Investigational Cushing's Drug Eases Symptoms, Ups Hyperglycemia

BOSTON – In the largest clinical trial ever conducted in Cushing’s disease, pasireotide, an investigational somatostatin analogue, was shown to result in a rapid and sustained reduction in urinary free cortisol in the majority of patients, and significantly improved signs and symptoms of the disease.

One troubling finding was that three-quarters of patients experienced at least one hyperglycemic episode, a side effect not found with other somatostatin analogues, according to Dr. Annamaria Colao, who presented the findings at the annual meeting of the Endocrine Society.

Pasireotide presents a new therapeutic possibility for Cushing’s disease, since there is no medical treatment currently approved for the condition, said Dr. Colao, professor of endocrinology and chief of the neuroendocrine unit at the University of Naples (Italy) "Federico II." In Cushing’s disease, a benign pituitary tumor stimulates the adrenal glands to synthesize excess cortisol, leading to weight gain, a moon-shaped face, severe fatigue and weakness, hypertension, and hyperglycemia. Pasireotide is also being studied in patients with carcinoid syndrome, acromegaly, and neuroendocrine tumors, and is not approved for use anywhere in the world.

In this double-blind, phase III study known as the PASPORT (Pasireotide Clinical Trial Portfolio) trial, 162 patients who had confirmed persistent, recurrent, or de novo Cushing’s disease and who were not considered to be surgical candidates were enrolled. Patients came from 18 countries and 62 clinical sites. Inclusion criteria included baseline mean urinary free cortisol (UFC) levels falling between 1.5 and 5 times the upper limit of normal (ULN, defined as 145 nmol/24 hours) and confirmation of pituitary adenoma. Any patient with poorly controlled diabetes was excluded from the trial.

Patients were randomized to receive either pasireotide 600 mcg (n = 82) or 900 mcg (n = 80) subcutaneously twice a day for 3 months. After 3 months, patients with UFC greater than twice the ULN or with UFC levels greater than baseline were unblinded, and the dose was increased by 300 mcg b.i.d. All others remained on the same dosage regimen until 6 months. Between 6 and 12 months, the trial was open label, with dose titration adjusted as needed. The primary end point was UFC levels below or at the ULN at 6 months without dose up-titration from the randomized dose.

Pooled results from both groups showed that within 2 months, there was a 48% mean reduction from baseline in UFC levels, and a drop in UFC levels was seen for a majority of patients. After 6 months of treatment, 15% of those treated with 600 mcg pasireotide and 26% of those treated with 900 mcg reached the primary end point. The effect was sustained, with 13% of the 600-mcg group and 25% of the 900-mcg group meeting the primary end point at 12 months.

"Notice how quickly the effect happens: Most of the decrease is seen within the first month of treatment," noted Dr. Colao. Similar trends were seen for serum and salivary cortisol as well as plasma adrenocorticotropic hormone.

Pasireotide treatment also appeared to normalize UFC levels in a subset of patients, especially those with low levels of elevated baseline UFC.

Because most patients responded quickly to treatment, lack of response within the first weeks of treatment can signal those who will be nonresponders. "Within 1-2 months, patients who will not have an adequate biochemical response can be identified with a high degree of accuracy. This might prove clinically useful," says Dr. Colao.

As UFC levels decreased, significant improvements in signs and symptoms of Cushing’s disease became apparent, including reductions in systolic and diastolic blood pressure, weight, and LDL cholesterol levels. Gains were also noted on a Cushing’s disease quality of life assessment, although Dr. Colao noted that interpretation of such findings was limited by lack of a placebo control group. Although Dr. Colao did not show the results of radiologic assessment of tumors, she said that an overall decrease in tumor size was seen after 12 months of pasireotide treatment.

