Review 445
Author
S. L. Samson
Affiliation
Medical Director, The Pituitary Center, Baylor St. Luke’s Medical Center, Division of Endocrinology, Department of Medicine, Baylor College of Medicine, Houston
Key words
Abstract
▶ cushing ● ▶ cushing’s syndrome ● ▶ somatostatin analog ● ▶ corticotroph adenoma ●
received 31.12.2013 first decision 28.04.2014 accepted 12.05.2014 Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1376988 Published online: July 8, 2014 Exp Clin Endocrinol Diabetes 2014; 122: 445–450 © J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York ISSN 0947-7349 Correspondence S. L. Samson, MD, PhD, FRCPC, FACE Medical Director The Pituitary Center Baylor St. Luke’s Medical Center Division of Endocrinology Department of Medicine Baylor College of Medicine One Baylor Plaza ABBR R615 Houston TX 77030 Tel.: + 1/713/798 3076 Fax: + 1/713/798 8764 [email protected]
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Cushing’s disease is a rare condition of chronic hypercortisolism caused by an adrenocorticotropic hormone-secreting pituitary adenoma and associated with debilitating complications and excess mortality. Transsphenoidal adenomectomy is generally first-line treatment but is contraindicated in some patients and associated with significant post-surgical recurrence. While there are few data to support long-term use of most pharmacologic treatments, pasireotide (a multireceptor-targeted somatostatin analog) recently demonstrated sustained benefit in a 12-month, multicenter, Phase III trial and in 2 long-term extension studies. The Phase III trial (N = 162) demonstrated reductions in urinary free cortisol in most patients, with durable treatment effect over 12 months. Biochemical improvement was generally paralleled by reductions in Cushing’s-related signs and symptoms and enhanced health-related quality of
Introduction
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Cushing’s disease (CD) is a condition of chronic hypercortisolism caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma. While CD is rare (estimated at approximately 6.9 new cases/million people/year in the US [1]), it is associated with significant morbidity and mortality. Patients with CD face potentially debilitating conditions secondary to chronic hypercortisolism including cardiovascular disease, type 2 diabetes mellitus, osteoporosis, depression, and anxiety. Additionally, untreated CD confers a 1.8- to 4.8-fold increase in risk of mortality compared with the general population [2]. These sequelae represent a significant burden to individual patients, their families, and to healthcare systems worldwide.
life. Long-term treatment was evaluated in 58 patients who entered a planned 12-month extension phase. Reductions in urinary free cortisol remained stable throughout the extension, with further improvements noted in clinical signs and symptoms. Similar results were reported in the smaller Phase II extension (N = 18; median treatment duration, 9.7 months; range, 2 months–4.8 years). Case reports have recently emerged demonstrating sustained disease control for upto 7 years in some patients. Safety considerations for long-term medical treatment with pasireotide are generally similar to those for other somatostatin analogs, except for the incidence and severity of hyperglycemia. Most patients experience new or worsening hyperglycemia with pasireotide treatment. Expert recommendations for treatment of pasireotide-associated hyperglycemia have recently been published and new studies are planned to elucidate the optimal treatment approach for pasireotide-associated hyperglycemia.
Transsphenoidal surgery (TSS) is generally the first-line treatment of choice but is not always curative and is contraindicated in some patients. Furthermore, post-surgical recurrence is a significant concern, possibly affecting up to 35 % [3] and 69 % [4] of patients within 5 and 10 years after surgery, respectively. As a result, patients frequently require additional, secondary treatment options. Radiotherapy, a second-line approach, is also associated with significant rates of persistence/ recurrence and often requires several months or years to achieve a beneficial effect. It is also accompanied by a substantial risk of hypopituitarism. Bilateral adrenalectomy is an option for patients with particularly severe, intractable symptoms, or in whom the underlying corticotropinoma is undetectable or surgery is contrain-
Samson SL. Long-term Pasireotide Treatment in CD … Exp Clin Endocrinol Diabetes 2014; 122: 445–450
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Long-term Medical Treatment of Cushing’s Disease with Pasireotide: A Review of Current Evidence and Clinical Experience
dicated. While this treatment offers a definitive resolution for endogenous hypercortisolism, it requires life-long glucocorticoid and mineralocorticoid replacement and may lead to the development of Nelson’s syndrome, a condition of aggressive pituitary tumor growth that may be life-threatening if not controlled. Pharmacologic treatments have historically been regarded as adjunctive therapies; however, such medications may be the only available (or most attractive) treatment options for certain patients. Unfortunately, because pituitary surgery remains the established, first-line treatment for CD, clinical trials that explore the long-term efficacy and safety of many of these compounds are lacking. Moreover, many of the current CD medications do not directly treat the underlying cause of hypercortisolism and/or are accompanied by debilitating adverse effects. Adrenocortical steroidogenesis inhibitors (e. g., ketoconazole, metyrapone) block the synthesis of cortisol but do not affect the underlying adenoma. The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) [5, 6] have limited use of oral ketoconazole to a specific subset of fungal infections due to concerns of potentially fatal liver injury, risk of drug interactions, and adrenal dysfunction. The glucocorticoid receptor antagonist mifepristone has been shown to control Cushing’s-related hyperglycemia but, like adrenal-targeted agents, it does not treat the underlying tumor. It also increases circulating cortisol levels, potentially resulting in adverse events related to binding of aldosterone receptors (e. g., hypokalemia), or progesterone receptors (e. g., vaginal bleeding, endometrial thickening with cystic changes) [7, 8]. The dopamine receptor agonist cabergoline has been shown to inhibit ACTH secretion and decrease tumor size. These data, however, are derived only from case reports [9], retrospective analysis [10], and a small singlecenter trial [11], and suggest that the compound is effective for only a small proportion of patients, generally at high doses associated with increased risk of valvular heart disease when employed in the treatment of Parkinson’s disease. Pasireotide, a multireceptor-targeted somatostatin analog (SSA), was recently approved by the US FDA and the EMA for the treatment of patients with CD. As a pituitary-targeted therapy, pasireotide addresses the underlying etiology of hypercortisolism in CD. Results from a 12-month, multicenter, Phase III trial and 2 long-term extension studies demonstrate promise for pasireotide as an option for extended treatment in patients for whom other options are unavailable or unsuccessful. This review summarizes the current body of clinical data for patients with CD treated with pasireotide.
Efficacy
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SSAs have long been used for the treatment of patients with acromegaly; however, as a result of differing somatostatin receptor (SSTR) subtype expression profiles between somatotroph and corticotroph tumors, the previously developed SSAs (octreotide and lanreotide) are not effective for treating CD. Pasireotide binds with high affinity to SSTR subtype 5 (SSTR5), the predominant subtype expressed in corticotroph adenomas. Importantly, the terminal elimination half-life of short-acting pasireotide is approximately 23 h – more than 10-fold greater than octreotide.
