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PubMed | University of Kiel, Federal Institute for Drugs and Medical Devices, Janssen Research & Development, Ferring Research Institute Inc. and University of Milan
Type: | Journal: Journal of Crohn's & colitis | Year: 2016

The role of placebo in clinical trials for drug development in inflammatory bowel disease [IBD] was the topic of a panel discussion held during the 10th Congress of the European Crohns and Colitis Organisation [ECCO], in Barcelona, Spain, in 2015. Panellists discussed a number of issues around placebo-controlled trials in IBD, noting issues such as difficulties with recruitment, leading to less then representative patient populations in clinical studies. It was noted that, whereas the easiest answer may be to drop placebo, it is much more complicated than that. The relevance of placebo is affected by a number of factors, including the phase of the trial, as well as the nature of the drug. In most cases where placebo has been left out in drug development, it has been for trials involving a new formulation, a new dosing schedule, or a biosimilar, for example. The panel agreed that placebo-controlled trials are of particular importance early in the development programme, perhaps not so much in phase III, although placebo is important for monitoring safety. The current trial paradigm, in which patients remain on a plethora of, likely ineffective and toxic, background medication, was also questioned. The applicability of placebo in the paediatric population was also discussed. The overall consensus from this panel discussion was that placebo is still necessary in clinical trials in inflammatory bowel disease, but there remain questions as to how and when placebo should be used.


Maybauer M.O.,University of Texas Medical Branch | Maybauer M.O.,University of Marburg | Maybauer D.M.,University of Texas Medical Branch | Maybauer D.M.,University of Marburg | And 13 more authors.
Critical Care Medicine | Year: 2014

OBJECTIVE:: To determine if the selective vasopressin type 1a receptor agonist selepressin (FE 202158) is as effective as the mixed vasopressin type 1a receptor/vasopressin V2 receptor agonist vasopressor hormone arginine vasopressin when used as a titrated first-line vasopressor therapy in an ovine model of Pseudomonas aeruginosa pneumonia-induced severe sepsis. DESIGN:: Prospective, randomized, controlled laboratory experiment. SETTING:: University animal research facility. SUBJECTS:: Forty-five chronically instrumented sheep. INTERVENTIONS:: Sheep were anesthetized, insufflated with cooled cotton smoke via tracheostomy, and P. aeruginosa were instilled into their airways. They were then placed on assisted ventilation, awakened, and resuscitated with lactated Ringer's solution titrated to maintain hematocrit ± 3% from baseline levels. If, despite fluid management, mean arterial pressure fell by more than 10 mm Hg from baseline level, an additional continuous IV infusion of arginine vasopressin or selepressin was titrated to raise and maintain mean arterial pressure within no less than 10 mm Hg from baseline level. Effects of combination treatment of selepressin with the selective vasopressin V2 receptor agonist desmopressin were similarly investigated. MEASUREMENTS AND MAIN RESULTS:: In septic sheep, MAP fell by ~30 mm Hg, systemic vascular resistance index decreased by ~50%, and ~7 L of fluid were retained over 24 hours; this fluid accumulation was partially reduced by arginine vasopressin and almost completely blocked by selepressin; and combined infusion of selepressin and desmopressin increased fluid accumulation to levels similar to arginine vasopressin treatment. CONCLUSIONS:: Resuscitation with the selective vasopressin type 1a receptor agonist selepressin blocked vascular leak more effectively than the mixed vasopressin type 1a receptor/vasopressin V2 receptor agonist arginine vasopressin because of its lack of agonist activity at the vasopressin V2 receptor. © 2014 by the Society of Critical Care Medicine.


