Pasireotide (SOM230): a novel pituitary-targeted medical therapy for the treatment of patients with Cushing’s disease

Moloney, Kelley J.; Mercado, Jennifer; Ludlam, W.H.; Mayberg, Marc R.

doi:10.1586/eem.12.49

Cited by 6 publications

(4 citation statements)

References 52 publications

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“…Pasireotide LAR is a second-generation, multireceptor-targeted SSA that is approved by the US Food and Drug Administration, the European Medicines Agency, and several South American countries for the treatment of patients with acromegaly who have had an inadequate response to surgery and/or for whom surgery is not an option [14–17]. Compared with octreotide LAR and lanreotide ATG, which bind with highest affinity to sst 2 , pasireotide has higher binding affinity for sst 5 [14, 18, 19]. In a large, randomized, 12-month, Phase 3 trial (C2305 study) in medically naive patients with acromegaly, pasireotide LAR demonstrated superior biochemical control (composite end point of age-normalized IGF-1 and GH <2.5 ng/mL) in comparison with octreotide LAR (31.3 vs. 19.2 %; P = 0.007) [20].…”

Section: Introductionmentioning

confidence: 99%

Safety and tolerability of pasireotide long-acting release in acromegaly—results from the acromegaly, open-label, multicenter, safety monitoring program for treating patients who have a need to receive medical therapy (ACCESS) study

2016

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PurposePasireotide long-acting release is a somatostatin analog that is indicated for treatment of patients with acromegaly. This analysis documents the safety of pasireotide long-acting release in patients with acromegaly enrolled in the ACCESS trial (ClinicalTrials.gov identifier: NCT01995734).MethodsACCESS is an open-label, multicenter, single-arm, expanded-treatment protocol designed to provide patients access to pasireotide long-acting release pending regulatory approval. Patients received pasireotide long-acting release 40 mg administered intramuscularly every 28 days. The primary outcome was the proportion of patients having a treatment-emergent grade ≥3 or serious adverse event. Efficacy data were not collected.ResultsForty-four adult patients with active acromegaly were enrolled in the study for an average of 37.6 weeks (range, 4–70 weeks). Twenty-five grade ≥3 treatment-emergent adverse events were reported in 11 patients (25.0 %), 3 of whom (27.3 %) experienced grade ≥3 hyperglycemia. In patients treated with pasireotide long-acting release for ≥3 months (n = 42), mean glycated hemoglobin and fasting plasma glucose levels increased significantly from 5.9 % and 100.4 mg/dL at baseline to 6.8 % and 135.9 mg/dL at 3 months, respectively. Ten patients (22.7 %) were treated with pasireotide long-acting release for ≥15 months, after which mean glycated hemoglobin and fasting plasma glucose levels were 6.3 % and 123 mg/dL, respectively. Twenty-one patients (48 %) initiated antidiabetic medication.ConclusionsGrade ≥3 adverse events (primary outcome) were reported in 25.0 % of acromegaly patients treated with pasireotide long-acting release in a clinical setting. Hyperglycemia-related adverse events were reported in 45.5 % of patients, but were typically manageable, supporting the role of pasireotide long-acting release as a safe treatment option for acromegaly patients.

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Section: Introductionmentioning

confidence: 99%

Safety and tolerability of pasireotide long-acting release in acromegaly—results from the acromegaly, open-label, multicenter, safety monitoring program for treating patients who have a need to receive medical therapy (ACCESS) study

2016

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“…This vast class of compounds shows remarkable therapeutic potential. Such potential is enabled by the conformational rigidity of cyclic structures, which gives rise to improved metabolic stability, target specificity, membrane permeability, and bioavailability. − To date, many natural and non-natural macrocycles have been discovered with promising pharmacological activities. , Examples of widely studied macrocyclic therapeutic agents include naturally occurring antibiotic vancomycin, immunosuppressant cyclosporin A, and synthetic ligands of GPCRs such as bremelanotide and pasireotide. ,− …”

