Pasireotide Long-acting Release Research Articles

Real-world evidence of effectiveness and safety of pasireotide in the treatment of acromegaly: a systematic review and meta-analysis.

Pasireotide long-acting release (PAS-LAR) is a second-generation somatostatin receptor ligand (SRL) approved for acromegaly treatment. This meta-analysis aimed to evaluate the real-world effectiveness and safety of PAS-LAR in patients with acromegaly resistant to first-generation somatostatin receptor ligands (fgSRL). A systematic literature search was conducted in PubMed and Web of Science for real-world studies on PAS-LAR in acromegaly published between 2014 and 2023. Random-effects meta-analyses were performed on biochemical control rates, tumor shrinkage, and metabolic parameters. Twelve studies comprising 409 patients were included. The pooled rate of insulin-like growth factor 1 (IGF-1) control was 57.9% [95% CI: 48.4-66.8] and the percentage of patients with tumor shrinkage was 33.3% [95%CI: 19.7-50.4]. Significant reductions were observed in growth hormone standardized mean difference (SMD) 0.6 ng/mL [95% CI: 0.3 to 1.0] and IGF-1 levels SMD 0.9 ULN [95% CI: 0.4 to 1.4]. However, as expected, a worsening in glucose metabolism was noted as an increase in fasting glucose SMD - 0.8mg/dL [95% CI: -1.0 to -0.5, p < 0.01], glycated hemoglobin SMD - 0.5% [95% CI: -0.7 to -0.2]. and type 2 diabetes mellitus prevalence SMD - 11.5% (95% CI: -17.5 to -5.5). PAS-LAR demonstrated higher effectiveness in real-world settings, with over 60% of patients achieving IGF-1 control compared to the around 30% efficacy observed in clinical trials. These findings suggest that PAS-LAR is an effective option for acromegaly patients resistant to fgSRL, but careful monitoring of glucose levels is essential. The high heterogeneity observed across studies emphasizes the need for identifying PAS-LAR response biomarkers to set-up individualized treatment approaches for optimizing patient outcomes.

Pharmacokinetics and pharmacodynamics of a pasireotide subcutaneous depot (CAM4071) and comparison with immediate and long-acting release pasireotide.

To assess the pharmacokinetics, pharmacodynamics, safety and tolerability of subcutaneous depot CAM4071, a novel, ready-to-use pasireotide formulation. This was a phase 1, randomised, open-label study in healthy volunteers. After a single 600 µg dose of pasireotide immediate release (IR), participants were randomised to one of eight groups to receive either a CAM4071 upper thigh (5, 10, 20, 40 or 80 mg) or buttock (20 mg) injection or multiple pasireotide IR 900 µg upper thigh injections twice daily or a single pasireotide long-acting release (LAR) 60 mg intramuscular buttock injection. Ninety-four participants were randomised. For all CAM4071 doses, initial pasireotide release was relatively rapid compared to pasireotide LAR and sustained over the 2-month observation period, with a slow decay in plasma concentrations. CAM4071 maximum plasma concentrations increased slightly greater than dose proportionally; area under the curve extrapolated to infinity increased approximately dose proportionally. Relative bioavailability of pasireotide for different doses of CAM4071 versus pasireotide IR 600 μg ranged from 0.752 (90% confidence interval [CI]: 0.58, 0.98) to 1.68 (1.32, 2.14), and versus pasireotide LAR: 0.517 (0.37, 0.72) to 1.15 (0.84, 1.58). CAM4071 doses >5 mg exhibited rapid initial reductions of insulin-like growth factor 1 (IGF-1) compared to pasireotide LAR. Maximum IGF-1 inhibition was greatest for CAM4071 80 mg. CAM4071 injections ≤40 mg were well tolerated and comparable with currently available pasireotide formulations. CAM4071 provided long-acting release of pasireotide over at least one month, with high bioavailability and onset and duration of IGF-1 suppression similar to pasireotide LAR. EudraCT: 2014-003783-20.

GH receptor polymorphisms guide second-line therapies to prevent acromegaly skeletal fragility: preliminary results of a pilot study.