News Article | February 15, 2017
Site: www.businesswire.com

SAINT-PREX, Switzerland--(BUSINESS WIRE)--Ferring today announced the recipients of the 2016-2017 Ferring Innovation Grants program, an annual initiative of the Ferring Research Institute (FRI) which provides grants of up to $100,000 for early stage research. The program focuses on novel extracellular drug targets addressable with peptides or proteins within Ferring’s core therapeutic areas: reproductive health, gastroenterology, urology, and endocrinology. The 2016-2017 awardees and their research subjects are: Stuart Brierley - Flinders University, Australia Venom-derived NaV1.1 inhibitors as novel candidates for treating chronic visceral pain associated with IBS James Deane - Hudson Institute of Medical Research, Australia Investigating the requirement for Notch and Hedgehog signalling in the endometrial stem/progenitor populations that cause endometriosis Marie van Dijk - University of Amsterdam, Netherlands ELABELA as a potential biomarker and therapeutic for pre-eclampsia Florenta Kullmann - University of Pittsburgh, USA Artemin: a novel target for treatment of interstitial cystitis/bladder pain syndrome Mireille Lahoud - Monash University, Australia The development of Clec12A-ligands as a therapeutic approach to regulate gastrointestinal inflammation Padma Murthi - Monash University, Australia Investigating the role of novel peptide receptor as an effective target to improve placental function in preeclampsia Markus Muttenthaler - The University of Queensland, Australia Mapping the location and function of oxytocin and vasopressin receptors throughout the gut Rodrigo Pacheco – Fundación Ciencia & Vida and Universidad Andres Bello, Santiago, Chile Targeting heteromers formed by G-protein coupled receptors involved in the gut-homing of T-cells in inflammatory bowel diseases Aritro Sen – The University of Rochester, USA Regulation of AMH expression by GDF9+BMP15 and FSH during follicular development as a novel therapeutic option “We look forward to the outcomes of the research being carried out by our grant awardees,” said Keith James, President of FRI and Senior Vice President, Research and Development. “Ferring is committed to stimulating basic research, with the ultimate aim of developing innovative products that improve the lives of patients.” Applications for the 2017-2018 Ferring Innovation Grants programme will open in spring/summer 2017. For more information on this year’s program, visit www.ferring-research.com/ferring-grants. About Ferring Research Institute Inc Located in San Diego, California Ferring Research Institute Inc. (FRI) is the global peptide therapeutics research center for Ferring Pharmaceuticals. FRI is committed to building a portfolio of novel, innovative peptide-based drugs and biologicals to address the high unmet medical need for patients in our therapeutic areas of interest. For more detailed information please visit www.ferring-research.com. About Ferring Pharmaceuticals Headquartered in Switzerland, Ferring Pharmaceuticals is a research-driven, specialty biopharmaceutical group active in global markets. The company identifies, develops and markets innovative products in the areas of reproductive health, urology, gastroenterology, endocrinology and orthopaedics. Ferring has its own operating subsidiaries in nearly 60 countries and markets its products in 110 countries. To learn more about Ferring or its products please visit www.ferring.com.


He X.,Free University of Colombia | He X.,Sun Yat Sen University | Su F.,Free University of Colombia | Taccone F.S.,Free University of Colombia | And 7 more authors.
Critical Care Medicine | Year: 2016

Objective: Selective vasopressin V1A receptor agonists may have advantages over arginine vasopressin in the treatment of septic shock. We compared the effects of selepressin, a selective V1A receptor agonist, arginine vasopressin, and norepinephrine on hemodynamics, organ function, and survival in an ovine septic shock model. Design: Randomized animal study. Setting: University hospital animal research laboratory. Subjects: Forty-six adult female sheep. Interventions: Fecal peritonitis was induced in the anesthetized, mechanically ventilated, fluid-resuscitated sheep, and they were randomized in two successive phases. Three late-intervention groups (each n = 6) received IV selepressin (1 pmol/kg/min), arginine vasopressin (0.25 pmol [0.1 mU]/kg/min), or norepinephrine (3 nmol [0.5 μg]/kg/min) when mean arterial pressure remained less than 70 mm Hg despite fluid challenge; study drugs were thereafter titrated to keep mean arterial pressure at 70-80 mm Hg. Three early-intervention groups (each n = 7) received selepressin, arginine vasopressin, or norepinephrine at the same initial infusion rates as for the late intervention, but already when mean arterial pressure had decreased by 10% from baseline; doses were then titrated as for the late intervention. A control group (n = 7) received saline. All animals were observed until death or for a maximum of 30 hours. Measurements and Main Results: In addition to hemodynamic and organ function assessment, plasma interleukin-6 and nitrite/nitrate levels were measured. In the late-intervention groups, selepressin delayed the decrease in mean arterial pressure and was associated with lower lung wet/dry weight ratios than in the other two groups. In the early-intervention groups, selepressin maintained mean arterial pressure and cardiac index better than arginine vasopressin or norepinephrine, slowed the increase in blood lactate levels, and was associated with less lung edema, lower cumulative fluid balance, and lower interleukin-6 and nitrite/nitrate levels. Selepressin-treated animals survived longer than the other animals. Conclusions: In this clinically relevant model, selepressin, a selective V1A receptor agonist, was superior to arginine vasopressin and to norepinephrine in the treatment of septic shock, especially when administered early. Copyright © 2015 by the Society of Criti.


