Drugs DOI 10.1007/s40265-015-0413-y

ADIS DRUG EVALUATION

Pasireotide in Acromegaly: A Review Kate McKeage1

Ó Springer International Publishing Switzerland 2015

Abstract Pasireotide (SigniforÒ, SigniforÒ LAR) is a somatostatin analogue recently approved for the treatment of acromegaly. Unlike the first-generation agents, octreotide and lanreotide, which bind preferentially to somatostatin receptor (SSTR)-2, pasireotide binds to multiple SSTRs. This article reviews the clinical use and summarizes the pharmacological properties of intramuscular pasireotide in the treatment of acromegaly. The efficacy of pasireotide 40 mg every 28 days was superior to that of intramuscular octreotide 20 mg every 28 days with regard to biochemical control in a 12-month, phase III trial in medically naive patients. Similarly, in a 6-month, phase III trial in patients with acromegaly inadequately controlled with somatostatin analogues for at least 6 months, the efficacy of pasireotide 40 or 60 mg was superior to that of continued octreotide 30 mg or lanreotide autogel 120 mg (each drug was administered once every 28 days) with regard to biochemical control. The tolerability profile of

intramuscular pasireotide is generally similar to that of first-generation agents, except for a higher incidence of hyperglycaemia-related adverse events with pasireotide. In clinical trials, the risk of developing pasireotide-associated hyperglycaemia was numerically greater in patients categorized as diabetic or prediabetic at baseline than in those with normal glucose tolerance. Careful monitoring of glycaemic status is required prior to and during pasireotide treatment and antidiabetic therapy should be commenced as indicated. Thus, in the treatment of acromegaly, pasireotide may be a more effective somatostatin analogue than other approved agents of the same class; however, the increased risk of hyperglycaemia needs to be considered and proactively managed.

Pasireotide in acromegaly: a summary Intramuscular formulation for administration once every 4 weeks More effective in achieving biochemical control than intramuscular octreotide in medically naive patients

The manuscript was reviewed by: M. Gadelha, Section of Endocrinology, Hospital Universita´rio Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; L. F. Grasso, Department of Clinical Medicine and Surgery, Endocrinology Section, University ‘‘Federico II’’, Naples, Italy; J. S. Kuo, Department of Neurological Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; S Melmed, Pituitary Center, Cedars Sinai Medical Center, Los Angeles, CA, USA. & Kate McKeage [email protected] 1

Springer, Private Bag 65901, Mairangi Bay 0754, Auckland, New Zealand

More effective in achieving biochemical control than continued intramuscular octreotide or lanreotide autogel in patients inadequately controlled with somatostatin analogues Associated with a greater risk of hyperglycaemiarelated adverse events than octreotide or lanreotide autogel Glycaemic status should be monitored at baseline and throughout treatment and antidiabetic medication initiated as indicated

K. McKeage

1 Introduction Acromegaly is a chronic disorder characterized by hypersecretion of growth hormone (GH), usually as a result of a pituitary adenoma [1]. The condition is rare, with an estimated incidence of approximately 3–4 cases per million population per year and an estimated population prevalence of 60 per million [2]. The hypersecretion of GH leads to the production of excess insulin-like growth factor (IGF)-1 from the liver and systemic tissues, which in turn leads to multiple effects, including somatic overgrowth, multiple comorbidities and premature mortality [1]. Treatment modalities include surgery, medical therapy and radiation therapy [3, 4], with somatostatin analogues recommended for first-line adjuvant use [4]. Until recently, the long-acting formulations of intramuscular octreotide and lanreotide autogel were the only somatostatin analogues approved for use in acromegaly, but recently, the long-acting, intramuscular formulation of pasireotide (SigniforÒ; SigniforÒ LAR) was also approved in this indication in the EU [5] and USA [6]. This article focuses on the therapeutic efficacy and tolerability of intramuscular pasireotide in the treatment of acromegaly, and briefly reviews its pharmacological properties. Subcutaneous pasireotide is approved in the treatment of Cushing’s disease, and its use in this indication was reviewed in this journal previously [7].

2 Pharmacodynamic Properties Somatostatin analogues bind to somatostatin receptors (SSTRs) expressed on target tissues where they exert various biological effects [8]. This section focuses on the pharmacodynamic effects of pasireotide relevant to its use in the treatment of patients with acromegaly. The SSTR binding profile of pasireotide is distinct from that of other somatostatin analogues and has been well described previously [8]. Briefly, the drug binds with high affinity to 4 of the 5 SSTRs (SSTR-1, -2, -3 and -5), but has the highest affinity for SSTR-5. In contrast, octreotide and lanreotide bind preferentially to SSTR-2 [8]. Compared with octreotide and lanreotide, pasireotide displays a binding affinity for SSTR-5 that is approximately 39- and 106-fold higher, respectively, and a slightly lower binding affinity for SSTR-2 (approximately 0.4- and 0.5-times lower, respectively) [8]. As most GH-secreting pituitary adenomas express both SSTR-2 and -5, the SSTR binding profile of pasireotide is likely to lead to effective GH suppression [9]. Pasireotide (the subcutaneous and intramuscular formulations) effectively reduces GH levels in a generally