The efficacy of pasireotide in treating patients with CD was first demonstrated in an open-label, single-arm, multicenter Phase II trial, where 29 patients were treated with 600 μg bid of pasireotide for 15 days. Overall, 22/29 patients (76 %) experienced a reduction in mean urinary free cortisol (UFC) by day 15 and 5/29 (17 %) achieved UFC normalization [12]. Similar results were observed in the extension phase of the trial (median duration of 9.7 months, range of 2 months–4.8 years) where, after 6 months of treatment, 56 % of the 18 patients had lower UFC than at core baseline and 22 % achieved biochemical control [13]. Results from this Phase II study provided preliminary support of pasireotide’s efficacy in treating CD; however, the sample size was not large enough to test statistical significance. To address this concern and to further explore the efficacy of pasireotide, a Phase III, trial with randomization to either 600 or 900 μg bid was performed (N = 162). Dose was increased by 300 μg bid after 3 months in patients whose UFC levels remained higher than twice the upper limit of normal (ULN). Overall, 128/162 participants (79 %) had previous pituitary surgery, 78 (48 %) had received previous medical treatment for CD, and 7 (4 %) had prior pituitary irradiation. Those who had received radiotherapy within the past 10 years were excluded and washout periods for CD-related pharmacotherapies were mandatory. While patients were randomized in a double-blind fashion to one of 2 active dose groups, the absence of a placebo control arm is a noteworthy trial design limitation. However, since the study population included only patients with active CD who were not surgical candidates or who had postsurgical persistent/recurrent disease, inactive treatment was not an ethically practicable option. Results from this study, which represents the largest trial to date in patients with CD, further supported the efficacy of pasireotide. At Month 6, 91 of the 103 patients with evaluable data had ▶ Fig. 1). A posidecreased UFC levels compared with baseline (● tive response to pasireotide was noted within 3 months after treatment initiation: the proportions of patients with normalized UFC levels were 16 % and 28 % at Month 3, 16 % and 29 % at Month 6, and 13 % and 25 % at Month 12 in the 600- and 900-μg groups, respectively. Reductions in UFC levels were paralleled by mean overall improvements in quality of life scores, systolic and diastolic blood pressure, low-density-lipoprotein cholesterol and triglycerides, and body weight. After 12 months of treatment, patients with a measureable pituitary tumor on MRI (n = 75) demonstrated decreases in tumor volume compared with baseline (9.1 % and 43.8 % for the 600- and 900-μg groups, respectively). These data provide strong support for the efficacy of pasireotide during a 12-month treatment period [14]. To study long-term treatment, 58 patients who achieved UFC normalization or significant clinical benefit with pasireotide in the 12-month core study described above entered a planned, 12-month, open-label extension. Patients received pasireotide at the same dose that they received at the end of the core study (300–1 200 μg bid), but dose modifications (± 300 μg bid) were permitted according to observed efficacy or drug-related adverse events (mean daily doses have not yet been published). Many of these patients achieved biochemical control (UFC ≤ ULN) or partial biochemical control (UFC > ULN, but ≥ 50 % decrease from core baseline), sustained mean reductions in serum cortisol and plasma ACTH levels, and experienced clinically significant overall improvements in the clinical signs and symptoms of CD. Normal UFC at Months 12, 18, and 24 was achieved by 38.5 %, 46.2 %,
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446 Review
Review 447
4 000 2 000
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500 0
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Patients 600 g, twice daily
900 g, twice daily
6-Mo urinary free cortisol
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Baseline urinary free cortisol
6-Mo urinary free cortisol ≤ ULN
b
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8
Mean HbA1c (%)
∆ Mean UFC (%)
–10 –20 –30 –40 –50 –60
7 6 5
–70 Baseline
Month 12
Core study
Month 18 Extension phase
Month 24
Fig. 1 Absolute change in UFC in per-protocol B2305 trial participants from baseline to Month 6. Urinary free cortisol (UFC) data were available at baseline and at Month 6 in 103/162 patients. 91/103 (88 %) of patients experienced a reduction in UFC and 50/103 had a reduction of ≥ 50 %. The black dashed line represents the upper limit of the normal range (ULN; 145 nmol/24 h [52.5 μg/24 h]).[14] From N Engl J Med, Colao A, Petersenn S, Newell-Price J, et al., A 12-Month Phase 3 study of pasireotide in Cushing’s disease, 366: p.918. Copyright © 2012 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. (Color figure available online only).
Baseline
Month 12
Core study
and 30.8 % in the 600-μg group (n = 26) and by 59.4, 40.6, and 37.5 % in the 900-μg group (n = 32). In addition, the mean percentage decrease in UFC level (54.7 %) observed at Month 12 of the ▶ Fig. 2a). core study remained stable throughout the extension (● Further improvements in the clinical signs and symptoms of CD were also observed in the extension phase. After 24 months of treatment, mean reductions from baseline were observed in systolic blood pressure (− 11.3 mm Hg; − 8.2 % change), diastolic blood pressure (− 7.2 mm Hg; − 7.6 % change), and and weight (− 8.7 kg; − 9.6 % change) [15]. Beyond 24 months of treatment, published data are currently limited to case reports. MacKenzie Feder et al. [16] recently described the experience of 2 patients who completed 5.5 and 4.25 years of treatment with disease control. The first patient was a woman who presented with Cushingoid appearance and elevated UFC levels. MRI revealed a 3 mm pituitary lesion and inferior petrosal sinus sampling demonstrated a positive central-to-peripheral ACTH gradient, confirming a pituitary source. As a result of persistent disease following TSS, she enrolled in the Phase III trial of pasireotide and was randomized to 900 μg bid. Her UFC rapidly normalized from approximately 7-fold ULN and, except for a transient increase after 6 months of treatment, normal UFC has been maintained for > 5 years with correspondingly normal salivary cortisol levels. She is free of Cushingoid features and, notably, her pasireotide dose has been successfully reduced to 150 μg bid. Oral antidiabetics were initiated after a transient increase in fasting blood glucose (91.8 to 118.8 mg/dL); however, glycemic normalization, possibly as a result of the lowered pasireotide dose and/or controlled cortisol levels, allowed for the cessation of antidiabetic treatment.
Month 18 Extension phase
Month 24
Fig. 2 Change in a mean urinary free cortisol and b HbA1c from baseline to Month 24 among the 58 patients who entered the B2305 trial extension. Mean urinary free cortisol was markedly reduced ( − 54.7 %) from baseline to the end of the core trial (Month 12), and these initial reductions were sustained through the extension phase (Month 24) (ITT analysis; last observation carried forward) [15]. Mean HbA1c increased from 5.8 % at baseline to 7.2 %, 6.9 %, and 6.8 % at Months 12, 18, and 24, respectively [22].
The second patient, a woman with CD and a 4-mm pituitary lesion, underwent unsuccessful TSS and failed subsequent combined medical therapy with ketoconazole and cabergoline. After receiving pasireotide 900 μg bid in the Phase III trial, her mean UFC decreased from 777 to 416 nmol/D after 3 months of treatment. Pasireotide was increased to 1 200 μg bid at Month 4 and, by Month 6, her mean UFC was within normal range 55–330 nmol/D). Salivary cortisol levels were also reduced, and she demonstrated clinical improvements. After 45 months of treatment, pasireotide was reduced to 900 μg bid. Salivary cortisol levels were similarly reduced and she improved clinically. After initiating pasireotide, she developed glucose intolerance with postprandial hyperglycemia. After 6 months of treatment, her HbA1c level was 6.5 %. She was treated with metformin from Month 17 until Month 42 when glucose normalized; fasting glucose at Month 48 was 68.4 mg/dL and HbA1c was 5.8 % [16]. Libé et al. [17] reported long-term results of pasireotide therapy in a woman who began treatment in the Phase II study. This patient had pre-treatment UFC > 9 X ULN that normalized within 15 days of first dose and remained controlled at most monthly evaluations during a 7-year period. She also experienced clinical improvements including weight loss, reduced hirsutism, and regular menses. Her HbA1c increased from 5.7 % to 7.7 % but she experienced no serious adverse events [17]. Overall, these data demonstrate the efficacy of pasireotide for the treatment of some patients with CD. Long-term studies suggest that pasireotide can control hypercortisolism for at least 2 years in certain patients, highlighting the possibility of utilizing this compound as an enduring medical treatment strategy for patients not desiring surgery, or in whom surgery is contraindicated or has failed.
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Urinary Free Cortisol (nmol/24 h)
7 000
Combination Therapy
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Combination therapy may be useful in patients with highly refractory CD and/or acute complications of hypercortisolism, although further study is required to establish efficacy and safety. 2 small studies suggest increased pasireotide efficacy when combined with cabergoline and ketoconazole. Stepwise addition of cabergoline and/or ketoconazole to pasireotide over 80 days was found to normalize UFC in 10/12 patients who were unresponsive to pasireotide (100 μg TID) alone [18]. 6 patients participated in an extension phase of this study and experienced sustained biochemical remission for upto one year with no observed escape [19]. However, caution is warranted with pasireotide and ketoconazole coadministration, as both compounds may prolong QT interval [20, 21]. Ketoconazole (a p-glycoprotein inhibitor) may also potentially increase plasma concentration of pasireotide (likely a p-glycoprotein substrate). Combination therapy of pasireotide with octreotide could also have potential for the treatment of patients with CD. Octreotide predominantly binds SSTR2, whereas pasireotide binds SSTR5 with a high affinity. The expression of SSTR2 may be enhanced once cortisol levels are controlled by pasireotide, which could theoretically induce a tumor response to octreotide. However, further study is required to establish which combinations of agents can be safely administered with pasireotide over extended time periods in patients with CD.
