Long-Term Efficacy and Safety of Once-Monthly Pasireotide in Cushing's Disease

A Phase III Extension Study

Maria Fleseriu; Stephan Petersenn; Beverly M. K. Biller; Pinar Kadioglu; Christophe De Block; Guy T'Sjoen; Marie-Christine Vantyghem; Libuse Tauchmanova; Judi Wojna; Michael Roughton; André Lacroix; John Newell-Price


Clin Endocrinol. 2019;91(6):776-785. 

In This Article


In this large, prospective, extension study, patients were treated with long-acting pasireotide for a median of 2 years, allowing robust interpretation of its long-term efficacy and safety. Long-acting pasireotide provided sustained biochemical improvements and clinical benefit in a significant proportion of patients with CD and was generally well tolerated, with no new safety signals emerging over long-term treatment.

Achieving and maintaining normal cortisol levels is a key treatment goal for patients with CD in order to prevent or alleviate the clinical signs and complications of hypercortisolism and improve life expectancy.[8] Almost half (47%) of patients who entered this extension study had controlled mUFC after 2 years of long-acting pasireotide treatment; 25% (n = 38/150) of patients who were enrolled in the core study had controlled mUFC at month 24. Baseline characteristics for patients who entered this extension study were similar to those reported previously for all patients who participated in the initial core phase of the study (N = 150).[11] Patients could continue receiving pasireotide beyond month 24 until there was an option to enter a separate long-term study of pasireotide. Over two-thirds (72.2%; n = 13/18) of patients who were still participating in the extension at month 36 had controlled mUFC at this time point. Furthermore, over half (53%) of patients who entered the extension had a normal mUFC level at their last assessment, which was marginally higher than the proportion of responders at extension start. These results support the long-term efficacy of pasireotide and are consistent with findings from a Phase III study, in which 69% (n = 11/16) of ongoing patients had controlled mUFC after 5 years of twice-daily, subcutaneous pasireotide therapy.[14,15] Improvements in median mUFC, morning serum cortisol and LNSC levels were reported overall and for patients who received ≥2 or ≥3 years of treatment. Unlike mUFC and morning serum cortisol, median LNSC remained >ULN during the extension. Additional studies are needed to examine the effect of cortisol-lowering therapies on salivary cortisol and the role of LNSC in monitoring medical treatment response.

Cardiovascular disease is the leading cause of death in patients with CD.[16] Consequences of cortisol excess that can contribute to cardiovascular disease include hypertension, truncal obesity, impaired glucose tolerance, insulin resistance, dyslipidaemia and hypercoagulability.[17] In our study, improvements in blood pressure, BMI and waist circumference were maintained for up to 3 years of pasireotide treatment. Such improvements may confer a reduction in mortality risk, given that small reductions in blood pressure can significantly reduce the risk of cardiovascular events in patients with hypertension.[18] Contrary to previous reports, we did not observe any consistent changes in cholesterol or triglycerides during our study.[18,19]

It is important to note that concomitant medications were allowed during this study, which could have contributed to the observed changes in clinical signs over time. Persistent hypercortisolism is associated with progressive bone degradation resulting in increased fracture risk for patients with CD.[20] Encouragingly, BMD was stable throughout 36 months of pasireotide treatment, although additional studies are warranted to confirm the effects of pasireotide on the prevention/reversal of bone deterioration in patients with CD.

Hypercortisolism and its clinical effects detrimentally impact on QoL; the effects often persist after the resolution of hypercortisolism.[21] Patients who participated in the current extension had significantly impaired QoL (CushingQoL score, 41.7 points) prior to starting treatment with long-acting pasireotide. Importantly, CushingQoL score improved from baseline over 3 years of treatment, potentially reflecting the improvements in clinical signs of hypercortisolism during pasireotide treatment.

Pituitary tumour volume decreased or remained stable in most patients during long-term treatment with pasireotide, consistent with previous reports.[22–25] Given its tumour-shrinkage effects, it has been proposed that pasireotide may be particularly beneficial in patients with a clinically relevant tumour mass and/or tumour progression.[9,10,26] This assertion is supported by our findings that almost half (46%; n = 6/13) of patients with a macroadenoma before initiation of pasireotide treatment had a significant (≥20% change) decrease in tumour volume by month 24, with the remainder exhibiting stable tumour size.

The safety profile of long-acting pasireotide during this extension was similar to that during the core study, with no new safety signals emerging. AEs were generally mild/moderate and occurred less frequently in the extension than in the first 12 months of treatment. The lower rate of AEs in the extension phase than in the core study may be explained by the early onset and effective management of side effects during pasireotide treatment, while patients who tolerated pasireotide may have been more likely to continue into the extension phase. These findings are similar to those of a previous prospective study of subcutaneous twice-daily pasireotide, in which AEs related to hyperglycaemia, liver safety, the gallbladder and bradycardia tended to emerge during the first 6 months of treatment and did not usually worsen over 5 years' treatment.[14]

According to the American Diabetes Association and European Association for the Study of Diabetes, glycaemic targets should be individualized based on key patient characteristics. As such, while an HbA1c level of <7% represents a reasonable goal for many adults, less stringent targets (such as <8%) are appropriate in some patients, such as those with extensive comorbid conditions.[27,28] In our study, mean HbA1c and FPG levels were stable; mean HbA1c remained <7% over the course of the extension, and most (85%) patients had HbA1c < 8.0% at their last assessment.

Initiation and escalation of antidiabetic therapy was at the discretion of the investigator; 26% of patients who were not receiving antidiabetic therapy at extension baseline were receiving at least one agent at their last assessment, while 29% of patients who were already receiving 1–2 antidiabetic drugs were receiving at least one additional agent. Taken together, these findings demonstrate that if hyperglycaemia occurs, it tends to emerge soon after initiation of pasireotide and can be effectively managed in some patients with antidiabetic therapy.

Few studies have examined the efficacy and safety of long-term treatment with other medical therapies for CD. In a retrospective analysis of 51 patients who had received long-term (≥2 years) ketoconazole treatment, a normal mUFC level was seen in 65% of patients at their last available assessment, with clinical improvements seen in hypertension, diabetes and hypokalaemia.[29] One-fifth (20.5%) of patients discontinued treatment because of intolerance.[29] In a retrospective analysis of metyrapone treatment, 64% (n = 9/14) of patients who had an available mUFC assessment after ≥6 months of treatment had a normal mUFC level at their last available assessment, while there was a low incidence (11%; n = 4/38) of AEs in these patients.[30] In another retrospective study, 40% (n = 21/53) of patients receiving cabergoline therapy initially achieved normal UFC levels, with treatment escape seen in 39% (n = 7/18) of patients who remained on treatment for ≥12 months.[31] Published data on mifepristone and osilodrostat are limited to shorter durations of treatment.[32,33] The choice of medical treatment options should be tailored to the individual clinical situation, taking into consideration the patient, disease and tumour characteristics.[8]