dose dependent manner in patients with acromegaly [10– 13]. In a randomized, crossover, phase II study in patients (n = 60) who had previously received medical therapy for acromegaly and those who had not, more than a quarter of all patients achieved biochemical control (GH \2.5 lg/L and normalized IGF-1 for age and sex) after 3 months of subcutaneous pasireotide 200, 400 or 600 lg twice daily (each dose was given for 4 weeks) subsequent to completing 4 weeks’ treatment with octreotide 100 lg three times daily [13]. After 4 weeks of octreotide treatment, 9 % of patients achieved biochemical control, which increased to 19 % after 4 weeks treatment with one of the pasireotide doses, then 27 % after 3 months. Among 51 patients with magnetic resonance imaging (MRI) data, 39 % experienced a significant (C20 %) reduction in tumour volume [13]. An extension (n = 30) of the phase II study, including treatment periods of up to 24 months, demonstrated that subcutaneous pasireotide (400–1800 lg/day) provides sustained biochemical control and reductions in tumour volume [14]. A randomized, double-blind, crossover study in patients (n = 12) with acromegaly demonstrated that subcutaneous pasireotide 100 and 250 lg inhibited free IGF-1 in a more sustained manner than subcutaneous octreotide 100 lg [11]. Free IGF-1 levels 48 h after injection were significantly lower than pre-dose levels with both doses of pasireotide (p \ 0.01), but the difference versus pre-dose levels was not significant with octreotide 100 lg [11]. GH and IGF-1 levels were rapidly suppressed following the first intramuscular injection of pasireotide 20, 40 or 60 mg, and suppression was maintained throughout treatment in a randomised, phase I study in patients with acromegaly (n = 35) [12]. Following a washout period if prior medical therapy had been used, pasireotide was administered once every month for 3 months. At day 91, 51 % of patients across all groups had mean GH levels of B2.5 lg/L (compared with 11 % at baseline), and over the 3-month period, mean GH levels had decreased by 67, 60 and 63 % in groups receiving pasireotide 20, 40 or 60 mg, respectively [12]. At month 3, mean serum IGF-1 levels had decreased to below the upper limit of normal (ULN) in 57 % of patients, and decreases from baseline of 40, 51 and 50 % were observed in each group, respectively. 2.1 Effects on Glucose Metabolism Somatostatin analogues inhibit the secretion of insulin from pancreatic cells and, as such, are associated with hyperglycaemia [15]. In a dose-escalation study in healthy volunteers, subcutaneous pasireotide 150–1500 lg once daily and 150–750 lg twice daily for 8 days led to dosedependent hyperglycaemia (fasting and postprandial), which appeared to result from marked suppression of

Pasireotide: A Review

insulin secretion and mild inhibition of glucagon secretion [15]. Similarly, after 7 days’ treatment with subcutaneous pasireotide 600 and 900 lg twice daily in a randomized, phase II study in healthy volunteers, there were significant decreases from baseline in mean insulin area under the plasma concentration-time curve (AUC) from time zero to 3 h (AUC3) during a hyperglycaemic clamp test and an oral glucose tolerance test (OGTT) [p \ 0.001 for both dosages and endpoints] [16]. In addition, during the OGTT, compared with baseline, mean glucose AUC3 increased significantly (p \ 0.001), glucagon-like peptide-1 (GLP-1) AUC3 decreased significantly (p B 0.009) and glucosedependent insulinotropic polypeptide (GIP) AUC3 decreased significantly (p B 0.001). No significant changes in hepatic or peripheral insulin sensitivity were observed [16]. Pasireotide-associated hyperglycaemia was attenuated to varying degrees when pasireotide was co-administered with glucose-lowering therapies in a phase I study in healthy volunteers [17]. After 7 days’ treatment with subcutaneous pasireotide 600 lg twice daily, mean plasma glucose AUC4 post-OGTT was increased by 69 % from baseline. The co-administration of pasireotide with oral metformin 500 mg twice daily, oral nateglinide 60 mg three times daily, oral vildagliptin 50 mg twice daily or subcutaneous liraglutide 0.6 mg once daily for 7 days reduced this effect by 13, 29, 45 and 72 %, respectively. The pasireotide-associated decrease in serum insulin AUC4 after 7 days’ treatment was attenuated by 6, 3, 71 and 34 % after 7 days of combination therapy with corresponding agents [17]. In a phase I study in patients (n = 35) with acromegaly, mean fasting blood glucose (FBG) values in groups receiving intramuscular pasireotide 20, 40 or 60 mg every month for 3 months increased from baseline by 30.8, 20.7 and 31.4 %, respectively [12]. FBG levels of 100 to \126 mg/dL were the highest levels reported throughout treatment in 37 % of patients and C126 mg/dL were the highest reported in 63 % of patients. Among patients (n = 30) with available baseline glycated haemoglobin (HbA1c) measurements in the pasireotide 20, 40 or 60 mg groups, mean HbA1c increased from baseline to day 91 in corresponding groups as follows: 5.7–6.2, 5.4–5.6, and 5.9–7.1 %. Mean fasting insulin levels decreased from baseline to day 91 by 4.0, 3.3 and 9.4 mU/L in each dosage group, respectively [12]. There were no clinically relevant changes from baseline in fasting blood glucagon levels in any dosage group.

