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      Pasireotide Versus Octreotide in Acromegaly: A Head-to-Head Superiority Study


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          Biochemical control reduces morbidity and increases life expectancy in patients with acromegaly. With current medical therapies, including the gold standard octreotide long-acting-release (LAR), many patients do not achieve biochemical control.


          Our objective was to demonstrate the superiority of pasireotide LAR over octreotide LAR in medically naive patients with acromegaly.

          Design and Setting:

          We conducted a prospective, randomized, double-blind study at 84 sites in 27 countries.


          A total of 358 patients with medically naive acromegaly (GH >5 μg/L or GH nadir ≥1 μg/L after an oral glucose tolerance test (OGTT) and IGF-1 above the upper limit of normal) were enrolled. Patients either had previous pituitary surgery but no medical treatment or were de novo with a visible pituitary adenoma on magnetic resonance imaging.


          Patients received pasireotide LAR 40 mg/28 days (n = 176) or octreotide LAR 20 mg/28 days (n = 182) for 12 months. At months 3 and 7, titration to pasireotide LAR 60 mg or octreotide LAR 30 mg was permitted, but not mandatory, if GH ≥2.5μg/L and/or IGF-1 was above the upper limit of normal.

          Main Outcome Measure:

          The main outcome measure was the proportion of patients in each treatment arm with biochemical control (GH <2.5 μg/L and normal IGF-1) at month 12.


          Biochemical control was achieved by significantly more pasireotide LAR patients than octreotide LAR patients (31.3% vs 19.2%; P = .007; 35.8% vs 20.9% when including patients with IGF-1 below the lower normal limit). In pasireotide LAR and octreotide LAR patients, respectively, 38.6% and 23.6% ( P = .002) achieved normal IGF-1, and 48.3% and 51.6% achieved GH <2.5 μg/L. 31.0% of pasireotide LAR and 22.2% of octreotide LAR patients who did not achieve biochemical control did not receive the recommended dose increase. Hyperglycemia-related adverse events were more common with pasireotide LAR (57.3% vs 21.7%).


          Pasireotide LAR demonstrated superior efficacy over octreotide LAR and is a viable new treatment option for acromegaly.

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          Most cited references22

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          A consensus on criteria for cure of acromegaly.

          The Acromegaly Consensus Group met in April 2009 to revisit the guidelines on criteria for cure as defined in 2000. Participants included 74 neurosurgeons and endocrinologists with extensive experience of treating acromegaly. EVIDENCE/CONSENSUS PROCESS: Relevant assays, biochemical measures, clinical outcomes, and definition of disease control were discussed, based on the available published evidence, and the strength of consensus statements was rated. Criteria to define active acromegaly and disease control were agreed, and several significant changes were made to the 2000 guidelines. Appropriate methods of measuring and achieving disease control were summarized.
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            Guidelines for acromegaly management: an update.

            The Acromegaly Consensus Group reconvened in November 2007 to update guidelines for acromegaly management. The meeting participants comprised 68 pituitary specialists, including neurosurgeons and endocrinologists with extensive experience treating patients with acromegaly. EVIDENCE/CONSENSUS PROCESS: Goals of treatment and the appropriate imaging and biochemical and clinical monitoring of patients with acromegaly were enunciated, based on the available published evidence. The group developed a consensus on the approach to managing acromegaly including appropriate roles for neurosurgery, medical therapy, and radiation therapy in the management of these patients.
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              SOM230: a novel somatostatin peptidomimetic with broad somatotropin release inhibiting factor (SRIF) receptor binding and a unique antisecretory profile.