Pasireotide-associated Hyperglycemia
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The most common adverse events associated with pasireotide – including gastrointestinal disorders, cholelithiasis, and hyperglycemia – are similar to those observed with other SSAs. Most adverse events reported in the 12-month Phase III core trial were grade 1 or 2 (mild or moderate), according to Common Terminology Criteria for Adverse Events (CTCAE), and did not require discontinuation or dose adjustment. Rare but significant AEs include prolonged QTcF (> 480 ms) in 2 % of patients and clinical symptoms consistent with adrenal insufficiency in 8 % of patients [14, 20]. Of particular concern are hyperglycemia-related adverse events, which occurred in 73 % of patients in the Phase III trial and prompted pasireotide discontinuation in 6 %. 41 % of patients not on an antidiabetic agent at baseline required new medication, and 64 % of those already on antidiabetic therapy required additional medication [14]. Mean HbA1c increased from 5.8 % at core baseline to 7.2 % and 6.8 % following 12 and 24 months of treat▶ Fig. 2b) and 11.7 % and 8.6 % of patients ment respectively (● experienced CTCAE Grade 3 (fasting plasma glucose (FPG) > 250– 500 mg/dL) or 4 (FPG > 500 mg/dL) hyperglycemia and diabetes mellitus, respectively. Overall, mean FPG level increased from 97.8 mg/dL to 117.7 mg/dL at Month 12, but remained stable between Months 12 and 24. Data are limited, however, on the specific types and relative efficacy of antidiabetic interventions prescribed and their efficacy [22]. These clinical trial results suggest that hyperglycemia occurs significantly more frequently with pasireotide than with other SSAs. Studies in healthy volunteers suggest that pasireotide reduces insulin secretion and incretin hormone responses but does not alter insulin sensitivity or glucose disposal [23, 24]. In one recent study, short-acting pasireotide was administered at usual treatment doses (600 or 900 μg subcutaneously bid) to
healthy, normal-weight male volunteers for 7 days [24]. Hyperglycemic clamps confirmed lowered insulin and C-peptide levels in the presence of high glucose administered intravenously. Oral glucose tolerance testing revealed a slower time to peak glucose (120 vs. 30 min), possibly as a result of delayed gastric emptying, and there was a markedly blunted insulin secretory response even at the time of the delayed glucose peak. Glucagon levels were mildly suppressed with pasireotide treatment, suggesting that hyperglucagonemia does not contribute significantly to hyperglycemia. Importantly, the incretin response was abrogated. In pasireotide-treated subjects, neither glucagon-like peptide 1 (GLP-1) nor glucose-dependent insulinotropic polypeptide levels increased after oral glucose administration, the classic stimulus for their secretion suggestive of pasireotideinduced inhibition of incretin secretion [Henry 2011]. Dipeptidyl peptidase 4 (DPP-4) inhibitors and GLP-1 agonists were more effective than either metformin or nateglinide at reducing hyperglycemia in healthy male volunteers. These results are consistent with previously published data suggesting that somatostatin could dampen GLP1 secretion, most likely mediated through SSTR5 [25, 26]. Schmid and Brueggen [27] recently published findings describing the effects of pasireotide on blood glucose, insulin, and glucagon levels in Lewis rats. Interestingly, continuous infusion of short-acting pasireotide or injection of long-acting pasireotide resulted only in small, transient elevations in plasma glucose. Glucose elevation with short-acting pasireotide was also transient, with tachyphylaxis after repeated or continuous administration. While no tachyphylaxis with respect to hyperglycemia (or escape from cortisol-lowering response) has been described in human trials, the observed glycemic improvements after long-term pasireotide treatment in 2 individuals recently reported by MacKenzie Feder et al. [16] could represent a parallel to these observations. One strategy that has been proposed to combat pasireotideassociated hyperglycemia is coadministration with an antidiabetic agent. While no studies have been completed to determine optimal treatment for pasireotide-associated hyperglycemia in patients with CD, the finding of blunted insulin and incretin secretion helps to guide current proposals for hyperglycemia management with pasireotide. In February 2012, an advisory board of 10 European experts in pituitary disorders and diabetes mellitus convened to obtain recommendations for monitoring and treatment of hyperglycemia in pasireotide-treated patients with CD. The board recommended that pasireotide-associated hyperglycemia be managed by initiation of medical therapy with metformin to decrease hepatic glucose output along with staged treatment intensification with a DPP-4 inhibitor, with a switch to a GLP-1 receptor agonist and initiation of insulin, as required, to achieve and maintain glycemic control [28]. Although combination therapies of metformin with sulfonylureas and/or pioglitazone may also be possible theoretically, these are not recommended as sulfonylureas stimulate insulin secretion in a glucose-independent manner and are therefore associated with risk of hypoglycemia and weight gain. Furthermore, treatment failure as a result of a decline of pancreatic beta-cell function may occur more rapidly with sulfonylurea therapy. Pioglitazone primarily targets insulin resistance and therefore does not represent a pathophysiologically oriented treatment option for pasireotide-associated hyperglycemia. Pioglitazone has also been associated with increases in body
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448 Review
Review 449
Conclusions and Future Directions
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Management of patients with refractory CD represents an unremitting challenge. While surgery remains the primary treatment of choice, many individuals will likely rely on life-long pharmacotherapy to control cortisol levels and CD-related symptoms. It is therefore essential to understand the long-term implications, benefits, and risks associated with available medical treatment options for CD. Because no head-to-head trials have been performed, it has not been possible to generate an evidence-based algorithm to guide the medical treatment of CD. Historically, clinicians have often used adrenal steroidogenesis inhibitors, adrenolytics, and dopamine agonists to treat CD; however, none of these drugs have obtained regulatory approval for this indication. This has severely limited the broad, prolonged use of these compounds, particularly in the US. Pasireotide is currently the only medical treatment option for patients with CD that has demonstrated sustained, long-term control of hypercortisolism and improvement in several associated clinical laboratory parameters in a prospective, multicenter clinical trial. Study results demonstrated that pasireotide reduced UFC in most patients, normalized UFC in approximately 20 % of patients after 6 months of treatment, and that pasireotide provides clinical benefit for many patients with CD. For some patients, long-term treatment with pasireotide has resulted in sustained improvements in mean UFC, serum cortisol, plasma ACTH, blood pressure, cholesterol, and body weight. In most regards, safety considerations for long-term medical treatment with pasireotide are similar to those for other SSAs. However, hyperglycemia and incident type 2 diabetes remain significant concerns and further research is needed to determine the most efficacious way treat elevated blood glucose levels. At this juncture, experts recommend metformin treatment with the addition of incretin-based therapy, as appropriate. With an estimated annual cost of approximately $175,000 [30], long-term treatment with pasireotide may seem a costly proposition. However, untreated or undertreated CD often engenders many debilitating sequelae associated with substantial healthcare cost. While it is also costly (roughly equivalent to 3–5 months of pasireotide treatment) [30], repeat TSS is potentially curative; but surgical outcomes are highly dependent upon surgical expertise [3]. As they are both less costly than pasireotide and have demonstrated efficacy for some patients, it is reasonable to consider initial treatment with cabergoline or ketoconazole in patients who have failed surgery or who are not surgical candidates. However, sustained response with cabergoline is only achieved in a small subset of patients (often transiently) [10, 11], and ketoconazole is associated with potential hepatotoxicity [5, 6]. Weighed against the cost of inadequately managed CD complications, long-term pasireotide therapy might be an economically reasonable treatment for selected patients. Moreover, patients unlikely to respond to pasireotide can be identified within the first few months of treatment [14]. More long-term studies to evaluate this topic will be needed. Since completion of the Phase III trial extension, many patients have continued pasireotide treatment through an expanded access, compassionate-use protocol. Additional future trials of
pasireotide include Phase III evaluation of a long-acting formulation administered monthly [31], and a study aiming to elucidate the effect of antidiabetic medications on pasireotide-associated hyperglycemia in patients with CD. New data from these and other studies will further our understanding of the benefits and risks of long-term pasireotide treatment. This ongoing research may provide treatment guidelines for health care professionals and new therapeutic options for patients, thereby mitigating the deleterious effects of prolonged chronic hypercortisolism.