3 Pharmacokinetic Properties 3.1 General Properties The pharmacokinetics of subcutaneous pasireotide have been summarized previously [18, 19]. This section focuses on the pharmacokinetic properties of intramuscular pasireotide. Intramuscular pasireotide is widely distributed, primarily in the plasma [5, 6]. Plasma protein binding (88 %) is independent of concentration. Steady-state levels of pasireotide were achieved after 3 intramuscular, monthly injections of pasireotide 20, 40 or 60 mg in patients with acromegaly [12]. After the first injection of each dose, pasireotide plasma levels increased rapidly between 2 to 10 h, then plateaued or decreased. Following monthly intramuscular injections of pasireotide in the dose range of 20–60 mg, approximately dose-proportional pharmacokinetic exposures were observed [12]. In vitro data indicate that pasireotide is a substrate of the efflux transporter P-glycoprotein (P-gp), but the impact of P-gp on the pharmacokinetics of pasireotide is expected to be low [6]. Pasireotide exhibits high metabolic stability and in vitro data indicate that it is not a substrate, inhibitor or inducer of the cytochrome P450 (CYP) enzyme [5]. Pasireotide is mainly eliminated via hepatic clearance, and &48 and &8 % of the drug was eliminated in the faeces and urine, respectively, in the 10 days following a single radiolabelled subcutaneous dose [5, 6]. The mean apparent clearance of intramuscular pasireotide in healthy volunteers was 4.5–8.5 L/h [5, 6]. 3.2 Special Patient Populations Clinical studies have not been performed with intramuscular pasireotide in patients with hepatic impairment [5]. Following a single dose of subcutaneous pasireotide 600 lg in patients with moderate or severe hepatic impairment (Child Pugh B and C), exposure to pasireotide increased compared with that observed in adults with normal hepatic function (Sect. 6) [20]. The systemic exposure of pasireotide is not expected to be influenced significantly in patients with mild or moderate renal impairment; however, the possibility cannot be excluded [5]. The pharmacokinetic parameters of pasireotide are not thought to be influenced to a clinically relevant extent by advanced age, body weight, sex or race [5].

K. McKeage

4 Therapeutic Efficacy The efficacy of intramuscular pasireotide in adults with acromegaly has been evaluated in two randomized, multicentre, phase III studies [21, 22]. In both studies, GH and IGF-1 levels were assessed by immunoassay and tumour volume was assessed by MRI. Somatostatin analogues were administered via intramuscular injection.

4.1 Patients Naive to Medical Therapy 4.1.1 Core Phase III Study Patients (n = 358) with medically naive acromegaly, defined as mean GH [5 lg/L or GH nadir C1 lg/L after an OGTT and IGF-1 above the ULN for age and sex, were randomized to intramuscular pasireotide 40 mg or octreotide 20 mg every 28 days in a double-blind, 12-month study [21]. Eligible patients were stratified into two groups: post-surgery or de novo. Key exclusion criteria included previous therapy with somatostatin analogues, dopamine agonists or a GH receptor antagonist, pituitary irradiation within the past 10 years, significant cardiovascular morbidity, and HbA1c [8 % [21]. Previous pituitary surgery (C1 procedure) had been performed in 42 % of patients; median time since surgery was 7 months. In the pasireotide and octreotide groups at baseline, the mean GH level was 21.9 and 18.8 lg/L, respectively, the mean standardized IGF-1 level was 3.1 times ULN in both groups, and the mean tumour volume was 2421 and 2259 mm3, respectively. The primary efficacy endpoint was to determine if pasireotide was superior to octreotide with regard to achieving biochemical control (GH \2.5 lg/L and normalized IGF-1 for age and sex) at month 12 in the intentto-treat (ITT) population [21]. After 12 months’ treatment, the efficacy of pasireotide was superior to that of octreotide, with significantly more pasireotide recipients achieving biochemical control (Table 1) [21]. Biochemical control was also achieved by significantly more post-surgical patients receiving pasireotide than octreotide, but the difference between treatment groups did not reach significance in de novo patients (Table 1). With regard to secondary endpoints at month 12, IGF-1 was normalized in more recipients of pasireotide than octreotide (Table 1). The proportion of patients in corresponding groups who achieved GH levels \2.5 lg/L was generally similar overall (48.3 and 51.6 %), as well as in post-surgery (52 vs. 51 %) and de novo (46 vs. 52 %) treatment groups [21]. In both pasireotide and octreotide groups, mean GH and IGF-1 levels decreased rapidly within the first 3 months, and the treatment effect was