Skeletal fragility is characterized by increased frequency of vertebral fractures (VFs) in acromegaly. Several trials were conducted to identify modifiable risk factors and predictors of VFs, with limited data on the prognostic role of GH receptor (GHR) isoforms. In this study, we investigated the potential role of GHR polymorphism on the occurrence of incidental VFs (i-VFs), in patients treated with second-line medical therapies. A longitudinal, retrospective, observational study was conducted on a cohort of 45 acromegalic patients not-responsive to first-generation somatostatin receptor ligands (fg-SRLs) and treated with GHR antagonist (Pegvisomant) or with the second-generation SRLs (Pasireotide long-acting release). Second line treatments were Pegvisomant plus fg-SRLs in 26 patients and Pasireotide LAR in 19 patients. From the group treated with fg-SRLs+Peg-V, the fl-GHR isoform was identified in 18 patients (69.2%) and the d3-GHR isoform in 8 patients (30.8%). I-VFs arose exclusively in fl-GHR isoform carriers (p=0.039). From the group treated with Pasireotide LAR, the fl-GHR isoform was identified in 11 patients (57.9%), and the d3-GHR isoform in 8 patients (42.1%). I-VFs arose exclusively in d3-GHR isoform carriers (p=0.018). Patients with fl-GHR isoform had a higher risk for i-VFs if treated with fg-SRL+Peg-V (OR: 1.6 95%IC: 1.1-2.3, p=0.04), and a lower risk if treated with Pasi-LAR (OR: 0.26 IC95%: 0.11-0.66, p=0.038). Our data support a predictive role of the GHR isoforms for the occurrence of i-VFs in acromegalic patients treated with second-line drugs, tailored to the individual patient. The knowledge of the GHR polymorphism may facilitate the choice of second-line therapies, improving the therapeutic approach, in the context of personalized medicine.

Pasireotide: potential treatment option for McCune-Albright-associated acromegaly.

Only 30% of patients with McCune-Albright syndrome (MAS)-associated acromegaly achieve biochemical control under first-generation somatostatin receptor ligands (fg-SRLs), while pegvisomant fails to normalize insulin-like growth factor 1 (IGF-I) in >20% of cases. Here, we report all the patients with MAS-associated acromegaly treated with pasireotide long-acting release (LAR) in our center. Pasireotide LAR 20 mg/month resulted in rapid and long-term IGF-I normalization in patients #1 and #3. Patient #3 was resistant to fg-SRLs, while patient #1 was also controlled on fg-SRLs. In patient #2, resistant to fg-SRLs and uncontrolled on pegvisomant 40 mg/day combined with cabergoline 0.5 mg/day, pegvisomant was replaced with pasireotide LAR 40 mg/month, resulting in the near normalization of IGF-I levels. All 3 patients developed intermittent impaired fasting glucose, without the need for glucose-lowering drugs. Thus, pasireotide LAR is clearly useful as third-line therapy, and potentially even as second-line therapy, in MAS-associated acromegaly.

THU066 An 8-year Interim Report Of The B2412 Study, An Open-label, Multicenter Pasireotide Rollover Study For Patients Who Continued To Receive Benefit From Pasireotide At Completion Of An Earlier Trial

