Pasireotide Treatment Research Articles

8594 Pasireotide and Pasireotide Combined Treatment in Aggressive, Giant Pituitary Neuroendocrine Tumours

Abstract Disclosure: K. Ciszek: None. A. Bogusławska: None. M. Komisarz-Calik: None. J. Kunicki: None. A. Hubalewska-Dydejczyk: None. A. Gilis-Januszewska: None. Pasireotide is a second-generation somatostatin analogue that gained recognition as a treatment option for acromegaly and Cushing disease. Recently, there are single reports of pasireotide treatment in other subtype of pituitary neuroendocrine tumours (PitNETs).We present a case series of aggressive, giant PitNETs which were treated with pasireotide alone or as combined multimodal treatment. Case 1: A 59-year-old male presented in our Unit due to severe headaches and visual field deficits. The patient underwent transsphenoidal surgery (TSS) ten years ago. Histopathology results showed partially acidophilic adenoma (FSH- LH- GH- ACTH- PRL-). Control MRI showed tumour regrowth - 56x56x89mm and invasion of local structures. The patient was qualified for radiotherapy, to which he did not consent. Due to the progression of symptoms, temozolomide and pasireotide were introduced. After 5 months, significant improvement in headaches and vision was observed. In MRI stable pituitary mass was noted. Case 2: A 17-year-old male presented in our clinic due to daily severe headaches and peripheral vision loss who underwent two non-radical surgeries for dopamine-resistant giant prolactinoma. In control MRIs progressing mass 38x34x33mm invading local structures was observed. Due to resistance to dopamine agonists and worsening of the symptoms, pasireotide was introduced resulting in a decrease of headaches and improvement in vision. The tumour size remained stationary. Case 3: A 59-year-old male presented with severe headaches and life threatening tumour mass effect.In MRI a 48x48x33mm mass was observed. The patient underwent two non-radical TSS, 4 cycles of pasireotide, and cyberknife treatment. Histopathology showed gonadotroph PitNET. MRI showed tumour shrinkage to 45x46x29mm, with persistent severe headaches. The patient was re-qualified for pasireotide treatment. Case 4: A 33-year-old male reported to the Clinic due to severe headaches and vomiting. In MRI pituitary mass 33x39x55mm and a cerebral oedema were revealed. TSS with external ventricular drainage was performed -histopathology results showed densely granulated silent corticotroph adenoma subtype 1, Ki67<1%. After 3 months, MRI showed tumour progression to 39x40x30mm. Two emergency TSS followed by stereotactic radiotherapy were performed. Combined therapy with pasireotide, cabergoline and temozolomide was introduced. After 18 months, stabilization of the disease was observed with the complete disappearance of headaches. Conclusions: Our study demonstrates the clinical potential of pasireotide treatment in aggressive, giant PitNETs. The therapy alone, or in combination has a potential role in reducing the tumour size, and allows the stabilization of the disease. The analgesic and anti-inflammatory effect of pasireotide could potentially alleviate headaches in this subset of patients. Presentation: 6/2/2024

Managing high blood sugar (hyperglycemia) during pasireotide treatment: A plain language summary of the B2219 study

What is this summary about? Pasireotide is a medication used to treat people with acromegaly or Cushing's disease, both of which are hormonal disorders caused by a non-cancerous tumor (adenoma) in the pituitary gland. Because of the way pasireotide works to treat these conditions, sometimes blood sugar levels can increase during treatment, causing a side effect known as hyperglycemia. This is a summary about a study called B2219 (ClinicalTrials.gov ID: NCT02060383), which was designed specifically to look at which additional medication(s) work(s) best to reduce blood sugar levels (antihyperglycemic medication) for people who require treatment for hyperglycemia while receiving pasireotide. What were the results? Researchers found that 4 in every 10 people who took part in the; study did not develop hyperglycemia and therefore did not require antihyperglycemic medication. For those who did, metformin was a good treatment option, followed by incretin-based therapy (sitagliptin and/or liraglutide) if hyperglycemia continued. What do the results of the study mean? This study shows that if hyperglycemia occurs during pasireotide treatment, it is manageable in most people. As such, people with acromegaly or Cushing's disease can experience long-term treatment benefits with pasireotide. Clinical Trial Registration: NCT02060383 ( ClinicalTrials.gov ) (B2219 study); 2012-002916-16 (B2219 study)