sustained throughout the study [21]. At month 3, 30.1 versus 21.4 % of patients in each group, respectively, had achieved biochemical control. The decrease in mean tumour volume from baseline to month 12 was generally similar in both treatment groups (40 % in the pasireotide group vs. 38 % in the octreotide group) [21]. A similar degree of tumour volume reduction was recorded in post-surgical and de novo patients. During the 12 month treatment period, dose up-titration (based on the degree of biochemical response) was implemented in 50.6 % of pasireotide recipients (to pasireotide 60 mg/28 days) and 67.6 % of octreotide recipients (to octreotide 30 mg/28 days) [21]. Both treatments led to improvements in acromegaly symptoms and health-related quality of life (HR-QOL) [21]. At month 12, improvements in symptom severity scores for all symptoms assessed (headache, fatigue, perspiration, paraesthesia and osteoarthralgia) were generally similar in pasireotide and octreotide treatment groups. HRQOL scores, as assessed by the 22-item AcroQOL questionnaire, improved by a mean of 7.0 points in the pasireotide group versus 4.9 points in the octreotide group (baseline AcroQOL scores were 58.4 vs. 55.6; lower scores indicate worse HR-QOL) [21]. 4.1.2 Extension Phase Results of a 12-month, double-blind, multicentre extension phase demonstrated that intramuscular pasireotide provides sustained biochemical control in patients with acromegaly [23]. At completion of the core, 12-month study [21], patients who were benefiting from treatment, i.e. those who had achieved biochemical control or were considered to be experiencing clinical benefit, were eligible to continue their study treatment. Patients who had not achieved biochemical control were eligible to switch treatments at month 13 [23]. Among patients enrolled in the extension (n = 239), 74 patients in the pasireotide group and 46 patients in the octreotide group continued on their randomized therapy. At the end of 26 months’ treatment, 48.6 and 45.7 % of patients in each group, respectively, were experiencing continued biochemical control, and 60.8 and 52.2 %, respectively, had a mean GH\2.5 lg/L and IGF-1 B1 times ULN [23]. Among patients enrolled in the extension who had not achieved biochemical control at month 12 (n = 119), 81 switched from octreotide to pasireotide and 38 switched from pasireotide to octreotide at month 13 (results reported in an abstract and poster) [24]. After a further 12 months’ treatment (month 25), biochemical control was achieved in 14 (17 %) patients who switched to pasireotide, and no patients who switched to octreotide. From the time of treatment switch to month 25, tumour volume decreased by

Pasireotide: A Review Table 1 Efficacy of intramuscular pasireotide in patients with acromegaly. Results of randomized, double-blind [21] or partial-blind [22] studies at 6 [22] and 12 [21] months Pt population

Treatmenta (mg)

Pt no.b

Biochemical controlc (% pts)

OR [21] or tmt difference (%) [22] vs. active control [95 % CI]

Normalized IGF-1 (% pts)

OR [21] or tmt difference (%) [22] vs. active control [95 % CI]

PAS 40d

176

31.3e

d

OCT 20 PAS 40d

182 71

19.2e 39.4

OR 1.94* [1.19–3.17]

38.6

OR 2.09* [1.32–3.31]

OR 2.34f [1.14–4.79]

23.6 50.7

d

78

21.8

OR 2.79 [1.41–5.53]

PAS 40d

105

25.7

OCT 20d

104

17.3

Medically naive pts [21] All pts Postsurgery De novo

OCT 20

26.9 OR 1.65 [0.85–3.23]

30.5

OR 1.63 [0.87–3.06]

21.2

Pts inadequately controlled with somatostatin analogue therapy [22] All pts

65

15.4e

PAS 60

65

e

20.0

OCT 30 or LAN ATG 120

68

0e

PAS 40

15.4** [7.6–26.5]

24.6

24.6** [14.8–36.9]

20.0*** [11.1–31.8]

26.2

26.2*** [16.0–38.5]

0

GH growth hormone, IGF-1 insulin-like growth factor-1, LAN ATG lanreotide autogel, OCT octreotide, OR odds ratio, PAS pasireotide, pt/s patient/s, tmt treatment * p \ 0.01, ** p \ 0.001, *** p \ 0.0001 vs. active control a

All drugs were administered via intramuscular injection once every 28 days

b

Intent-to-treat [21] or full analysis set [22] population

c

GH \2.5 lg/L and normal IGF-1 for age and sex

d

Dose up-titration (to pasireotide 60 mg/28 days or octreotide 30 mg/28 days) performed at month 3 or 7 at the discretion of the investigator Primary endpoint

e f

Significant vs. OCT 20 mg at the 0.05 level

a mean of 24.7 % in the pasireotide group and 17.9 % in the octreotide group [24]. A reduction in tumour volume of [20 % throughout the same period was observed in 54.3 and 42.3 % of patients in each group, respectively. 4.2 Patients with Inadequately Controlled Acromegaly 4.2.1 Phase III PAOLA Study The Paola study evaluated patients (n = 198) with inadequately controlled acromegaly (mean GH [2.5 lg/L and IGF-1 [1.3 times ULN for age and sex) despite receiving monotherapy with maximum approved doses of intramuscular octreotide 30 mg or lanreotide autogel 120 mg every 28 days for C6 months [22]. Patients were randomized to intramuscular pasireotide 40 or 60 mg every 28 days in a double-blind manner, or to continue existing open-label therapy (active control group) for 6 months [22]. Patients who had received combination therapy with a GH receptor antagonist (14 % of patients) or dopamine agonist (32 %) were eligible for inclusion, but only if these agents had been discontinued C8 weeks previously. Key