Abstract Disclosure: M. Gadelha: Advisory Board Member; Self; Novo Nordisk, Recordati, Crinetics Pharmaceuticals. Speaker; Self; Recordati, Novo Nordisk, Ipsen, Crinetics Pharmaceuticals. M.D. Bronstein: None. E. Grineva: Advisory Board Member; Self; Ipsen, Merck, Pfizer, Inc. Speaker; Self; Recordati, Ipsen, Pfizer Berlin Chemie, Teva Pharmaceutical Industries Ltd., A. Menarini, Siemens Healthineers. N. Kapoor: None. C. De Block: Consulting Fee; Self; Abbott Laboratories, AstraZeneca, Boehringer Ingelheim, A Menarini Diagnostics, Eli Lilly &amp; Company, Insulet Corporation, Medtronic, Novo Nordisk, Roche Pharmaceuticals. Research Investigator; Self; AstraZeneca, Boehringer Ingelheim, Indigo Diabetes, Novo Nordisk. Speaker; Self; Abbott Laboratories, AstraZeneca, Boehringer Ingelheim, A Menarini Diagnostics, Eli Lilly &amp; Company, Insulet Corporation, Medtronic, Novo Nordisk, Roche Pharmaceuticals. J.M. Escalante Pulido: None. G. Rollin: Advisory Board Member; Self; Merck Serono. Speaker; Self; Novo Nordisk, Abbott Laboratories, AstraZeneca, Merck Serono. R. Baggenstoss: None. A. Piacentini: Employee; Self; Recordati. A.M. Pedroncelli: Employee; Self; Recordati. W. Gallardo: Speaker; Self; Pfizer, Inc., Merck, Ipsen, Novartis Pharmaceuticals. Introduction: A robust clinical development program of 14 trials demonstrated that the second-generation somatostatin receptor ligand, pasireotide, is an effective treatment for patients (pts) with rare endocrine disorders, including acromegaly and Cushing’s disease (CD). Pts with acromegaly or CD have significant morbidity, reduced quality of life and, if inadequately treated, a higher mortality risk than the general population. This 8-year interim analysis evaluated the long-term safety of pasireotide treatment in pts with acromegaly, CD or other endocrine disorders. Methods: This ongoing, open-label, multicenter study allows continued treatment for pts who completed a previous pasireotide parent trial (NCT01794793). Pts who continued to receive clinical benefit, as determined by the investigator in the parent study, entered the rollover study and remained on pasireotide. Depending on the route of administration in the parent study, pts received pasireotide long-acting release (LAR; n=303) or subcutaneous (sc; n=38) as monotherapy (n=36), or sc in combination with cabergoline (n=2). The primary objective was to evaluate long-term safety, determined by frequency of adverse events (AEs)/serious adverse events (SAEs). Results: Overall, 341 pts from 29 countries have entered the study from 14 parent studies; 228 pts had acromegaly, 64 CD and 49 other endocrine disorders, including melanoma, dumping syndrome and neuroendocrine tumors. Median (min−max) exposure to all pasireotide formulations from rollover baseline to data cut-off and across all indications was 45.3 months (0.9−100.8). Median (min−max) dose from rollover baseline was 45.4 mg/month (5.3−128.3) with pasireotide LAR and 1200 µg/day (300−1800) with pasireotide sc. In total, 89 (26.1%) pts discontinued treatment; the most common reason was consent withdrawal (n=21, 6.2%). Most common AEs during rollover (≥10% in all pts) were nasopharyngitis (acromegaly n=13, 5.7%; CD n=14, 21.9%; other diseases n=14, 28.6%), hyperglycemia (acromegaly n=29, 12.7%; CD n=2, 3.1%; other diseases n=7, 14.3%), back pain (acromegaly n=20, 8.8%; CD n=7, 10.9%; other diseases n=8, 16.3%) and headache (acromegaly n=21, 9.2%; CD n=6, 9.4%; other diseases n=7, 14.3%). SAEs were reported in 87 (25.5%) pts; the most common were cholelithiasis and COVID-19 (both n=9, 2.6%). Overall, 18 (5.3%) pts discontinued treatment because of AEs. Incidence of new hyperglycemia-related AEs during rollover was low. No new safety signals were identified. Conclusions: Hyperglycemia is an expected AE during pasireotide treatment, often occurring in the first 3 months of therapy. These data in pts with acromegaly, CD or other endocrine disorders support pasireotide as a well-tolerated long-term treatment and affirm that pts continue to receive long-term benefit, with a low discontinuation rate over 8 years. Presentation: Thursday, June 15, 2023

Long-term, real-world experience of pasireotide dose reduction in patients with acromegaly.

Pasireotide long-acting release is effective in achieving biochemical control and reducing tumour volume in patients with acromegaly inadequately controlled by first-line therapy. As part of a long-term, real-world study at our centre, 20 of 50 patients receiving pasireotide benefited from a reduction in pasireotide dose. Pasireotide reduced insulin-like growth factor I (IGF-I) levels to below the upper limit of the normal range, with some patients responding within 1-3 months of treatment (n=11) and others after ≥4 months (n=9). Following pasireotide dose reduction, IGF-I levels showed a mild increase but remained within the normal range after a median of 39 months in the early responders and 17 months in the late responders. Glucose and glycated haemoglobin levels decreased following dose reduction. Identifying patients who may benefit from a reduction in pasireotide dose warrants further research as it may improve the management of pasireotide-associated hyperglycaemia in susceptible patients.