Most adverse events were gastrointestinal in nature, including nausea (52%) and diarrhea (58%). "Adverse events were generally similar to those seen with other agents in this class of somatostatin analogues, with the exception of hyperglycemia," said Dr. Colao. She noted that 75% of patients treated with pasireotide had at least one hyperglycemic adverse event, which resolved by discontinuing the medication. Of 67 patients who were normoglycemic at baseline, 34% became diabetic during treatment, 43% became prediabetic, and 21% remained normal. Dr. Colao also noted that 8% of treated patients experienced hypocortisolism, a finding she felt would be expected with any effective treatment for Cushing’s disease.

Dr. Colao had nothing to disclose. The study was supported by Novartis Pharma AG.

Two posters at meeting shed light on pasireotide’s biochemical mechanisms of action. Dr. Rob van der Pas of Erasmus Medical Center in Rotterdam, the Netherlands, suggested that the reason the somatostatin analogue octreotide is not effective in Cushing’s disease is because it prefers the somatostatin receptor subtype 2 (sst2), whereas it is the somatostatin receptor 5 (sst5) that plays a key role in sst targeted therapy for Cushing’s disease (Endocr. Rev. 2011;32:P3-520). Dr. Robert R. Henry of the University of California, San Diego, found that the hyperglycemia associated with pasireotide is related to decreases in insulin secretion, with no change in insulin sensitivity, and this effect is most likely mediated by the sst5 receptor, which may also play an important role in glucose metabolism (Endocr. Rev. 2011;32:P3-274).

BOSTON – In the largest clinical trial ever conducted in Cushing’s disease, pasireotide, an investigational somatostatin analogue, was shown to result in a rapid and sustained reduction in urinary free cortisol in the majority of patients, and significantly improved signs and symptoms of the disease.

One troubling finding was that three-quarters of patients experienced at least one hyperglycemic episode, a side effect not found with other somatostatin analogues, according to Dr. Annamaria Colao, who presented the findings at the annual meeting of the Endocrine Society.

Pasireotide presents a new therapeutic possibility for Cushing’s disease, since there is no medical treatment currently approved for the condition, said Dr. Colao, professor of endocrinology and chief of the neuroendocrine unit at the University of Naples (Italy) "Federico II." In Cushing’s disease, a benign pituitary tumor stimulates the adrenal glands to synthesize excess cortisol, leading to weight gain, a moon-shaped face, severe fatigue and weakness, hypertension, and hyperglycemia. Pasireotide is also being studied in patients with carcinoid syndrome, acromegaly, and neuroendocrine tumors, and is not approved for use anywhere in the world.

In this double-blind, phase III study known as the PASPORT (Pasireotide Clinical Trial Portfolio) trial, 162 patients who had confirmed persistent, recurrent, or de novo Cushing’s disease and who were not considered to be surgical candidates were enrolled. Patients came from 18 countries and 62 clinical sites. Inclusion criteria included baseline mean urinary free cortisol (UFC) levels falling between 1.5 and 5 times the upper limit of normal (ULN, defined as 145 nmol/24 hours) and confirmation of pituitary adenoma. Any patient with poorly controlled diabetes was excluded from the trial.

Patients were randomized to receive either pasireotide 600 mcg (n = 82) or 900 mcg (n = 80) subcutaneously twice a day for 3 months. After 3 months, patients with UFC greater than twice the ULN or with UFC levels greater than baseline were unblinded, and the dose was increased by 300 mcg b.i.d. All others remained on the same dosage regimen until 6 months. Between 6 and 12 months, the trial was open label, with dose titration adjusted as needed. The primary end point was UFC levels below or at the ULN at 6 months without dose up-titration from the randomized dose.

Pooled results from both groups showed that within 2 months, there was a 48% mean reduction from baseline in UFC levels, and a drop in UFC levels was seen for a majority of patients. After 6 months of treatment, 15% of those treated with 600 mcg pasireotide and 26% of those treated with 900 mcg reached the primary end point. The effect was sustained, with 13% of the 600-mcg group and 25% of the 900-mcg group meeting the primary end point at 12 months.