exclusion criteria included pituitary irradiation within the past 10 years, significant cardiovascular morbidity, and HbA1c [8 %. At baseline, the median time since diagnosis was approximately 53 months, two-thirds of patients had undergone pituitary surgery, and the median time since surgery was approximately 47 months [22]. In the pasireotide 40 and 60 mg and active control groups at baseline, the mean GH level was 17.6, 12.1 and 9.5 lg/L, respectively, and the mean standardized IGF-1 level was 2.6, 2.8 and 2.9 times ULN. The primary endpoint was the proportion of patients achieving biochemical control, as defined previously (Sect 4.1), at month 6 in the full analysis set [22]. After 6 months of treatment, biochemical control was achieved by significantly more patients in both pasireotide dosage groups than in the active control group, in which no patients achieved biochemical control (Table 1) [22]. Similarly, IGF-1 normalization was achieved by significantly more pasireotide recipients than octreotide or lanreotide autogel recipients (Table 1). In an analysis based on baseline GH levels, biochemical control was achieved by numerically fewer patients with high baseline GH levels (i.e. [10 lg/L) [11 % of patients receiving pasireotide

K. McKeage

40 mg and 6 % of patients receiving pasireotide 60 mg] than those with baseline GH levels ranging from 2.5 to 10 lg/L (17 and 26 % of patients, respectively) [22]. In both pasireotide dosage groups, mean GH and IGF-1 levels decreased within the first 3 months and the treatment effect was sustained throughout 6 months’ treatment, whereas the decrease in levels of both hormones was only slight in the active control group [22]. At week 24 in the pasireotide 40 and 60 mg groups and the active control group, the mean percentage decrease in IGF-1 values from baseline was 28.0, 38.6 and 7.2 %, respectively, and the mean percentage decrease in GH levels from baseline was 23.1, 50.9 and 3.2 %. By week 24, more patients receiving pasireotide 40 or 60 mg than active control achieved mean GH levels of \2.5 lg/L [35 % (p = 0.0024) and 43 % (p = 0.0001) vs. 13 %; p values given for exploratory purposes] [22]. A reduction in tumour volume of [25 % from baseline to week 24 was achieved by more patients receiving pasireotide 40 or 60 mg than active control (18.5 and 10.8 vs. 1.5 %; levels of significance not reported) [22]. Overall, improvements in acromegaly symptoms from baseline to week 24 were numerically greater with pasireotide 40 or 60 mg than active control [22]. AcroQOL scores improved by 2.6, 5.2 and 1.6 in each group, respectively (baseline scores were 59.9, 57.2 and 55.5).

5 Tolerability Intramuscular pasireotide once every 28 days was generally well tolerated in patients with acromegaly in phase III clinical trials (Sect. 4). Overall, the tolerability profile was similar to that of other somatostatin analogues, except for a higher incidence of hyperglycaemia with pasireotide (Sect. 5.2).

In the 6-month PAOLA study in patients with inadequately controlled acromegaly, two patients in the pasireotide 40 mg group (n = 63), one patient in the pasireotide 60 mg group (n = 62) and no patients in the active control group (receiving octreotide 30 mg or lanreotide autogel 120 mg; n = 66) experienced a serious adverse event thought to be drug related [22]. Five patients discontinued treatment because of a treatment-related adverse event, including one case of hyperglycaemia in the pasireotide 40 mg group and one case of diabetes mellitus and three cases of hyperglycaemia in the pasireotide 60 mg group [22]. One patient receiving pasireotide 40 mg required dose interruption due to liver injury. Bradycardiarelated adverse events (regardless of study drug relationship) in the pasireotide 40 or 60 mg or active control groups occurred in 7.9, 3.2 and 0 % of patients, respectively [22]. Across both trials, the most common adverse events associated with pasireotide regardless of causality were diarrhoea, hyperglycaemia, cholelithiasis, diabetes, headache, nasopharyngitis and abdominal pain [21, 22]. A summary of the most common adverse events reported in the trial in medically naive patients with acromegaly is provided in Fig. 1 [21]. The incidence of adverse events, other than hyperglycaemia and diabetes, tended to be higher in the trial in medically naive patients than in the trial in patients who had previously received somatostatin analogue therapy. For example, the incidence of diarrhoea in medically naive patients receiving pasireotide 40 mg or octreotide 20 mg was 39 and 45 %, respectively (Fig. 1)

↑ Blood CPK PAS (n = 178) OCT (n = 180)

Nausea Nasopharyngis Abdo pain

5.1 General Profile In the phase III trials, most adverse events associated with intramuscular pasireotide were mild to moderate in severity [21, 22], including during treatment periods of up to 26 months [23]. In medically naive patients, at least one treatment-related serious adverse event occurred in 4.5 % of patients in the pasireotide 40 mg group (n = 178) and 2.8 % of patients in the octreotide 20 mg group (n = 180) throughout 12 months’ treatment [21], and 6.2 and 6.1 %, respectively, throughout 26 months’ treatment [23]. Eight (4.5 %) patients, all in the pasireotide group, discontinued treatment during the 12-month core study due to a serious drug-related adverse event [21]. The most common adverse events leading to treatment discontinuation were related to elevated blood glucose.