Experiences with pasireotide treatment in subjects with acromegaly

Experiences with pasireotide treatment in subjects with acromegaly

The efficacy of pasireotide treatment in invasive crooke's cell corticotropinoma - case report

The efficacy of pasireotide treatment in invasive crooke's cell corticotropinoma - case report

Efficacy of pasireotide treatment in acromegaly: a systematic review and meta-analysis

Efficacy of pasireotide treatment in acromegaly: a systematic review and meta-analysis

Pasireotide-induced hyperglycemia in Cushing's disease and Acromegaly: A clinical perspective and algorithms proposal.

Pasireotide is an effective treatment for both Cushing's disease (CD) and acromegaly due to its ability to suppress adrenocorticotropic hormone and growth hormone, and to normalize insulin-like growth factor-1 levels, resulting in tumor shrinkage. However, it may also cause hyperglycemia as a side effect in some patients. The aim of this study was to review previous recommendations regarding the management of pasireotide-induced hyperglycemia in patients with CD and acromegaly and to propose efficient monitoring and treatment algorithms based on recent evidence and current guidelines for type 2 diabetes treatment. In about 25% of patients with CD and 50% of patients with acromegaly, pasireotide-induced hyperglycemia does not require drug therapy or can be managed with diet and oral antidiabetic agents. The risk of pasireotide-induced hyperglycemia is higher in patients with diabetes or prediabetes at baseline. Moreover, pasireotide used in the treatment of CD may lead to more frequent and difficult-to-treat glycemic disorders than those observed in acromegaly. Based on the pathomechanism of hyperglycemia, we suggest using metformin as the first-line therapy, followed by glucagon-like peptide-1 and/or sodium-glucose co-transporter-2 inhibitor, and finally insulin in patients with pasireotide-induced hyperglycemia. We propose algorithms for the management of glucose metabolic disorders caused by pasireotide treatment in patients with CD and acromegaly, including those with chronic kidney disease and at high cardiovascular risk.

THU054 A Post Hoc Analysis Of The Phase IV B2219 Study To Determine Predictive Factors For Hyperglycemia During Treatment With Pasireotide

