Pasireotide (SOM230): development, mechanism of action and potential applications

Pasireotide (SOM230) is a multi-receptor ligand somatostatin analogue with high binding affinity for somatostatin receptor subtypes sst(1,2,3) and sst(5). Pasireotide potently suppresses GH, IGF-I and ACTH secretion, indicating potential efficacy in acromegaly and Cushing's disease. The prolonged inhibition of hormone secretion by pasireotide in animal models and expression of multiple sst receptors in carcinoid tumors suggests that pasireotide may have clinical advantages over octreotide in patients with carcinoid tumors. Direct and indirect antitumor activity has been observed in vitro with pasireotide, including sst receptor-mediated apoptosis and antiangiogenesis, suggesting a possible role for pasireotide in antineoplastic therapy. In summary, preclinical evidence, as well as preliminary results from clinical studies suggests that pasireotide is a promising new treatment for patients with symptoms of metastatic carcinoid tumors refractory or resistant to octreotide, de novo or persistent acromegaly, and that pasireotide has the potential to be the first directed medical therapy for Cushing's disease.     

Pasireotide monotherapy in Cushing’s disease: a single-centre experience with 5-year extension of phase III Trial

Purpose

A recent phase III randomized controlled trial (NCT00434148) showed efficacy of pasireotide in the treatment of patients with Cushing’s disease (CD). Patients were invited to participate in an extension phase of the protocol and a subgroup had a sustained response. We report the experience with 4 patients in our center of which 2 full responders have completed 5.5 and 4.25 years of treatment with disease control.

Methods

The trial protocol was described previously. The extension phase consisted of 3-monthly visits with clinical, biochemical, and imaging evaluation and investigator-driven pasireotide titration. Research charts were retrospectively analyzed.

Results

Four patients with persistent CD following pituitary surgery completed the first 6 months of the trial and 3 continued in the next 6 month open-label phase. Two patients with baseline urinary free cortisol (UFC) 5.3–6.7 times the upper limit of normal had a rapid sustained response to pasireotide and entered the extension phase after 12 months. They remain in clinical and biochemical disease remission and 1 patient now only requires 300 μg daily of pasireotide. All 4 patients developed glucose intolerance; however, the two patients in the extension phase were eventually able to discontinue all diabetes pharmacotherapy. Adverse events included second degree atrioventicular block type 1 without QT prolongation in a patient with pre-existing sinus bradycardia, and symptomatic cholelithiasis requiring cholecystectomy in a second patient.

Conclusions

Pasireotide therapy can provide normalization of UFC and of clinical symptoms and signs of CD during up to 5 years of follow-up. This study demonstrates the possible recuperation of normoglycemia after continued use of pasireotide and control of underlying hypercortisolemia. Longer-term monitoring for potential adverse events related to continued use of pasireotide is indicated.     

Extended treatment of Cushing’s disease with pasireotide: results from a 2-year,Phase II study

In a previous 15-day, Phase II study of patients with de novo or persistent/recurrent Cushing’s disease (core study), treatment with pasireotide 600 μg sc bid reduced urinary free cortisol (UFC) levels in 76 % of patients and normalized UFC in 17 %. The objective of this study was to evaluate the efficacy and safety of extended treatment with pasireotide. This was a planned, open-ended, single-arm, multicenter extension study (primary endpoint: 6 months). Patients aged ≥18 years with Cushing’s disease who completed the core study could enter the extension if they achieved UFC normalization at core study end and/or obtained significant clinical benefit. Of the 38 patients who completed the core study, 19 entered the extension and 18 were included in the efficacy analyses (three responders, 11 reducers, four non-reducers in the core study). At data cut-off, median treatment duration in the extension was 9.7 months (range: 2 months to 4.8 years). At extension month 6, 56 % of the 18 patients had lower UFC than at core baseline and 22 % had normalized UFC. Of the four patients who remained on study drug at month 24, one had normalized UFC. Reductions in serum cortisol, plasma adrenocorticotropic hormone, body weight and diastolic blood pressure were observed. The most common adverse events were mild-to-moderate gastrointestinal disorders and hyperglycemia. Pasireotide offers a tumor-directed medical therapy that may be effective for the extended treatment of some patients with Cushing’s disease.

