Cushing's Drug Benefits Some, but Has New Adverse Effects

Jenni Laidman

March 07, 2012

March 7, 2012 — Pasireotide normalized cortisol levels in 20% of patients with Cushing's disease who participated in a year-long phase 3 trial, according to a study published in the March 7 issue of the New England Journal of Medicine. However, the drug also led to hyperglycemia-related adverse events in almost three quarters of the participants.

Annamaria Colao, MD, PhD, associate professor of endocrinology and chief of the Neuroendocrine Unit at the Department of Molecular and Clinical Endocrinology and Oncology, "Federico II" University of Naples, Italy, and colleagues found that pasireotide, although unable to normalize urinary free cortisol in most participants, did lower cortisol levels by half in more than 50% of 162 participants.

Investigators in the double-blind trial randomly assigned 82 trial participants to receive 600 μg of subcutaneously delivered pasireotide twice daily, and 80 patients to receive 900 μg of the drug twice daily. In the lower-dose group, 12 participants (15%) met the trial's primary endpoint (free urinary cortisol levels at or below the upper limit of normal with no dose increase at month 6), and 21 (26%) of the higher-dosage group met the primary endpoint. In addition, nearly 60% of 103 patients for whom urinary free cortisol levels were available at baseline and at 6 months saw cortisol levels fall by half or more.

The mean percentage change in urinary free cortisol from baseline at 6 months in the lower-dose group was −27.5% (95% confidence interval [CI], −55.9% to 0.9%), and in the 900-μg group, it was −48.4% (95% CI, −56.6% to −40.2%). The mean change at 12 months was −41.3% (95% CI, −66.0% to −16.6%) in the low-dose group and −54.5% (95% CI, −65.2% to −43.7%) in the high-dose group.

The median percentage change from baseline at 6 months was −47.9% (95% CI, −74.1% to −40.7%) in the low-dose group, and −47.9− (95% CI, −66.9% to −35.5%) in the 900-μg group. The median percentage change at 12 months in the low-dose group was −67.6% (95% CI, −72.7% to −42.4%) and −62.4% (95% CI, −78.7% to −38.5%) in the high-dose group.

Treatment with pasireotide also led to mean improvements in systolic blood pressure, −6.1 mm Hg (95% CI, −9.8 to −2.4; P = .03); diastolic blood pressure, −3.7 mm Hg (95% CI, −6.2 to −1.2 mm Hg; P = .03); low-density lipoprotein cholesterol, −15 mg/dL (95% CI, −23 to −8 mg/dL; P < .001); weight, −6.7 kg (95% CI, −8.0 to −5.4 kg; P < .001); and health-related quality of life, improving scores by 11.1 points on a 100-point scale (95% CI, 6.8 - 15.5). Reviewers also found diminished facial rubor and supraclavicular and dorsal fat pads at 6 months.

At 12 months, there was a mean reduction of tumor volume among the 75 patients with measurable pituitary tumor at baseline. Among the lower-dose group, the average reduction was −9.1% (95% CI, −46.3% to 28.0%). In the 900-μg group, the mean reduction was −43.8% (95% CI, −68.4% to −19.2%).

Seventy-three percent of study participants had a hyperglycemia-related adverse event, leading to 6% of the patients leaving the study. Nearly half (74/162 participants; 46%) of the patients required a new glucose-lowering medication during the study. Among the 129 patients not receiving glucose-lowering medication at baseline, at least 1 medication was started in 53 patients (41%). At baseline, 55 patients (34%) had diabetes and 39 (24%) were prediabetic. At study end, 51 (48%) of the 107 patients who did not have diabetes at baseline had a glycated hemoglobin level of 6.5% or more. The International Diabetes Federation and the American College of Endocrinology recommends values below this level.

"This intervention has some promise," William F. Young Jr, MD, told Medscape Medical News. Dr. Young is a professor in the Department of Endocrinology at the Mayo Clinic, Rochester, Minnesota, and president of the Endocrine Society, and was not involved in the trial. "However, the results are not as effective as we had hoped. It's helpful, but it is not enough. What's unique about this agent is the frequency of hyperglycemia and diabetes." With regard to other adverse effects, he noted, pasireotide was similar to other somatostatin-receptor-binding drugs.

The treatment was most effective among those patients with lower cortisol levels at baseline, the authors note. In addition, if a patient was going to respond to treatment, he or she did so earlier, rather than later.

"The reduction in mean urinary free cortisol levels was rapid and sustained," the authors write. "Among the 72 patients with uncontrolled hypercortisolism at months 1 and 2, hypercortisolism remained uncontrolled in 66 patients (92%) at month 6 and in 64 patients (89%) at month 12."

The preferred intervention in Cushing's disease is surgical excision of the pituitary adenoma that causes Cushing's, Dr. Young said. Depending on the surgeon's skill and the location of the tumor, surgery can reverse Cushing's syndrome 80% of the time, he added. When surgery is not curative, a second surgery (a bilateral adrenalectomy) is often recommended, Dr. Young said.

There are a handful of adrenal enzyme inhibitors used on patients with severe Cushing's when surgery is delayed, Dr. Young noted, including aminoglutethimide and ketoconazole. "These drugs can be life saving in that setting for patients so ill from Cushing's syndrome they are not good surgical risks," he said. After treatment with such drugs, patients are often able to undergo surgery. Mifepristone (the abortifacient RU486), approved in February by the US Food and Drug Administration for use in Cushing's disease, works by blocking cortisol receptors, and is also used in this manner.

"I think pasireotide does join that group," Dr. Young said. "Although the study didn't look at this, it is very likely it could be synergistic with other drugs, so the drugs could be used at lower doses with fewer side effects."

The study was supported by Novartis Pharma AG, which provided research funding to institutions that employ study authors. Dr. Colao, receives board membership fees from Novartis unrelated to this study, as well as lecture fees unrelated to this study. Complete conflict-of-interest information for the other authors is available on the journal's Web site. Dr. Young has disclosed no relevant financial relationships.

N Engl J Med. 2012;366:914-924.