Abstract Disclosure: S.L. Samson: Consulting Fee; Self; Novartis Pharmaceuticals, Chiasma. M. Bolanowski: Grant Recipient; Self; Amryt, Recordati, Pfizer, Inc., Novartis Pharmaceuticals, Ipsen, IBSA, Teva Pharmaceutical Industries Ltd., Berlin Chemie. Speaker; Self; Amryt, Recordati, Pfizer, Inc., Novartis Pharmaceuticals, Ipsen, IBSA, Teva Pharmaceutical Industries Ltd., Berlin Chemie. S. Zhang: None. Y. Yu: None. P. Witek: Grant Recipient; Self; Novartis Pharmaceuticals, Ipsen, Recordati, Novo Nordisk, Xeris Pharmaceuticals (Strongbridge), Lilly USA, LLC. Speaker; Self; Novartis Pharmaceuticals, Ipsen, Recordati, Novo Nordisk, Xeris Pharmaceuticals (Strongbridge), Lilly USA, LLC. N. Kietsiriroje: None. A. Piacentini: Employee; Self; Recordati. A.M. Pedroncelli: Employee; Self; Recordati. U. Feldt-Rasmussen: Advisory Board Member; Self; Novartis Pharmaceuticals, Recordati, Novo Nordisk, Xeris Pharmaceuticals (Strongbridge). Grant Recipient; Self; Ipsen, Recordati, Novo Nordisk. Speaker; Self; Ipsen, Recordati, Novo Nordisk. Introduction: Pasireotide efficacy and safety in persons with acromegaly or Cushing’s disease (CD) is confirmed in a comprehensive clinical trial program. Pasireotide-induced hyperglycemia events, expected based on the drug’s mechanism of action, are manageable with low rates of treatment discontinuation. To advance knowledge on pasireotide-induced hyperglycemia management, a prospective randomized Phase IV study (B2219, NCT02060383) was conducted. This secondary analysis assessed factors that might predict development of pasireotide-induced hyperglycemia. Methods: In B2219, participants (Pts) with acromegaly or CD who did not need therapy for hyperglycemia or were managed with metformin alone entered the non-randomized observational arm. Pts who developed hyperglycemia not managed with metformin alone were randomized to incretin-based therapy or insulin. This analysis evaluated Pts according to whether therapy for hyperglycemia during pasireotide treatment was needed. Logistic regression analyses evaluated quantitative and qualitative predictive factors associated with pasireotide-induced hyperglycemia. Results: Of 190 Pts with acromegaly and 59 with CD, 88 and 15, respectively, did not need antihyperglycemic medication during pasireotide treatment; Pt characteristics were generally balanced across subgroups at study baseline (BL). Most Pts who did not develop hyperglycemia had a mean age of <40 years (acromegaly 62.5%, CD 86.7%), BL glycated hemoglobin (HbA1c) <6.5% (acromegaly 98.9%, CD 100.0%) and BL fasting plasma glucose (FPG) <100 mg/dL (acromegaly 76.1%, CD 100.0%). Age (odds ratio [OR] 1.0, 95% CI 1.0−1.1), BL HbA1c (OR 3.5, 95% CI 1.3−9.9) and prediabetes or diabetes conditions (OR 3.0, 95% CI 1.2−7.6) were identified as risk factors associated with pasireotide-induced hyperglycemia in Pts with acromegaly. BL FPG (OR 1.2, 95% CI 1.0−1.3) was associated with increased risk of pasireotide-induced hyperglycemia in Pts with CD. Overall, adverse events (AEs) of hyperglycemia and diabetes mellitus (investigator reported) occurred in 21.1% and 14.2% of Pts with acromegaly and 28.8% and 11.9% of Pts with CD, respectively. More Pts who had diabetes or prediabetes conditions at BL had hyperglycemia-related AEs than Pts with normal glucose levels. Hyperglycemia-related AEs were managed with antihyperglycemic medication (acromegaly 26.3%, CD 30.5%); few Pts temporarily interrupted treatment (acromegaly 3.7%, CD 10.2%). Conclusions: These data suggest that age, HbA1c, FPG and having prediabetes or diabetes conditions at BL are associated with increased risk of developing pasireotide-induced hyperglycemia. AEs were manageable with antihyperglycemic medication. Potential risk factors associated with pasireotide-induced hyperglycemia may be used to identify Pts who need vigilant monitoring to ensure optimal outcomes during pasireotide treatment. Presentation: Thursday, June 15, 2023

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 & 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 & 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

THU019 Osilodrostat As An Emergency Alternative For Hypercortisolism In A Patient With An Impaired Liver Function

Abstract Disclosure: M. Minasyan: None. A. Bogusławska: None. A. Gamrat: None. A. Hubalewska-Dydejczyk: None. A. Gilis-Januszewska: None. Osilodrostat as an emergency alternative for hypercortisolism in a patient with an impaired liver function. A case presents a 34 year old woman with an active Cushing Disease, who underwent non-radical surgery of invasive pituitary adenoma in 2014 and CyberKnife radiotherapy in 2018. Patient demonstrates many complications of long lasting hypercortisolemia- poorly controlled diabetes mellitus, heart failure, hypertension, hypercholesterolemia, mental disturbances and severe hepatic impairment. Challenges in this case are aggravated by very difficult compliance. Due to elevated liver function tests, the patient couldn’t have started ketoconazole and relacorilant treatment. Because of non-controlled DM, pasireotide treatment was contraindicated in her case. She didn’t agree either for metyrapone treatment or for adrenalectomy. Finally osilodrostat has been implemented as the last-chance alternative given at the time of severe hepatic impairment. At the dose of 2x2mg we observe clinical improvement, normalisation of UFC, decrease of Hba1c and spectacular improvement of liver function. However the current data on use of osilodrostat in patients with hepatic impairment are limited, our case shows that osilodrostat can be an emergency alternative for severe hypercortisolism with impaired liver function. The mechanism of improvement of liver function may be indirect through decreasing the level of hypercortisolemia, however potential direct beneficial influence of osilodrostat on liver function seems to be an interesting subject worth further investigation. More studies on the link between hypercortisolemia, liver function and steroidogenesis inhibitors are needed. Presentation: Thursday, June 15, 2023