Section: Introductionmentioning

confidence: 99%

Targeting Melanocortin Receptors Using S_NAr-Type Macrocyclization: A Doubly Orthogonal Route to Cyclic Peptide Conjugates

et al. 2023

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While a range of strategies exist to accomplish peptide macrocyclization, they are frequently limited by the need for orthogonal protection or provide little opportunity for structural diversification. We have evaluated an efficient macrocyclization method that employs nucleophilic aromatic substitution (S N Ar) to create thioether macrocycles. This versatile macrocyclization, orthogonal to conventional peptide synthesis, can be performed in solution on unprotected peptidomimetics or on resin-bound peptides with side-chain protection in place. We show that the electron-withdrawing groups present in the products can be further utilized in subsequent orthogonal reactions to alter the peptide properties or to add prosthetic groups. The macrocyclization strategy was applied to the design of melanocortin ligands, generating a library of potent melanocortin agonists that exhibit distinct subtype selectivity.

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“…However, disadvantages of adrenal-directed medical therapy are that it does not treat the underlying tumor that causes CD and is associated with various adverse events including gastrointestinal-related events, hypokalemia, hypogonadism, hirsutism, and elevations in liver function test results [2,10]. It has been proposed that pituitary-directed medical therapies may provide broader clinical benefit including tumor control as well as reversal of hypercortisolism [2,13,16].…”

Section: Introductionmentioning

confidence: 99%

“…Somatostatin receptors (SSRs) are highly expressed in corticotroph pituitary tumors-particularly SSR type 5 (SSR 5 )-and are therefore a logical target for pharmacologic inhibition [2,4,10,16]. Pasireotide is a multireceptor-targeted somatostatin analog (SSA) that binds with high affinity to 4 of the 5 types of human SSR, but exhibits the greatest binding affinity for SSR 5 [2,10,16,17]. In corticotroph tumors, pasireotide binds to and activates the SSRs, resulting in inhibition of ACTH secretion, which in turn leads to decreased cortisol secretion [17].…”

Section: Introductionmentioning

confidence: 99%

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

Lacroix

Schopohl

et al. 2019

Pituitary

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Purpose In 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. Methods Patients 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. Results Of 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. Conclusions Measurable 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 identifier NCT00434148.

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Pasireotide (SOM230): a novel pituitary-targeted medical therapy for the treatment of patients with Cushing’s disease

Cited by 6 publications

References 52 publications

Safety and tolerability of pasireotide long-acting release in acromegaly—results from the acromegaly, open-label, multicenter, safety monitoring program for treating patients who have a need to receive medical therapy (ACCESS) study

Safety and tolerability of pasireotide long-acting release in acromegaly—results from the acromegaly, open-label, multicenter, safety monitoring program for treating patients who have a need to receive medical therapy (ACCESS) study

Targeting Melanocortin Receptors Using S_NAr-Type Macrocyclization: A Doubly Orthogonal Route to Cyclic Peptide Conjugates

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

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Pasireotide (SOM230): a novel pituitary-targeted medical therapy for the treatment of patients with Cushing’s disease

Cited by 6 publications

References 52 publications

Safety and tolerability of pasireotide long-acting release in acromegaly—results from the acromegaly, open-label, multicenter, safety monitoring program for treating patients who have a need to receive medical therapy (ACCESS) study

Safety and tolerability of pasireotide long-acting release in acromegaly—results from the acromegaly, open-label, multicenter, safety monitoring program for treating patients who have a need to receive medical therapy (ACCESS) study

Targeting Melanocortin Receptors Using SNAr-Type Macrocyclization: A Doubly Orthogonal Route to Cyclic Peptide Conjugates

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

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Targeting Melanocortin Receptors Using S_NAr-Type Macrocyclization: A Doubly Orthogonal Route to Cyclic Peptide Conjugates