     

Pasireotide (SOM230) shows efficacy and tolerability in the treatment of patients with advanced neuroendocrine tumors refractory or resistant to octreotide LAR: results from a phase II study

Pasireotide (SOM230) is a novel multireceptor-targeted somatostatin (sst) analog with high binding affinity for sst receptor subtype 1, 2, 3 (sst(1,2,3)) and sst(5). Because of this binding profile, pasireotide may offer symptom control in patients with neuroendocrine tumors (NETs) and carcinoid syndrome no longer responsive to octreotide LAR. This was a phase II, open-label, multicenter study of pasireotide in patients with advanced NET whose symptoms of carcinoid syndrome (diarrhea/flushing) were inadequately controlled by octreotide LAR. Patients received s.c. pasireotide 150?μg twice daily (bid), escalated to a maximum dose of 1200?μg bid until a clinical response was achieved. Forty-four patients were evaluated for efficacy and 45 for tolerability. Pasireotide 600-900?μg s.c. bid effectively controlled the symptoms of diarrhea and flushing in 27% of patients. Evaluation of tumor response in 23 patients showed 13 with stable disease and ten with progressive disease at study end. The most common drug-related adverse events were nausea (27%), abdominal pain (20%), weight loss (20%), and hyperglycemia (16%) and most were of mild or moderate severity. Pasireotide 600-900?μg s.c. bid was effective and generally well tolerated in controlling the symptoms of carcinoid syndrome in 27% of patients with advanced NET refractory or resistant to octreotide LAR therapy.     

Hyperglycemia induced by pasireotide in patients with Cushing’s disease or acromegaly

Purpose

Cushing’s disease (CD) and acromegaly are characterized by excessive hormone secretion resulting in comorbidities such as impaired glucose metabolism, diabetes and hypertension. Pasireotide is a new-generation, multireceptor-targeted somatostatin receptor ligand approved for CD (subcutaneous [SC] injection formulation) and acromegaly (long-acting release [LAR] formulation). In clinical studies of pasireotide, hyperglycemia-related adverse events (AEs) were frequently observed. This review highlights differences in reported rates of hyperglycemia in pasireotide trials and discusses risk factors for and management of pasireotide-associated hyperglycemia.

Methods

Clinical trials evaluating pasireotide in patients with CD or acromegaly were reviewed.

Results

The frequency of hyperglycemia-related AEs was lower in patients with acromegaly treated with pasireotide LAR (57.3–67.0 %) than in patients with CD treated with pasireotide SC (68.4–73.0 %). Fewer patients with acromegaly treated with pasireotide LAR discontinued therapy because of hyperglycemia-related AEs (Colao et al. in J Clin Endocrinol Metab 99(3):791–799, 2014, 3.4 %; Gadelha et al. in Lancet Diabetes Endocrinol 2(11):875–884, 2014, 4.0 %) than did patients with CD treated with pasireotide SC (Boscaro et al. in Pituitary 17(4):320–326, 2014, 5.3 %; Colao et al. in N Engl J Med 366(10):914–924, 2012, 6.0 %). Hyperglycemia-related AEs occurred in 40.0 % of patients with acromegaly treated with pasireotide SC, and 10.0 % discontinued treatment because of hyperglycemia. Ongoing studies evaluating pasireotide LAR in patients with CD and management of pasireotide-induced hyperglycemia in patients with CD or acromegaly (ClinicalTrials.gov identifiers NCT01374906 and NCT02060383, respectively) will address these key safety issues.

Conclusions

Disease pathophysiology, drug formulation, and physician experience potentially influence the differences in reported rates of pasireotide-induced hyperglycemia in CD and acromegaly. Hyperglycemic effects associated with pasireotide have a predictable pattern, can be managed with antidiabetic agents, and are reversible upon discontinuation.

     

Oral estroprogestin: an alternative low cost therapy for women with postoperative persistent acromegaly?