Long-term Efficacy and Safety of Pasireotide in Patients With Acromegaly: 14 Years of Single-Center Real-World Experience.

Acromegaly is a rare, chronic, debilitating disorder caused by prolonged hypersecretion of growth hormone (GH) and overproduction of insulin-like growth factor I (IGF-I). Medical therapies, including the somatostatin receptor ligand (SRL) pasireotide, are frequently used to restore biochemical control. As patients often receive therapy over prolonged periods, long-term data from real-life settings are needed. A retrospective analysis was performed using a prospectively maintained database of all patients with acromegaly from our primary care center who were enrolled in clinical studies with pasireotide (first visit November 2008). The main outcome measures were safety and biochemical control (age-adjusted IGF-I ≤ upper limit of normal). Patients (n = 50) entered 4 parental studies and 30 continued in the rollover; at data cutoff (June 2022), 27 were still receiving pasireotide. Overall, median (range) exposure was 58 (3-137) months. Normal IGF-I was achieved in 54%, and acromegaly symptoms and quality of life were improved with treatment. No predictors of pasireotide response were identified; however, controlled patients had smaller tumors and lower GH at baseline. Tumor volume reduction occurred in 63% of evaluable patients (n = 10/16). Most patients presented hyperglycemic events, including 63.2% of patients with normal glucose before treatment. Older patients and those with higher IGF-I, glucose, and HbA1c at baseline had higher glucose and HbA1c during pasireotide treatment. Pasireotide provided clinical benefit and was well tolerated for more than 11 years of treatment in acromegaly patients, most of whom were resistant to first-generation SRLs.

Protein kinase C delta mediates Pasireotide effects in an ACTH-secreting pituitary tumor cell line

PurposeClinical control of corticotroph tumors is difficult to achieve since they usually persist or relapse after surgery. Pasireotide is approved to treat patients with Cushing’s disease for whom surgical therapy is not an option. However, Pasireotide seems to be effective only in a sub-set of patients, highlighting the importance to find a response marker to this approach. Recent studies demonstrated that the delta isoform of protein kinase C (PRKCD) controls viability and cell cycle progression of an in vitro model of ACTH-secreting pituitary tumor, the AtT-20/D16v-F2 cells. This study aims at exploring the possible PRKCD role in mediating Pasireotide effects.MethodsIt was assessed cell viability, POMC expression and ACTH secretion in AtT20/D16v-F2 cells over- or under-expressing PRKCD.ResultsWe found that Pasireotide significantly reduces AtT20/D16v-F2 cell viability, POMC expression and ACTH secretion. In addition, Pasireotide reduces miR-26a expression. PRKCD silencing decreases AtT20/D16v-F2 cell sensitivity to Pasireotide treatment; on the contrary, PRKCD overexpression increases the inhibitory effects of Pasireotide on cell viability and ACTH secretion.ConclusionOur results provide new insights into potential PRKCD contribution in Pasireotide mechanism of action and suggest that PRKCD might be a possible marker of therapeutic response in ACTH-secreting pituitary tumors.

Complete and sustained remission of hypercortisolism with pasireotide treatment of an adrenocorticotropic hormone (ACTH)-secreting thoracic neuroendocrine tumour: an n-of-1 trial.