Acknowledgement
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Financial support for editorial and administrative support was provided by Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. The author thanks David Wolff (Mudskipper, Inc.) for providing medical editorial and administrative support on this manuscript.
Author conflict of interest disclosure statement: SLS is a site principal investigator and receives research funds from Novartis Pharmaceuticals Corporation for clinical trials of pasireotide for patients with Cushing’s disease and acromegaly. Conflict of interest: I am the site PI for multicenter clinical trials on the use of pasireotide for acromegaly and Cushing’s disease. References 1 Broder M, Neary M, Chang E et al. Incidence of Cushing’s Disease in the United States. Endocr Rev 2013;34:MON-91. Presented at ENDO 95th Annual Meeting, June 17, 2013, in San Francisco, CA, USA 2 Feelders RA, Pulgar SJ, Kempel A et al. The burden of Cushing’s disease: clinical and health-related quality of life aspects. Eur J Endocrinol 2012; 167: 311–326 3 Biller BM, Grossman AB, Stewart PM et al. Treatment of adrenocorticotropin-dependent Cushing’s syndrome: a consensus statement. J Clin Endocrinol Metab 2008; 93: 2454–2462 4 Kim JH, Shin CS, Paek SH et al. Recurrence of Cushing’s disease after primary transsphenoidal surgery in a university hospital in Korea. Endocr J 2012; 59: 881–888 5 European Medicines Authority. European Medicines Agency recommends suspension of marketing authorisations for oral ketoconazole. 2013; Available at http://www.ema.europa.eu/docs/en_GB/document_ library/Press_release/2013/07/WC500146613.pdf Accessed December 18, 2013 6 FDA Drug Safety Communications. FDA limits usage of Nizoral (ketoconazole) oral tablets due to potentially fatal liver injury and risk of drug interactions and adrenal gland problems. 2013; Available at: http://www.fda.gov/downloads/Drugs/DrugSafety/UCM362444.pdf Accessed December 18, 2013 7 Korlym™ (mifepristone) full prescribing information. Corcept Therapeutics. Menlo Park, CA. Available at http://www.korlym.com/docs/ KorlymPrescribingInformation.pdf Accessed December 18, 2013 8 Fleseriu M, Biller BM, Findling JW et al. SEISMIC Study Investigators. Mifepristone, a glucocorticoid receptor antagonist, produces clinical and metabolic benefits in patients with Cushing’s syndrome. J Clin Endocrinol Metab 2009; 97: 2039–2049 9 Illouz F, Dubois-Ginouves S, Laboureau S et al. Use of cabergoline in persisting Cushing’s disease. Annales d’Endocrinologie 2006; 67: 353–356 10 Godbout A, Manavela M, Danilowicz K et al. Cabergoline monotherapy in the long-term treatment of Cushing’s disease. Eur J Endocrinol 2010; 163: 709–716 11 Pivonello R, De Martino MC, Cappabianca P et al. Lamberts SW, Colao A. The medical treatment of Cushing’s disease: effectiveness of chronic treatment with the dopamine agonist cabergoline in patients unsuccessfully treated by surgery. J Clin Endocrinol Metab 2009; 94: 223–230 12 Boscaro M, Ludlam WH, Atkinson B et al. Treatment of pituitarydependent Cushing’s disease with the multireceptor ligand somatostatin analog pasireotide (SOM230): a multicenter, phase II trial. J Clin Endocrinol Metab 2009; 94: 115–122
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weight, fluid retention, and bone fractures – all adverse events that are most unwanted in patients with CD [28, 29].
13 Boscaro M, Bertherat J, Findling J et al. Extended treatment of Cushing’s disease with pasireotide: results from a 2-year, Phase II study. Pituitary 2013, Aug 14. [Epub ahead of print] doi:10.1007/s11102013-0503-3 14 Colao A, Petersenn S, Newell-Price J et al.Pasireotide B2305 Study Group. A 12-Month Phase 3 study of pasireotide in Cushing’s disease. N Engl J Med 2012; 366: 914–924 15 Schopohl J, Bertherat J, Ludlam WH et al. on behalf of the Pasireotide B2305 Study Group. Long-term pasireotide use leads to improvements in the biochemical parameters of Cushing’s disease: 24-month results from a randomized Phase III study. Abs P1410. Presented at the joint 15th International Congress of Endocrinology and the 14th European Congress of Endocrinology (ICE/ECE), Florence, Italy, 5–9 May 2012 16 MacKenzie Feder J, Bourdeau I, Vallette S et al. Pasireotide monotherapy in Cushing’s disease: a single-centre experience with 5-year extension of Phase III trial. Pituitary 2013, Nov 28. [Epub ahead of print] doi:10.1007/s11102-013-0539-4 17 Libé R, Groussin L, Bertherat J. Pasireotide in Cushing’s Disease. N Engl J Med 2012; 366: 2134–2135 18 Feelders RA, de Bruin C, Pereira AM et al. Pasireotide alone or with cabergoline and ketoconazole in Cushing’s disease. N Engl J Med 2010; 362: 1846–1848 19 van der Pas R, de Bruin C, Pereira AM et al. Cortisol diurnal rhythm and quality of life after successful medical treatment of Cushing’s disease. Pituitary 2013; 16: 536–544 20 Signifor® (pasireotide) full prescribing information. Novartis Pharmaceuticals Corporation. Basel, Switzerland: Available at http://www. pharma.us.novartis.com/product/pi/pdf/signifor.pdf Accessed December 18, 2013 21 Paserchia LA, Hewett J, Woosley RL. Effects of ketoconazole on QTc [abstr]. Clin Pharmacol Ther 1994; 55: 146 22 Bertherat J, Ludlam WH, Pivonello R et al.on behalf of the Pasireotide B2305 Study Group. Long-Term Use of Pasireotide in Cushing’s Disease: 24-Month Safety Results from a Randomized Phase III Study. Abs P1405. Presented at the joint 15th International Congress of Endocrinology and the 14th European Congress of Endocrinology (ICE/ ECE), Florence, Italy, 5–9 May 2012
23 Shenouda M, Maldonado M, Wang Y et al. An open-label dose-escalation study of once-daily and twice-daily pasireotide in healthy volunteers: Safety, tolerability, and effects on glucose, insulin, and glucagon levels. Am J Ther 2012, Jun 16. [Epub ahead of print] doi:10.1097/ MJT.0b013e31824c3eb4 24 Henry RR, Mudaliar S, Hermosillo Reséndiz K et al. Mechanism and Management of Hyperglycemia Associated with Pasireotide: Results from Studies in Healthy Volunteers. Abs. P260. Presented at the 13th European Congress of Endocrinology (ECE), Rotterdam, The Netherlands, 30 April – 4 May 2011 25 Chisholm C, Greenberg GR. Somatostatin-28 regulates GLP-1 secretion via somatostatin receptor subtype 5 in rat intestinal cultures. Am J Physiol Endocrinol Metab 2002; 283: E311–E317 26 Hansen L, Hartmann B, Bisgaard T et al. Somatostatin restrains the secretion of glucagon-like peptide-1 and -2 from isolated perfused porcine ileum. Am J Physiol Endocrinol Metab 2000; 278: E1010– E1018 27 Schmid HA, Brueggen J. Effects of somatostatin analogs on glucose homeostasis in rats. Journal of Endocrinology 2012; 212: 49–60 28 Colao A, De Block C, Gaztambide MS et al. Managing hyperglycemia in patients with Cushing’s disease treated with pasieotide: medical expert recommendations. Pituitary 2013, 7. Apr 7 [Epub ahead of print] doi:10.1007/s11102-013-0483-3 29 Shah P, Mudaliar S.. Pioglitazone: side effect and safety profile. Expert Opin Drug Saf 2010; 9: 347–354 30 Truong HL, Nellesen D, Ludlam WH et al. Budget impact of pasireotide for the treatment of Cushing’s disease, a rare endocrine disorder associated with considerable comorbidities. J Med Econ 2014; 17: 288–295 31 ClinicalTrials.gov. Efficacy and Safety of Pasireotide Administered Monthly in Patients With Cushing’s Disease. NCT01374906. Available at http://www.clinicaltrials.gov/ct2/show/NCT01374906 Accessed December 18, 2013
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Author
S. L. Samson
Affiliation
Medical Director, The Pituitary Center, Baylor St. Luke’s Medical Center, Division of Endocrinology, Department of Medicine, Baylor College of Medicine, Houston
Key words
Abstract
▶ cushing ● ▶ cushing’s syndrome ● ▶ somatostatin analog ● ▶ corticotroph adenoma ●
received 31.12.2013 first decision 28.04.2014 accepted 12.05.2014 Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1376988 Published online: July 8, 2014 Exp Clin Endocrinol Diabetes 2014; 122: 445–450 © J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York ISSN 0947-7349 Correspondence S. L. Samson, MD, PhD, FRCPC, FACE Medical Director The Pituitary Center Baylor St. Luke’s Medical Center Division of Endocrinology Department of Medicine Baylor College of Medicine One Baylor Plaza ABBR R615 Houston TX 77030 Tel.: + 1/713/798 3076 Fax: + 1/713/798 8764 [email protected]
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Cushing’s disease is a rare condition of chronic hypercortisolism caused by an adrenocorticotropic hormone-secreting pituitary adenoma and associated with debilitating complications and excess mortality. Transsphenoidal adenomectomy is generally first-line treatment but is contraindicated in some patients and associated with significant post-surgical recurrence. While there are few data to support long-term use of most pharmacologic treatments, pasireotide (a multireceptor-targeted somatostatin analog) recently demonstrated sustained benefit in a 12-month, multicenter, Phase III trial and in 2 long-term extension studies. The Phase III trial (N = 162) demonstrated reductions in urinary free cortisol in most patients, with durable treatment effect over 12 months. Biochemical improvement was generally paralleled by reductions in Cushing’s-related signs and symptoms and enhanced health-related quality of
Introduction
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Cushing’s disease (CD) is a condition of chronic hypercortisolism caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma. While CD is rare (estimated at approximately 6.9 new cases/million people/year in the US [1]), it is associated with significant morbidity and mortality. Patients with CD face potentially debilitating conditions secondary to chronic hypercortisolism including cardiovascular disease, type 2 diabetes mellitus, osteoporosis, depression, and anxiety. Additionally, untreated CD confers a 1.8- to 4.8-fold increase in risk of mortality compared with the general population [2]. These sequelae represent a significant burden to individual patients, their families, and to healthcare systems worldwide.