EE402 Cost-Effectiveness Analysis of Pasireotide Long-Acting Release As a Second Line Treatment for Adult Acromegaly Patients

This study evaluates the cost-effectiveness of second line treatments of acromegaly in adults for whom surgery is no option or has not been curative and who were previously inadequately controlled with somatostatin receptor ligands (SRL).

Patients with acromegaly continue to derive clinical benefit from pasireotide long-acting release (LAR) for up to 12 years of treatment: Follow-up analysis of patients who received pasireotide during the clinical trial programme

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

A systematic literature review to evaluate extended dosing intervals in the pharmacological management of acromegaly

PurposeThis systematic literature review investigated whether extended dosing intervals (EDIs) of pharmacological acromegaly treatments reduce patient burden and costs compared with standard dosing, while maintaining effectiveness.MethodsMEDLINE/Embase/the Cochrane Library (2001–June 2021) and key congresses (2018–2021) were searched and identified systematic literature review bibliographies reviewed. Included publications reported on efficacy/effectiveness, safety and tolerability, health-related quality of life (HRQoL), and patient-reported and economic outcomes in longitudinal/cross-sectional studies in adults with acromegaly. Interventions included EDIs of pegvisomant, cabergoline, and somatostatin receptor ligands (SRLs): lanreotide autogel/depot (LAN), octreotide long-acting release (OCT), pasireotide long-acting release (PAS), and oral octreotide; no comparator was required.ResultsIn total, 35 publications reported on 27 studies: 3 pegvisomant monotherapy, 11 pegvisomant combination therapy with SRLs, 9 LAN, and 4 OCT; no studies reported on cabergoline, PAS, or oral octreotide at EDIs. Maintenance of normal insulin-like growth factor I (IGF-I) was observed in ≥ 70% of patients with LAN (1 study), OCT (1 study), and pegvisomant monotherapy (1 study). Achievement of normal IGF-I was observed in ≥ 70% of patients with LAN (3 studies) and pegvisomant in combination with SRLs (4 studies). Safety profiles were similar across EDI and standard regimens. Patients preferred and were satisfied with EDIs. HRQoL was maintained and cost savings were provided with EDIs versus standard regimens.ConclusionsClinical efficacy/effectiveness, safety, and HRQoL outcomes in adults with acromegaly were similar and costs lower with EDIs versus standard regimens. Physicians may consider acromegaly treatment at EDIs, especially for patients with good disease control.

MSR61 Comparative Efficacy of Osilodrostat Versus Pasireotide Subcutaneous and Pasireotide Long-Acting Release for the Treatment of Cushing's Disease – A Patient-Level Data Indirect Treatment Comparison Using Propensity Score Weighting

Cushing's Disease (CD) is a rare, chronic condition that results in high morbidity, caused by prolonged elevation of circulating free cortisol levels. Osilodrostat, a newly approved steroidogenesis inhibitor has been shown to achieve fast and high rates of cortisol normalisation. This research evaluates the relative time to complete response (CR) of osilodrostat compared with pasireotide subcutaneous (SC) and long-acting release (LAR) for patients with CD.

A Multicenter Randomized Phase II Study of Single Agent Efficacy and Optimal Combination Sequence of Everolimus and Pasireotide LAR in Advanced Thyroid Cancer.

