Pasireotide

Overview
Pasireotide is a cyclic hexapeptide that was discovered using a rational approach to design a stable somatostatin analog with a receptor selectivity profile resembling that of native somatostatin. Pasireotide (Fig. 2c), has high affinity for sstr1,2,3 and 5 (Table 1), with much higher affinity for subtypes 1 and 5, and lower affinity for subtype 2, compared with octreotide [40]. In preclinical studies, pasireotide demonstrated inhibition of ACTH secretion in cultured human corticotroph adenomas [19, 20] and in murine AtT20 cells [17, 19]; one study has also reported reduced cell proliferation in cultured human corticotropinomas [20]. Compared with octreotide, pasireotide demonstrated greater suppression of CRH-stimulated ACTH release from AtT20cells [17, 19]. Further, consistent with the model of glucocorticoid-mediated downregulation of sstr2, pretreatment of AtT20 cells with dexamethasone abolished the inhibitory effects of octreotide on ACTH secretion, but had no effect on the inhibitory action of pasireotide or somatostatin-14 [33]. Together, these findings support the conclusion that pasireotide inhibits ACTH secretion from corticotroph adenomas by acting predominantly at sstr5. Subsequent supportive in vivo results [41, 42] established the rationale for studies on the use of pasireotide in patients with CD.

Clinical trial experience with pasireotide in Cushing’s disease
After promising results in a 15-day Phase 2 trial [40], a randomized, double-blind phase 3 trial of pasireotide was conducted in adult patients with de novo, persistent, or recurrent CD (UFC ≥1.5× upper limit of normal [ULN]) who were not candidates for surgery and with no pituitary radiotherapy in the preceding 10 years. Eligible patients (N = 162) were randomized to receive 600 or 900 mcg of pasireotide twice daily for an initial period of 3 months. After 3 months, those with UFC <baseline and <2× ULN continued blinded therapy for another 3 months. Other patients were unblinded, and their dose was increased by 300 mcg twice daily. At 6 months, all patients entered the open-label phase of the study and could have their dose increased again to a maximum of 1200 mcg twice daily, if necessary [43].
Figure 3 shows changes from baseline to 6 months in UFC levels for patients in the two dose groups of the phase 3 trial. The majority of patients had declines in UFC levels at 6 months; 6 patients had increases. At 6 months, 15 % of patients in the 600 mcg group and 26 % of patients in the 900 mcg group met the primary endpoint of UFC level within the normal range without dose increase. Median percentage changes in UFC levels from baseline to 6 months were −47.9 % in the 600 mcg group and −47.9 % in the 900 mcg group. Among the 36 patients who achieved normalization of UFC levels at 6 months, 20 maintained normal levels at 12 months, including some patients who had dose reductions. Moreover, patients who responded to treatment could generally be identified within the first 2 months of treatment [43].
Fig. 3 Changes in UFC levels from baseline to 6 months in individual patients in the phase 3 trial of pasireotide. The dashed black line represents the upper limit of the normal range for UFC. From Colao A, Petersenn S, Newell-Price J, Findling JW, Gu F, Maldonado M, et al., for the Pasireotide B2305 Study Group (2012) N Engl J Med, volume 366, page 918 [43]. Reproduced with permission
Mean plasma ACTH levels and serum and salivary cortisol levels were reduced at both 6 and 12 months, and patients had significant improvements in signs and symptoms of hypercortisolism during the trial, including reductions in systolic and diastolic blood pressure, triglycerides, low-density lipoprotein cholesterol, and body weight. The time-course of many of these improvements closely followed the time-course UFC reduction. Patients also reported significant increases in health-related quality of life. Finally, among the 75 patients who had measurable pituitary tumors on magnetic resonance images at baseline, tumor volume changed by an average of −9.1 and −43.8 % in the 600 and 900 mcg groups, respectively [43].
