Pasireotide

• CAT Number: I003446
• CAS Number: 396091-73-9
• Molecular Formula: C58H66N10O9
• Molecular Weight: 1047.21
• Purity: ≥95%
• Target: Somatostatin Receptor
• Solubility: 10 mM in DMSO
• Storage: Store at -20C
• IC50: 8.2/9.0/9.1/<7.0/9.9(pKi, sst1/2/3/4/5) [1]
• IUPAC Name: [(3S,6S,9S,12R,15S,18S,20R)-9-(4-aminobutyl)-3-benzyl-12-(1H-indol-3-ylmethyl)-2,5,8,11,14,17-hexaoxo-15-phenyl-6-[(4-phenylmethoxyphenyl)methyl]-1,4,7,10,13,16-hexazabicyclo[16.3.0]henicosan-20-yl] N-(2-aminoethyl)carbamate
• InChI: InChI=1S/C58H66N10O9/c59-27-13-12-22-46-52(69)64-47(30-38-23-25-42(26-24-38)76-36-39-16-6-2-7-17-39)53(70)66-49(31-37-14-4-1-5-15-37)57(74)68-35-43(77-58(75)61-29-28-60)33-50(68)55(72)67-51(40-18-8-3-9-19-40)56(73)65-48(54(71)63-46)32-41-34-62-45-21-11-10-20-44(41)45/h1-11,14-21,23-26,34,43,46-51,62H,12-13,22,27-33,35-36,59-60H2,(H,61,75)(H,63,71)(H,64,69)(H,65,73)(H,66,70)(H,67,72)/t43-,46+,47+,48-,49+,50+,51+/m1/s1
• InChIKey: VMZMNAABQBOLAK-DBILLSOUSA-N
• SMILES: C1C(CN2C1C(=O)NC(C(=O)NC(C(=O)NC(C(=O)NC(C(=O)NC(C2=O)CC3=CC=CC=C3)CC4=CC=C(C=C4)OCC5=CC=CC=C5)CCCCN)CC6=CNC7=CC=CC=C76)C8=CC=CC=C8)OC(=O)NCCN

Pasireotide (CAT: I003446) is a synthetic peptide analog of somatostatin. It acts as a potent and selective multi receptor-targeted somatostatin analog, binding to several somatostatin receptor subtypes (sst1, sst2, sst3, and sst5) with high affinity. Pasireotide is primarily used for the treatment of Cushing’s disease, a condition characterized by excessive cortisol production. By binding to somatostatin receptors in the pituitary gland, pasireotide suppresses the secretion of adrenocorticotropic hormone (ACTH), which in turn reduces cortisol production. It has also demonstrated efficacy in the management of acromegaly, a hormonal disorder characterized by excessive growth hormone production.

Overview of Clinical Research

Originator： Novartis
Developer： H. Lee Moffitt Cancer Center and Research Institute; Novartis; UNC Lineberger Comprehensive Cancer Center; University of Arkansas for Medical Sciences; University of Miami
Class： Analgesics; Antineoplastics; Antisecretories; Cyclic peptides; Macrocyclic compounds; Oligopeptides; Peptidomimetics
Mechanism of Action： Corticotropin releasing hormone inhibitors; Growth hormone-releasing hormone inhibitors; Insulin-like growth factor I inhibitors; Vascular endothelial growth factor A inhibitors
Orphan Drug Status： Yes – Acromegaly; Pituitary ACTH hypersecretion; Neuroendocrine tumours
New Molecular Entity： Yes

Reference

[1]. J Clin Endocrinol Metab. 2019 Jun 1;104(6):1978-1988. doi: 10.1210/jc.2018-01979.
How to Position Pasireotide LAR Treatment in Acromegaly.
Coopmans EC(1), Muhammad A(1), van der Lely AJ(1), Janssen JAMJL(1), Neggers SJCMM(1).
Author information: (1)Department of Internal Medicine, Endocrinology Section, Pituitary Center Rotterdam, Erasmus University Medical Center, CB Rotterdam, Netherlands.
CONTEXT: 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. EVIDENCE ACQUISITION: 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. EVIDENCE SYNTHESIS: 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. CONCLUSIONS: In contrast to the current consensus criteria, we recommend a more reluctant use of pasireotide LAR therapy for the treatment of acromegaly.
DOI: 10.1210/jc.2018-01979 PMID: 30608534 [Indexed for MEDLINE]

[2]. Pasireotide.
LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012–. 2017 Apr 20.
Pasireotide is a synthetic polypeptide analogue of somatostatin that resembles the native hormone in its ability to suppress levels and activity of growth hormone, insulin, glucagon and many other gastrointestinal peptides. Because its half-life is longer than somatostatin, pasireotide can be used clinically to treat neuroendocrine pituitary tumors that secrete excessive amounts of growth hormone causing acromegaly, or adrenocorticotropic hormone (ACTH) causing Cushing disease. Pasireotide has many side effects including suppression of gall bladder contractility and bile production, and maintenance therapy can cause cholelithiasis and accompanying elevations in serum enzymes and bilirubin.
PMID: 31644171

