After priority review and fast-track and orphan drug designations, the US Food and Drug Administration has approved pasireotide diaspartate injection for the treatment of patients with Cushing's disease for whom surgery has been unsuccessful or who are not surgical candidates.
Pasireotide, to be marketed under the name Signifor by Novartis Pharma Stein AG, is a somatostatin analogue that blocks the release of adrenocorticotrophin from somatostatin receptors in the pituitary.
"Although surgery tends to be first line therapy to treat Cushing's disease, Signifor is a new treatment option for patients when surgery hasn't worked or isn't an option," said Mary Parks, MD, director of the Division of Metabolism and Endocrinology Products in the FDA's Center for Drug Evaluation and Research, in an FDA statement.
Pasireotide is administered twice daily and will be dispensed with a medication guide for patients and caregivers explaining possible risks, including hyperglycemia.
Data for pasireotide came from a year-long double-blind phase 3 trial in which 162 patients were randomly assigned to receive either 600 or 900 μg subcutaneously delivered pasireotide twice daily.
Twelve (15%) participants in the lower-dose group and 21 (26%) of the higher-dosage group 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).
Although those success rates were relatively low, nearly 60% of 103 patients for whom urinary free cortisol levels were available at baseline and at 6 months had cortisol reductions of at least 50%.
The study also found that pasireotide was associated with improvements in systolic and diastolic blood pressure, low-density lipoprotein cholesterol, weight, and health-related quality of life.
However, nearly three quarters of the study participants experienced hyperglycemia-related adverse events, leading to 6% leaving the study and 46% requiring a new glucose-lowering medication. At study end, 48% of the 107 patients who did not have diabetes at baseline had reached a glycated hemoglobin level of 6.5% or more, which several expert groups consider diagnostic of diabetes.
Other common adverse events observed in the clinical trial included diarrhea, nausea, abdominal pain, and gallstones.
The FDA will require 3 postmarketing studies for pasireotide, including a clinical trial to assess hyperglycemia management, a long-term prospective observational cohort study (registry) of patients with Cushing's disease treated with the drug, and focused safety monitoring for reports of serious hyperglycemia, acute liver injury, and adrenal insufficiency.
In an interview with Medscape Medical News earlier this year, William F. Young Jr, MD, said that although pasireotide "has some promise," the study 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."
Dr. Young, professor in the Department of Endocrinology at the Mayo Clinic, Rochester, Minnesota, said that the preferred intervention in Cushing's disease is surgical excision of the pituitary adenoma that causes Cushing's. Depending on the surgeon's skill and the location of the tumor, surgery can reverse Cushing's syndrome 80% of the time.
However, he noted, pasireotide might be useful in conjunction with other available drugs for patients who are not good surgical candidates. "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."
Pasireotide is expected to be available in the United States by March 2013 and will be dispensed exclusively through a single specialty pharmacy, according to a Novartis statement.
The study was supported by Novartis Pharma AG, which provided research funding to institutions that employ the study authors. Dr. Young has disclosed no relevant financial relationships.
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Cite this: FDA Approves Pasireotide for Cushing's Disease - Medscape - Dec 17, 2012.