Hyperglycemia-related adverse events occurred in 118 of 162 patients (73 %), and 10 patients discontinued because of such events. Twenty one patients (13 %) had grade 3 or 4 hyperglycemia, and 74 patients initiated a new antidiabetic medication during the study [43]. While no glycemic intervention studies have been completed in pasireotide-treated CD patients, the mechanism of pasireotide-induced hyperglycemia was investigated in 90 healthy volunteers [44]. Results indicate that pasireotide-induced hyperglycemia is mediated by a reduction in secretion of insulin and incretin hormones glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP). Glucagon secretion was only mildly inhibited, and pasireotide appears to have no effect on peripheral or hepatic insulin sensitivity in healthy individuals. Treatment with the GLP-1 analog liraglutide or the dipeptidyl peptidase 4 (DPP-4) inhibitor vildagliptin was most effective in countering hyperglycemia in this population, while metformin and nateglinide had little effect.
Patients with CD, however, are often insulin-resistant. A recently published proposal for management of hyperglycemia in patients with CD treated with pasireotide recommends metformin as first-line medical treatment for CD patients who develop new or worsening hyperglycemia with pasireotide, with an adjunctive DPP-4 inhibitor, sulfonylurea/glinide, and/or GLP-1 analog as required to achieve glycemic control. Metformin plus insulin is recommended if such combination therapy is not tolerated or insufficient and early intervention with insulin is recommended on a case-by-case basis [45].
Other than the degree and severity of hyperglycemia-related events, the safety and adverse event profiles of pasireotide in the phase 3 trial were similar to those observed with other somatostatin analogs. Other common adverse events were diarrhea (58 %), nausea (52 %), cholelithiasis (30 %), headache (28 %), and abdominal pain (24 %). Among the 137 patients who had a normal gallbladder at baseline, 27 had gallstones at their latest assessment and 6 had a cholecystectomy [43]. Pasireotide was recently approved in the US [46] and Europe [47] for the treatment of adult CD patients for whom pituitary surgery is not an option or has failed.

Dopamine receptors and dopamine receptor agonists
Like somatostatin receptors, dopamine receptors are widely expressed in normal neuro-endocrine tissues and pituitary adenomas, including approximately 80 % of corticotroph adenomas [48, 49]. Five dopamine receptor subtypes have been characterized, usually classified as D1-like or D2-like, with most D2-like receptors associated with inhibitory actions [50]. The dopamine agonists bromocriptine and cabergoline have both been used to treat pituitary adenomas; however, cabergoline is more selective at D2 receptors and has been found to be more effective and better tolerated than bromocriptine in women receiving treatment for hyperprolactinemia [51].
In clinical studies, bromocriptine has had small and variable effects on ACTH secretion in patients with CD [50]. In contrast, a 2004 study demonstrated significant in vitro inhibition of ACTH secretion with cabergoline in 100 % of cases with confirmed D2 receptor expression, and significant in vivo reduction of cortisol levels in 60 % of cases—with 40 % normalization of cortisol secretion [48]. Altogether, 3 small, non-randomized studies (one with a long-term follow-up publication) have found evidence have found evidence for efficacy of cabergoline in this setting [48, 52, 53].
In a study of 10 patients, 6 achieved UFC normalization after 3 months’ treatment with cabergoline, and 2 additional patients achieved significant UFC reductions [48]. In a follow-up to this investigation, 20 patients were enrolled who had CD unsuccessfully treated by surgery [53]. After 3 months of cabergoline (1 mg/week with dose adjusted to a maximum of 7 mg/week), 7 patients (35 %) achieved eucortisolism and an additional 8 (40 %) experienced ≥25 % decline in UFC. The 8 partial responders all had dose increases, and 6 of these had normal UFC after 6–12 months. However, 5 patients who achieved normal UFC levels either initially or after dose increase escaped from treatment control. Thus, at 12 months, 10 patients (50 %) had normal UFC levels. However, 2 of these patients subsequently discontinued treatment because of severe asthenia, resulting in a long-term control rate of 40 %. Most responders exhibited improvements in signs and symptoms of CD, including significant mean declines in blood pressure, waist/hip ratio, serum glucose, and tumor volume, and significant improvements in β-cell function.