Oral estrogens reduce GH-induced IGF-1 production and preliminary studies have shown that adjuvant estroprogestin (EP) therapy with octreotide LAR may control disease activity in some female patients who are partially responsive to octreotide LAR. Our aim was to verify if EP alone or in combination with octreotide LAR can achieve remission of acromegaly in selected cases of patients uncontrolled by surgery. Eleven women with persistent active acromegaly following surgery participated in this unblinded open label pilot study. Their mean age was 49.8 ± 4.3 years. Two patients were drug naïve, two patients had stopped octreotide LAR because of intolerance and seven were treated with octreotide LAR. The patients received either EP (EP pill, 20 μg ethinylestradiol, 100 μg levonorgestrel) alone (4 patients) or added to octreotide LAR (7 patients). Fasting GH, IGF-1, glucose, HDL- and LDL-cholesterol, and triglycerides were measured at baseline and at last visit. MRI was controlled at baseline and at last visit. Duration of estrogen treatment was 3.1 ± 0.5 years. Serum IGF-1 levels were normalized in 8/11 patients (73%). Serum GH concentrations did not change significantly during treatment (11.6 ± 5.6 μg/L prior to EP vs 5.5 ± 1.2 μg/L following EP). In patients treated with EP alone, remission was achieved in 2/4 patients (IGF-1 percentages of the upper limit of normal age-matched range (%ULN): 211 ± 40% before EP compared to 95 ± 15% after EP, P = 0.028). In the seven patients treated by EP added to octreotide LAR, remission was achieved in 6 patients (IGF-1%ULN: 158 ± 9% before EP compared to 86 ± 4% after EP, P = 0.0003). Glucose and cholesterol levels were unchanged by EP treatment (data not shown). MRI did not show any evidence of tumour progression with EP in patients who had a tumour remnant. In conclusion, oral estrogen treatment appears to normalize serum IGF-1 concentrations in over 70% of women with acromegaly uncured by surgery irrespective of their sensitivity to octreotide LAR. We suggest that estrogens may be a temporary cost-effective and safe treatment for women with postoperative persistent acromegaly.     

The effects of somatostatin analogue therapy on pituitary tumor volume in patients with acromegaly

Introduction

In nearly all cases, acromegaly is caused by excess GH from a pituitary adenoma, resulting in elevated circulating levels of GH and, subsequently, IGF-1. Treatment goals are to eliminate morbidity and restore the increased mortality to normal rates. Therapeutic strategies aim to minimize tumor mass and normalize GH and IGF-1 levels. Somatostatin analogues are the medical treatment of choice in acromegaly, as first-line or post-surgical therapy, and have proven efficacy in pituitary tumor volume reduction (TVR).

Methods

Here we review the effects of somatostatin analogue therapy on pituitary tumor volume in patients with acromegaly.

Results

TVR with somatostatin analogues may be mediated by direct anti-proliferative effects via activation of somatostatin receptors, or by indirect effects, such as angiogenesis inhibition, and is more pronounced when they are administered as first-line therapy. Various studies of first-line treatment with octreotide LAR have shown significant TVR in ≥73 % of patients. First-line treatment with lanreotide Autogel has shown evidence of TVR, although more studies are needed. In a recent randomized, double-blind, 12-month trial in 358 medical-treatment-naïve acromegaly patients, significant TVR was achieved by 81 % of patients administered pasireotide LAR and 77 % administered octreotide LAR. Pre-operative somatostatin analogue therapy may also induce TVR and improve post-operative disease control compared with surgery alone. TVR is progressive with prolonged treatment, and decreased IGF-1 levels may be its best predictor, followed by age and degree of GH decrease. However, TVR does not always correlate with degree of biochemical control.

Conclusion

Somatostatin analogues (first- or second-line treatment) are the mainstay of medical therapy and, as first-line medical therapy, are associated with significant pituitary TVR in most patients.