Alopecia Diabetes mellitus Headache Cholelithiasis Hyperglycaemia Diarrhoea 0

10

20

30

40

50

Incidence (% of pts)

Fig. 1 Tolerability of intramuscular pasireotide in medically naive patients with acromegaly. Adverse events (all grades) irrespective of study drug relationship reported in C12 % of patients in the pasireotide group. Patients received pasireotide 40 mg or octreotide 20 mg once every 28 days for up to 26 months in a randomized, double-blind, multicentre study and extension [21, 23]. Abdo abdominal, CPK creatine phosphokinase, OCT octreotide, PAS pasireotide, pts patients

Pasireotide: A Review

[21], whereas the incidence of diarrhoea in the pasireotide 40 or 60 mg groups or the active control group in inadequately controlled patients was 16, 19 and 5 %, respectively [22]. This observation is consistent with there being a greater incidence of most adverse events at the start of treatment with a somatostatin analogue than after several months of therapy. 5.2 Hyperglycaemia Hyperglycaemia-related adverse events (including all terms relating to elevated blood glucose, e.g. hyperglycaemia and diabetes etc.) occurred frequently in patients receiving intramuscular pasireotide in the phase III trials [21–23].

stopped, as evidenced in patients who switched from pasireotide to octreotide after 13 months of treatment (reported in an abstract and poster) [24]. Among these patients (n = 38), mean FPG and HbA1c levels decreased from the time of treatment switch (127 mg/dL and 6.71 %, respectively) to month 3 (104 mg/dL and 6.15 %) and remained stable to month 12 (103 mg/dL and 6.0 %) [HbA1c levels were estimated from a figure] [24]. In contrast, among patients who switched from octreotide to pasireotide at month 13 (n = 81), mean FPG and HbA1c levels increased from the time of treatment switch (104 mg/dL and 6.19 %), peaking at month 1 (FPG 141.4 mg/dL) and 3 (HbA1c 7.0 %), then declining slightly and stabilizing to month 12 (125 mg/dL and 6.7 %, respectively). 5.2.2 Patients with Inadequately Controlled Acromegaly

5.2.1 Patients Naive to Medical Therapy During 26 months’ therapy in the core phase III study and extension in medically naive patients, the incidence of hyperglycaemia-related adverse events in the pasireotide 40 mg and octreotide 20 mg groups was 62.9 and 25.0 %, respectively [23]. Mean glucose and HbA1c levels increased in the first 3 months of pasireotide treatment and then stabilized to month 26 [21, 23]. In the octreotide group, mean glucose and HbA1c levels increased only slightly and gradually, peaking at about 9–12 months, and then remaining stable to month 26. In the core, 12-month phase of the trial, a grade 3 or 4 hyperglycaemia-related adverse event occurred in 9.0 % of pasireotide recipients compared with 1.7 % of octreotide recipients [21]. Numerically higher increases in mean glucose and HbA1c levels occurred in pasireotide recipients who were diabetic or prediabetic at baseline than in those with normal glucose tolerance [21]. Metformin-based antidiabetic therapy appears to control pasireotide-associated hyperglycaemia in acromegaly patients [25]. Among patients (n = 57) randomised to pasireotide who initiated antidiabetic therapy during the core, 12-month study, 24 received metformin alone, 19 received metformin plus another oral antidiabetic agent, and 10 received insulin with or without another oral antidiabetic agent (reported in an abstract and poster) [25]. The greatest difference in mean HbA1c and fasting plasma glucose (FPG) levels between the three groups was at month 3, with very little difference at month 12. At month 12, mean HbA1c levels in groups receiving pasireotide in combination with metformin or metformin plus another oral antidiabetic agent or insulin with or without another oral antidiabetic agent were 6.6, 6.7 and 7.2 %, respectively. The hyperglycaemia associated with intramuscular pasireotide appears to be reversible when treatment is

In the 6-month PAOLA study in patients with inadequately controlled acromegaly, a similar pattern of an early increase followed by stable levels of mean FPG and HbA1c was observed in pasireotide-treated patients to that reported in medically naive patients receiving pasireotide [22]. Throughout the study, the incidence of hyperglycaemiarelated adverse events in the pasireotide 40 and 60 mg and active control groups was 67, 61 and 30 %, respectively [22]. As reported in medically naive patients, baseline glucose levels were a key predictive factor for the development of hyperglycaemia-related adverse events, with 71, 70 and 30 % of patients who were categorized at baseline as diabetic, prediabetic, or having normal glucose tolerance, respectively, developing hyperglycaemia-related adverse events during therapy with pasireotide 40 mg every 28 days [22]. Percentages among corresponding patient groups receiving pasireotide 60 mg were 70, 50 and 46 %. Antidiabetic medication (most commonly metformin) was initiated in 38, 39 and 6 % of patients receiving pasireotide 40 or 60 mg or active control, respectively. Proactive monitoring of blood glucose levels and early intervention with antidiabetic agents appears to improve hyperglycaemic control in pasireotide-treated patients (reported in an abstract and poster) [26]. Among non-diabetic (n = 19), pre-diabetic (n = 24) and diabetic (n = 82) patients receiving pasireotide in the 6-month, PAOLA study, hyperglycaemia was reported in 26, 38 and 83 %, respectively. In diabetic patients who initiated or adjusted therapy with an antidiabetic agent early (i.e. within the first 2 weeks of pasireotide treatment) [no non-diabetic or prediabetic patients received an antidiabetic agent in the first 2 weeks], the decrease in FPG levels was greater than in patients who initiated or adjusted antidiabetic therapy later (i.e. [15 to \30 days, and C30 days after commencing pasireotide) (levels of significance not reported) [26].