"Notice how quickly the effect happens: Most of the decrease is seen within the first month of treatment," noted Dr. Colao. Similar trends were seen for serum and salivary cortisol as well as plasma adrenocorticotropic hormone.

Pasireotide treatment also appeared to normalize UFC levels in a subset of patients, especially those with low levels of elevated baseline UFC.

Because most patients responded quickly to treatment, lack of response within the first weeks of treatment can signal those who will be nonresponders. "Within 1-2 months, patients who will not have an adequate biochemical response can be identified with a high degree of accuracy. This might prove clinically useful," says Dr. Colao.

As UFC levels decreased, significant improvements in signs and symptoms of Cushing’s disease became apparent, including reductions in systolic and diastolic blood pressure, weight, and LDL cholesterol levels. Gains were also noted on a Cushing’s disease quality of life assessment, although Dr. Colao noted that interpretation of such findings was limited by lack of a placebo control group. Although Dr. Colao did not show the results of radiologic assessment of tumors, she said that an overall decrease in tumor size was seen after 12 months of pasireotide treatment.

Most adverse events were gastrointestinal in nature, including nausea (52%) and diarrhea (58%). "Adverse events were generally similar to those seen with other agents in this class of somatostatin analogues, with the exception of hyperglycemia," said Dr. Colao. She noted that 75% of patients treated with pasireotide had at least one hyperglycemic adverse event, which resolved by discontinuing the medication. Of 67 patients who were normoglycemic at baseline, 34% became diabetic during treatment, 43% became prediabetic, and 21% remained normal. Dr. Colao also noted that 8% of treated patients experienced hypocortisolism, a finding she felt would be expected with any effective treatment for Cushing’s disease.

Dr. Colao had nothing to disclose. The study was supported by Novartis Pharma AG.

Two posters at meeting shed light on pasireotide’s biochemical mechanisms of action. Dr. Rob van der Pas of Erasmus Medical Center in Rotterdam, the Netherlands, suggested that the reason the somatostatin analogue octreotide is not effective in Cushing’s disease is because it prefers the somatostatin receptor subtype 2 (sst2), whereas it is the somatostatin receptor 5 (sst5) that plays a key role in sst targeted therapy for Cushing’s disease (Endocr. Rev. 2011;32:P3-520). Dr. Robert R. Henry of the University of California, San Diego, found that the hyperglycemia associated with pasireotide is related to decreases in insulin secretion, with no change in insulin sensitivity, and this effect is most likely mediated by the sst5 receptor, which may also play an important role in glucose metabolism (Endocr. Rev. 2011;32:P3-274).

BOSTON – In the largest clinical trial ever conducted in Cushing’s disease, pasireotide, an investigational somatostatin analogue, was shown to result in a rapid and sustained reduction in urinary free cortisol in the majority of patients, and significantly improved signs and symptoms of the disease.

One troubling finding was that three-quarters of patients experienced at least one hyperglycemic episode, a side effect not found with other somatostatin analogues, according to Dr. Annamaria Colao, who presented the findings at the annual meeting of the Endocrine Society.

Pasireotide presents a new therapeutic possibility for Cushing’s disease, since there is no medical treatment currently approved for the condition, said Dr. Colao, professor of endocrinology and chief of the neuroendocrine unit at the University of Naples (Italy) "Federico II." In Cushing’s disease, a benign pituitary tumor stimulates the adrenal glands to synthesize excess cortisol, leading to weight gain, a moon-shaped face, severe fatigue and weakness, hypertension, and hyperglycemia. Pasireotide is also being studied in patients with carcinoid syndrome, acromegaly, and neuroendocrine tumors, and is not approved for use anywhere in the world.