N-of-1 trials can serve as useful tools in managing rare disease. We describe a patient presenting with a typical clinical picture of Cushing's Syndrome (CS). Further testing was diagnostic of ectopic Adrenocorticotropic Hormone (ACTH) secretion, but its origin remained occult. The patient was offered treatment with daily pasireotide at very low doses (300 mg bid), which resulted in clinical and biochemical control for a period of 5 years, when a pulmonary typical carcinoid was diagnosed and dissected. During the pharmacological treatment period, pasireotide was tentatively discontinued twice, with immediate flare of symptoms and biochemical markers, followed by remission after drug reinitiation. This is the first report of clinical and biochemical remission of an ectopic CS (ECS) with pasireotide used as first line treatment, in a low-grade lung carcinoid, for a prolonged period of 5 years. In conclusion, the burden of high morbidity caused by hypercortisolism can be effectively mitigated with appropriate pharmacological treatment, in patients with occult tumors. Pasireotide may lead to complete and sustained remission of hypercortisolism, until surgical therapy is feasible. The expression of SSTR2 from typical carcinoids may be critical in allowing the use of very low drug doses for achieving disease control, while minimizing the risk of adverse events.

Pasireotide treatment in Cushing's disease: A single tertiary center's experience.

Patients who were followed up for CD and treated with pasireotide between 2014-2020 at Cerrahpaşa Medical Faculty, were evaluated retrospectively. The efficacy and adverse effects of pasireotide were evaluated in this study. Thirty-two patients were evaluated. The mean duration of treatment was 26.5 [range, 12.0-37.0] months. The 24-h urinary free cortisol (UFC) decreased 46% during the treatment and normalized in 37.5% of patients. A significant decrement was found between pretreatment and last follow-up UFC (p = 0.001). Plasma ACTH decreased by 21%. A significant decrement was found between pre-treatment and the 3rd month, 6th month, and last follow-up ACTH levels (p = 0.014, p = 0.017, and p = 0.017, respectively). Serum cortisol levels decreased by 18% and a significant decrement was found between pretreatment and the 3rd month, and between pretreatment and the last follow-up (p = 0.034 and p = 0.013, respectively). While fasting blood glucose at the 3rd month was significantly higher than pretreatment fasting blood glucose, no significant difference was found between pretreatment fasting blood glucose and 6th month and last follow-up fasting blood glucose. Although there was a significant difference between pretreatment HbA1c levels and the HbA1c levels at the 3rd month (5.9% vs. 6.6% p = 0.007), 6th month (5.9% vs. 6.7% p = 0.003), and the last follow-up (5.9% vs. 7.1% p = 0.001), in the last follow-up, the majority (77%) of patients had adequate glycemic control (HbA1c ≤ 7.0 %).</AbstractText> <AbstractText Label="RESULTS">The authors declare that there is no conflict of interest. Pasireotide treatment is an alternative treatment in CD, remission is obtained in the first months of treatment, and continues for an extended period. Although hyperglycemia is the most common adverse effect, it can be successfully controlled.

Long-term safety and efficacy of long-acting pasireotide in acromegaly.

Pasireotide long acting (LAR) can be effective in normalizing insulin-like growth factor (IGF)-1 level in acromegaly patients inadequately controlled by octreotide or lanreotide. Determine the long-term efficacy and safety of pasireotide, including time to biochemical control and time to best response, and risk for diabetes mellitus. A retrospective multicenter study investigating the efficacy and safety of pasireotide LAR treatment in patients with active acromegaly treated for >12 months. The study included 19 patients (10 men; mean age ± SD, 48.0 ± 12.9 years) treated with pasireotide for a mean of 50 ± 36 months. During the follow-up, 4 patients discontinued pasireotide treatment. Pasireotide LAR produced a tolerable and long-term significant biochemical response in 15 of 19 patients (79.0%). Mean time to IGF-1 normalization from pasireotide LAR initiation was 13.6 ± 16.9 months with early biochemical normalization (<12 months) evident in 11 (64.7%) patients and delayed IGF-1 normalization in 6 (35.2%) patients. Nadir IGF-1 values were recorded within the first 12 months in 6 patients (35.3%), while in 11 patients (64.7%) lowest values were reported after >12 months of treatment, including 4 of 11 patients with early IGF-1 normalization. New-onset diabetes was documented in 5 of 7 patients with pre-diabetes and in 1 of 5 patients with normal glucose homeostasis at baseline. Among patients with pre-diabetes or diabetes mellitus prior to initiating pasireotide, mean HbA1c increase was 0.56 ± 1.0%. The results support the long-term efficacy and safety of pasireotide LAR for acromegaly and support the potential delayed effect of treatment on IGF-1 normalization.