K. McKeage

6 Dosage and Administration Pasireotide is approved for the treatment of adults with acromegaly in the EU [5] and USA [6], and is in phase III development for this indication in several other countries. In the EU, it is indicated for patients for whom surgery is not an option or has not been curative and those who are inadequately controlled on treatment with another somatostatin analogue [5]. In the USA, it is indicated for patients who have had an inadequate response to surgery and/or for whom surgery is not an option [6]. Pasireotide should be administered via deep intramuscular injection, and the recommended initial dose is 40 mg every 28 days [5, 6]. If GH and/or IGF-1 levels are not fully controlled after 3 months’ treatment, the dose may be increased to a maximum of pasireotide 60 mg every 28 days. A temporary or permanent decrease in the dose by 20 mg decrements may be needed to manage adverse reactions or over-response to treatment (i.e. age and sex-adjusted IGF-1 levels less than the lower limit of normal) [5, 6]. Pasireotide should not be administered in patients with severe hepatic impairment, and dosage adjustment is recommended for patients with moderate hepatic impairment [5, 6]. Dose adjustment is not required in patients with mild hepatic impairment, renal function impairment or the elderly (Sect. 3.2). Pasireotide is associated with hyperglycaemia (Sect. 5.2). Glycaemic status (FPG and HbA1c levels) should be assessed prior to starting treatment and monitored throughout [5, 6]. Antidiabetic medication should be initiated (or adjusted) if hyperglycaemia develops, and treatment guidelines for the management of hyperglycaemia should be followed. If uncontrolled hyperglycaemia persists, the dose of pasireotide should be reduced or treatment discontinued. As cholilithiasis is associated with the longterm use of somatostatin analogues (Sect. 5.1), ultrasound examination of the gallbladder should be performed periodically during pasireotide treatment [5, 6]. Mild transient elevations in aminotransferases have been observed in patients treated with pasireotide, and it is recommended that liver function be monitored prior to and at regular intervals during treatment [5, 6]. Bradycardia (Sect. 5.1) and prolongation of the QT interval have been reported in patients receiving pasireotide. Patients with cardiac disease and/or risk factors for bradycardia should be carefully monitored, and the drug should be used with caution in patients at risk of developing QT interval prolongation [5, 6]. Accordingly, pasireotide should be used with caution in patients receiving drugs that prolong the QT interval, and patient monitoring is recommended when pasireotide is coadministered with bradycardic agents.

The prescribing information should be consulted for further detailed information regarding special warnings and precautions.

7 Place of Pasireotide in the Management of Acromegaly A multimodal approach to treatment is usually required in patients with acromegaly [3, 4]. If disease persists following transphenoidal surgery (if indicated), medical management is recommended, with the possible use of radiation therapy if necessary [1, 3]. Current treatment guidelines recommend that management goals include a serum IGF-1 target normalized for age and sex and a serum GH target of \1.0 lg/L assessed using up-to-date sensitive immunoassay [3, 4]; the random serum GH target of \2.5 lg/L measured by radioimmunoassay specified in trials discussed in this review reflects earlier treatment practice. Currently, medical therapy in acromegaly includes three drug classes: somatostatin analogues (i.e. pasireotide, octreotide and lanreotide autogel), the GH receptor antagonist pegvisomant, and dopamine agonists (e.g. cabergoline) [3, 4]. Recent consensus treatment guidelines recommend the use of a somatostatin analogue as first-line adjuvant therapy in patients with a significant level of disease postsurgery, with a switch to pegvisomant if there is no response (i.e. GH and IGF-1 levels undergo minimal change) [4]. In patients with mild disease (IGF-1 \2 times ULN), primary therapy with cabergoline may be considered [4]. If an inadequate response is achieved with one drug, combination therapy may improve efficacy and minimize the potential adverse effects associated with increased doses of individual agents [3, 4]. Until the recent approval of intramuscular pasireotide for the treatment of acromegaly, the long-acting formulations of intramuscular octreotide and lanreotide autogel were the only somatostatin analogues approved for use in this indication. While the efficacy of these two agents has not been compared in a well-designed trial, a meta-analysis of trials of [3 months’ duration found no significant differences in efficacy, with a large variation between trials in biochemical outcomes [27]. Pasireotide has a unique SSTR binding profile compared with that of the first-generation agents octreotide and lanreotide (Sect. 2). Its ability to bind with high affinity to multiple SSTRs, two of which (SSTR-2 and -5) are expressed on most GH-secreting pituitary adenomas, may provide the rationale for the greater efficacy in achieving biochemical control demonstrated with pasireotide versus first-generation, SSTR-2 preferential agents in patients