life. Long-term treatment was evaluated in 58 patients who entered a planned 12-month extension phase. Reductions in urinary free cortisol remained stable throughout the extension, with further improvements noted in clinical signs and symptoms. Similar results were reported in the smaller Phase II extension (N = 18; median treatment duration, 9.7 months; range, 2 months–4.8 years). Case reports have recently emerged demonstrating sustained disease control for upto 7 years in some patients. Safety considerations for long-term medical treatment with pasireotide are generally similar to those for other somatostatin analogs, except for the incidence and severity of hyperglycemia. Most patients experience new or worsening hyperglycemia with pasireotide treatment. Expert recommendations for treatment of pasireotide-associated hyperglycemia have recently been published and new studies are planned to elucidate the optimal treatment approach for pasireotide-associated hyperglycemia.
Transsphenoidal surgery (TSS) is generally the first-line treatment of choice but is not always curative and is contraindicated in some patients. Furthermore, post-surgical recurrence is a significant concern, possibly affecting up to 35 % [3] and 69 % [4] of patients within 5 and 10 years after surgery, respectively. As a result, patients frequently require additional, secondary treatment options. Radiotherapy, a second-line approach, is also associated with significant rates of persistence/ recurrence and often requires several months or years to achieve a beneficial effect. It is also accompanied by a substantial risk of hypopituitarism. Bilateral adrenalectomy is an option for patients with particularly severe, intractable symptoms, or in whom the underlying corticotropinoma is undetectable or surgery is contrain-
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Long-term Medical Treatment of Cushing’s Disease with Pasireotide: A Review of Current Evidence and Clinical Experience
dicated. While this treatment offers a definitive resolution for endogenous hypercortisolism, it requires life-long glucocorticoid and mineralocorticoid replacement and may lead to the development of Nelson’s syndrome, a condition of aggressive pituitary tumor growth that may be life-threatening if not controlled. Pharmacologic treatments have historically been regarded as adjunctive therapies; however, such medications may be the only available (or most attractive) treatment options for certain patients. Unfortunately, because pituitary surgery remains the established, first-line treatment for CD, clinical trials that explore the long-term efficacy and safety of many of these compounds are lacking. Moreover, many of the current CD medications do not directly treat the underlying cause of hypercortisolism and/or are accompanied by debilitating adverse effects. Adrenocortical steroidogenesis inhibitors (e. g., ketoconazole, metyrapone) block the synthesis of cortisol but do not affect the underlying adenoma. The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) [5, 6] have limited use of oral ketoconazole to a specific subset of fungal infections due to concerns of potentially fatal liver injury, risk of drug interactions, and adrenal dysfunction. The glucocorticoid receptor antagonist mifepristone has been shown to control Cushing’s-related hyperglycemia but, like adrenal-targeted agents, it does not treat the underlying tumor. It also increases circulating cortisol levels, potentially resulting in adverse events related to binding of aldosterone receptors (e. g., hypokalemia), or progesterone receptors (e. g., vaginal bleeding, endometrial thickening with cystic changes) [7, 8]. The dopamine receptor agonist cabergoline has been shown to inhibit ACTH secretion and decrease tumor size. These data, however, are derived only from case reports [9], retrospective analysis [10], and a small singlecenter trial [11], and suggest that the compound is effective for only a small proportion of patients, generally at high doses associated with increased risk of valvular heart disease when employed in the treatment of Parkinson’s disease. Pasireotide, a multireceptor-targeted somatostatin analog (SSA), was recently approved by the US FDA and the EMA for the treatment of patients with CD. As a pituitary-targeted therapy, pasireotide addresses the underlying etiology of hypercortisolism in CD. Results from a 12-month, multicenter, Phase III trial and 2 long-term extension studies demonstrate promise for pasireotide as an option for extended treatment in patients for whom other options are unavailable or unsuccessful. This review summarizes the current body of clinical data for patients with CD treated with pasireotide.
Efficacy
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SSAs have long been used for the treatment of patients with acromegaly; however, as a result of differing somatostatin receptor (SSTR) subtype expression profiles between somatotroph and corticotroph tumors, the previously developed SSAs (octreotide and lanreotide) are not effective for treating CD. Pasireotide binds with high affinity to SSTR subtype 5 (SSTR5), the predominant subtype expressed in corticotroph adenomas. Importantly, the terminal elimination half-life of short-acting pasireotide is approximately 23 h – more than 10-fold greater than octreotide.
