Signifor Reduces Urinary Cortisol Levels, Enables Cushing’s Disease Control Over 12 Months, Small Study Reports

Treatment with Signifor (pasireotide) over 12 months reduced urinary cortisol levels and enabled full disease control in a subset of 14 patients with Cushing’s disease who were monitored at an Italian center and taking part in a Phase 3 trial, a study has found.

The study, “The treatment with pasireotide in Cushing’s disease: effect of long-term treatment on clinical picture and metabolic profile and management of adverse events in the experience of a single center,” appeared in the Journal of Endocrinological Investigation.

Cushing’s disease is caused by the excessive production of the adrenocorticotrophic hormone (ACTH) by the pituitary tumor, leading to a chronic increase in cortisol production by the adrenal glands — a condition called hypercortisolism.

Signifor, marketed by Novartis, is the first medicine approved for adults with Cushing’s disease who are not eligible for surgery or have experienced relapses after surgery. The therapy is an analogue of the hormone somatostatin and works by activating its receptors in the pituitary tumor and reducing the production of ACTH and cortisol.

A Phase 3 trial (CSOM230B2305) tested two Signifor doses (600 μg and 900 μg), both given under the skin and twice daily, in 162 patients.

Results showed that after 12 months of treatment, 29% of patients taking the lower dose achieved full or partial response, an outcome achieved by 28% of patients in the higher dose.

Of note, full disease control means that urinary free cortisol (UFC) levels were within normal range, while partial control occurs when levels are still high but have decreased by at least 50% from their initial levels.

Other benefits included reduced tumor size, including tumor disappearance in patients with de novo or persistent Cushing’s disease, lessened visceral obesity and hypertension, and normalized lipid (fat) levels.

As for safety, the findings revealed increased frequency and degree of high blood glucose levels, compared with first-generation somatostatin analogues.

The team at Università degli Studi di Napoli Federico II, in Italy, described the experience with Signifor at their center, which was one of the trial sites. Fourteen patients (12 women, mean age of 39.1 years) were treated, 12 of whom had a microadenoma (a tumor smaller than 10 mm in diameter). Efficacy was assessed in eight patients, as six dropped out before the six-month follow-up due to lack of efficacy or consent.

Six of the eight patients in the efficacy analysis received the 900 μg dose, while two received the lower (600 μg) dose. According to their UFC levels, five patients had moderate, two severe, and one very severe hypercortisolism at the study’s start.

After six months, UFC levels had dropped by 65% from baseline levels. Six patients achieved full or partial disease control at six months, which corresponded to 75% if considering the eight patients in the efficacy analysis or 42.8% if taking all 14 participants into account.

At 12 months, UFC levels had decreased by 70.5% from baseline. Six of the seven patients (85.7%) — one had discontinued after the six-month evaluation — achieved full or partial disease control. This corresponded to 42.9% if considering all 14 participants.

As for specific symptoms, Signifor led to reductions in excessive body hair in six women, with one showing significant worsening. A minority of patients also showed worsened fat deposition above the collarbone (one patient) and in the dorsal area (two), bruising (one), stretch marks (two), and reduced muscle strength (one).

At baseline, three patients were overweight, and two were obese. Treatment with Signifor lowered body weight, body mass index, and waist circumference at 12 months. No significant differences were seen in the prevalence of visceral obesity, high cholesterol, high levels of triglycerides, total, LDL, and HDL cholesterol, and blood pressure levels.

Based on fasting plasma glucose levels, four patients were diagnosed with metabolic syndrome at baseline, three at six months, and four at 12 months.

The most common adverse event was impaired glucose metabolism, in 71.4% of the patients, including a diagnosis of prediabetes in three patients and of diabetes in two cases. Two patients with prediabetes and the three with diabetes experienced a deterioration of their glucose metabolism during treatment. No patient discontinued treatment for high blood sugar.

A Mediterranean diet was commonly suggested as a first-line treatment, with metformin and/or long-acting insulin as second steps, and short-acting insulin as a third strategy. Other adverse events included fatigue, nausea, and vomiting, all spontaneously resolved within two months except in one patient unsuccessfully treated with metoclopramide and ondansetron.

One patient with millimetric gallstones (up to 4 mm) and biliary sludge received ursodeoxycholic acid, inducing formation of tone-like deposits and biliary sludge resolution. Another patient experienced moderate hypocortisolism, which was resolved with a dose reduction of Signifor.

“The current study, although conducted in a limited series of patients, confirmed that pasireotide [Signifor] treatment is able to induce full or partial hormone control in a majority of CD [Cushing’s disease] patients treated for 6–12 months, associated with a beneficial effect on clinical picture and main comorbidities,” the scientists wrote.

Also, the findings “confirmed that pasireotide [Signifor] may be considered a valid and safe option for CD patients either de novo for pituitary surgery or experiencing a failure of pituitary surgery.”