Pasireotide: A Review

with acromegaly (Sects. 4.1.1, 4.2), including those with long-standing disease not controlled with octreotide or lanreotide autogel (Sect. 4.2). Evidence also indicates heterogeneity of SSTR expression on pituitary tumours and, thus, advantages in efficacy achieved with pasireotide versus first-generation agents may be particularly evident in patients with tumours that have a low SSTR-2 to -5 ratio [28]. In both phase III studies in acromegaly patients, pasireotide led to a rapid reduction in GH and IGF-1 levels over the first 3 months, followed by sustained control throughout treatment, including periods of up to 26 months (Sect. 4). Improvements in tumour volume, acromegaly symptoms and HR-QOL were generally similar in pasireotide and octreotide groups in medically naive patients [21], but generally greater in the pasireotide group than the active control group in inadequately controlled patients [22]. The tolerability profile of pasireotide is generally similar to that observed with first-generation agents, except for a higher incidence and greater degree of severity of hyperglycaemia and diabetes (Sect 5.2). The increase in blood glucose levels during pasireotide treatment appears to result from suppression of insulin and incretin secretion, as there is no impact on insulin sensitivity (Sect. 2.1). In clinical trials in patients with acromegaly, about two-thirds of patients developed hyperglycaemia-related adverse events throughout treatment with pasireotide (Sect. 5.2). Careful monitoring of the glycaemic status should be continued throughout treatment, and antidiabetic medication should be initiated or adjusted as necessary (Sect. 6). The effect of antidiabetic medication on pasireotide-associated hyperglycaemia in acromegaly clinical trials was not analysed prospectively, so further studies are needed to explore the level of control that can be achieved. Indeed, an ongoing trial should help establish optimal treatment algorithms for the management of pasireotide-induced hyperglycaemia in patients with acromegaly or Cushing’s disease [29]. Preliminary results of an analysis of phase III trial data in patients with acromegaly indicate that metformin is an effective treatment option for the control of pasireotide-associated hyperglycaemia (Sect. 5.2.1). Metformin increases GLP-1 secretion and improves insulin sensitivity [30] and, therefore, may offset the effects of pasireotide on glucose homeostasis. Evidence also suggests that better hyperglycaemic control may be achieved with early rather than late intervention with antidiabetic therapy in pasireotide-treated patients (Sect. 5.2.2). Moreover, recommendations from a panel of experts regarding the treatment of hyperglycaemia secondary to pasireotide in patients with Cushing’s disease stipulate that if glycaemic control is not achieved or maintained

with metformin, the addition of an agent that targets the incretin pathway is recommended [31]. Accordingly, a dipeptidyl peptidase 4 inhibitor (DPP-4; e.g. linagliptin) is recommended as a first option for add-on therapy with metformin, and if glycaemic targets are still not met, the DPP-4 inhibitor may be replaced with a GLP-1 receptor agonist (e.g. liraglutide). For those patients who continue to be hyperglycaemic despite oral antidiabetic drugs, insulin therapy together with continued metformin may be required [31]. In both phase III trials in patients with acromegaly, mean glucose and HbA1c levels tended to increase until month 3 and then stabilize throughout treatment. Baseline glucose levels were a key predictive factor for the development of hyperglycaemia-related adverse events, with hyperglycaemia occurring most frequently in pre-diabetic and diabetic patients (Sect. 5.2). Importantly, pasireotideassociated increases in FBG and HbA1c are reversed when pasireotide is discontinued (Sect. 5.2.1). In conclusion, intramuscular pasireotide provided significantly greater biochemical control than other somatostatin analogues in two, well-designed trials in patients with acromegaly. However, the risk of hyperglycaemia-related adverse events is markedly higher with pasireotide than with octreotide or lanreotide autogel, particularly in patients with raised blood glucose levels at baseline. Careful monitoring of glycaemic status is required prior to and during pasireotide treatment and antidiabetic therapy should be commenced as indicated. Thus, in the treatment of acromegaly, pasireotide may be a more effective somatostatin analogue than other approved agents of the same class; however, the increased risk of hyperglycaemia needs to be considered and proactively managed. Data selection sources: Relevant medical literature (including published and unpublished data) on pasireotide was identified by searching databases including MEDLINE (from 1946) and EMBASE (from 1996) [searches last updated 12 May 2015], bibliographies from published literature, clinical trial registries/databases and websites. Additional information was also requested from the company developing the drug. Search terms: Pasireotide, acromegaly, Signifor, Som 230 Study selection: Studies in patients with acromegaly who received pasireotide. When available, large, well designed, comparative trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Disclosure The preparation of this review was not supported by any external funding. During the peer review process, the manufacturer of the agent under review was offered an opportunity to comment on this article. Changes resulting from comments received were made by the author on the basis of scientific and editorial merit. Kate McKeage is a salaried employee of Adis/Springer.

K. McKeage

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Pasireotide in Acromegaly: A Review.

Pasireotide (Signifor(®), Signifor(®) LAR) is a somatostatin analogue recently approved for the treatment of acromegaly. Unlike the first-generation a...
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