labeled specifically to treat hypercortisolemia.

Despite concerns on glucose control, the panel decided that the safety and efficacy data for pasireotide (Signifor, Novartis) is sufficient to support the marketing of this drug.

“It’s important that we don’t view this as the golden bullet and that research continues to occur that will find a medication that will lower cortisol and concomitantly lower glucose levels, but this drug may play an important role in current management,” Ellen W. Seely, MD, of Harvard Medical School and Brigham and Women’s Hospital, said during the vote. “It’s important that in the labeling of the drug for prescribers, as well as the information for patients, that hyperglycemia is fully stressed.”

Efficacy of pasireotide

Naomi Lowy, MD, clinical reviewer, presented data from Study B2305, a randomized, two-arm, two-dose, uncontrolled, “pivotal” trial in 182 patients with Cushing’s disease.

The aim of the trial was to examine response rates among two dose groups (600 mcg twice daily and 900 mcg twice daily). Researchers compared the percentage of patients whose urinary free cortisol (UFC) normalized after 6 months of treatment, with a prespecified “threshold” of 15% (the primary endpoint).

The response rate in the 900-mcg dose group was 26%, and the lower bound of the two-sided 95% CI was 17%, which exceeded the prespecified 15% threshold. However, the 600-mcg dose did not meet these criteria.

Additional exploratory analyses were performed in which “responders” were defined as those patients with mean UFC less than the upper limit of normal (ULN) or with a ≥50% reduction in UFC from baseline.  

Mean plasma adrenocorticotropic hormone concentrations declined in the exploratory analyses, and these were consistent with the mean UFC reductions observed during B2305 and the known mechanism of action of pasireotide.

Furthermore, there were decreases in systolic and diastolic blood pressure in both dose groups, although there were differences in systolic but not diastolic BP reductions among the doses: 11.4 mm Hg reduction with 900 mcg vs. 6.8 mm Hg reduction with 600 mcg. Patients enrolled in B2305 were allowed to use antihypertensive medications. Compared with statistics on use at baseline, there was an increase in some categories of antihypertensive drugs during the trial.

Health-related quality of life was also improved with both doses, with a mean percent change of 31.3% from baseline in the 600-mcg dose group and 73% in the 900-mcg dose group.

Safety and adverse events

In terms of safety, hepatic transaminases were elevated in several patients, accompanied by a pronounced early rise in bilirubin levels, according to the documents. Additionally, treatment with pasireotide was associated with impaired insulin secretion, resulting in dysglycemia and increases in HbA1c from baseline.

“Clinicians should really pay attention to the issue of glucose,” Abraham Thomas, MD, MPH, FACP, of Henry Ford Hospital, said during the meeting. “It’s important that it’s emphasized by the company to the clinicians that it’s an issue, and one that starts early and should be addressed. As part of that, clinicians have an obligation to discuss this with patients.”

The FDA received a new drug application Feb. 17 for pasireotide injection to treat hypercortisolemia in Cushing’s disease.

Currently, medical therapy is the initial intervention when a patient cannot undergo surgery due to poor general health, if a tumor is unresectable, if preoperative control of severe hypercortisolemia is necessary or if a patient refuses surgery, according to the FDA briefing document. Mifepristone (Korlym, Corcept Therapeutics), a glucocorticoid receptor antagonist, is the first and only FDA-approved drug for the treatment of hypercortisolemia in Cushing’s syndrome. It was approved Feb. 17 for patients who have failed surgery or are not candidates for surgery and demonstrate signs of glucose intolerance or type 2 diabetes.

“This might not be the ideal drug, but having high cortisol destroys the body, so anything that can help in any way to lower the cortisol and make life a little meaningful is a good thing,” Louise Pace, patient representative, said during the meeting. – by Stacey L. Fisher

The FDA Endocrinologic and Metabolic Drugs Advisory Committee has voted unanimously to approve pasireotide injection for the treatment of Cushing’s disease. This is the second drug labeled specifically to treat hypercortisolemia.

Despite concerns on glucose control, the panel decided that the safety and efficacy data for pasireotide (Signifor, Novartis) is sufficient to support the marketing of this drug.

“It’s important that we don’t view this as the golden bullet and that research continues to occur that will find a medication that will lower cortisol and concomitantly lower glucose levels, but this drug may play an important role in current management,” Ellen W. Seely, MD, of Harvard Medical School and Brigham and Women’s Hospital, said during the vote. “It’s important that in the labeling of the drug for prescribers, as well as the information for patients, that hyperglycemia is fully stressed.”

Efficacy of pasireotide

Naomi Lowy, MD, clinical reviewer, presented data from Study B2305, a randomized, two-arm, two-dose, uncontrolled, “pivotal” trial in 182 patients with Cushing’s disease.

The aim of the trial was to examine response rates among two dose groups (600 mcg twice daily and 900 mcg twice daily). Researchers compared the percentage of patients whose urinary free cortisol (UFC) normalized after 6 months of treatment, with a prespecified “threshold” of 15% (the primary endpoint).

The response rate in the 900-mcg dose group was 26%, and the lower bound of the two-sided 95% CI was 17%, which exceeded the prespecified 15% threshold. However, the 600-mcg dose did not meet these criteria.

Additional exploratory analyses were performed in which “responders” were defined as those patients with mean UFC less than the upper limit of normal (ULN) or with a ≥50% reduction in UFC from baseline.  

Mean plasma adrenocorticotropic hormone concentrations declined in the exploratory analyses, and these were consistent with the mean UFC reductions observed during B2305 and the known mechanism of action of pasireotide.

Furthermore, there were decreases in systolic and diastolic blood pressure in both dose groups, although there were differences in systolic but not diastolic BP reductions among the doses: 11.4 mm Hg reduction with 900 mcg vs. 6.8 mm Hg reduction with 600 mcg. Patients enrolled in B2305 were allowed to use antihypertensive medications. Compared with statistics on use at baseline, there was an increase in some categories of antihypertensive drugs during the trial.

Health-related quality of life was also improved with both doses, with a mean percent change of 31.3% from baseline in the 600-mcg dose group and 73% in the 900-mcg dose group.

Safety and adverse events

In terms of safety, hepatic transaminases were elevated in several patients, accompanied by a pronounced early rise in bilirubin levels, according to the documents. Additionally, treatment with pasireotide was associated with impaired insulin secretion, resulting in dysglycemia and increases in HbA1c from baseline.

“Clinicians should really pay attention to the issue of glucose,” Abraham Thomas, MD, MPH, FACP, of Henry Ford Hospital, said during the meeting. “It’s important that it’s emphasized by the company to the clinicians that it’s an issue, and one that starts early and should be addressed. As part of that, clinicians have an obligation to discuss this with patients.”

The FDA received a new drug application Feb. 17 for pasireotide injection to treat hypercortisolemia in Cushing’s disease.

Currently, medical therapy is the initial intervention when a patient cannot undergo surgery due to poor general health, if a tumor is unresectable, if preoperative control of severe hypercortisolemia is necessary or if a patient refuses surgery, according to the FDA briefing document. Mifepristone (Korlym, Corcept Therapeutics), a glucocorticoid receptor antagonist, is the first and only FDA-approved drug for the treatment of hypercortisolemia in Cushing’s syndrome. It was approved Feb. 17 for patients who have failed surgery or are not candidates for surgery and demonstrate signs of glucose intolerance or type 2 diabetes.

“This might not be the ideal drug, but having high cortisol destroys the body, so anything that can help in any way to lower the cortisol and make life a little meaningful is a good thing,” Louise Pace, patient representative, said during the meeting. – by Stacey L. Fisher