Similar supportive results were found in a retrospective, non-randomized analysis of 30 patients with CD in Buenos Ares and Montreal who received cabergoline (initially 0.5–1.0 mg/week adjusted to a maximum of 6 mg/week) for up to 5 years [54]. Within 3–6 months, 11 patients (37 %) achieved sustained normalization of UFC (≥2 normal values measured at 1–3 months apart; complete response). Nine of these patients achieved long-term UFC normalization after a mean of 37 months (range, 12–60) on a mean cabergoline dose of 2.1 mg/week. Four patients (13 %) achieved UFC <125 % ULN (partial response) within 3–6 months of cabergoline initiation, but none of these patients experienced long-term response. Escape from response was observed in 2 patients with long-term complete response after 2 and 5 years of treatment, although one patient transiently renormalized after cabergoline dose increase. Long-term tolerability was positive; no serious adverse events were reported during treatment. No symptoms of cardiovascular dysfunction were reported and no patients presented symptomatic adrenal insufficiency.
Although the results of these small studies have shown promise for the use of cabergoline as medical therapy for CD, no large-scale, double-blind trials have been conducted. Thus, it is difficult to draw conclusions about the overall efficacy and safety of this approach.
One potential concern regarding the use of DA agonists for CD has been the association of long-term ergot derivatives with increased risk of valvular heart disease [55–57]. However, this risk was identified in studies performed in patients using DA agonists for Parkinson’s disease at doses considerably higher (often >3 mg/day) than those used in CD (generally <7 mg/week). Schade et al. [56] reported that the relative risk of valvular heart disease was 50.3 (95 % CI 6.6–381.4) in patients receiving >3 mg/day compared to 2.6 (95 % CI 0.5–12.8) in patients receiving <3 mg/day. Furthermore, a study of 78 patients receiving DA agonists (including 47 who were using cabergoline) for an average of 8 years for prolactinoma found an increased risk of aortic valve calcification and mild tricuspid regurgitation, but no increase in the risk of clinically relevant valvular heart disease compared to control patients [58]. Among patients receiving cabergoline, the mean duration of therapy was 5.2 ± 0.4 years and the mean cumulative dose was 363 ± 55 mg. There was no relation between cumulative dose of cabergoline and the presence of mild, moderate or severe valve regurgitation. Thus, the evidence suggests that valvular heart disease associated with long-term use of DA agonists is much less of a concern for patients using the doses typical of treatment regimens for CD. A summary of current prospective studies with pituitary targeted medical therapy is provided in Table 2 [40, 43, 48, 52, 53, 59].
Table 2 Medical treatments for Cushing’s disease evaluated in prospective clinical studies
Compound Trial Patients (N) Treatment duration Outcome
Pasireotide Boscaro et al. [40] 29 15 days 5/29 patients (17 %) achieved UFC ≤ ULN; 22/29 patients (76 %) experienced reduction in mean UFC
Colao et al. [43] 162 12 months 33/162 patients (20 %) achieved UFC ≤ ULN within 6 months without increase from randomized dose; the majority of patients experienced reduction in UFC at month 6, sustained through month 12
Cabergoline Lila et al. [52] 18 5 months 5 patients (28 %) achieved MNSC <5 μg/dL or low-dose dexamethasone-suppressed serum cortisol <1.8 μg/dL
Pivonello et al. [48, 53] 20 3–24 months After 3 months, 15 patients (75 %) achieved UFC ≤ ULN or ≥25 % reduction from baseline; 8 patients (40 %) maintained UFC ≤ ULN at 24 months
Retinoic acid Pecori Girald et al. [59] 7 6–12 months 3/7 patients (43 %) achieved UFC ≤ ULN; 5/7 patients (71 %) experienced reduction in UFC
MNSC midnight salivary cortisol, UFC urinary free cortisol, ULN upper limit of normal