     

Effectiveness of self- or partner-administration of an extended-release aqueous-gel formulation of lanreotide in lanreotide-naïve patients with acromegaly

Surgical resection is often not curative in patients with acromegaly and long-acting somatostatin analogues (lanreotide or octreotide) are often needed. This study assessed the efficacy and safety of self- or partner-administration of lanreotide in patients with acromegaly. This was a six-month, single-arm, open-label study conducted at 13 endocrinology clinics. Fifty-nine patients received deep subcutaneous lanreotide injections every 28 days. Twelve patients started on 120 mg lanreotide and forty-seven started on 90 mg lanreotide. At week 16, the dose was adjusted to 60, 90 or 120 mg based on insulin-like growth factor-1 (IGF-1) levels at week 12. Fifty-nine patients with acromegaly either switched from long-acting octreotide (switch; n = 33) or were somatostatin analogue treatment-naïve or not currently taking long-acting octreotide (“other”; n = 26). The key endpoints included the percentage of patients/partners able to self- or partner-inject lanreotide and those with normal IGF-1 or growth hormone (GH) levels at week 24/early termination. 100% of patients/partners correctly self- (n = 41) or partner-injected (n = 18) lanreotide by week 4. By week 24/early termination, IGF-1 levels were controlled in 93.7% of switch and 46.2% of “other” patients, while GH levels were controlled in 76.9% and 39.1% of patients, respectively. Both IGF-1 and GH were controlled in 73.1% of switch and 30.4% of “other” patients. Most switch patients (81%) reported they preferred lanreotide over long-acting octreotide for future use (P = 0.0001). Self- or partner-administration of lanreotide is generally well tolerated and associated with IGF-1 and GH control in many lanreotide-naïve patients with acromegaly.     

Biochemical efficacy of long-acting lanreotide depot/Autogel in patients with acromegaly naïve to somatostatin-receptor ligands: analysis of three multicenter clinical trials

Purpose

In clinical research involving acromegalic patients naïve to somatostatin-receptor ligands (SRLs), 19 and 31% of those receiving the SRLs octreotide LAR and pasireotide LAR, respectively, achieved GH?<?2.5 ng/mL?+?normalized IGF-1 concentrations. The proportions achieving control appeared higher in the post-surgery compared with the de-novo setting with pasireotide, but more similar with octreotide. Using pooled data from multicenter clinical trials, we examined the biochemical efficacy of lanreotide depot/Autogel in similar settings.

Methods

Inclusion criteria: Ipsen-sponsored, 48–52-week trials in SRL-naïve acromegalic populations receiving lanreotide depot (60–120 mg); patients were included if de novo (no prior acromegaly treatment) or post-surgery (no medical treatment; radiotherapy allowed unless within previous 3 years). Efficacy endpoints included normalized IGF-1 levels and GH?<?2.5 ng/mL?+?normalized IGF-1 at study end/last value available. Analyses: all patients (analysis #1) and subset with baseline GH?>?5 ng/mL (analysis #2).

Results

Three studies were included. Analysis #1: normalized IGF-1 was achieved by 42% (71/171) of patients overall (post-surgery, 46% [21/46]; de-novo, 40% [50/125]); GH?<?2.5 ng/mL?+?normalized IGF-1 was achieved by 35% (59/171) (39% [18/46] and 33% [41/125], respectively). Analysis #2: normalized IGF-1 levels, 39% (46/118) (post-surgery, 40% [10/25]; de-novo, 39% [36/93]); GH?<?2.5 ng/mL?+?normalized IGF-1, 31% (36/118) (28% [7/25] and 31% [29/93], respectively).

Conclusion

In these pooled analyses of SRL-naïve patients receiving lanreotide depot, 39–42% achieved IGF-1 control and 31–35% achieved GH and IGF-1 control. Control rates within post-surgery cohorts did not differ markedly from those in corresponding de-novo cohorts.

     

IGF-1 levels may increase paradoxically with dopamine agonist treatment for prolactinomas

Objective

Hyperprolactinemia is common in acromegaly and in these patients, insulin-like growth factor (IGF)-1 level may decrease with dopamine agonist. We report a series of patients with prolactinoma and a paradoxical increase of IGF-1 levels during cabergoline treatment.

