Effective Long-Term Treatment for Cushing’s Disease—Pasireotide

Finally, a long-lasting, monthly injection of pasireotide promotes normalized urinary free cortisol levels and a shrinking or arresting of tumor growth in patients with Cushing’s disease.

With Maria Fleseriu, MD, FACE, and Vivien Bonert, MD

Cushing's syndrome is constellation of endocrine disorders marked by the overproduction of cortisol, secondary to an adrenocorticotropic hormone-secreting pituitary adenoma (corticotropinoma) that is linked with significant morbidity, impaired quality of life, and increased mortality when not adequately treated.

While surgery is the preferred first-line treatment to normalize hormone levels,1 many patients with pituitary tumors require chronic pharmacotherapy to control hypercortisolism, such that having a comprehensive understanding of the long-term efficacy and safety of cortisol drug therapy is crucial.

New drug offers long-term efficacy in treating Cushing's disease.Besides serum cortisol, patients with Cushing's disease should be checked for heart disease and diabetes. Photo: 123rf

Long-Term Pharmacotherapy Efficacious for Cushing’s Disease

The findings of an extension study of long-term data on the effects of pasireotide (Signifor)—a synthetic long-acting cyclic peptide that has a broad affinity to bind with somatostatin-receptor subtype 5—for persistent or recurring Cushing's disease, delivered favorable results.

The reported outcomes demonstrated sustained biochemical improvements and clinical benefits in a significant percent of patients who chose to continue in the extension study,2 according to the authors of the Pasireotide G2304 Study Group.

"What we knew before this extension study was that the drug worked in approximately half of the patients with mild Cushing's,"3 says lead author Maria Fleseriu, MD, FACE, professor of neurological surgery and medicine, division of endocrinology, diabetes and clinical nutrition at the Oregon Health and Science University (OHSU) School of Medicine. She is also director of OHSU's Northwest Pituitary Center and president of The Pituitary Society.

"It also offered clinical benefits, improvement in blood pressure, signs and symptoms and quality of life," said Dr. Fleseriu. She acknowledged the inherent bias in an extension study: "Typically, patients who agree to continue are good responders. However, "long term, for the patients who respond to pasireotide initially, this is a drug that can be continued with no new safety signals."

Examining Durability of Drug to Manage Cushing’s Disease 

The extension study ''was important because we didn't have any long-term data for this once-a-month medication for Cushing's," Dr. Fleseriu told EndocrineWeb. "If the response at the initiation of drug therapy is good, very few patients will lose control of their urinary-free cortisol over time.''

Among patients with large tumors, ''almost half had a significant decline and all the others had a stable tumor size,"2 she added.

While the selective surgical resection of a corticotropinoma is the first choice in treating Cushing’s disease, the success rates have varied with elevated cortisol persisting in up to 35% of patients after surgery. Also, recurrence rates have been reported as ranging from 15 to 66% after a variable duration of remission.1

As such, medical therapy may play a valuable role not only for persistent and recurrent Cushing's symptoms as well as in patients who are not candidates for surgery.1,2 The long-acting intramuscular formulation of pasireotide was approved based on data from a 12-month phase 3 study.3

Patient Participation in Drug Treatment Extension Trials 

In the original study,3 participants had a confirmed pituitary source of Cushing's disease. Given the robustness of the results, the researchers invited participants to remain in the trial for an optional 12-month open-label extension study from which they could enter a separate long-term safety study, allowing them to continue on pasireotide.

To be eligible for the 12-month extension, patients had to have mean urinary-free cortisol level not exceeding the upper limit of normal (166.5 nmol/24 hour) and/or be considered by the investigator to be getting significant clinical benefit from long-action pasireotide, and demonstrate tolerability of the drug.3

Of the 150 patients with Cushing’s disease in the initial phase 3 trial, 81 individuals or 54% of the cohort entered the extension.1 Of those, 39 completed it and consented to continue in another long-term safety study (the results of which are under preparation for publication).

During the initial trial, participants were randomly assigned to receive 10 mg or 30 mg of the drug every 28 days, with dose titration based on effectiveness and tolerability. Upon entering the extension arm, patients were given the same dose as they were taking at month 12.2

Of the patients who continued to be followed for 36 months of treatment, 72.2% (n=13 of 18) had controlled urinary-free cortisol levels to the endpoint, and their tumors shrank or did not grow, Dr.  Fleseriu said.

Of those (n=35) with a measurable adenoma at initial baseline and at the two-year point, 86% were deemed to have a reduction of 20% or more in tumor size, or less than a 20% change in tumor volume.2 No patients with a macroadenoma at baseline had a 20% or more increase in tumor size by months 24 or 36.  

The patients in the extension trial were also monitored for improvements in usual symptoms including systolic blood pressure, diastolic blood pressure, body mass index, and waist circumference—all endpoints were beneficially attaiined during the extension.Favorable outcomes of these factors was considered critical since they represented an increased risk of cardiovascular disease in these patients, the leading cause of death in patients witb Cushing's disease.4

As for adverse events, most patients (91.4%, n=74) reported at least one side effect during the extension study—the most common problem cited was hyperglycemia-related, which occurred in 39.5% of cases.2,5

Clinical Management of Cushing’s Disease—Consider Diabetes

Another important point of interest 81.5% of patients (n=66) had diabetes, were taking antidiabetic medication, or indicated a history of diabetes at the start of the extension arm, and at the final assessment, the number increased to 71 patients, or 88.9% of the cohort, indicating a need for diabetes management in addition to treatment for Cushing’s disease,1 said Dr. Fleseriu.

Additional take-home messages for physicians are:

  • Once the drug is working, ''it is important to follow patients for the long-term and to address their diabetes," Dr. Fleseriu said, "monitoring is particularly crucial. We used to think that just urinary cortisol was sufficient but in this study, we also looked at serum and salivary levels of cortisol."
  •  "The drug works on the tumor level," Dr. Fleseriu said, “so if the patient has a macroadenoma, pasireotide would be the preferred drug." Even so, this pharmacotherapy should be prescribed with caution in those with diabetes.

The researchers concluded that "the long-term safety profile of pasireotide was favorable and consistent with that reported during the first 12 months of treatment and the data support the use of long-acting pasireotide as an effective long-term treatment option for some patients with Cushing's disease."2

In supporting the findings, physicians will want to draw attention to—47% of patients had controlled mean urinary-free cortisol after 24 months with a once monthly injection of pasireotide, with 72% of the small subset of patients maintained their cortisol levels who treated for 36 months," said Vivien Bonert, MD, an endocrinologist at Cedars-Sinai Medical Center, Los Angeles who reviewed the findings for EndocrineWeb.

Furthermore, Dr. Bonert said: "The proportion of patents with controlled or partially controlled urinary-free cortisol levels was stable from baseline to month 24. And, the researchers provided  confirmation that no tumor grew larger."

As such, the drug should be considered in those with large tumor masses and with progressive tumor growth, she added. Yet, overall patient care must address that 40% of patients having hyperglycemia-related adverse events, and about 80% of those taking pasireotide were diagnosed as having prediabetes or diabetes.

''It is a long-term therapy in which patients will need to stay on this [drug] for far longer than 24-46 months but the data may not be able to be extrapolated," said Dr. Bonert.

Dr. Fleseriu reports research support paid to Oregon Health & Science University from Novartis and other companies and consultancy fees from Novartis and Strongbridge Biopharma. Dr. Bonert has no relevant disclosures. The study was sponsored by Novartis Pharma AG which manufactures Signifor.

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