Simple SummaryPrior clinical studies showed modest activity for single agent everolimus and somatostatin analogues in different subtypes of thyroid cancer; the combination of everolimus and somatostatin analogue was synergistic in preclinical models of thyroid cancer. This randomized trial showed that the combination was more effective than a single agent and the sequence of single agent everolimus followed by the delayed combination of everolimus and pasireotide-LAR achieved the best efficacy and was the optimal combination strategy.Purpose: Aberrant mTOR pathway and somatostatin receptor signaling are implicated in thyroid cancer and offer potential therapeutic targets. We assessed the clinical efficacy of everolimus and Pasireotide long-acting release (LAR) in radioiodine-refractory differentiated thyroid cancer (DTC) and medullary thyroid cancer (MTC). Patients and methods: Adults with progressive MTC and DTC untreated or treated with no more than one systemic agent were eligible. The trial was designed to establish the most promising regimen and the optimal combination sequence. Patients were randomized to start treatment with single agent everolimus (10 mg QD; Arm A), pasireotide-LAR (60 mg intramuscular injection, Q4 weeks; Arm B), or the combination (Arm C). At initial progression (PFS1), patients on Arm A or B switched to the combination and continued until progression (PFS2). Efficacy was measured by RECIST criteria. Results: Study enrolled 42 patients: median age 65 years; female 17 (40.5%); White 31 (73.8%), African American 6 (14.3%), others 5 (11.9); DTC 32 (76.2%); MTC 10 (23.8%). There was no objective response by RECIST criteria across the three arms. Median and 1-year PFS1 rates were 8.3, 1.8, 8.1 months and 49.9%, 36.4%, 25.0% for Arms A, B, C, respectively. Median and 1-year PFS2 rates were 26.3, 17.5, 8.1 months and 78.4%, 70.0%, 25% for Arms A, B, C, respectively. The most frequent adverse events were anemia, stomatitis, fatigue, hyperglycemia, and hypercholesterolemia. Conclusions: The combination of everolimus and pasireotide-LAR showed promising efficacy over single agent. The delayed combination of everolimus and pasireotide-LAR following progression on single agent everolimus appeared intriguing as a combination strategy.

Gender-Specific Efficacy Revealed by Head-to-Head Comparison of Pasireotide and Octreotide in a Representative In Vivo Model of Nonfunctioning Pituitary Tumors.

Simple SummaryNo effective medical therapy exists for residual/recurrent nonfunctioning pituitary tumors (NFPTs). First-generation somatostatin analogs (SSAs) like octreotide targeting somatostatin receptor type 2 (SSTR2) are the mainstay therapy for functioning PTs, but have shown little effect in NFPTs. This is in agreement with an SSTR profile characterized by low SSTR2, and high SSTR3 levels in the latter. Pasireotide a multi-SSTR-preferring SSA, should be effective against NFPTs. To test this hypothesis, we conducted a head-to-head comparison of octreotide and pasireotide in the only spontaneous in vivo model of NFPTs (MENX rats), which recapitulates the human disease. Pasireotide showed a superior anti-tumor effect vs. octreotide, especially in females. Interestingly, Sstr3 levels were higher in female vs. male NFPTs. A sex-related SSTR3 expression may extend to human NFPTs, thereby representing a tool for patient stratification. Our results have translational relevance for the medical treatment of patients with residual/recurrent NFPTs currently lacking efficacious therapeutic options.Invasive nonfunctioning pituitary tumors (NFPTs) are non-resectable neoplasms associated with frequent relapse and significant comorbidities. Current treatments, including somatostatin receptor 2 (SSTR2)-directed somatostatin analogs (SSAs), often fail against NFPTs. Thus, identifying effective therapies is clinically relevant. As NFPTs express SSTR3 at high levels, pasireotide, a multireceptor-targeted SSA, might be beneficial. Here we evaluated pasireotide in the only representative model of spontaneous NFPTs (MENX rats) in vivo. Octreotide long-acting release (LAR), pasireotide LAR, or placebo, were administered to age-matched, tumor-bearing MENX rats of both sexes for 28 d or 56 d. Longitudinal high-resolution magnetic resonance imaging monitored tumor growth. While tumors in placebo-treated rats increased in volume over time, PTs in drug-treated rats displayed significant growth suppression, and occasional tumor shrinkage. Pasireotide elicited stronger growth inhibition. Radiological responses correlated with tumors’ proliferation rates. Both SSAs, but especially pasireotide, were more effective in female vs. male rats. Basal Sstr3 expression was significantly higher in the former group. It is noteworthy that female human NFPTs patients also have a trend towards higher SSTR3 expression. Altogether, our studies provide the rationale for testing pasireotide in patients with residual/recurrent NFPTs. If confirmed, the sex-related SSTR3 expression might be used as criteria to stratify NFPTs patients for treatment with pasireotide.

The Effect of 6 Months' Treatment With Pasireotide LAR on Glucose Metabolism in Patients With Resistant Acromegaly in Real-World Clinical Settings.