Fernandez-Varo G.,University of Barcelona | Oro D.,University of Barcelona | Cable E.E.,Ferring Research Institute Inc. | Reichenbach V.,University of Barcelona | And 6 more authors.
Hepatology | Year: 2016

Patients and rats with cirrhosis and ascites have portal hypertension and circulatory dysfunction. Synthetic arginine vasopressin (AVP) receptor agonists able to induce systemic and mesenteric vasoconstriction have shown their usefulness in reducing portal pressure (PP) in this condition. We assessed the potential therapeutic value of a new V1 a-AVP receptor partial agonist with a preferential splanchnic vasoconstrictor effect (FE 204038) in rats with cirrhosis and ascites. The hemodynamic effects of cumulative intravenous doses of FE 204038, terlipressin, or vehicle were investigated. Mean arterial pressure and PP were continuously recorded and cardiac output and systemic vascular resistance (SVR) assessed at 30-minute intervals for 90 minutes. Urine volume, urine osmolality, and urinary excretion of sodium and creatinine were measured in basal conditions and following twice-daily subcutaneous doses of FE 204038 or vehicle. PP, mean arterial pressure, cardiac output, SVR, and ascites volume were also measured after 6 days. The expression of an array of vasoactive genes was assessed in the thoracic aorta and the mesenteric circulation of control rats and rats with cirrhosis and ascites. FE 204038 dose-dependently decreased PP, did not modify mean arterial pressure, and increased SVR. The effect of the V1a-AVP receptor partial agonist on PP was associated with an improvement in urine volume and urinary excretion of sodium during the first day of treatment. SVR was higher and cardiac output and ascites volume were lower in rats with cirrhosis and ascites treated with FE 204038. V1a-AVP receptor expression in rats with cirrhosis and ascites was markedly enhanced in the mesenteric circulation compared to the thoracic aorta. Conclusion: FE 204038 increases sodium excretion and reduces portal hypertension and ascites in experimental cirrhosis. V1a-AVP receptor partial agonism could be a useful pharmacological treatment in decompensated patients with cirrhosis. © 2016 by the American Association for the Study of Liver Diseases.


Kalhor-Monfared S.,University of Alberta | Jafari M.R.,University of Alberta | Patterson J.T.,Ferring Research Institute Inc. | Kitov P.I.,University of Alberta | And 3 more authors.
Chemical Science | Year: 2016

In this manuscript, we describe modification of Cys-residues in peptides and proteins in aqueous solvents via aromatic nucleophilic substitution (SNAr) with perfluoroarenes (fAr). Biocompatibility of this reaction makes it attractive for derivatization of proteins and peptide libraries comprised of 20 natural amino acids. Measurement of the reaction rates for fAr derivatives by 19F NMR with a model thiol donor (β-mercaptoethanol) in aqueous buffers identified decafluoro-diphenylsulfone (DFS) as the most reactive SNAr electrophile. Reaction of DFS with thiol nucleophiles is >100000 faster than analogous reaction of perfluorobenzene; this increase in reactivity enables application of DFS at low concentrations in aqueous solutions compatible with biomolecules and protein complexes irreversibly degraded by organic solvents (e.g., bacteriophages). DFS forms macrocycles when reacted with peptides of the general structure Xn-Cys-Xm-Cys-Xl, where X is any amino acid and m = 1-15. It formed cyclic peptides with 6 peptide hormones - oxytocin, urotensin II, salmon calcitonin, melanin-concentrating hormone, somatostatin-14, and atrial natriuretic factor (1-28) as well as peptides displayed on M13 phage. Rates up to 180 M-1 s-1 make this reaction one of the fastest Cys-modifications to-date. Long-term stability of macrocycles derived from DFS and their stability toward oxidation further supports DFS as a promising method for modification of peptide-based ligands, cyclization of genetically-encoded peptide libraries, and discovery of bioactive macrocyclic peptides. © 2016 American Chemical Society.


Bhat A.,Ipsen | Roberts L.R.,Pfizer | Dwyer J.J.,Ferring Research Institute Inc.
European Journal of Medicinal Chemistry | Year: 2015

Peptide macrocycles represent a chemical space where the best of biological tools can synergize with the best of chemical approaches in the quest for leads against undruggable targets. Peptide macrocycles offer some key advantages in both lead discovery and lead optimization phases of drug discovery when compared to natural product and synthetic macrocycles. In addition, they are uniquely positioned to capitalize on the therapeutic potential of peptides because cyclization can help drive selectivity, potency and overcome the common limitations of metabolic instability of peptides. © 2014 Elsevier Masson SAS.