Effects and Side Effects of Pasireotide Treatment in Cushing’s Disease: Experience of a Single Tertiary Center

Abstract Context: Cushing’s disease (CD), when uncontrolled despite surgery, requires medical treatment. In this vein, treatments with long-term effectiveness and safety profiles are needed. We aimed to evaluate the effects and side effects of pasireotide treatment in Cushing’s disease in the real world. Methods: Patients who were followed up for Cushing’s disease and treated with pasireotide between 2001-2019 at Cerrahpaşa Medical Faculty Endocrinology, Metabolism and Diabetes Department were evaluated. Pasireotide efficacy and side effects were evaluated. Results: Thirty-four patients were included in the study. The mean duration of treatment was 24.59 (SD ± 15.21) months. Urinary free cortisol (UFC) decreased in 40.59 % of the patients and normalized in 33.3 %. A total of %71.4 of the patients who were in remission at the 3rd month of the treatment preserved their remission status at last follow-up. A significant difference was found between pre-treatment and final UFC (p = 0.001), but the absence of remission at 3 months did not predict final remission (p = 0.274). ACTH decreased by 9.16 % (SD ± 46.67). A significant difference was found between ACTH levels at 3rd, 6 months, and last control (p = 0.014, 0.017, and 0.017, respectively). Serum cortisol decreased by 13.89 %. A significant difference was found between pre-treatment and 3rd month, pre-treatment and final cortisol (p = 0.034 and 0.013, respectively). The body weight decreased by an average of 5.5 [IQR (0.0-11.5)] kg. Cholecystectomy was performed in 3 patients (9%). The percentage of patients requiring antidiabetic medication increased from 33.3% at diagnosis to 81.8% at the last follow-up visit. A significant difference was found between pre-treatment and 3rd month fasting plasma glucose levels ​​(p = 0.008). HbA1c increased by 17 %. There was a positive correlation between UFC and 3rd month HbA1c. All patients with hyperglycemia were controlled with effective antidiabetic therapy. Conclusion: Pasireotide treatment in CD is effective and safe, remission occurs in the first months of treatment and continues for a long time. Although hyperglycemia is the most common side effect, it is successfully controlled with antidiabetic medication.

Pasireotide Treatment in Cushing?s Disease: A Single Tertiary Center's Experience

Pasireotide Treatment in Cushing?s Disease: A Single Tertiary Center's Experience

Risk factors and management of pasireotide-associated hyperglycemia in acromegaly.