ObjectiveThe aim of the study was to evaluate glucose metabolism, as measured by glycated hemoglobin (HbA1c) levels and the need for antidiabetic medical treatment, in patients with acromegaly resistant to first-generation somatostatin receptors ligands (SRLs) treated with pasireotide long-acting release (LAR) in real-world clinical practice. Biochemical control of acromegaly, as measured by growth hormone (GH) and insulin-like growth factor 1 (IGF-1) levels, was also assessed.Study DesignTwo-center retrospective cohort of consecutive patients with acromegaly treated with first-generation SRLs at maximum doses, who had not achieved biochemical disease control. After SRLs were discontinued, patients were given pasireotide LAR 40 mg i.m. every 28 days. The dose was increased to 60 mg i.m. in patients for whom adequate control was not achieved after 3 months. Patients were given dietary and lifestyle advice, and antihyperglycemic treatment was modified as needed.Main Outcome MeasuresBiochemical disease control parameters (GH and IGF-1 concentration), as well as HbA1c level at baseline and after 6 months.ResultsIn total, 39 patients with acromegaly were enrolled. GH concentration decreased (Δme =-1.56 µg/L, range -21.38–3.62, p <0.001) during 6 months of pasireotide LAR treatment. A worsening of metabolic status was observed, with an increase of median HbA1c (Δme =0.40%, range -0.20%–2.30%, p <0.001), and antihyperglycemic treatment intensification in 23 (59.0%) patients. The median decline in IGF-1 concentration was: -283.0 µg/L, range -682.7–171.6, p <0.001. IGF-1 reached the age- and gender-specific upper level of normal in 23 (59%) patients.ConclusionsPasireotide LAR is an effective therapeutic option in patients with acromegaly refractory to first-generation SRLs. However, this therapy may result in pasireotide LAR-associated hyperglycemia, which requires early and aggressive antidiabetic medical therapy to prevent glucose homeostasis alterations.

Medical Treatment of Cushing's Disease: An Overview of the Current and Recent Clinical Trials.

Cushing's disease (CD) is a serious endocrine disorder characterized by chronic hypercortisolism, or Cushing's syndrome (CS), caused by a corticotroph pituitary tumor, which induces an excessive adrenocorticotropic hormone (ACTH) and consequently cortisol secretion. CD presents a severe clinical burden, with impairment of the quality of life and increase in mortality. Pituitary surgery represents the first-line therapy, but it is non-curative in one third of patients, requiring additional treatments. Among second-line treatments, medical therapy is gradually gaining importance, although the current medical treatments are unable to reach optimal efficacy and safety profile. Therefore, new drugs and new formulations of presently available drugs are currently under clinical investigation in international clinical trials, in order to assess their efficacy and safety in CD, or in the general population of CS. Among pituitary-directed agents, pasireotide, in the twice-daily subcutaneous formulation, has been demonstrated to be an effective treatment both in clinical trials and in real-world studies, and extension studies of the phase II and III clinical trials reported evidence of long-term efficacy with general good safety profile, although associated with frequent hyperglycemia, which requires monitoring of glucose metabolism. Moreover, the most recent once-monthly intramuscular formulation, pasireotide long-acting release (LAR), showed similar efficacy and safety, but associated with potential better compliance profile in CD. Roscovitine is an experimental drug currently under investigation. Among adrenal-directed agents, metyrapone is the only historical agent currently under investigation in a prospective, multicenter, international clinical trial, that would likely clarify its efficacy and safety in a large population of patients with CS. Osilodrostat, a novel agent with a mechanism of action similar to metyrapone, seems to offer a rapid, sustained, and effective disease control of CD, according to recently completed clinical trials, whereas levoketoconazole, a different chemical formulation of the historical agent ketoconazole, is still under investigation in clinical trials, with preliminary evidences showing an effective and safe control of CS. ATR-101 is an experimental drug currently under investigation. Among glucocorticoid receptor-directed drugs, mifepristone has been demonstrated to improve clinical syndrome and comorbidities, especially hypertension and impairment of glucose metabolism, but the occurrence of hypokalemia and in women uterine disorders, due to the concomitant action on progestin receptor, requires caution, whereas the preliminary evidence on relacorilant, characterized by high selectivity for glucocorticoid receptor, suggested good efficacy in the control of hypertension and impairment of glucose metabolism, as well as a good safety profile, in CS. Finally, a limited experience has demonstrated that combination therapy might be an interesting approach in the management of CD. The current review provides a summary of the available evidences from current and recent clinical trials on CD, with a specific focus on preliminary data.