In this double-blind, phase III study known as the PASPORT (Pasireotide Clinical Trial Portfolio) trial, 162 patients who had confirmed persistent, recurrent, or de novo Cushing’s disease and who were not considered to be surgical candidates were enrolled. Patients came from 18 countries and 62 clinical sites. Inclusion criteria included baseline mean urinary free cortisol (UFC) levels falling between 1.5 and 5 times the upper limit of normal (ULN, defined as 145 nmol/24 hours) and confirmation of pituitary adenoma. Any patient with poorly controlled diabetes was excluded from the trial.

Patients were randomized to receive either pasireotide 600 mcg (n = 82) or 900 mcg (n = 80) subcutaneously twice a day for 3 months. After 3 months, patients with UFC greater than twice the ULN or with UFC levels greater than baseline were unblinded, and the dose was increased by 300 mcg b.i.d. All others remained on the same dosage regimen until 6 months. Between 6 and 12 months, the trial was open label, with dose titration adjusted as needed. The primary end point was UFC levels below or at the ULN at 6 months without dose up-titration from the randomized dose.

Pooled results from both groups showed that within 2 months, there was a 48% mean reduction from baseline in UFC levels, and a drop in UFC levels was seen for a majority of patients. After 6 months of treatment, 15% of those treated with 600 mcg pasireotide and 26% of those treated with 900 mcg reached the primary end point. The effect was sustained, with 13% of the 600-mcg group and 25% of the 900-mcg group meeting the primary end point at 12 months.

"Notice how quickly the effect happens: Most of the decrease is seen within the first month of treatment," noted Dr. Colao. Similar trends were seen for serum and salivary cortisol as well as plasma adrenocorticotropic hormone.

Pasireotide treatment also appeared to normalize UFC levels in a subset of patients, especially those with low levels of elevated baseline UFC.

Because most patients responded quickly to treatment, lack of response within the first weeks of treatment can signal those who will be nonresponders. "Within 1-2 months, patients who will not have an adequate biochemical response can be identified with a high degree of accuracy. This might prove clinically useful," says Dr. Colao.

As UFC levels decreased, significant improvements in signs and symptoms of Cushing’s disease became apparent, including reductions in systolic and diastolic blood pressure, weight, and LDL cholesterol levels. Gains were also noted on a Cushing’s disease quality of life assessment, although Dr. Colao noted that interpretation of such findings was limited by lack of a placebo control group. Although Dr. Colao did not show the results of radiologic assessment of tumors, she said that an overall decrease in tumor size was seen after 12 months of pasireotide treatment.

Most adverse events were gastrointestinal in nature, including nausea (52%) and diarrhea (58%). "Adverse events were generally similar to those seen with other agents in this class of somatostatin analogues, with the exception of hyperglycemia," said Dr. Colao. She noted that 75% of patients treated with pasireotide had at least one hyperglycemic adverse event, which resolved by discontinuing the medication. Of 67 patients who were normoglycemic at baseline, 34% became diabetic during treatment, 43% became prediabetic, and 21% remained normal. Dr. Colao also noted that 8% of treated patients experienced hypocortisolism, a finding she felt would be expected with any effective treatment for Cushing’s disease.

Dr. Colao had nothing to disclose. The study was supported by Novartis Pharma AG.

Two posters at meeting shed light on pasireotide’s biochemical mechanisms of action. Dr. Rob van der Pas of Erasmus Medical Center in Rotterdam, the Netherlands, suggested that the reason the somatostatin analogue octreotide is not effective in Cushing’s disease is because it prefers the somatostatin receptor subtype 2 (sst2), whereas it is the somatostatin receptor 5 (sst5) that plays a key role in sst targeted therapy for Cushing’s disease (Endocr. Rev. 2011;32:P3-520). Dr. Robert R. Henry of the University of California, San Diego, found that the hyperglycemia associated with pasireotide is related to decreases in insulin secretion, with no change in insulin sensitivity, and this effect is most likely mediated by the sst5 receptor, which may also play an important role in glucose metabolism (Endocr. Rev. 2011;32:P3-274).