The efficacy of pasireotide in treating patients with CD was first demonstrated in an open-label, single-arm, multicenter Phase II trial, where 29 patients were treated with 600 μg bid of pasireotide for 15 days. Overall, 22/29 patients (76 %) experienced a reduction in mean urinary free cortisol (UFC) by day 15 and 5/29 (17 %) achieved UFC normalization [12]. Similar results were observed in the extension phase of the trial (median duration of 9.7 months, range of 2 months–4.8 years) where, after 6 months of treatment, 56 % of the 18 patients had lower UFC than at core baseline and 22 % achieved biochemical control [13]. Results from this Phase II study provided preliminary support of pasireotide’s efficacy in treating CD; however, the sample size was not large enough to test statistical significance. To address this concern and to further explore the efficacy of pasireotide, a Phase III, trial with randomization to either 600 or 900 μg bid was performed (N = 162). Dose was increased by 300 μg bid after 3 months in patients whose UFC levels remained higher than twice the upper limit of normal (ULN). Overall, 128/162 participants (79 %) had previous pituitary surgery, 78 (48 %) had received previous medical treatment for CD, and 7 (4 %) had prior pituitary irradiation. Those who had received radiotherapy within the past 10 years were excluded and washout periods for CD-related pharmacotherapies were mandatory. While patients were randomized in a double-blind fashion to one of 2 active dose groups, the absence of a placebo control arm is a noteworthy trial design limitation. However, since the study population included only patients with active CD who were not surgical candidates or who had postsurgical persistent/recurrent disease, inactive treatment was not an ethically practicable option. Results from this study, which represents the largest trial to date in patients with CD, further supported the efficacy of pasireotide. At Month 6, 91 of the 103 patients with evaluable data had ▶ Fig. 1). A posidecreased UFC levels compared with baseline (● tive response to pasireotide was noted within 3 months after treatment initiation: the proportions of patients with normalized UFC levels were 16 % and 28 % at Month 3, 16 % and 29 % at Month 6, and 13 % and 25 % at Month 12 in the 600- and 900-μg groups, respectively. Reductions in UFC levels were paralleled by mean overall improvements in quality of life scores, systolic and diastolic blood pressure, low-density-lipoprotein cholesterol and triglycerides, and body weight. After 12 months of treatment, patients with a measureable pituitary tumor on MRI (n = 75) demonstrated decreases in tumor volume compared with baseline (9.1 % and 43.8 % for the 600- and 900-μg groups, respectively). These data provide strong support for the efficacy of pasireotide during a 12-month treatment period [14]. To study long-term treatment, 58 patients who achieved UFC normalization or significant clinical benefit with pasireotide in the 12-month core study described above entered a planned, 12-month, open-label extension. Patients received pasireotide at the same dose that they received at the end of the core study (300–1 200 μg bid), but dose modifications (± 300 μg bid) were permitted according to observed efficacy or drug-related adverse events (mean daily doses have not yet been published). Many of these patients achieved biochemical control (UFC ≤ ULN) or partial biochemical control (UFC > ULN, but ≥ 50 % decrease from core baseline), sustained mean reductions in serum cortisol and plasma ACTH levels, and experienced clinically significant overall improvements in the clinical signs and symptoms of CD. Normal UFC at Months 12, 18, and 24 was achieved by 38.5 %, 46.2 %,
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4 000 2 000
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500 0
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Patients 600 g, twice daily
900 g, twice daily
6-Mo urinary free cortisol
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Baseline urinary free cortisol
6-Mo urinary free cortisol ≤ ULN
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Mean HbA1c (%)
∆ Mean UFC (%)
–10 –20 –30 –40 –50 –60
7 6 5
–70 Baseline
Month 12
Core study
Month 18 Extension phase
Month 24
Fig. 1 Absolute change in UFC in per-protocol B2305 trial participants from baseline to Month 6. Urinary free cortisol (UFC) data were available at baseline and at Month 6 in 103/162 patients. 91/103 (88 %) of patients experienced a reduction in UFC and 50/103 had a reduction of ≥ 50 %. The black dashed line represents the upper limit of the normal range (ULN; 145 nmol/24 h [52.5 μg/24 h]).[14] From N Engl J Med, Colao A, Petersenn S, Newell-Price J, et al., A 12-Month Phase 3 study of pasireotide in Cushing’s disease, 366: p.918. Copyright © 2012 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. (Color figure available online only).
Baseline
Month 12
Core study
and 30.8 % in the 600-μg group (n = 26) and by 59.4, 40.6, and 37.5 % in the 900-μg group (n = 32). In addition, the mean percentage decrease in UFC level (54.7 %) observed at Month 12 of the ▶ Fig. 2a). core study remained stable throughout the extension (● Further improvements in the clinical signs and symptoms of CD were also observed in the extension phase. After 24 months of treatment, mean reductions from baseline were observed in systolic blood pressure (− 11.3 mm Hg; − 8.2 % change), diastolic blood pressure (− 7.2 mm Hg; − 7.6 % change), and and weight (− 8.7 kg; − 9.6 % change) [15]. Beyond 24 months of treatment, published data are currently limited to case reports. MacKenzie Feder et al. [16] recently described the experience of 2 patients who completed 5.5 and 4.25 years of treatment with disease control. The first patient was a woman who presented with Cushingoid appearance and elevated UFC levels. MRI revealed a 3 mm pituitary lesion and inferior petrosal sinus sampling demonstrated a positive central-to-peripheral ACTH gradient, confirming a pituitary source. As a result of persistent disease following TSS, she enrolled in the Phase III trial of pasireotide and was randomized to 900 μg bid. Her UFC rapidly normalized from approximately 7-fold ULN and, except for a transient increase after 6 months of treatment, normal UFC has been maintained for > 5 years with correspondingly normal salivary cortisol levels. She is free of Cushingoid features and, notably, her pasireotide dose has been successfully reduced to 150 μg bid. Oral antidiabetics were initiated after a transient increase in fasting blood glucose (91.8 to 118.8 mg/dL); however, glycemic normalization, possibly as a result of the lowered pasireotide dose and/or controlled cortisol levels, allowed for the cessation of antidiabetic treatment.
Month 18 Extension phase
Month 24
Fig. 2 Change in a mean urinary free cortisol and b HbA1c from baseline to Month 24 among the 58 patients who entered the B2305 trial extension. Mean urinary free cortisol was markedly reduced ( − 54.7 %) from baseline to the end of the core trial (Month 12), and these initial reductions were sustained through the extension phase (Month 24) (ITT analysis; last observation carried forward) [15]. Mean HbA1c increased from 5.8 % at baseline to 7.2 %, 6.9 %, and 6.8 % at Months 12, 18, and 24, respectively [22].
The second patient, a woman with CD and a 4-mm pituitary lesion, underwent unsuccessful TSS and failed subsequent combined medical therapy with ketoconazole and cabergoline. After receiving pasireotide 900 μg bid in the Phase III trial, her mean UFC decreased from 777 to 416 nmol/D after 3 months of treatment. Pasireotide was increased to 1 200 μg bid at Month 4 and, by Month 6, her mean UFC was within normal range 55–330 nmol/D). Salivary cortisol levels were also reduced, and she demonstrated clinical improvements. After 45 months of treatment, pasireotide was reduced to 900 μg bid. Salivary cortisol levels were similarly reduced and she improved clinically. After initiating pasireotide, she developed glucose intolerance with postprandial hyperglycemia. After 6 months of treatment, her HbA1c level was 6.5 %. She was treated with metformin from Month 17 until Month 42 when glucose normalized; fasting glucose at Month 48 was 68.4 mg/dL and HbA1c was 5.8 % [16]. Libé et al. [17] reported long-term results of pasireotide therapy in a woman who began treatment in the Phase II study. This patient had pre-treatment UFC > 9 X ULN that normalized within 15 days of first dose and remained controlled at most monthly evaluations during a 7-year period. She also experienced clinical improvements including weight loss, reduced hirsutism, and regular menses. Her HbA1c increased from 5.7 % to 7.7 % but she experienced no serious adverse events [17]. Overall, these data demonstrate the efficacy of pasireotide for the treatment of some patients with CD. Long-term studies suggest that pasireotide can control hypercortisolism for at least 2 years in certain patients, highlighting the possibility of utilizing this compound as an enduring medical treatment strategy for patients not desiring surgery, or in whom surgery is contraindicated or has failed.
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Urinary Free Cortisol (nmol/24 h)
7 000
Combination Therapy
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Combination therapy may be useful in patients with highly refractory CD and/or acute complications of hypercortisolism, although further study is required to establish efficacy and safety. 2 small studies suggest increased pasireotide efficacy when combined with cabergoline and ketoconazole. Stepwise addition of cabergoline and/or ketoconazole to pasireotide over 80 days was found to normalize UFC in 10/12 patients who were unresponsive to pasireotide (100 μg TID) alone [18]. 6 patients participated in an extension phase of this study and experienced sustained biochemical remission for upto one year with no observed escape [19]. However, caution is warranted with pasireotide and ketoconazole coadministration, as both compounds may prolong QT interval [20, 21]. Ketoconazole (a p-glycoprotein inhibitor) may also potentially increase plasma concentration of pasireotide (likely a p-glycoprotein substrate). Combination therapy of pasireotide with octreotide could also have potential for the treatment of patients with CD. Octreotide predominantly binds SSTR2, whereas pasireotide binds SSTR5 with a high affinity. The expression of SSTR2 may be enhanced once cortisol levels are controlled by pasireotide, which could theoretically induce a tumor response to octreotide. However, further study is required to establish which combinations of agents can be safely administered with pasireotide over extended time periods in patients with CD.