Pasireotide for a Patient with Acromegaly and Chronic Kidney Disease on Hemodialysis

Acromegaly is a rare disease. Medical management with somatostatin analogs and the growth hormone receptor antagonist pegvisomant can normalize insulin-like growth factor-1 (IGF1) levels after failed surgery and decrease mortality and comorbidities. We present a case report of a patient with acromegaly on chronic hemodialysis resistant to first-generation, long-acting somatostatin analogs with remarkable response to pasireotide long-acting release (PAS-LAR). A 66-year-old woman with acromegaly and chronic renal failure on hemodialysis resistant to lanreo-tide autogel (at 120 mg) was treated successfully with PAS-LAR. Acromegaly was diagnosed in 1996 and transsphenoidal resection of macroadenoma was performed with normalization of IGF1 levels. Nine years later, recurrence of the tumor led to a second operation. Lanreotide autogel was initiated due to persistently high levels of IGF1, but the patient was resistant to treatment. A positive response was observed with pegvisomant. However, the patient was nonadherent and treatment was discontinued. PAS-LAR was initiated and normalization of IGF1 and growth hormone was achieved. This is the first case report of a patient with acromegaly on chronic hemodialysis who was resistant to first-generation, long-acting somatostatin analogs and successfully treated with PAS-LAR.

How to Position Pasireotide LAR Treatment in Acromegaly.

Pasireotide long-acting release (LAR) is a somatostatin multireceptor ligand, and in the current consensus criteria pasireotide LAR is considered the second-line medical treatment for acromegaly. We present in this article our recommendations to define the position of pasireotide LAR in the treatment of acromegaly and provide recommendations for the management of pasireotide-induced hyperglycemia. Our recommendations are based on our experiences with the pasireotide LAR and pegvisomant (PEGV) combination study and the available basic or clinical articles published in peer-reviewed international journals on pasireotide LAR and acromegaly. In accordance with the current consensus criteria, we recommend pasireotide LAR monotherapy as a second-line therapy in young patients who show tumor growth during first-generation somatostatin receptor ligand (SRL) therapy and in patients who show tumor growth during PEGV therapy. In addition, we recommend pasireotide LAR monotherapy in patients with headache not responsive to first-generation SRL therapy and in patients who experience side effects or are intolerant to PEGV monotherapy. In contrast to the current consensus criteria, we recommend considering combination therapy with pasireotide LAR and PEGV as third-line treatment in patients without diabetes at low PEGV dosages (≤80 mg/week) and in patients with tumor growth or symptoms of active acromegaly during first-generation SRL and PEGV combination therapy. With respect to pasireotide-induced hyperglycemia, we recommend a more liberal strategy of blood glucose monitoring during pasireotide treatment. In contrast to the current consensus criteria, we recommend a more reluctant use of pasireotide LAR therapy for the treatment of acromegaly.

Sodium Glucose Co-transporter Inhibitors in Patients with Acromegaly and Diabetes

Acromegaly per se predisposes to diabetes. Somatostatin analogs (SSAs) have an overall neutral effect on glycemic control. However, a marked increase in hyperglycemia was observed recently since the introduction of pasireotide long-acting release (PAS-LAR). Sodium glucose cotransporter inhibitors (SGLT2is) have proven their efficacy, cardiovascular safety, and superiority in the management of type 2 diabetes mellitus (T2DM). However, this class is rarely recommended for patients with diabetes and acromegaly. A decreased circulating insulin level is considered unique for this class and might have a beneficial role in the growth hormone-insulin-like growth factor-I (GH-IGF-I) axis. Therefore, SGLT2is should be considered in the management of diabetes in patients with acromegaly. This article highlights the role of this novel class for the management of diabetes in patients with acromegaly.

Pasireotide Responsiveness in Acromegaly Is Mainly Driven by Somatostatin Receptor Subtype 2 Expression.