Methods

Clinical characteristics and response to treatment of patients with prolactinomas, in whom normal or slightly elevated baseline IGF-1 levels increased with cabergoline.

Results

The cohort consisted of ten prolactinoma patients (nine males, mean age 48?±?14 years). Mean adenoma size was 23.8?±?16.2 mm, with cavernous sinus invasion in eight. In five patients baseline IGF-1 levels were normal and in four levels were 1.2–1.5-fold the upper limit of the normal (ULN). One patient had IGF-1 measured shortly after initiating cabergoline and it was 1.4?×?ULN. During cabergoline treatment (dose range 0.5–2 mg/week) PRL normalization was achieved in all and tumor shrinkage occurred in seven patients. The mean IGF-1 increase on cabergoline was 1.7?±?0.4?×?ULN. Cabergoline dose reduction or interruption was attempted in five patients and resulted in decreased IGF-1 levels in all, including normalization in two patients. Three patients were eventually diagnosed with acromegaly, one was referred for pituitary surgery followed by complete remission, another patient was switched to somatostatin analogue, and the third was treated by combination of somatostatin analogues with pegvisomant, with reduction of IGF-1 in all these patients.

Conclusion

IGF-1 levels may increase to clinically significant levels during cabergoline treatment for PRL-adenoma. We suggest IGF-1 monitoring in all patients treated with dopamine agonists and not only in those presenting symptoms of acromegaly.

     

Paradoxical and atypical responses to pasireotide in aggressive ACTH-secreting pituitary tumors

Purpose

Pasireotide is the only pituitary targeted medication registered for the treatment of Cushing’s disease. Drug efficacy data are largely based on a major prospective study in which the vast majority of patients had microadenomas. The purpose of this study was to summarize results of pasireotide treatment of ACTH secreting macroadenomas from our center.

Methods

Retrospective review of data extracted from clinical files.

Results

Three patients presented with large and invasive macroadenomas that required several surgical interventions and radiotherapy treatments. Patient 1 is a 57 year-old male who developed an extreme (27-fold) paradoxical response of urinary free cortisol (UFC) levels as measured 2 weeks after pasireotide institution, which increased further (71-fold) in response to dose increment but decreased to baseline levels after treatment interruption. Patient 2 is a 44 year old woman with a long standing (26 years) ACTH-secreting carcinoma metastatic to bone and after bilateral adrenalectomy. After an initial excellent response to pasireotide treatment, ACTH levels escaped suppression and a further rebound was noted 6 weeks after treatment interruption. Patient 3 is a 53 year old man that after escape from temozolomide therapy was started on pasireotide and rapidly responded by almost normalizing UFC excretion after 4 weeks, but returned to baseline UFC levels after four additional weeks of treatment.

Conclusions

We describe as yet unreported atypical responses to pasireotide treatment in patients with aggressive ACTH-secreting tumors. Increased vigilance is recommended during pasireotide treatment of such patients.

     

Multiple once-daily subcutaneous doses of pasireotide were well tolerated in healthy male volunteers: a randomized, double-blind, placebo-controlled, cross-over, Phase I study

A randomized, double-blind, placebo-controlled, cross-over, dose-escalating, single-center study was conducted to evaluate the safety, tolerability, and pharmacokinetic (PK) profile of multiple once-daily (qd) subcutaneous (sc) doses of pasireotide in healthy male subjects. Subjects received pasireotide 50, 200, or 600?μg?sc?qd for 14?days and placebo in separate sequences. Thirty-three subjects were randomized. The most frequently reported drug-related adverse events were injection-site reactions (n?=?18), diarrhea (n?=?14) and nausea (n?=?10), which were mostly mild or moderate in intensity. Pasireotide 600?μg?sc was associated with pre- and post-prandial elevations in glucose levels relative to placebo; however, this effect was less pronounced on day 14 compared with day 1. PK steady state appeared to be achieved after 3?days of dosing and PK exposures had a moderate accumulation of 20-40?% across doses. Pasireotide demonstrated fast absorption (T (max,ss): 0.25-0.5?h), low clearance (CL/F (ss): 8.10-9.03?L/h), long effective half-life (T (?,eff): ~12?h, on average between 9.7 and 13.1?h for 50, 200, and 600?μg?sc?qd), and large volume of distribution (V (z)/F (ss): 251-1,091?L) at steady state. Dose proportionality was confirmed for C (max,ss); other PK parameters (C (max), AUC(0-24?h) and AUC(tau)) were approximately dose proportional. Growth hormone inhibition was observed with pasireotide 200 and 600?μg?sc?qd. Gallbladder volume increased post-prandially with pasireotide 200 and 600?μg?sc?qd, which appeared to correlate with reduced levels of cholecystokinin at these doses. Pasireotide was generally well tolerated up to the tested dose of 600?μg?qd, with a linear and time-independent PK profile after sc qd dosing in healthy subjects.     