Pasireotide, a multireceptor-targeted somatostatin analog with highest affinity for somatostatin receptor subtype (SST) 5, has demonstrated superior efficacy over the SST2-preferential somatostatin analogs octreotide and lanreotide. The safety profile is similar to those of octreotide and lanreotide, except for a higher frequency and degree of hyperglycemia. This analysis investigated baseline characteristics and occurrence and management of hyperglycemia during pasireotide treatment in patients with acromegaly treated in two prospective clinical studies, SOM230C2305 (C2305) and SOM230C2402 (C2402; PAOLA). One hundred and seventy-eight patients naïve to medical therapy at baseline (C2305) and 125 uncontrolled on first-generation somatostatin analogs at baseline (C2402) received long-acting pasireotide in these studies. Of patients treated with pasireotide in studies C2305 and C2402, respectively, 75.3 (134/178) and 65.6% (82/125) developed hyperglycemia or experienced worsening of existing hyperglycemia. Occurrence of hyperglycemia during pasireotide treatment was less frequent in patients with lower age (<40 years, C2402; <30 years, C2305), normal glucose tolerance, and no history of hypertension or dyslipidemia at baseline. Thirteen (4%) patients discontinued pasireotide because of hyperglycemia-related adverse events. Metformin alone or in combination with other oral antidiabetic medications controlled elevations in glucose levels in most pasireotide-treated patients; 78% of C2305 patients and 73 (pasireotide 40 mg) and 60% (pasireotide 60 mg) of C2402 patients achieved the ADA/EASD goal of HbA1c <7% (<53 mmol/mol) at the end of the core phase. Not all patients develop hyperglycemia, and it is reversible upon pasireotide withdrawal. Close monitoring, patient education and prompt action remain key elements in addressing hyperglycemia during pasireotide treatment.

MON-311 Glucose Metabolism in Acromegaly Patients Resistant to First Generation Somatostatin Receptor Ligands Treated with Pegvisomant And/Or Pasireotide Lar

Introduction: Acromegaly (Acro) is a systemic disease characterized by high growth hormone (GH) and insulin like growth factor-I (IGF-I), insulin resistance, glucose intolerance (IGT) and higher diabetes mellitus (DM) risk in 15% - 38% of patients (pts). Moreover, different medical therapies of Acro are reported to have variable effects on glucose metabolism. An association between blood glucose (BG) and serum IGF-I levels in patients with DM and Acro has been suggested, while IGF-I levels and hemoglobin A1c (HbA1c) correlation is still controversial because of the multifactorial influence.Study aim: to investigate glucose metabolism in pts with Acro resistant to 1st gen somatostatin receptor ligands (SRLs) treated with Pegvisomant (Peg) or Pasireotide LAR (Pasi). Patients and Methods: Retrospective, international, multicenter study; consecutive pts enrolled according to following inclusion criteria for at least 6 consecutive months: (1) resistant to 1st gen SRLs, (2) treated with Pasi or Peg for active Acro. Patients with concomitant treatments with known action on glucose metabolism were excluded, with the exception of glucocorticoid replacement for central hypoadrenalism. Results: 72 pts with active Acro, mean age at study entry 37 ±15 yrs, 47 females (65.3%). 28 (38.9%) pts were treated with Pasi and 44 pts with Peg (61.1%). Peg was monotherapy in 18 pts (40.9%) and in combo with first generation SRLs for 26 pts (59.1%). The number of pts with IGT and DM2 was superimposable between the 2 groups (Pasi and Peg). In Pasi group, 19 pts had Acro control (67.9%); glucose metabolism worsened in 16 pts (57.1%). Worsening of glucose metabolism occurred most frequently in pts with persistently active Acro (62.5%) and in pts with higher BG and HbA1c values at study start. Similarly, HbA1c was higher in pts with active Acro, although HbA1c worsened during Pasi treatment both in euglycemic and IGT at study entry, regardless of Acro control. In Peg group, 31 pts reached Acro control (73%); glucose metabolism worsened in 12 (27.3%) but improved in 5 pts (11.4%). All pts who experienced glucose metabolism improvement had controlled Acro, regardless of the use of a combo with first generation SRL. Among the 13 pts with active Acro after Peg, BG worsened in 5 cases (38.4%). Moreover, we found that pts with worsening BG control had higher HbA1c (p=0.03) and required higher Peg doses (mean ±SD 25 ±10 mg/day; p=0.04). Patients with higher HbA1c had higher IGF-I, both at study entry and at study end and were treated with higher Peg dose (mean 25 mg/day). Conclusion: Impaired glucose metabolism was more frequent after Pasireotide treatment and in patients of both Pasireotide and Pegvisomant groups with altered pre-treatment glucose and persistently active disease. Therefore, in such acromegaly patients close monitoring of glucose status is recommended during treatment.