The response to first-generation somatostatin receptor ligands (SRLs) treatment in acromegaly correlates with expression of somatostatin receptor subtype 2 (SSTR2). However, pasireotide shows the highest binding affinity for SSTR subtype 5 (SSTR5). It has been suggested that in acromegaly, SSTR5 expression is better at predicting the response to pasireotide long-acting release (PAS-LAR) treatment than SSTR2 expression. To investigate in patients with active acromegaly whether response to SRL treatment correlates to PAS-LAR treatment and to what extent SSTR2 and SSTR5 expression are correlated to the response to PAS-LAR treatment. We included 52 patients from a cohort that initially received SRL treatment, followed by SRL and pegvisomant combination treatment, and finally PAS-LAR treatment. The long-term response to PAS-LAR was evaluated using a PAS-LAR score. In 14 out of 52 patients, somatotroph adenoma tissue samples were available to evaluate SSTR2 and SSTR5 expression using a previously validated immunoreactivity score (IRS). The percentage IGF-I (times the upper limit of normal) reduction, which was observed after SRL treatment, correlated with PAS-LAR response score during follow-up (r = 0.40; P = 0.003; n = 52). After exclusion of SRL-pretreated patients, SSTR2 IRS was positively correlated to PAS-LAR score (r = 0.58; P = 0.039; n = 9), whereas SSTR5 IRS showed no relation (r = 0.35; P = 0.36; n = 9). In a cohort of patients partially responsive to SRLs, the IGF-I-lowering effects of PAS-LAR treatment correlated with the effect of SRL treatment and seemed to be mainly driven by SSTR2 expression instead of SSTR5.

Efficacy and Safety of switching to Pasireotide in Acromegaly Patients controlled with Pegvisomant and Somatostatin Analogues: PAPE extension study.

to assess the efficacy and safety after 48 weeks of treatment with pasireotide long-acting-release (PAS-LAR) alone or in combination with pegvisomant in patients with acromegaly. In addition, we assessed the relation between insulin secretion and pasireotide-induced hyperglycemia. The PAPE extension study is a prospective follow-up study until 48 weeks after the core study of 24 weeks. 59 out of 61 patients entered the extension study. Efficacy was defined as the percentage of patients achieving IGF-I normalization (≤ 1.2 x the Upper Limit of Normal (ULN)) at 48-weeks through protocol-based adjustment of pegvisomant and PAS-LAR doses. At baseline, insulin secretion was assessed by an oral glucose tolerance test (OGTT). At the end of the study median IGF-I was 0.98 x ULN, and 77% of patients achieved normal IGF-I levels with a mean pegvisomant dose of 64 mg/week, and an overall cumulative pegvisomant dose reduction of 52%. Frequency of diabetes mellitus increased from 68% at 24 weeks to 77% at 48 weeks, and 9 patients discontinued PAS-LAR treatment, mainly because of severe hyperglycemia. Pasireotide-induced hyperglycemia was inversely correlated with baseline insulin secretion (r = -0.37, P < 0.005). PAS-LAR normalizes IGF-I levels in most acromegaly patients, with a fifty percent pegvisomant-sparing effect. However, PAS-LAR treatment coincided with a high incidence of diabetes mellitus. The risk for developing diabetes during PAS-LAR treatment seems inversely related to insulin secretion at baseline.

Pasireotide: A potential therapeutic alternative for resistant prolactinoma

ContextAbout 10% of prolactinomas are resistant to dopamine-agonists (DAs). The only alternatives for tumor and prolactin control are surgery or radiotherapy. While studies on first generation somatostatin analogs have shown no efficacy against prolactinomas, no study has been conducted on the new multireceptor-targeted somatostatin receptor ligand pasireotide, which presents high affinity for 5, 3, 2 and 1 receptor subtypes. Case descriptionA 41 year-old woman presented with a macroprolactinoma showing resistance to all available DAs. She was first diagnosed at 17 years old after which she had undergone two incomplete debulking surgeries. Under pasireotide long-acting release (LAR) treatment, plasma prolactin levels normalized and symptoms disappeared within one month after initiation. The clinical benefits of the monotherapy (specifically, prolactin levels within normal range and stable tumor volume) were maintained for seven years. Glucose tolerance was satisfactory. Pathological analysis of the tumor revealed high SSTR5 and low SSTR2 expression (25 and 5% of cells respectively). ConclusionThis is a promising first report of a patient with a DA-resistant macroprolactinoma who achieved long-term control, in terms of prolactin normalization and tumor volume, under pasireotide treatment alone. Pasireotide could thus be an alternative in prolactinomas resistant to DA. SSTR expression analysis on pathology could guide patient selection.