[3]. Curr Drug Metab. 2018;19(10):876-882. doi: 10.2174/1389200219666180328113801.
Pasireotide – Mechanism of Action and Clinical Applications.
Sawicka-Gutaj N(1), Owecki M(2), Ruchala M(1).
Author information: (1)Department of Endocrinology, Metabolism, and Internal Medicine, Faculty of Medicine II, Poznan University of Medical Sciences, Poznan, Poland. (2)Department of Public Health, Faculty of Medicine I, Poznan University of Medical Sciences, Poznan, Poland.
BACKGROUND: Pasireotide (SOM230) is a multi-receptor ligand somatostatin analogue (SSA) developed as the successor of the first-generation SSAs. Currently, pasireotide is recommended for the treatment of patients with Cushing's disease in whom surgery was unsuccessful, and patients with acromegaly who either remain uncontrolled after surgical therapy or in whom tumor resection is not possible. METHODS AND RESULTS: Phase II and III clinical trials have shown pasireotide efficacy in these diseases, with a similar rate of adverse events when compared with first-line SSA, although higher incidence of hyperglycemia has been observed. CONCLUSION: Pasireotide therapy provides biochemical control, tumor volume reduction, and improves the quality of life in patients with those disorders. Furthermore, pasireotide might be considered as second-line therapy in patients with metastatic neuroendocrine tumors, and it also might be effective in other neoplasms with a high expression of somatostatin receptors. In addition, therapy with this novel agent has been effective in prevention of postoperative complications after pancreatectomy. However, considering the diversified responsiveness to this drug in vivo, future studies should identify factors predicting better clinical response to pasireotide.
DOI: 10.2174/1389200219666180328113801 PMID: 29595102 [Indexed for MEDLINE]

[4]. Eur J Endocrinol. 2020 Jun;182(6):583. doi: 10.1530/EJE-19-0762.
Pasireotide for acromegaly: long-term outcomes from an extension to the Phase III PAOLA study.
Colao A(1), Bronstein MD(2), Brue T(3), De Marinis L(4), Fleseriu M(5), Guitelman M(6), Raverot G(7), Shimon I(8), Fleck J(9), Gupta P(10), Pedroncelli AM(9), Gadelha MR(11).
Author information: (1)Università Federico II di Napoli, Naples, Italy. (2)University of São Paulo Medical School, São Paulo, Brazil. (3)Aix-Marseille Université, Institut National de la Santé et de la Recherche Médicale INSERM U1251, Marseille Medical Genetics and Assistance Publique Hôpitaux de Marseille (APHM), Hôpital de la Conception, Marseille, France. (4)Università Cattolica del Sacro Cuore, Rome, Italy. (5)Northwest Pituitary Center, Oregon Health & Science University, Portland, Oregon, USA. (6)Endocrinology Division, Carlos G Durand Hospital, Buenos Aires, Argentina. (7)Groupement Hospitalier Est, Hospices Civils de Lyon and Lyon 1 University, Lyon, France. (8)Rabin Medical Center and Sackler School of Medicine, Tel-Aviv University, Petah-Tiqva, Israel. (9)Novartis Pharma AG, Basel, Switzerland. (10)Novartis Healthcare Private Limited, Hyderabad, India. (11)Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
OBJECTIVE: In the Phase III PAOLA study (clinicaltrials.gov: NCT01137682), enrolled patients had uncontrolled acromegaly despite ≥6 months of octreotide/lanreotide treatment before study start. More patients achieved biochemical control with long-acting pasireotide versus continued treatment with octreotide/lanreotide (active control) at month 6. The current work assessed the extent of comorbidities at baseline and outcomes during a long-term extension. DESIGN/METHODS: Patients receiving pasireotide 40 or 60 mg at core study end could continue on the same dose in an extension phase if biochemically controlled or receive pasireotide 60 mg if uncontrolled. Uncontrolled patients on active control were switched to pasireotide 40 mg, with the dose increased at week 16 of the extension if still uncontrolled (crossover group). Efficacy and safety are reported to 304 weeks (~5.8 years) for patients randomized to pasireotide (core + extension), and 268 weeks for patients in the crossover group (extension only). RESULTS: Almost half (49.5%; 98/198) of patients had ≥3 comorbidities at core baseline. During the extension, 173 patients received pasireotide. Pasireotide effectively and consistently reduced GH and IGF-I levels for up to 5.8 years' treatment; 37.0% of patients achieved GH <1.0 µg/L and normal IGF-I at some point during the core or extension. Improvements were observed in key symptoms. The long-term safety profile was similar to that in the core study; 23/173 patients discontinued treatment because of adverse events. CONCLUSIONS: In this patient population with a high burden of comorbid illness, pasireotide was well tolerated and efficacious, providing prolonged maintenance of biochemical control and improving symptoms.
DOI: 10.1530/EJE-19-0762 PMCID: PMC7222286 PMID: 32217809 [Indexed for MEDLINE]

[5]. Pasireotide.
Drugs and Lactation Database (LactMed) [Internet]. Bethesda (MD): National Library of Medicine (US); 2006–. 2019 May 1.
The excretion of pasireotide into breastmilk has not been studied. However, because it has a high molecular weight of 1047 daltons it is likely to be poorly excreted into breastmilk and it is a peptide that is likely digested in the infant's gastrointestinal tract. It is unlikely to reach the clinically important levels in infant serum. However, the manufacturer states that nursing mothers should not use pasireotide.
PMID: 31145573