OR23-04 SST5 Expression and USP8 Mutation in Functioning and Silent Corticotroph Pituitary Tumors

Context. Somatostatin receptor type 5 (SST5), a target of pasireotide, is inconsistently expressed by corticotroph tumors. Somatic driver mutations in the ubiquitin-specific protease 8 (USP8) gene have been describes in 35% to 60% of corticotropinomas. SST5 expression has been found to be higher in USP8mut corticotropinomas. Objective. To study the correlation between clinical and biochemical characteristics of a large cohort of functioning and silent corticotroph tumor and SST5 expression or USP8 mutation status. To describe SST5 expression and the response to pasireotide in 5 patients. Design. Retrospective cohort study. Setting. University hospitals of Lyon. Patients. 62 patients operated for a corticotroph tumors between 2013 and 2017.Intervention. None. Main Outcome Measure. Clinical, biological, radiological and pathological data were evaluated depending on SST5 expression measured by immunohistochemistry (rabbit monoclonal antibody, clone UMB-4, Abcam). Membrane immune-positivity with an IRS>1 was considered positive. USP8 analysis was performed by Sanger sequencing in 50 tumors. Results. SST5 expression was positive in 26 (41.9%) pituitary tumors. A moderate or strong IRS was found in 24.2% of the cohort and in 32.5% of the functioning pituitary tumors. Compared to SST5-negative pituitary tumors, those expressing SST5 were more frequent in women (92.3% vs 55.6%; p=0.002), fewer were silent (7.7% vs 58.3%; p<0.001), smaller (7 vs 19mm; p=0.001) and less invasive (15.4% vs 44.4%; p=0.03).USP8 mutations were identified in 26% of the cohort and more frequent in functioning (n=11/30, 36.7%) compared to silent corticotroph tumors (n=2/20, 10%; p=0.05). SST5 expression was more frequent in USP8mut vs USP8neg tumors (58.8% vs 7.7%; p<0.001).Among treated patients, normal urinary free cortisol (UFC) levels were obtained in 3 patients (IRS 0, 2, and 6) and a 4-fold decrease of UFC in one patient (IRS 4). Conclusion. SST5 expression seems to be associated with functioning, well-differentiated pituitary tumors and USP8 mutation. However, a correlation between SST5 expression or USP8mut and response to pasireotide treatment remains to be confirmed.

Pasireotide treatment significantly reduces tumor volume in patients with Cushing\u2019s disease: results from a Phase 3 study

PurposeIn the multinational, randomized, double-blind, Phase 3 B2305 study of patients with Cushing’s disease (CD; ClinicalTrials.gov identifier NCT00434148), pasireotide substantially decreased urinary-free cortisol (UFC) levels, decreased mean corticotroph tumor volume, and improved clinical signs of disease. The current post hoc analysis further assesses the effects of pasireotide on corticotroph pituitary tumor volume.MethodsPatients enrolled in the B2305 study had persistent or recurrent CD or newly diagnosed CD but were not surgical candidates. Enrollees were randomized to receive subcutaneous pasireotide, either 600-μg or 900-μg twice daily. Tumor volume was assessed independently at months 6 and 12 by 2 blinded radiologists and compared with baseline value and UFC response.ResultsOf 162 patients enrolled in the trial, 53 had measurable tumor volume data and were included in the post hoc analysis. Reductions in tumor volume were both dose and time dependent. Tumor volume reduction was more frequently observed at month 6 in the 900-μg group (75%) than in the 600-μg group (44%). Similarly, at month 12 (n = 32), tumor volume reduction was observed more frequently in the 900-µg group (89%) than in the 600-µg group (50%). Control of UFC levels was not required for reduction of tumor volume. No relationship was noted between baseline tumor size and change in tumor size.ConclusionsMeasurable decreases in pituitary tumor volume were observed in a large proportion of patients with CD and measurable tumor volume who were enrolled in the trial and treated with subcutaneous pasireotide; this decrease was not correlated with UFC control.ClinicalTrials.gov identifierNCT00434148.