Pasireotide-associated Hyperglycemia
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The most common adverse events associated with pasireotide – including gastrointestinal disorders, cholelithiasis, and hyperglycemia – are similar to those observed with other SSAs. Most adverse events reported in the 12-month Phase III core trial were grade 1 or 2 (mild or moderate), according to Common Terminology Criteria for Adverse Events (CTCAE), and did not require discontinuation or dose adjustment. Rare but significant AEs include prolonged QTcF (> 480 ms) in 2 % of patients and clinical symptoms consistent with adrenal insufficiency in 8 % of patients [14, 20]. Of particular concern are hyperglycemia-related adverse events, which occurred in 73 % of patients in the Phase III trial and prompted pasireotide discontinuation in 6 %. 41 % of patients not on an antidiabetic agent at baseline required new medication, and 64 % of those already on antidiabetic therapy required additional medication [14]. Mean HbA1c increased from 5.8 % at core baseline to 7.2 % and 6.8 % following 12 and 24 months of treat▶ Fig. 2b) and 11.7 % and 8.6 % of patients ment respectively (● experienced CTCAE Grade 3 (fasting plasma glucose (FPG) > 250– 500 mg/dL) or 4 (FPG > 500 mg/dL) hyperglycemia and diabetes mellitus, respectively. Overall, mean FPG level increased from 97.8 mg/dL to 117.7 mg/dL at Month 12, but remained stable between Months 12 and 24. Data are limited, however, on the specific types and relative efficacy of antidiabetic interventions prescribed and their efficacy [22]. These clinical trial results suggest that hyperglycemia occurs significantly more frequently with pasireotide than with other SSAs. Studies in healthy volunteers suggest that pasireotide reduces insulin secretion and incretin hormone responses but does not alter insulin sensitivity or glucose disposal [23, 24]. In one recent study, short-acting pasireotide was administered at usual treatment doses (600 or 900 μg subcutaneously bid) to
healthy, normal-weight male volunteers for 7 days [24]. Hyperglycemic clamps confirmed lowered insulin and C-peptide levels in the presence of high glucose administered intravenously. Oral glucose tolerance testing revealed a slower time to peak glucose (120 vs. 30 min), possibly as a result of delayed gastric emptying, and there was a markedly blunted insulin secretory response even at the time of the delayed glucose peak. Glucagon levels were mildly suppressed with pasireotide treatment, suggesting that hyperglucagonemia does not contribute significantly to hyperglycemia. Importantly, the incretin response was abrogated. In pasireotide-treated subjects, neither glucagon-like peptide 1 (GLP-1) nor glucose-dependent insulinotropic polypeptide levels increased after oral glucose administration, the classic stimulus for their secretion suggestive of pasireotideinduced inhibition of incretin secretion [Henry 2011]. Dipeptidyl peptidase 4 (DPP-4) inhibitors and GLP-1 agonists were more effective than either metformin or nateglinide at reducing hyperglycemia in healthy male volunteers. These results are consistent with previously published data suggesting that somatostatin could dampen GLP1 secretion, most likely mediated through SSTR5 [25, 26]. Schmid and Brueggen [27] recently published findings describing the effects of pasireotide on blood glucose, insulin, and glucagon levels in Lewis rats. Interestingly, continuous infusion of short-acting pasireotide or injection of long-acting pasireotide resulted only in small, transient elevations in plasma glucose. Glucose elevation with short-acting pasireotide was also transient, with tachyphylaxis after repeated or continuous administration. While no tachyphylaxis with respect to hyperglycemia (or escape from cortisol-lowering response) has been described in human trials, the observed glycemic improvements after long-term pasireotide treatment in 2 individuals recently reported by MacKenzie Feder et al. [16] could represent a parallel to these observations. One strategy that has been proposed to combat pasireotideassociated hyperglycemia is coadministration with an antidiabetic agent. While no studies have been completed to determine optimal treatment for pasireotide-associated hyperglycemia in patients with CD, the finding of blunted insulin and incretin secretion helps to guide current proposals for hyperglycemia management with pasireotide. In February 2012, an advisory board of 10 European experts in pituitary disorders and diabetes mellitus convened to obtain recommendations for monitoring and treatment of hyperglycemia in pasireotide-treated patients with CD. The board recommended that pasireotide-associated hyperglycemia be managed by initiation of medical therapy with metformin to decrease hepatic glucose output along with staged treatment intensification with a DPP-4 inhibitor, with a switch to a GLP-1 receptor agonist and initiation of insulin, as required, to achieve and maintain glycemic control [28]. Although combination therapies of metformin with sulfonylureas and/or pioglitazone may also be possible theoretically, these are not recommended as sulfonylureas stimulate insulin secretion in a glucose-independent manner and are therefore associated with risk of hypoglycemia and weight gain. Furthermore, treatment failure as a result of a decline of pancreatic beta-cell function may occur more rapidly with sulfonylurea therapy. Pioglitazone primarily targets insulin resistance and therefore does not represent a pathophysiologically oriented treatment option for pasireotide-associated hyperglycemia. Pioglitazone has also been associated with increases in body
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Conclusions and Future Directions
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Management of patients with refractory CD represents an unremitting challenge. While surgery remains the primary treatment of choice, many individuals will likely rely on life-long pharmacotherapy to control cortisol levels and CD-related symptoms. It is therefore essential to understand the long-term implications, benefits, and risks associated with available medical treatment options for CD. Because no head-to-head trials have been performed, it has not been possible to generate an evidence-based algorithm to guide the medical treatment of CD. Historically, clinicians have often used adrenal steroidogenesis inhibitors, adrenolytics, and dopamine agonists to treat CD; however, none of these drugs have obtained regulatory approval for this indication. This has severely limited the broad, prolonged use of these compounds, particularly in the US. Pasireotide is currently the only medical treatment option for patients with CD that has demonstrated sustained, long-term control of hypercortisolism and improvement in several associated clinical laboratory parameters in a prospective, multicenter clinical trial. Study results demonstrated that pasireotide reduced UFC in most patients, normalized UFC in approximately 20 % of patients after 6 months of treatment, and that pasireotide provides clinical benefit for many patients with CD. For some patients, long-term treatment with pasireotide has resulted in sustained improvements in mean UFC, serum cortisol, plasma ACTH, blood pressure, cholesterol, and body weight. In most regards, safety considerations for long-term medical treatment with pasireotide are similar to those for other SSAs. However, hyperglycemia and incident type 2 diabetes remain significant concerns and further research is needed to determine the most efficacious way treat elevated blood glucose levels. At this juncture, experts recommend metformin treatment with the addition of incretin-based therapy, as appropriate. With an estimated annual cost of approximately $175,000 [30], long-term treatment with pasireotide may seem a costly proposition. However, untreated or undertreated CD often engenders many debilitating sequelae associated with substantial healthcare cost. While it is also costly (roughly equivalent to 3–5 months of pasireotide treatment) [30], repeat TSS is potentially curative; but surgical outcomes are highly dependent upon surgical expertise [3]. As they are both less costly than pasireotide and have demonstrated efficacy for some patients, it is reasonable to consider initial treatment with cabergoline or ketoconazole in patients who have failed surgery or who are not surgical candidates. However, sustained response with cabergoline is only achieved in a small subset of patients (often transiently) [10, 11], and ketoconazole is associated with potential hepatotoxicity [5, 6]. Weighed against the cost of inadequately managed CD complications, long-term pasireotide therapy might be an economically reasonable treatment for selected patients. Moreover, patients unlikely to respond to pasireotide can be identified within the first few months of treatment [14]. More long-term studies to evaluate this topic will be needed. Since completion of the Phase III trial extension, many patients have continued pasireotide treatment through an expanded access, compassionate-use protocol. Additional future trials of
pasireotide include Phase III evaluation of a long-acting formulation administered monthly [31], and a study aiming to elucidate the effect of antidiabetic medications on pasireotide-associated hyperglycemia in patients with CD. New data from these and other studies will further our understanding of the benefits and risks of long-term pasireotide treatment. This ongoing research may provide treatment guidelines for health care professionals and new therapeutic options for patients, thereby mitigating the deleterious effects of prolonged chronic hypercortisolism.
Acknowledgement
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Financial support for editorial and administrative support was provided by Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA. The author thanks David Wolff (Mudskipper, Inc.) for providing medical editorial and administrative support on this manuscript.
