by Megan Brooks
October 1, 2010 (Liege, Belgium) — In a phase 3 study of patients with Cushing's disease, the investigational somatostatin analogue SOM230 (pasireotide; Novartis) significantly reduced urinary free cortisol (UFC) levels in a majority of subjects and normalized UFC levels in about one fourth.
As mean UFC decreased, there was improvement in associated clinical signs and symptoms, including reductions in blood pressure, total cholesterol, and body weight, the investigators say.
The study results were presented here at the European Neuroendocrine Association 14th Congress by Beverly M. Biller, MD, an endocrinologist at Massachusetts General Hospital in Boston.
"Cushing's disease represents a high unmet medical need," Dr. Biller and colleagues write in a meeting abstract.
"A sizable number of patients with Cushing's disease are not adequately treated with surgery, and there is currently no effective medical treatment for Cushing's," William H. Ludlam, MD, PhD, who has been involved in studies of pasireotide, added in an interview with Medscape Medical News. Dr. Ludlam is director of the Seattle Pituitary Center at the Swedish Neuroscience Institute in Washington.
"While there are other somatostatin analogues available, they do not have as broad an effect as pasireotide," noted Dr. Ludlam. "There are 5 subtype receptors of somatostatin," he explained, "and most available drugs only target 1 subtype. Pasireotide targets 4 of them, and, importantly, it targets subtype 5, which is frequently expressed by the pituitary tumors common in Cushing's disease."
"Several studies on this drug have shown an effect in Cushing's, with approximately half of the patients having clinically relevant improvement," Dr. Ludlam said.
The PASPORT-CUSHINGS Study
PASPORT-CUSHINGS (Pasireotide Clinical Trial Portfolio–Cushing's Disease) is the largest randomized study to evaluate a medical therapy in patients with Cushing's disease. In the 12-month trial, 135 patients with moderate to severe persistent/recurrent Cushing's disease and 27 with de novo Cushing's disease who were not eligible for surgery were randomized in a double-blind fashion to receive either 600 or 900 μg subcutaneous injections of pasireotide. In the group as a whole, baseline UFC levels were higher in the 600- than in the 900-µg group (1156 vs 782 nmol/24 h). The primary end point was the proportion of patients who achieved normalization of UFC after 6 months without dose up-titration, relative to randomized dose.
At 6 months, 12 patients in the 600-µg group (14.6%; 95% confidence interval [CI], 7.0 - 22.3) and 21 in the 900-µg group (26.3%; 95% CI, 16.6 - 35.9) met the primary end point. After 12 months, the proportion of responders, regardless of dose up-titration, was 13.4% and 25.0%, respectively, for the 600 and 900-μg groups.
The median reduction in UFC at 6 months was 47.9% for both groups. At 12 months, median UFC was reduced by 67.6% in the 600-μg group and by 62.4% in the 900-μg group. Serum and salivary cortisol and plasma ACTH decreased with both doses, the study team notes.
They also report that patients who failed to achieve a reduction of 50% from baseline in UFC levels by month 2 were unlikely to show improvement at 6 or 12 months.
Adverse Effects Were Common But Mostly Mild
The most frequently reported adverse effects with pasireotide were diarrhea (58.0%), nausea (46.9%), hyperglycemia (38.9%), cholelithiasis (29.6%), abdominal pain (20.4%), diabetes mellitus (17.9%), fatigue (11.7%), and increased glycosylated hemoglobin (10.5%). Most adverse effects were grade 1 or 2.
"Most of the drugs used to treat Cushing's have significant side effects," Dr. Ludlam said. "Cholelithiasis is not ideal, but is not a life-threatening side effect, and hyperglycemia can easily be managed; besides, cortisol itself causes hyperglycemia. I have had a number of patients on the drug and have seen first hand that the drug is pretty well tolerated, and I have seen the benefits," Dr. Ludlam added.
Linda S. Werner, MD, a diabetes, metabolism, and endocrinology specialist with Endocrine Associates, of Bridgeport, Connecticut, who was not involved in the study, said: "If this new drug can normalize the free cortisol in one fourth and reduce the UFC in 48% [of patients], it should have a real role in treating Cushing's."
Dr. Werner made the point that "drugs are used to treat Cushing's when surgery is either not possible or doesn't fully work. Cushing's is so rare," she added, "that even tertiary care centers only have a handful of patients. I do have one patient, but he had successful surgery and so doesn't need anticortisol drugs."
According to a statement from Novartis, the data from this trial will form the basis for regulatory filing for pasireotide later this year. The drug currently has orphan drug status for Cushing's disease in the United States and Europe.
The study was funded by Novartis AG. Several of the investigators work for Novartis or have financial relationships with the company. Dr. Werner has disclosed no relevant financial relationships.
European Neuroendocrine Association (ENEA) 14th Congress: Abstract OC-1.7. Presented September 22, 2010.