Signifor with cabergoline may aid persistent Cushing’s disease

Combination could be used in event of poor response to standard treatment

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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Patients with persistent Cushing’s disease may benefit from combining Signifor (pasireotide) with cabergoline, according to the findings of a Phase 2 clinical trial.

The results suggest the combo therapy “could be an effective long-term strategy for enhancing the control of CD [Cushing’s disease]” in patients who fail to respond or respond poorly to standard treatment strategies, the researchers wrote in “Long-term efficacy and safety of subcutaneous pasireotide alone or in combination with cabergoline in Cushing’s disease,” which was published in Frontiers in Endocrinology.

Cushing’s disease is marked by hypercortisolism, or higher than normal levels of cortisol, due to benign tumors in the pituitary gland. These tumors lead to the excessive production and release of the adrenocorticotropic hormone (ACTH), which stimulates the adrenal glands atop the kidneys to produce cortisol.

Surgery to remove pituitary tumors is the first-line treatment for Cushing’s, but not all patients are eligible and the disease returns in about 50% of those who have surgery.

Pasireotide, sold as Signifor and Signifor LAR, is the only pituitary-targeted therapy approved for Cushing’s patients for whom surgery is ineffective or not an option. It reduces the secretion of ACTH to normalize cortisol levels and ease Cushing’s symptoms. Signifor, approved in 2012, is injected subcutaneously, or under the skin, twice daily. Signifor LAR, approved in 2018, is given once a month through intramuscular, or into-the-muscle, injections.

Cabergoline, sold under the brand name Dostinex, among others, mimics the action of dopamine, a major brain chemical messenger that in the pituitary gland suppresses ACTH production. It’s frequently used off-label for treating Cushing’s.

A 2010 pilot study involving 17 Cushing’s patients suggested that combining pasireotide and cabergoline may result in greater therapeutic efficacy.

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Testing combo therapy in Cushing’s disease

Novartis launched an international Phase 2 trial (NCT01915303) in 2014 to test if this was true in a larger patient population. The study investigated the short- and long-term safety and effectiveness of Signifor alone or with cabergoline in 68 adults with Cushing’s disease. Eligible patients could have had prior pituitary surgery or not, and had either never been treated with Signifor or had discontinued it for other than safety reasons.

The participants’ mean age was 41.4 and 88.2% women. More than three-quarters (79.4%) had been submitted to surgery to remove the pituitary tumor, most (97.1%) hadn’t received Signifor treatment, and 66.2% hadn’t been treated with cabergoline.

Cushing’s disease was defined by a mean urinary free cortisol (mUFC) above the upper limit of normal (ULN), defined as 137.95 nanomoles during a period of 24 hours (nmol/24h).

Participants were given 0.6 mg of Signifor twice daily for eight weeks. Those still showing a mUFC above ULN after treatment received 0.9 mg twice daily for another eight weeks.

If mUFC remained elevated, oral cabergoline (0.5 mg once daily) was added to the Signifor regimen for eight weeks. After that, the cabergoline dose could be increased to 1 mg once daily for the next eight weeks. This came to about 35 weeks, or about eight months, of treatment in the trial’s core phase.

Those completing the core phase could enter the extension phase, where all the participants continued their current treatment for up to about five years. During this period, cabergoline could be increased or the therapy could be added at the discretion of researchers.

During the core phase, 26 patients (38.2%) received Signifor alone and 42 (61.8%) received Signifor plus cabergoline. In the core phase, 16 patients discontinued treatment.

The trial’s main goal was the proportion of patients with a mUFC level not exceeding the ULN at week 35. It was achieved by 34 patients (50%), half of them on Signifor alone and half on the combo therapy.

Effect of treatment on hypercortisolism

Patients with mild hypercortisolism at the start of the study were more likely to respond to Signifor with and without cabergoline.

In the overall population, mUFC levels were rapidly reduced after four weeks of treatment and remained low up to week 35. For those who didn’t achieve mUFC normalization on Signifor alone, adding cabergoline resulted in a further reduction. Mean blood levels of cortisol and ACTH were also reduced at the end of the core phase relative to the start.

A total of 29 patients (42.6%) entered the extension. Ten (34.5%) received Signifor alone and 19 (65.5%) the combo therapy. More than half (58.6%) discontinued treatment before the study’s end, mostly due to side effects.

Available mUFC data from 25 patients in the extension showed that 12 (48%) achieved levels below the ULN by the study’s end. During this phase, mUFC levels fluctuated around the ULN limit, mean blood cortisol levels were kept below the limit, and ATCH levels remained above normal.

Overall, “[21] of 38 (55%) patients achieved control with combination therapy at some point during the core or extension study, of whom 13 (62%) experienced escape (at least one UFC >ULN after previous control),” the researchers wrote.

Treatment with Signifor resulted in reductions in the signs and symptoms of Cushing’s, including blood pressure, weight, waist circumference, and total cholesterol, that were sustained over time.

“Clinical improvements were also seen following the addition of cabergoline, particularly for hirsutism [excessive hair growth],” wrote the researchers, who noted quality of life improvements were seen for the whole patient population.

Nearly all the patients (97.1%) has treatment-related side effects, with the most common being high blood sugar and nausea (47.1% each), diarrhea (39.7%), and gallstones (32.4%). Fourteen patients (20.6%) had at least one side effect that led to the treatment being discontinued. Three (4.4%) patients died during the study, two during the core phase and one during the extension. All the deaths were considered unrelated to the medications.

The findings suggest the combo therapy is “an effective and well-tolerated long-term strategy for enhancing control of hypercortisolism in some CD patients,” the researchers said.