A prospective longitudinal study of Pasireotide in Nelson’s syndrome

Purpose

Nelson’s syndrome is a challenging condition that can develop following bilateral adrenalectomy for Cushing’s disease, with high circulating ACTH levels, pigmentation and an invasive pituitary tumor. There is no established medical therapy. The aim of the study was to assess the effects of pasireotide on plasma ACTH and tumor volume in Nelson’s syndrome.

Methods

Open labeled multicenter longitudinal trial in three steps: (1) a placebo-controlled acute response test; (2) 1 month pasireotide 300–600 μg s.c. twice-daily; (3) 6 months pasireotide long-acting-release (LAR) 40–60 mg monthly.

Results

Seven patients had s.c. treatment and 5 proceeded to LAR treatment. There was a significant reduction in morning plasma ACTH during treatment (mean?±?SD; 1823?±?1286 ng/l vs. 888.0?±?812.8 ng/l during the s.c. phase vs. 829.0?±?1171 ng/l during the LAR phase, p?<?0.0001). Analysis of ACTH levels using a random intercept linear mixed-random effects longitudinal model showed that ACTH (before the morning dose of glucocorticoids) declined significantly by 26.1 ng/l per week during the 28-week of treatment (95% CI ??45.2 to ??7.1, p?<?0.01). An acute response to a test dose predicted outcome in 4/5 patients. Overall, there was no significant change in tumor volumes (1.4?±?0.9 vs. 1.3?±?1.0, p?=?0.86). Four patients withdrew during the study. Hyperglycemia occurred in 6 patients.

Conclusions

Pasireotide lowers plasma ACTH levels in patients with Nelson’s syndrome. A longer period of treatment may be needed to assess the effects of pasireotide on tumor volume.Trial registration: Clinical Trials.gov ID, NCT01617733

     

Pasireotide does not prevent postoperative pancreatic fistula: a prospective study

Background

Pancreatic fistula is a major cause of morbidity after pancreas surgery. In 2014, a single-center, randomized-controlled trial found pasireotide decreased pancreatic fistula rates. However, this finding has not been validated, nor has pasireotide been widely adopted.

Growth hormone granulation pattern and somatostatin receptor subtype 2A correlate with postoperative somatostatin receptor ligand response in acromegaly: a large single center experience