              The aim of the present study was to identify a small, metabolically stable somatotropin release inhibiting factor (SRIF) analog with a more universal binding profile similar to that of natural somatostatin, resulting in improved pharmacological properties and hence new therapeutic uses. A rational drug design approach was followed by synthesizing alanine-substituted SRIF-14 analogs to determine the importance of single amino acids in SRIF-14 for SRIF receptor subtype binding. The incorporation of structural elements of SRIF-14 in a stable cyclohexapeptide template in the form of modified unnatural amino acids resulted in the identification of the novel cyclohexapeptide SOM230. SOM230 binds with high affinity to SRIF receptor subtypes sst1, sst2, sst3 and sst5 and displays a 30- to 40-fold higher affinity for sst1 and sst5 than Sandostatin (octreotide; SMS 201-995) or Somatuline (BIM 23014). In vitro, SOM230 effectively inhibited the growth hormone releasing hormone (GHRH)-induced growth hormone (GH) release in primary cultures of rat pituitary cells with an IC(50) of 0.4+/-0.1 nmol/l (n=5). In vivo, SOM230 also potently suppressed GH secretion in rats. The ED(50) values determined at 1 h and 6 h post injection of SOM230 indicated its very long duration of action in vivo. This property was also reflected in pharmacokinetic studies comparing plasma levels of SMS 201-995 and SOM230 after subcutaneous application. Whereas SMS 201-995 had a terminal elimination half life of 2 h, this was markedly prolonged in SOM230-treated animals (t(1/2)=23 h). Furthermore, in rats SOM230 demonstrated a much higher efficacy in lowering plasma insulin-like growth factor-I (IGF-I) levels compared with SMS 201-995. The infusion of 10 microg/kg/h of SOM230 using subcutaneously implanted minipumps decreased plasma IGF-I levels far more effectively than SMS 201-995. After 126 days of continuous infusion of SOM230 plasma IGF-I levels were decreased by 75% of placebo-treated control animals. For comparison SMS 201-995, when used under the same experimental conditions, resulted in only a 28% reduction of plasma IGF-I levels, indicating a much higher efficacy for SOM230 in this animal model. It is important to note that the inhibitory effect of SOM230 was relatively selective for GH and IGF-I in that insulin and glucagon secretion was inhibited only at higher doses of SOM230. This lack of potent inhibition of insulin and glucagon release was also reflected in the lack of effect on plasma glucose levels. Even after high dose treatment over 126 days no obvious adverse side effects were noticed, including changes in plasma glucose levels. We have identified a novel short synthetic SRIF peptidomimetic, which exhibits high affinity binding to four of the five human SRIF receptor subtypes and has potent, long lasting inhibitory effects on GH and IGF-I release. Therefore SOM230 is a promising development candidate for effective GH and IGF-I inhibition and is currently under evaluation in phase 1 clinical trials.

                Author and article information

                J Clin Endocrinol Metab
                J. Clin. Endocrinol. Metab
                The Journal of Clinical Endocrinology and Metabolism
                Endocrine Society (Chevy Chase, MD )
                March 2014
                13 January 2014
                13 January 2014
                : 99
                : 3
                : 791-799
                Dipartimento di Medicina Clinica e Chirurgia (A.C.), Università Federico II di Napoli, 80131 Naples, Italy; Neuroendocrine Unit (M.D.B.), Division of Endocrinology and Metabolism, University of São Paulo Medical School, 3858-Jardim Paulista, São Paulo, Brazil; Department of Medicine (P.F.), Columbia University College of Physicians and Surgeons, New York, New York 10032; Department of Endocrinology (F.G.), Key Laboratory of Endocrinology, Ministry of Health, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China; Department of Neurosurgery (C.-C.S.), Taichung Veterans General Hospital, Taichung 40705, Taiwan; Department of Physical Therapy (C.-C.S.), Hungkuang University, Taichung 43302, Taiwan; Department of Medicine and Tri-Service General Hospital (C.-C.S.), National Defense Medical Center, Taipei 11490, Taiwan; Endocrine Unit (M.G.), Hospital Universitário Clementino Fraga Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, 22421020, Brazil; Department of Medicine and Neurological Surgery (M.F.), Northwest Pituitary Center, Oregon Health and Science University, Portland, Oregon 97239; Department of Medicine (A.J.v.d.L.), Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands; Brain Research Imaging Centre (A.J.F.), University of Edinburgh, Edinburgh EH4 2XU, United Kingdom; Clinical Development (K.H.R., Y.C.), Novartis Pharmaceuticals Corporation, Florham Park, New Jersey 07932; Clinical Development (M.R.), Oncology Business Unit, Novartis Pharma AG, CH-4057 Basel, Switzerland; and Centre for Endocrinology, Diabetes, and Metabolism (M.S.), University of Birmingham, Edgbaston, Birmingham, B152TT.
                Author notes
                Address all correspondence and requests for reprints to: Professor A. Colao, Dipartimento di Medicina Clinica e Chirurgia, Università Federico II di Napoli, Via S Pansini 5, 80131 Naples, Italy. E-mail: colao@ 123456unina.it .
                Copyright © 2014 by The Endocrine Society

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0/us/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                : 10 June 2013
                : 20 December 2013
                Endocrine Care

                Endocrinology & Diabetes
                Endocrinology & Diabetes


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