Wisniewski K.,Ferring Research Institute Inc. | Galyean R.,Ferring Research Institute Inc. | Tariga H.,Ferring Research Institute Inc. | Alagarsamy S.,Ferring Research Institute Inc. | And 7 more authors.
Journal of Medicinal Chemistry | Year: 2011

[Arg8]vasopressin (AVP) produces vasoconstriction via V 1a receptor (V1aR)-mediated vascular smooth muscle cell contraction and is being used to increase blood pressure in septic shock, a form of vasodilatory hypotension. However, AVP also induces V2 receptor (V2R)-mediated antidiuresis, vasodilation, and coagulation factor release, all deleterious in septic shock. The V1aR agonist terlipressin (H-Gly3[Lys8]VP) also lacks selectivity vs the V2R and has sizably longer duration of action than AVP, preventing rapid titration of its vasopressor effect in the clinic. We designed and synthesized new short acting V1aR selective analogues of general structure [Xaa2,Ile3,Yaa4,Zaa8]VP. The most potent and selective compounds in in vitro functional assays (e.g., [Phe2,Ile3,Asn(Me2)4,Orn 8]VP (31), [Phe2,Ile3,Asn((CH2) 3OH)4,Orn8]VP (34), [Phe2,Ile 3,Hgn4,Orn(iPr)8]VP (45), [Phe 2,Ile3,Asn(Et)4,Dab8]VP (49), [Thi2,Ile3,Orn(iPr)8]VP (59), [Cha 2,Ile3,Asn4,Orn(iPr)8]VP (68)) were tested by intravenous bolus in rats for duration of vasopressive action. Analogues 31, 34, 45, and 49 were as short-acting as AVP. Compound 45, FE 202158, is currently undergoing clinical trials in septic shock. © 2011 American Chemical Society.


PubMed | Ferring Research Institute Inc. and University of North Carolina at Chapel Hill
Type: | Journal: Peptides | Year: 2016

Adrenomedullin (AM) and calcitonin gene-related peptide (CGRP) are potent vasodilator peptides and serve as ligands for the G-protein coupled receptor (GPCR) calcitonin receptor-like receptor (CLR/Calcrl). Three GPCR accessory proteins called receptor activity-modifying proteins (RAMPs) modify the ligand binding affinity of the receptor such that the CLR/RAMP1 heterodimer preferably binds CGRP, while CLR/RAMP2 and CLR/RAMP3 have a stronger affinity for AM. Here we determine the contribution of each of the three RAMPs to blood pressure control in response to exogenous AM and CGRP by measuring the blood pressure of mice with genetic reduction or deletion of the receptor components. Thus, the cardiovascular response of Ramp1


PubMed | Ferring Research Institute Inc.
Type: Journal Article | Journal: Journal of medicinal chemistry | Year: 2016

Glucagon-like peptide-2 receptor agonists have therapeutic potential for the treatment of intestinal diseases. The native hGLP-2, a 33 amino acid gastrointestinal peptide, is not a suitable clinical candidate, due to its very short half-life in humans. In search of GLP-2 receptor agonists with better pharmacokinetic characteristics, a series of GLP-2 analogues containing Gly substitution at position 2, norleucine in position 10, and hydrophobic substitutions in positions 11 and/or 16 was designed and synthesized. In vitro receptor potency at the human GLP-2, selectivity vs the human GLP-1 and GCG receptors, and PK profile in rats were determined for the new analogues. A number of compounds more potent at the hGLP-2R than the native hormone, showing excellent receptor selectivity and very low systemic clearance (CL) were discovered. Analogues 69 ([Gly(2),Nle(10),D-Thi(11),Phe(16)]hGLP-2-(1-30)-NH2), 72 ([Gly(2),Nle(10),D-Phe(11),Leu(16)]hGLP-2-(1-33)-OH), 73 ([Gly(2),Nle(10),D-Phe(11),Leu(16)]hGLP-2-(1-33)-NH2), 81 ([Gly(2),Nle(10),D-Phe(11),Leu(16)]hGLP-2-(1-33)-NHEt), and 85 ([Gly(2),Nle(10),D-Phe(11),Leu(16)]hGLP-2-(1-33)-NH-((CH2)2O)4-(CH2)2-CONH2) displayed the desired profiles (EC50 (hGLP-2R) < 100 pM, CL in rat <0.3 mL/min/kg, selective vs hGLP-1R and hGCGR). Compound 73 (FE 203799) was selected as a candidate for clinical development.

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