Acromegaly is associated with serious morbidity and mortality, if not well controlled. Approved somatostatin receptor ligands (SRLs) are a mainstay of medical therapy and exhibit preferential affinity for somatostatin receptor (SSTR) subtype 2. Our objective was to assess whether characteristic features of individual growth hormone (GH)-secreting adenomas at diagnosis, correlated with SRL sensitivity, using defined tumor markers. A retrospective review of 86 consecutive acromegaly surgeries (70 patients) performed between January 2006 and December 2011 was undertaken. Patients with any preoperative medical treatment were excluded. Response to SRL therapy was defined as normalization of insulin-like growth factor 1 (IGF1) and random GH < 1.0 ng/dl. Immunohistochemical staining pattern: sparsely granulated, densely granulated, mixed growth hormone-prolactin (GH/PRL) and SSRT2 positivity (+) were correlated with clinicopathologic features, adenoma recurrence, and SRL treatment response. Two-tailed t test, univariate ANOVA, Kruskal–Wallis and bivariate correlation were performed using PAWS 18. The cohort eligible for analysis comprised 59 patients (41 female and 18 male). Based on pre-surgery adenoma imaging dimensions, 81.3 % (48) were macroadenomas and average maximum tumor diameter was 18.1 ± 9.9 mm. Patients on SRLs were followed for 13.4 ± 15.8 (mean ± SD) months. Sparsely granulated adenomas were significantly larger at diagnosis, exhibited lower SSTR2 positivity and had a lower rate of biochemical normalization to SRLs. Densely granulated adenomas were highly responsive to SRLs. Overall, patients with SSTR2A+ adenomas responded more favorably to SRL treatment than those with SSTR2A? adenomas. Eighty-one percent of patients with SSTR2A+ adenomas were biochemically controlled (both GH and IGF1) on SRL treatment, e.g. a much higher normalization rate than that reported in the unselected acromegaly population (20–30 %). Detailed knowledge of adenoma GH granularity and the immunohistochemical SSTR2A+ status is a predictor of SRL response. These immunoreactive markers should be assessed routinely on surgical specimens to assess subsequent SRL responsiveness and potential need for adjunctive therapy after surgery.     

Phase I study of pasireotide (SOM 230) and everolimus (RAD001) in advanced neuroendocrine tumors

Octreotide and everolimus have demonstrated efficacy in neuroendocrine tumors. Pasireotide is a somatostatin analog with binding affinity to a broader range of somatostatin receptor subtypes than octreotide. We performed a phase I study to evaluate the safety and feasibility of combining pasireotide with everolimus in patients with advanced neuroendocrine tumors. Cohorts of patients with advanced neuroendocrine tumors were treated with escalating doses of pasireotide (600-1200?μg s.c. b.i.d., followed by pasireotide LAR 40-60?mg i.m. monthly) and everolimus (5-10?mg daily). Twenty-one patients were treated. Dose-limiting toxicities consisting of grade 3 rash and grade 3 diarrhea were observed. Twelve patients were safely treated at the maximum protocol-defined dose level of pasireotide LAR 60?mg i.m. monthly and everolimus 10?mg daily. Hyperglycemia was common; other observed toxicities were consistent with the known toxicities of either agent alone. Partial tumor response was observed in one patient; 17 (81%) patients experienced at least some tumor regression as their best response to therapy. In conclusion, pasireotide LAR 60?mg i.m. monthly in combination with everolimus 10?mg daily is feasible and associated with preliminary evidence of antitumor activity in patients with advanced neuroendocrine tumors. Further studies evaluating this combination are warranted.     

Effects of somatostatin analogs on glucose homeostasis in rats

Pasireotide (SOM230) is a multireceptor-targeted somatostatin analog with high binding affinity for sstr(1,2,3) and sstr(5). The effects of pasireotide and octreotide on blood glucose, insulin, and glucagon levels in rats were evaluated alone and in combination. Single-dose s.c. pasireotide acutely elevated plasma glucose, whereas single-dose s.c. octreotide had no or a small hypoglycemic effect. Glucose elevation with s.c. pasireotide was transient with tachyphylaxis after repeated or continuous administration. Pasireotide and octreotide caused similar inhibitory effects on insulin secretion, whereas pasireotide had a weaker inhibitory effect on glucagon secretion than octreotide. Continuous infusion of pasireotide or injection of pasireotide long-acting release (LAR) resulted in only small and transient elevations of plasma glucose. Based on these results, and differences in the sstr binding affinity of pasireotide vs octreotide, it was hypothesized that the sstr(5) vs sstr(2) receptor activation ratio is the main driver of hyperglycemia after pasireotide. The results also suggest that stronger activation of sstr(2) may counteract the hyperglycemic effect. Indeed, co-administration of octreotide, which has a high affinity for sstr(2), with a hyperglycemic dose of pasireotide did not cause significant changes in plasma glucose levels. In conclusion, although pasireotide and octreotide inhibited insulin to a similar degree, only pasireotide administration was associated with hyperglycemia. The strong glucagon inhibitory effect exhibited by octreotide but not pasireotide may explain this observation. The lack of hyperglycemia during co-administration of pasireotide and octreotide may be explained by the greater activation of sstr(2) compared with pasireotide alone, causing the insulin-glucagon balance to shift within the normoglycemic range. Extrapolation of these data to humans must account for species differences in islet cell sstr expression.     