Author conflict of interest disclosure statement: SLS is a site principal investigator and receives research funds from Novartis Pharmaceuticals Corporation for clinical trials of pasireotide for patients with Cushing’s disease and acromegaly. Conflict of interest: I am the site PI for multicenter clinical trials on the use of pasireotide for acromegaly and Cushing’s disease. References 1 Broder M, Neary M, Chang E et al. Incidence of Cushing’s Disease in the United States. Endocr Rev 2013;34:MON-91. Presented at ENDO 95th Annual Meeting, June 17, 2013, in San Francisco, CA, USA 2 Feelders RA, Pulgar SJ, Kempel A et al. The burden of Cushing’s disease: clinical and health-related quality of life aspects. Eur J Endocrinol 2012; 167: 311–326 3 Biller BM, Grossman AB, Stewart PM et al. Treatment of adrenocorticotropin-dependent Cushing’s syndrome: a consensus statement. J Clin Endocrinol Metab 2008; 93: 2454–2462 4 Kim JH, Shin CS, Paek SH et al. Recurrence of Cushing’s disease after primary transsphenoidal surgery in a university hospital in Korea. Endocr J 2012; 59: 881–888 5 European Medicines Authority. European Medicines Agency recommends suspension of marketing authorisations for oral ketoconazole. 2013; Available at http://www.ema.europa.eu/docs/en_GB/document_ library/Press_release/2013/07/WC500146613.pdf Accessed December 18, 2013 6 FDA Drug Safety Communications. FDA limits usage of Nizoral (ketoconazole) oral tablets due to potentially fatal liver injury and risk of drug interactions and adrenal gland problems. 2013; Available at: http://www.fda.gov/downloads/Drugs/DrugSafety/UCM362444.pdf Accessed December 18, 2013 7 Korlym™ (mifepristone) full prescribing information. Corcept Therapeutics. Menlo Park, CA. Available at http://www.korlym.com/docs/ KorlymPrescribingInformation.pdf Accessed December 18, 2013 8 Fleseriu M, Biller BM, Findling JW et al. SEISMIC Study Investigators. Mifepristone, a glucocorticoid receptor antagonist, produces clinical and metabolic benefits in patients with Cushing’s syndrome. J Clin Endocrinol Metab 2009; 97: 2039–2049 9 Illouz F, Dubois-Ginouves S, Laboureau S et al. Use of cabergoline in persisting Cushing’s disease. Annales d’Endocrinologie 2006; 67: 353–356 10 Godbout A, Manavela M, Danilowicz K et al. Cabergoline monotherapy in the long-term treatment of Cushing’s disease. Eur J Endocrinol 2010; 163: 709–716 11 Pivonello R, De Martino MC, Cappabianca P et al. Lamberts SW, Colao A. The medical treatment of Cushing’s disease: effectiveness of chronic treatment with the dopamine agonist cabergoline in patients unsuccessfully treated by surgery. J Clin Endocrinol Metab 2009; 94: 223–230 12 Boscaro M, Ludlam WH, Atkinson B et al. Treatment of pituitarydependent Cushing’s disease with the multireceptor ligand somatostatin analog pasireotide (SOM230): a multicenter, phase II trial. J Clin Endocrinol Metab 2009; 94: 115–122
Samson SL. Long-term Pasireotide Treatment in CD … Exp Clin Endocrinol Diabetes 2014; 122: 445–450
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weight, fluid retention, and bone fractures – all adverse events that are most unwanted in patients with CD [28, 29].
13 Boscaro M, Bertherat J, Findling J et al. Extended treatment of Cushing’s disease with pasireotide: results from a 2-year, Phase II study. Pituitary 2013, Aug 14. [Epub ahead of print] doi:10.1007/s11102013-0503-3 14 Colao A, Petersenn S, Newell-Price J et al.Pasireotide B2305 Study Group. A 12-Month Phase 3 study of pasireotide in Cushing’s disease. N Engl J Med 2012; 366: 914–924 15 Schopohl J, Bertherat J, Ludlam WH et al. on behalf of the Pasireotide B2305 Study Group. Long-term pasireotide use leads to improvements in the biochemical parameters of Cushing’s disease: 24-month results from a randomized Phase III study. Abs P1410. Presented at the joint 15th International Congress of Endocrinology and the 14th European Congress of Endocrinology (ICE/ECE), Florence, Italy, 5–9 May 2012 16 MacKenzie Feder J, Bourdeau I, Vallette S et al. Pasireotide monotherapy in Cushing’s disease: a single-centre experience with 5-year extension of Phase III trial. Pituitary 2013, Nov 28. [Epub ahead of print] doi:10.1007/s11102-013-0539-4 17 Libé R, Groussin L, Bertherat J. Pasireotide in Cushing’s Disease. N Engl J Med 2012; 366: 2134–2135 18 Feelders RA, de Bruin C, Pereira AM et al. Pasireotide alone or with cabergoline and ketoconazole in Cushing’s disease. N Engl J Med 2010; 362: 1846–1848 19 van der Pas R, de Bruin C, Pereira AM et al. Cortisol diurnal rhythm and quality of life after successful medical treatment of Cushing’s disease. Pituitary 2013; 16: 536–544 20 Signifor® (pasireotide) full prescribing information. Novartis Pharmaceuticals Corporation. Basel, Switzerland: Available at http://www. pharma.us.novartis.com/product/pi/pdf/signifor.pdf Accessed December 18, 2013 21 Paserchia LA, Hewett J, Woosley RL. Effects of ketoconazole on QTc [abstr]. Clin Pharmacol Ther 1994; 55: 146 22 Bertherat J, Ludlam WH, Pivonello R et al.on behalf of the Pasireotide B2305 Study Group. Long-Term Use of Pasireotide in Cushing’s Disease: 24-Month Safety Results from a Randomized Phase III Study. Abs P1405. Presented at the joint 15th International Congress of Endocrinology and the 14th European Congress of Endocrinology (ICE/ ECE), Florence, Italy, 5–9 May 2012
23 Shenouda M, Maldonado M, Wang Y et al. An open-label dose-escalation study of once-daily and twice-daily pasireotide in healthy volunteers: Safety, tolerability, and effects on glucose, insulin, and glucagon levels. Am J Ther 2012, Jun 16. [Epub ahead of print] doi:10.1097/ MJT.0b013e31824c3eb4 24 Henry RR, Mudaliar S, Hermosillo Reséndiz K et al. Mechanism and Management of Hyperglycemia Associated with Pasireotide: Results from Studies in Healthy Volunteers. Abs. P260. Presented at the 13th European Congress of Endocrinology (ECE), Rotterdam, The Netherlands, 30 April – 4 May 2011 25 Chisholm C, Greenberg GR. Somatostatin-28 regulates GLP-1 secretion via somatostatin receptor subtype 5 in rat intestinal cultures. Am J Physiol Endocrinol Metab 2002; 283: E311–E317 26 Hansen L, Hartmann B, Bisgaard T et al. Somatostatin restrains the secretion of glucagon-like peptide-1 and -2 from isolated perfused porcine ileum. Am J Physiol Endocrinol Metab 2000; 278: E1010– E1018 27 Schmid HA, Brueggen J. Effects of somatostatin analogs on glucose homeostasis in rats. Journal of Endocrinology 2012; 212: 49–60 28 Colao A, De Block C, Gaztambide MS et al. Managing hyperglycemia in patients with Cushing’s disease treated with pasieotide: medical expert recommendations. Pituitary 2013, 7. Apr 7 [Epub ahead of print] doi:10.1007/s11102-013-0483-3 29 Shah P, Mudaliar S.. Pioglitazone: side effect and safety profile. Expert Opin Drug Saf 2010; 9: 347–354 30 Truong HL, Nellesen D, Ludlam WH et al. Budget impact of pasireotide for the treatment of Cushing’s disease, a rare endocrine disorder associated with considerable comorbidities. J Med Econ 2014; 17: 288–295 31 ClinicalTrials.gov. Efficacy and Safety of Pasireotide Administered Monthly in Patients With Cushing’s Disease. NCT01374906. Available at http://www.clinicaltrials.gov/ct2/show/NCT01374906 Accessed December 18, 2013
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