Managing pasireotide-associated hyperglycemia: a randomized,open-label,Phase IV study

Purpose

Pasireotide is an effective treatment for acromegaly and Cushing’s disease, although treatment-emergent hyperglycemia can occur. The objective of this study was to assess incretin-based therapy versus insulin for managing pasireotide-associated hyperglycemia uncontrolled by metformin/other permitted oral antidiabetic drugs.

Methods

Multicenter, randomized, open-label, Phase IV study comprising a core phase (≤?16-week pre-randomization period followed by 16-week randomized treatment period) and optional extension (ClinicalTrials.gov ID: NCT02060383). Adults with acromegaly (n?=?190) or Cushing’s disease (n?=?59) received long-acting (starting 40 mg IM/28 days) or subcutaneous pasireotide (starting 600 µg bid), respectively. Patients with increased fasting plasma glucose (≥?126 mg/dL on three consecutive days) during the 16-week pre-randomization period despite metformin/other oral antidiabetic drugs were randomized 1:1 to open-label incretin-based therapy (sitagliptin followed by liraglutide) or insulin for another 16 weeks. The primary objective was to evaluate the difference in mean change in HbA_1c from randomization to end of core phase between incretin-based therapy and insulin treatment arms.

Results

Eighty-one (32.5%) patients were randomized to incretin-based therapy (n?=?38 received sitagliptin, n?=?28 subsequently switched to liraglutide; n?=?12 received insulin as rescue therapy) or insulin (n?=?43). Adjusted mean change in HbA_1c between treatment arms was – 0.28% (95% CI – 0.63, 0.08) in favor of incretin-based therapy. The most common AE other than hyperglycemia was diarrhea (incretin-based therapy, 28.9%; insulin, 30.2%). Forty-six (18.5%) patients were managed on metformin (n?=?43)/other OAD (n?=?3), 103 (41.4%) patients did not require any oral antidiabetic drugs and 19 patients (7.6%) were receiving insulin at baseline and were not randomized.

Conclusion

Many patients receiving pasireotide do not develop hyperglycemia requiring oral antidiabetic drugs. Metformin is an effective initial treatment, followed by incretin-based therapy if needed.

ClinicalTrials.gov ID: NCT02060383.

     

Absence of immunostaining for growth hormone in a subset of patients with acromegaly

The presence of growth hormone (GH) immunostaining in patients who lack the biochemical and clinical features of acromegaly has been described. In contrast, there is little information on the absence of GH immunostaining in patients with acromegaly. We describe five patients with acromegaly with no intratumoral immunostaining for GH. We reviewed all patients undergoing surgery for acromegaly. Out of 136 patients treated surgically in a 10 year period, five (3.7 %) were found to have no GH immunostaining on repetitive testing at pathological examination. Their pathology slides were re-examined by an experienced neuropathologist, along with twenty nonfunctional pituitary tumors and ten GH-positive adenomas as negative and positive controls, respectively. All patients had clinical features consistent with acromegaly and elevated baseline insulin-like growth factor-1 (IGF-1) and GH. All patients had no immunostaining for GH on multiple inspections. Of twenty patients with nonfunctional tumors, two had ≤25 % staining for GH in a scattered and non-coherent pattern and the rest were negative. In all ten positive control patients >25 % of the tumor cells stained diffusely for GH. All five patients achieved biochemical remission at 1.4–8 years post-op using a combination of primary surgery alone (n = 1), repeat surgery (n = 1), radiotherapy (n = 3) and/or medical therapy (n = 2). GH immunostaining of an adenoma may not be sufficient to confirm the diagnosis of acromegaly. All patients in our small series achieved remission by multimodality therapies. Further studies are needed to evaluate the significance of our observation and whether this subset of patients follows a distinct long term clinical course.